Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism, is a condition which is characterized by hypogonadism due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production and elevated gonadotropin levels (as an attempt of compensation by the body). HH may present as either congenital or acquired, but the majority of cases are of the former nature.[1][2]

There are a multitude of different etiologies of HH. Congenital causes include the following:[1][3][4]

Acquired causes (due to damage to or dysfunction of the gonads) include ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted diseases), toxins (e.g., endocrine disruptors), and drugs (e.g., antiandrogens, opioids, alcohol).[1][3][4]

Examples of symptoms of hypogonadism include delayed, reduced, or absent puberty, low libido, and infertility.

Treatment of HH is usually with hormone replacement therapy, consisting of androgen and estrogen administration in males and females, respectively.[3]

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Recommendation and review posted by simmons

Genetic testing can help estimate your chance of developing cancer in your lifetime. It does this by searching for specific changes in your genes, chromosomes, or proteins. These changes are called mutations.

Genetic tests are available for breast, ovarian, colon, thyroid, and some other cancers. Genetic testing may help:

Predict your risk of a particular disease

Find if you have genes that may pass increased cancer risk to your children

Manage increased cancer risk by having more regular cancer screening or taking steps to lower risk

No genetic test can say you will, certainly, develop cancer. However, a test can tell you if you have a higher risk of developing cancer than most people.

Only some people with a gene mutation will develop cancer. For example, a woman with a 75% chance of breast cancer may never develop the disease. Meanwhile, a woman with a 25% chance may develop breast cancer.

A hereditary cancer is any cancer caused by a gene mutation. The following factors suggest that a person may be at risk:

Family history of cancer. Having 3 or more relatives on the same side of the family with the same or related forms of cancer

Cancer at an early age. Having 2 or more relatives diagnosed with cancer at an early age, which may be different depending on the type of cancer

Multiple cancers. Having 2 or more types of cancer occurring in the same relative

Genetic testing is a personal decision made for various reasons. And its a complex decision best made in collaboration. Engage your family, doctor, and genetic counselor in the process.

ASCO recommends considering genetic testing in the following cases:

You have a personal or family history that suggests a genetic cause of cancer

The test can clearly show a specific genetic change

Results help with diagnosis or management of the genetic condition or cancer(s).For example, you may choose steps to lower your risk. Steps may include surgery, medication, frequent screening, or lifestyle changes.

In addition, ASCO recommends genetic counseling before and after genetic testing. Learn more about ASCO's latest recommendations on genetic testing for cancer susceptibility.

Genetic testing has limitations and emotional implications.

Depression, anxiety, or guilt. A positive test result means a gene mutation exists. This result may bring difficult emotions. Some people may think of themselves as sick, even if they never develop cancer. Others may experience guilt if family members have a mutation but they dont.

Family tension. A person may feel responsible for telling family members about test results. This information may complicate family dynamics. Learn more about sharing genetic test results with your family.

A false sense of security. A negative result means that a person doesnt have a specific genetic mutation. However, a person with a negative result may still develop cancer. A negative result only means the persons risk is average. Additionally, each persons risk is affected by lifestyle, environmental factors, and medical history.

Unclear results. A gene may have a mutation not linked with cancer risk. This is called a variant of unknown significance. It means its unclear whether the mutation will increase risk. Or, a person may have a mutation that current tests cannot detect. Many cancers are not yet tied to a specific gene. Moreover, some genes may interact unpredictably with other genes or environmental factors. And these interactions may cause cancer. Thus, it may be impossible to calculate the cancer risk.

High cost. Genetic testing can be expensive. Its particularly expensive if insurance doesnt pay for it.

Discrimination and privacy concerns. Some people fear genetic discrimination from test results. Others worry about the privacy of their genetic information. The Genetic Information Nondiscrimination Act (GINA) protects against employment or health coverage discrimination based on genetic information. Discuss concerns about potential employment, health, or life insurance discrimination with a genetic counselor or doctor.

Before undergoing genetic testing, learn about its risks and limitations. Identify your reasons for wanting a test. And consider how you will cope with test results.

Here are some questions to help you make a decision:

Do Ihave a family history of cancer?

Have Ideveloped cancer at an earlier-than-average age?

Howwill I interpret the results of genetic testing? Who will help me use thisinformation?

Willthe test results affect my medical care or the medical care of my family?

If Ihave a genetic condition, can I lower my cancer risk?

A genetic counselor can help address these questions. This professional is trained to advise about genetic testings risks and benefits. A genetic counselor also helps people through the genetic testing process. Learn more about what to expect when meeting with a genetic counselor.

Understanding Cancer Risk

The Genetics of Cancer

Understanding Statistics Used to Estimate Risk and Recommend Screening

National Human Genome Research Institute: Issues in Genetics

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Genetic Testing for Cancer Risk | Cancer.Net

Recommendation and review posted by Bethany Smith

In genetics, a mosaic (or mosaicism) means the presence of two different genotypes in an individual which developed from a single fertilized egg. As a result, the individual has two or more genetically different cell lines derived from a single zygote.[1]

Mosaicism may result from:

The phenomenon was discovered by Curt Stern. In 1936, he demonstrated that recombination, normal in meiosis, can also take place in mitosis.[2] When it does, it results in somatic (body) mosaics. These are organisms which contain two or more genetically distinct types of tissue.[3]

A genetic chimera is an organism composed of two or more sets of genetically distinct cells. Dispermic chimeras happen when two fertilized eggs fuse together. Mosaics are a different kind of chimerism: they originate from a single fertilized egg.

This is easiest to see with eye colours. When eye colours vary between the two eyes, or within one or both eyes, the condition is called heterochromia iridis (= 'different coloured iris'). It can have many different causes, both genetic and accidental. For example, David Bowie has the appearance of different eye colours due to an injury that caused one pupil to be permanently dilated.

On this page, only genetic mosaicism is discussed.

The most common cause of mosaicism in mammalian females is X-inactivation. Females have two X chromosomes (and males have only one). The two X chromosomes in a female are rarely identical. They have the same genes, but at some loci (positions) they may have different alleles (versions of the same gene).

In the early embryo, each cell independently and randomly inactivates one copy of the X chromosome.[4] This inactivation lasts the lifetime of the cell, and all the descendants of the cell inactivate that same chromosome.

This phenomenon shows in the colouration of calico cats and tortoiseshell cats. These females are heterozygous for the X-linked colour genes: the genes for their coat colours are carried on the X chromosome. X-inactivation causes groups of cells to carry either one or the other X-chromosome in an active state.[5]

X-inactivation is reversed in the female germline, so that all egg cells contain an active X chromosome.

Mosaicism refers to differences in the genotype of various cell populations in the same individual, but X-inactivation is an epigenetic change, a switching off of genes on one chromosome. It is not a change in the genotype.[6] Descendent cells of the embryo carry the same X-inactivation as the original cells. This may give rise to mild symptoms in female 'carriers' of X-linked genetic disorders.[7]

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Mosaic (genetics) - Simple English Wikipedia, the free ...

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Recommendation and review posted by sam

Calico cats are domestic cats with a spotted or particolored coat that is predominantly white, with patches of two other colors (often, the two other colors are orange and black). Outside North America, the pattern is more usually called tortoiseshell-and-white. In the province of Quebec, Canada, they are sometimes called chatte d'Espagne (French for '(female) cat of Spain'). Other names include brindle, tricolor cat, tobi mi-ke (Japanese for 'triple fur'), and lapjeskat (Dutch for 'patches cat'); calicoes with diluted coloration have been called calimanco or clouded tiger. Occasionally, the tri-color calico coloration is combined with a tabby patterning. This calico patched tabby is called a caliby.[1]

"Calico" refers only to a color pattern on the fur, not to a breed.[2] Among the breeds whose standards allow calico coloration are the Manx, American Shorthair, British Shorthair, Persian, Japanese Bobtail, Exotic Shorthair, Siberian, Turkish Van, Turkish Angora and Norwegian Forest Cat.

Because genetic determination of coat colors in calico cats is linked to the X chromosome, calicoes are nearly always female, with one color linked to the maternal X chromosome and a second color linked to the paternal X chromosome.[2][3] Because males only have one X chromosome, a male calico would have to have a rare condition where they have three sex chromosomes (two X chromosomes and one Y chromosome) in order to be calico. In addition to other symptoms caused by the condition, these male calicos are often sterile.

There is also a calico cat referred to as a Dilute Calico. Dilute Calicos are not necessarily rare. They are recognized by their grey, silver, and gold colors instead if the traditional white, black, brown or red patched coat of a calico. Dilute calicos are also called light calicos; because they usually have no dark colored fur.

The coat pattern of calico cats does not define any breed, but occurs incidentally in cats that express a range of color patterns; accordingly the effect has no definitive historical background. However, the existence of patches in calico cats was traced to a certain degree by Neil Todd in a study determining the migration of domesticated cats along trade routes in Europe and Northern Africa.[4] The proportion of cats having the orange mutant gene found in calicoes was traced to the port cities along the Mediterranean in Greece, France, Spain and Italy, originating from Egypt.[5]

In genetic terms, calico cats are tortoiseshells in every way, except that in addition they express a white spotting gene. There is however one anomaly: as a rule of thumb the larger the areas of white, the fewer and larger the patches of ginger and dark or tabby coat.[citation needed] In contrast a non-white-spotted tortoiseshell usually has small patches of color or even something like a salt-and-pepper sprinkling. This reflects the genetic effects on relative speeds of migration of melanocytes and X-inactivation in the embryo.[6]

Serious study of calico cats seems to have begun about 1948 when Murray Barr and his graduate student E.G. Bertram noticed dark, drumstick-shaped masses inside the nuclei of nerve cells of female cats, but not in male cats. These dark masses became known as Barr bodies.[7] In 1959, Japanese cell biologist Susumu Ohno determined the Barr bodies were X chromosomes.[7] In 1961, Mary Lyon proposed the concept of X-inactivation: one of the two X chromosomes inside a female mammal shuts off.[7] She observed this in the coat color patterns in mice.[8]

Calico cats are almost always female because the locus of the gene for the orange/non-orange coloring is on the X chromosome. In the absence of other influences, such as color inhibition that causes white fur, the alleles present in those orange loci determine whether the fur is orange or not. Female cats like all female placental mammals normally have two X chromosomes. In contrast, male placental mammals, including chromosomally stable male cats, have one X and one Y chromosome.[2][7][9] Since the Y chromosome does not have any locus for the orange gene, there is no chance that an XY male could have both orange and non-orange genes together, which is what it takes to create tortoiseshell or calico coloring.[citation needed]

One exception is that in rare cases faulty cell division may leave an extra X chromosome in one of the gametes that produced the male cat. That extra X then is reproduced in each of his cells, a condition referred to as XXY, or Klinefelter syndrome. Such a combination of chromosomes could produce tortoiseshell or calico markings in the male, in the same way as XX chromosomes produce them in the female.[citation needed]

All but about one in three thousand of the rare calico or tortoiseshell male cats are sterile because of the chromosome abnormality, and breeders reject any exceptions for stud purposes because they generally are of poor physical quality and fertility. In any event, because the genetic conditions for calico coloring are X linked, a fertile male calico's coloring would not have any determination in the coloring of any male offspring (who would receive the Y, not the X chromosome from their father).

As Sue Hubble stated in her book Shrinking the Cat: Genetic Engineering before We Knew about Genes,

The mutation that gives male cats a ginger-colored coat and females ginger, tortoiseshell, or calico coats produced a particularly telling map. The orange mutant gene is found only on the X, or female, chromosome. As with humans, female cats have paired sex chromosomes, XX, and male cats have XY sex chromosomes. The female cat, therefore, can have the orange mutant gene on one X chromosome and the gene for a black coat on the other. The piebald gene is on a different chromosome. If expressed, this gene codes for white, or no color, and is dominant over the alleles that code for a certain color (i.e. orange or black), making the white spots on calico cats. If that is the case, those several genes will be expressed in a blotchy coat of the tortoiseshell or calico kind. But the male, with his single X chromosome, has only one of that particular coat-color gene: he can be not-ginger or he can be ginger (although some modifier genes can add a bit of white here and there), but unless he has a chromosomal abnormality he cannot be a calico cat.[5]

It is currently impossible to reproduce the fur patterns of calico cats by cloning. Penelope Tsernoglou wrote "This is due to an effect called x-linked inactivation which involves the random inactivation of one of the X chromosomes. Since all female mammals have two X chromosomes, one might wonder if this phenomenon could have a more widespread impact on cloning in the future."[10]

Calico cats may have already provided findings relating to physiological differences between male and female mammals. This insight may be one day broadened to the fields of psychology, psychiatry, sociology, biology and medicine as more information becomes available regarding the complete effect of random X-inactivation in female mammals.[7][9][11]

Cats of this coloration are believed to bring good luck in the folklore of many cultures.[12] In the United States, these are sometimes referred to as money cats.[13] A cat of the calico coloration is also the state cat of Maryland in the United States.[14] In the late nineteenth century, Eugene Field published "The Duel", a beloved poem for children also known as "The Gingham Dog and the Calico Cat." In Japan, the Maneki-Neko figures depict Calico cats, bringing good luck.

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Recommendation and review posted by Bethany Smith

This article is about the general scientific term. For the scientific journal, see Genetics (journal).

Genetics is the study of genes, genetic variation, and heredity in living organisms.[1][2] It is generally considered a field of biology, but it intersects frequently with many of the life sciences and is strongly linked with the study of information systems.

The father of genetics is Gregor Mendel, a late 19th-century scientist and Augustinian friar. Mendel studied "trait inheritance," patterns in the way traits are handed down from parents to offspring. He observed that organisms (pea plants) inherit traits by way of discrete "units of inheritance." This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.

Trait inheritance and molecular inheritance mechanisms of genes are still primary principles of genetics in the 21st century, but modern genetics has expanded beyond inheritance to studying the function and behavior of genes. Gene structure and function, variation, and distribution are studied within the context of the cell, the organism (e.g. dominance), and within the context of a population. Genetics has given rise to a number of sub-fields, including epigenetics and population genetics. Organisms studied within the broad field span the domain of life, including bacteria, plants, animals, and humans.

Genetic processes work in combination with an organism's environment and experiences to influence development and behavior, often referred to as nature versus nurture. The intra- or extra-cellular environment of a cell or organism may switch gene transcription on or off. A classic example is two seeds of genetically identical corn, one placed in a temperate climate and one in an arid climate. While the average height of the two corn stalks may be genetically determined to be equal, the one in the arid climate only grows to half the height of the one in the temperate climate due to lack of water and nutrients in its environment.

The word genetics stems from the Ancient Greek genetikos meaning "genitive"/"generative", which in turn derives from genesis meaning "origin".[3][4][5]

The observation that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding.[6] The modern science of genetics, seeking to understand this process, began with the work of Gregor Mendel in the mid-19th century.[7]

Prior to Mendel, Imre Festetics, a Hungarian noble, who lived in Kszeg before Mendel, was the first who used the word "genetics." He described several rules of genetic inheritance in his work The genetic law of the Nature (Die genetische Gestze der Natur, 1819). His second law is the same as what Mendel published. In his third law, he developed the basic principles of mutation (he can be considered a forerunner of Hugo de Vries.)[8]

Other theories of inheritance preceded his work. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents.[9] Mendel's work provided examples where traits were definitely not blended after hybridization, showing that traits are produced by combinations of distinct genes rather than a continuous blend. Blending of traits in the progeny is now explained by the action of multiple genes with quantitative effects. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrongthe experiences of individuals do not affect the genes they pass to their children,[10] although evidence in the field of epigenetics has revived some aspects of Lamarck's theory.[11] Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited.[12]

Modern genetics started with Gregor Johann Mendel, a scientist and Augustinian friar who studied the nature of inheritance in plants. In his paper "Versuche ber Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brnn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically.[13] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until the 1890s, after his death, when other scientists working on similar problems re-discovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905.[14][15] (The adjective genetic, derived from the Greek word genesis, "origin", predates the noun and was first used in a biological sense in 1860.)[16] Bateson both acted as a mentor and was aided significantly by the work of female scientists from Newnham College at Cambridge, specifically the work of Becky Saunders, Nora Darwin Barlow, and Muriel Wheldale Onslow.[17] Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.[18]

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1911, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies.[19] In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.[20]

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA, and scientists did not know which of the two is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, the AveryMacLeodMcCarty experiment identified DNA as the molecule responsible for transformation.[21] The role of the nucleus as the repository of genetic information in eukaryotes had been established by Hmmerling in 1943 in his work on the single celled alga Acetabularia.[22] The HersheyChase experiment in 1952 confirmed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance.[23]

James Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA has a helical structure (i.e., shaped like a corkscrew).[24][25] Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what look like rungs on a twisted ladder.[26] This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for replication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand. This property is what gives DNA its semi-conservative nature where one strand of new DNA is from an original parent strand.[27]

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production.[28] It was discovered that the cell uses DNA as a template to create matching messenger RNA, molecules with nucleotides very similar to DNA. The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide sequences and amino acid sequences is known as the genetic code.[29]

With the newfound molecular understanding of inheritance came an explosion of research.[30] A notable theory arose from Tomoko Ohta in 1973 with her amendment to the neutral theory of molecular evolution through publishing the nearly neutral theory of molecular evolution. In this theory, Ohta stressed the importance of natural selection and the environment to the rate at which genetic evolution occurs.[31] One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger. This technology allows scientists to read the nucleotide sequence of a DNA molecule.[32] In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of DNA from a mixture.[33] The efforts of the Human Genome Project, Department of Energy, NIH, and parallel private efforts by Celera Genomics led to the sequencing of the human genome in 2003.[34][35]

At its most fundamental level, inheritance in organisms occurs by passing discrete heritable units, called genes, from parents to offspring.[36] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[13][37] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or whitebut never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of the pea, which is a diploid species, each individual plant has two copies of each gene, one copy inherited from each parent.[38] Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[39]

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Geneticists use diagrams and symbols to describe inheritance. A gene is represented by one or a few letters. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.[40]

In fertilization and breeding experiments (and especially when discussing Mendel's laws) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.

When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits.[41] These charts map the inheritance of a trait in a family tree.

Organisms have thousands of genes, and in sexually reproducing organisms these genes generally assort independently of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "law of independent assortment," means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all or are white. When a plant has two copies of this white allele, its flowers are whiteregardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.[42]

Many traits are not discrete features (e.g. purple or white flowers) but are instead continuous features (e.g. human height and skin color). These complex traits are products of many genes.[43] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability.[44] Measurement of the heritability of a trait is relativein a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a trait with complex causes. It has a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.[45]

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.[46]Viruses are the only exception to this rulesometimes viruses use the very similar molecule RNA instead of DNA as their genetic material.[47] Viruses cannot reproduce without a host and are unaffected by many genetic processes, so tend not to be considered living organisms.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.[48]

Genes are arranged linearly along long chains of DNA base-pair sequences. In bacteria, each cell usually contains a single circular genophore, while eukaryotic organisms (such as plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length.[49] The DNA of a chromosome is associated with structural proteins that organize, compact, and control access to the DNA, forming a material called chromatin; in eukaryotes, chromatin is usually composed of nucleosomes, segments of DNA wound around cores of histone proteins.[50] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene.[38] The two alleles for a gene are located on identical loci of the two homologous chromosomes, each allele inherited from a different parent.

Many species have so-called sex chromosomes that determine the gender of each organism.[51] In humans and many other animals, the Y chromosome contains the gene that triggers the development of the specifically male characteristics. In evolution, this chromosome has lost most of its content and also most of its genes, while the X chromosome is similar to the other chromosomes and contains many genes. The X and Y chromosomes form a strongly heterogeneous pair.

When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid).[38] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes such as sperm or eggs.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium.[52] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genomes, a phenomenon known as transformation.[53] These processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would be otherwise unrelated.

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently or be separated from their homologous pair during sexual reproduction wherein haploid gametes are formed. In this way new combinations of genes can occur in the offspring of a mating pair. Genes on the same chromosome would theoretically never recombine. However, they do, via the cellular process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes.[54] This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid cells.

The first cytological demonstration of crossing over was performed by Harriet Creighton and Barbara McClintock in 1931. Their research and experiments on corn provided cytological evidence for the genetic theory that linked genes on paired chromosomes do in fact exchange places from one homolog to the other.[55]

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between the points. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated.[56] For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage; alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.[57]

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are made up of one or more polypeptide chains, each of which is composed of a sequence of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific amino acid sequence. This process begins with the production of an RNA molecule with a sequence matching the gene's DNA sequence, a process called transcription.

This messenger RNA molecule is then used to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds either to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence; this correspondence is called the genetic code.[58] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but it never transfers from protein back into the sequence of DNAa phenomenon Francis Crick called the central dogma of molecular biology.[59]

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of proteins are related to their functions.[60][61] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the -globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties.[62] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clog or degrade, causing the medical problems associated with this disease.

Some DNA sequences are transcribed into RNA but are not translated into protein productssuch RNA molecules are called non-coding RNA. In some cases, these products fold into structures which are involved in critical cell functions (e.g. ribosomal RNA and transfer RNA). RNA can also have regulatory effects through hybridization interactions with other RNA molecules (e.g. microRNA).

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotypes an organism displays. This is the complementary relationship often referred to as "nature and nurture." The phenotype of an organism depends on the interaction of genes and the environment. An interesting example is the coat coloration of the Siamese cat. In this case, the body temperature of the cat plays the role of the environment. The cat's genes code for dark hair, thus the hair-producing cells in the cat make cellular proteins resulting in dark hair. But these dark hair-producing proteins are sensitive to temperature (i.e. have a mutation causing temperature-sensitivity) and denature in higher-temperature environments, failing to produce dark-hair pigment in areas where the cat has a higher body temperature. In a low-temperature environment, however, the protein's structure is stable and produces dark-hair pigment normally. The protein remains functional in areas of skin that are coldersuch as its legs, ears, tail and faceso the cat has dark-hair at its extremities.[63]

Environment plays a major role in effects of the human genetic disease phenylketonuria.[64] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive intellectual disability and seizures. However, if someone with the phenylketonuria mutation follows a strict diet that avoids this amino acid, they remain normal and healthy.

A popular method for determining how genes and environment ("nature and nurture") contribute to a phenotype involves studying identical and fraternal twins, or other siblings of multiple births.[65] Because identical siblings come from the same zygote, they are genetically the same. Fraternal twins are as genetically different from one another as normal siblings. By comparing how often a certain disorder occurs in a pair of identical twins to how often it occurs in a pair of fraternal twins, scientists can determine whether that disorder is caused by genetic or postnatal environmental factors whether it has "nature" or "nurture" causes. One famous example is the multiple birth study of the Genain quadruplets, who were identical quadruplets all diagnosed with schizophrenia.[66] However such tests cannot separate genetic factors from environmental factors affecting fetal development.

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to DNA, either promoting or inhibiting the transcription of a gene.[67] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genestryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.[68]

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes, there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells.[69] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.[70]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low1 error in every 10100million basesdue to the "proofreading" ability of DNA polymerases.[71][72] Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure.[73] Chemical damage to DNA occurs naturally as well and cells use DNA repair mechanisms to repair mismatches and breaks. The repair does not, however, always restore the original sequence.

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations.[74] Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence duplications, inversions, deletions of entire regions or the accidental exchange of whole parts of sequences between different chromosomes (chromosomal translocation).

Mutations alter an organism's genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive fitness.[75] Mutations that do have an effect are usually detrimental, but occasionally some can be beneficial.[76] Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations will be harmful with the remainder being either neutral or weakly beneficial.[77]

Population genetics studies the distribution of genetic differences within populations and how these distributions change over time.[78] Changes in the frequency of an allele in a population are mainly influenced by natural selection, where a given allele provides a selective or reproductive advantage to the organism,[79] as well as other factors such as mutation, genetic drift, genetic draft,[80]artificial selection and migration.[81]

Over many generations, the genomes of organisms can change significantly, resulting in evolution. In the process called adaptation, selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment.[82] New species are formed through the process of speciation, often caused by geographical separations that prevent populations from exchanging genes with each other.[83] The application of genetic principles to the study of population biology and evolution is known as the "modern evolutionary synthesis."

By comparing the homology between different species' genomes, it is possible to calculate the evolutionary distance between them and when they may have diverged. Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form evolutionary trees; these trees represent the common descent and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).[84]

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research.[85] Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenienceshort generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medical genetics seeks to understand how genetic variation relates to human health and disease.[86] When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a method especially useful for multigenic traits not clearly defined by a single gene.[87] Once a candidate gene is found, further research is often done on the corresponding (or homologous) genes of model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of pharmacogenetics: the study of how genotype can affect drug responses.[88]

Individuals differ in their inherited tendency to develop cancer,[89] and cancer is a genetic disease.[90] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process; signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Normally, a cell divides only in response to signals called growth factors and stops growing once in contact with surrounding cells and in response to growth-inhibitory signals. It usually then divides a limited number of times and dies, staying within the epithelium where it is unable to migrate to other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (three to seven) that allow it to bypass this regulation: it no longer needs growth factors to divide, continues growing when making contact to neighbor cells, ignores inhibitory signals, keeps growing indefinitely and is immortal, escapes from the epithelium and ultimately may be able to escape from the primary tumor, cross the endothelium of a blood vessel, be transported by the bloodstream and colonize a new organ, forming deadly metastasis. Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny (somatic mutations). The most frequent mutations are a loss of function of p53 protein, a tumor suppressor, or in the p53 pathway, and gain of function mutations in the Ras proteins, or in other oncogenes.

DNA can be manipulated in the laboratory. Restriction enzymes are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA.[91] DNA fragments can be visualized through use of gel electrophoresis, which separates fragments according to their length.

The use of ligation enzymes allows DNA fragments to be connected. By binding ("ligating") fragments of DNA together from different sources, researchers can create recombinant DNA, the DNA often associated with genetically modified organisms. Recombinant DNA is commonly used in the context of plasmids: short circular DNA molecules with a few genes on them. In the process known as molecular cloning, researchers can amplify the DNA fragments by inserting plasmids into bacteria and then culturing them on plates of agar (to isolate clones of bacteria cells). ("Cloning" can also refer to the various means of creating cloned ("clonal") organisms.)

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR).[92] By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing, one of the most fundamental technologies developed to study genetics, allows researchers to determine the sequence of nucleotides in DNA fragments. The technique of chain-termination sequencing, developed in 1977 by a team led by Frederick Sanger, is still routinely used to sequence DNA fragments.[93] Using this technology, researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive, researchers have sequenced the genomes of many organisms using a process called genome assembly, which utilizes computational tools to stitch together sequences from many different fragments.[94] These technologies were used to sequence the human genome in the Human Genome Project completed in 2003.[34] New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars.[95]

Next-generation sequencing (or high-throughput sequencing) came about due to the ever-increasing demand for low-cost sequencing. These sequencing technologies allow the production of potentially millions of sequences concurrently.[96][97] The large amount of sequence data available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. A common problem to these fields of research is how to manage and share data that deals with human subject and personally identifiable information. See also genomics data sharing.

On 19 March 2015, a leading group of biologists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited.[98][99][100][101] In April 2015, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[102][103]

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Recommendation and review posted by simmons

Cardiac muscle cells or cardiomyocytes (also known as myocardiocytes[1] or cardiac myocytes[2]) are the muscle cells (myocytes) that make up the cardiac muscle. Each myocardial cell contains myofibrils, which are specialized organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells. Cardiomyocytes show striations similar to those on skeletal muscle cells. Unlike multinucleated skeletal cells, the majority of cardiomyocytes contain only one nucleus, although they may have as many as four.[3] Cardiomyocytes have a high mitochondrial density, which allows them to produce adenosine triphosphate (ATP) quickly, making them highly resistant to fatigue.

There are two types of cells within the heart: the cardiomyocytes and the cardiac pacemaker cells. Cardiomyocytes make up the atria (the chambers in which blood enters the heart) and the ventricles (the chambers where blood is collected and pumped out of the heart). These cells must be able to shorten and lengthen their fibers and the fibers must be flexible enough to stretch. These functions are critical to the proper form during the beating of the heart.[4]

Cardiac pacemaker cells carry the impulses that are responsible for the beating of the heart. They are distributed throughout the heart and are responsible for several functions. First, they are responsible for being able to spontaneously generate and send out electrical impulses. They also must be able to receive and respond to electrical impulses from the brain. Lastly, they must be able to transfer electrical impulses from cell to cell.[5]

All of these cells are connected by cellular bridges. Porous junctions called intercalated discs form junctions between the cells. They permit sodium, potassium and calcium to easily diffuse from cell to cell. This makes it easier for depolarization and repolarization in the myocardium. Because of these junctions and bridges the heart muscle is able to act as a single coordinated unit.[6][7]

The cardiomyocytes are about 100 to 150 micrometers long and 15 to 20 micrometers in diameter.[citation needed]

Humans are born with a set number of heart muscle cells, or cardiomyocytes, which increase in size as our heart grows larger during childhood development. Recent evidence suggests that cardiomyocytes are actually slowly turned over as we age, but that less than 50% of the cardiomyocytes we are born with are replaced during a normal life span.[8] The growth of individual cardiomyocytes not only occurs during normal heart development, it also occurs in response to extensive exercise (athletic heart syndrome), heart disease, or heart muscle injury such as after a myocardial infarction. A healthy adult cardiomyocyte has a cylindrical shape that is approximately 100m long and 10-25m in diameter. Cardiomyocyte hypertrophy occurs through sarcomerogenesis, the creation of new sarcomere units in the cell. During heart volume overload, cardiomyocytes grow through eccentric hypertrophy.[9] The cardiomyocytes extend lengthwise but have the same diameter, resulting in ventricular dilation. During heart pressure overload, cardiomyocytes grow through concentric hypertrophy.[9] The cardiomyocytes grow larger in diameter but have the same length, resulting in heart wall thickening.

Cardiac action potential consists of two cycles, a rest phase and an active phase. These two phases are commonly understood as systole and diastole. The rest phase is considered polarized. The resting potential during this phase of the beat separates the ions such as sodium, potassium and calcium. Myocardial cells possess the property of automaticity or spontaneous depolarization. This is the direct result of a membrane which allows sodium ions to slowly enter the cell until the threshold is reached for depolarization. Calcium ions follow and extend the depolarization even further. Once calcium stops moving inward, potassium ions move out slowly to produce repolarization. The very slow repolarization of the CMC membrane is responsible for the long refractory period.[10][11]

Myocardial infarction, commonly known as a heart attack, occurs when the heart's supplementary blood vessels are obstructed by an unstable build-up of white blood cells, cholesterol, and fat. With no blood flow, the cells die, causing whole portions of cardiac tissue to die. Once these tissues are lost, they cannot be replaced, thus causing permanent damage. Current research indicates, however, that it may be possible to repair damaged cardiac tissue with stem cells,[12] as human embryonic stem cells can differentiate into cardiomyocytes under appropriate conditions.[13]

The cardiomyopathies are a group of diseases characterized by disruptions to cardiac muscle cell growth and / or organization. Presentation can range from asymptomatic to sudden cardiac death.

Cardiomyopathy can be caused by genetic, endocrine, environmental, or other factors.

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Recommendation and review posted by Bethany Smith

In August, 2011 an all natural rejuvenating serum that uses your own adult stem cells to decrease wrinkles and increase moisture retention and elasticity was launched in the United States, and subsequently in Australia. This is a mocha based fusion of the world's most restorative ingredients and a blend of six cytokines that stimulate the proliferation and migration of the skin's stem cells by more than 225%.

There are a number of stem cell based serums and skin care products that have appeared on the marketplace over the past few years, and they constitute a novel frontier in skin care. Although many of them are nothing more than simple skin care products with misleading or spurious stem cell claims, a few are legitimate products. The legitimate ones are all based on the use of compounds called cytokines, which are growth factors supporting the functions of stem cells in the skin. Some of them contain an extract from apple stem cells, whose effectiveness really remains to be proven there is an obvious difference between human skin and an apple! Others contained cytokines from human stem cells. The latter are obviously the premium products.

One of the questions the developers of this product asked was: Of all the natural compounds and herbal extracts known to benefit the skin, which do so by supporting the natural role of stem cells in the skin? Are there natural compounds that can support the intrinsic ability of the skin to renew itself? They studied a broad array of plants and herbal extracts for their effect on the proliferation and differentiation of human skin stem cells grown in vitro, and they discovered a handful of natural compounds that have an effect on the very stem cells of your skin. By supporting the natural role of your skins stem cells, you support the process of rejuvenation of your skin from within.......the way nature intended. These compounds include AFA, the same product from which stem cell nutrition is derived.

AFA alone increased the proliferation of skin stem cells by nearly 100% in the study. Other natural ingredients include: Aloe vera (which increased skin stem cell proliferation by 87%) and a proprietary fucoidan that increased proliferation by 55%. When blended together, the effect of these plants on skin stem cell proliferation was further synergistically increased by ingredients like vanilla, maqui berry, cacao, old mans weed and others. All these ingredients taken together constitute the Stem Cell Complex unique to this product with a Stem Cell Index exceeding 250%

Hyaluronic acid is part of the infrastructure (skeleton of the skin) and is one of the main components forming the matrix of the skin. One of the main roles of hyaluronic acid is to retain moisture in the skin. Good hydration is the hallmark of young skin, and it comes from the presence of hyaluronic acid. Recently a group of scientists discovered that as we age, although we continue to produce hyaluronic acid, its structure is less and less branched. The highly branched hyaluronic acid in young skin allows for greater retention of water in the skin. Since these branches are formed of a derivative of glucosamine, scientists discovered that the best results are obtained when this derivative of glucosamine is applied on the skin, instead of hyaluronic acid itself. This product is the first in the US to contain that very derivative of glucosamine, produced by fermentation.

An all-natural formula Of all the stem cell based skin care products, this is the only one that is truly natural ......even though many make the claim. In essence, all skin care products are oils blended with water extracts of various plants. Since oil and water do not mix, it is necessary to use compounds called emulsifiers that can dissolve in both water and in lipids, thereby helping to create an emulsion. There are very few natural emulsifiers and none that are known to be effective at making a cold emulsion which is essential to the preservation of all the delicate actives found in herbal extracts. This is the only skin care product made cold with an all-natural emulsification system. Products like glycerin are relatively natural and can be used as emulsifiers; however, they are known for their drying effect on the skin. There is no glycerin here. Once produced, natural skin care products are essentially food for bacteria, so they need to be preserved. And this is the biggest challenge, as there are virtually no natural preservatives commercially available. Although the best products claim to have none of the dangerous carcinogenic parabens, they have other compounds just as dangerous such as phenoxyethanol and various forms of benzoic acid, all known to be irritants to the skin. The developers asked the question, Where in nature can we find natural antibacterial compounds? They harvested several flowers known to grow in very moist areas while blooming for weeks, unaffected by bacterial or fungal growth, and they extracted their antibacterial power. To this they added a proprietary process called SoniPure that inactivates bacteria by the use of sound waves a breakthrough innovative process. So this skin serum is 100% stable without delivering harmful compounds to your skin.

The developers intention was to create a product to restructure the skin from within in order to increase water retention and skin elasticity, which in turn would naturally reduce wrinkles and fine lines and this is exactly what was demonstrated in an independent clinical trial. It was shown to increase water retention by 30% and skin elasticity by 10% and to reduce wrinkles by an average of 25% in 28 days. Some people saw significant benefits after only 7 days, while others report wrinkle reduction by as much as 75%. In all participants, wrinkle reduction was already statistically significant after 7 days. So you can easily see how both the developmental process and the resulting formula ensure that this product is undeniably second-to-none in stem cell based skin care.

In healthy individuals, skin youthfulness is maintained by epidermal stem cells which self-renew and generate daughter cells that become new skin. Therefore, part of skin aging is caused by impaired adult stem cell mobilization from the bone marrow and the reduced number of adult stem cells able to respond to repair signals. This means that, if we increase the number of circulating adult stem cells, we can affect the epidermal stem cells. Research also shows that topical application of cytokines stimulates the migration and proliferation of skin stem cells.

In much the same way as stem cell nutrition works with adult stem cells to deliver inner wellness, the rejuvenating skin serum applies the benefits of adult stem cell science to the bodys largest organ, the skin, to achieve and maintain outer vibrance! Taking care of this organ the skin, which exposed to the elements on a continual basis is essential. The rejuvenating skin serum assists in our daily process at the skin level, by a proprietary blend of over two dozen natural ingredients found during years of searching worldwide. Each natural ingredient has been selected for its nutrient-rich attributes that fight the appearance of aging, regenerating cells, decreasing fine lines and wrinkles, increasing moisture retention and increasing skin elasticity. In addition, some of the ingredients have natural sun-protecting components.

After using stem cell serum on one side of face only for only 10 days

Your skin's response to an increase in circulating adult stem cells. The most evident visual response in people's facial skin a few weeks after taking stem cell nutrition is that - it glows. People notice a smoothness and improvement in color of their skin. Skin may also show improvements in age related and hormonal pigmentation, decreased bruising and increased elasticity and tone.

Before and after using stem cell serum

This product is second to none, and early clinical tests have demonstrated the following dramatic results: Decreased fine line & coarse wrinkles 25% in 28 days Increased moisture retention 30% in 28 days Increased elasticity 10% in 28 days

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Recommendation and review posted by sam

Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a drug to treat disease.[1] The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful and approved[by whom?] nuclear gene transfer in humans was performed in May 1989.[2] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.

Between 1989 and February 2016, over 2,300 clinical trials had been conducted, more than half of them in phase I.[3]

It should be noted that not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.[4] Gene therapy is defined by the precision of the procedure and the intention of direct therapeutic effects.

Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[5][6] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[7] and even if he is correct, it's unlikely it produced any significant beneficial effects treating beta-thalassemia.[8]

After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on September 14, 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

The first somatic treatment that produced a permanent genetic change was performed in 1993.[10]

This procedure was referred to sensationally and somewhat inaccurately in the media as a "three parent baby", though mtDNA is not the primary human genome and has little effect on an organism's individual characteristics beyond powering their cells.

Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.

Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of 2014, it was still largely an experimental technique.[11] These include treatment of retinal diseases Leber's congenital amaurosis[12][13][14][15] and choroideremia,[16]X-linked SCID,[17] ADA-SCID,[18][19]adrenoleukodystrophy,[20]chronic lymphocytic leukemia (CLL),[21]acute lymphocytic leukemia (ALL),[22]multiple myeloma,[23]haemophilia[19] and Parkinson's disease.[24] Between 2013 and April 2014, US companies invested over $600 million in the field.[25]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[26] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.[27] In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[11][28]

Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered replacing or disrupting defective genes.[29] Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[28]

DNA must be administered, reach the damaged cells, enter the cell and express/disrupt a protein.[30] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[31][32]Naked DNA approaches have also been explored, especially in the context of vaccine development.[33]

Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of 2014 these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[34]

Gene editing is a potential approach to alter the human genome to treat genetic diseases,[35] viral diseases,[36] and cancer.[37] As of 2016 these approaches were still years from being medicine.[38][39]

Gene therapy may be classified into two types:

In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[40]

In germline gene therapy (GGT), germ cells (sperm or eggs) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland and the Netherlands[41] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[41] and higher risks versus SCGT.[42] The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[41][43][44][45]

The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA. (The term 'DNA' may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex, vaccinia and adeno-associated virus.[3] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.

Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency[citation needed].

Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Some of the unsolved problems include:

Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999.[52] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[53]

In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"[54] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[55]

In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[56]

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[57] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The effects were temporary, but successful.[58]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[59] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH n 1602, and FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase-deficiency (SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy and Germany.[61]

In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[citation needed]

Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[62][63] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[64]

The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n 1602)[65] using antisense / triple helix anti IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial - n 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This antigene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

Sickle-cell disease can be treated in mice.[66] The mice which have essentially the same defect that causes human cases used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which, unlike viral vectors, are small enough to cross the bloodbrain barrier.[70]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[26]

In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[12] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[12][13][14][15]

In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human -globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85]Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

Cancer immunogene therapy using modified anti gene, antisense / triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14.12.2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers, were treated (Trojan et al. 2016). [86][87]

In 2007 and 2008, a man was cured of HIV by repeated Hematopoietic stem cell transplantation (see also Allogeneic stem cell transplantation, Allogeneic bone marrow transplantation, Allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[21] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][27] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[96]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[97] The recommendation was endorsed by the European Commission in November 2012[11][28][98][99] and commercial rollout began in late 2014.[100]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[23]

In March researchers reported that three of five subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[22]

Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[101] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[102] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[103] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[104]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 732 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[105] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases and cancer.[106] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[107][108]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[19] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[109] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."[19]

Also in October researchers reported that they had treated six haemophilia sufferers in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[19][110]

Data from three trials on Topical cystic fibrosis transmembrane conductance regulator gene therapy were reported to not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections.[111]

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[112][113] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[16] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[114][115]

Clinical trials of gene therapy for sickle cell disease were started in 2014[116][117] although one review failed to find any such trials.[118]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[119]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza and hepatitis are underway.[120][121]

In March scientists, including an inventor of CRISPR, urged a worldwide moratorium on germline gene therapy, writing scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans until the full implications are discussed among scientific and governmental organizations.[122][123][124][125]

Also in 2015 Glybera was approved for the German market.[126]

In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. Two months after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]). Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.[127]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[128] but that basic research including embryo gene editing should continue.[129]

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis and recommended it be approved.[130][131] This treats children born with ADA-SCID and who have no functioning immune system - sometimes called the "bubble baby" disease. This would be the second gene therapy treatment to be approved in Europe.[132]

In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells. The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[133][134]

Speculated uses for gene therapy include:

Gene Therapy techniques have the potential to provide alternative treatments for those with infertility. Recently, successful experimentation on mice has proven that fertility can be restored by using the gene therapy method, CRISPR.[135] Spermatogenical stem cells from another organism were transplanted into the testes of an infertile male mouse. The stem cells re-established spermatogenesis and fertility.[136]

Athletes might adopt gene therapy technologies to improve their performance.[137]Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[138]

Genetic engineering could be used to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[139][140][141] For adults, genetic engineering could be seen as another enhancement technique to add to diet, exercise, education, cosmetics and plastic surgery.[142][143] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[144]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Associations Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."[145]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[146] and such concerns have continued as technology progressed.[147] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[122][123][124][125] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[135][148]

Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.

The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGOs document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[149]

No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering), must obey international and federal guidelines for the protection of human subjects.[150]

NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

An NIH advisory committee published a set of guidelines on gene manipulation.[151] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[152] The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[151]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[153][154]

Gene therapy is the basis for the plotline of the film I Am Legend[155] and the TV show Will Gene Therapy Change the Human Race?.[156]

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Gene therapy - Wikipedia

Recommendation and review posted by Bethany Smith

What is natural hormone replacment and why consider it an option for you?

Natural hormones are biologically identical to the hormones your body makes. Meaning, the chemical structures of the hormones are identical to those synthesized in your ovaries and other areas of the body. The body sees Prempro and Premarin and considers them foreign substances, but it recognizes bioidentical hormones as familiar and responds to them in natural ways.

Dosages are customized to each patient. One size does not fit all. Each patient is put on a dose specifically chosen according toindividualhormone levels, symptoms, genetic profile, stress level, and overall health assessment.

Since the product is compounded at special pharmacies, any dose of any hormone can be added, subtracted, and adjusted as appropriate. This is individualized hormone replacement therapy, which takes into account the fact that all women and men are not the same.

There are multiple modalities of administering natural hormones: creams, gels, sublingual drops, injections, capsules, hormone pellet implants.

All the benefits of hormone replacement therapymood, sex drive, heart, brain, bone density, and cancer protectionapply to natural hormone replacement without clinical evidence of the well documented side effects of the chemicalized, horse urine, conjuguated estrogens contained in conventional hormone replacement therapy (HRT).

What is the difference between bioidentical and chemical/synthetic hormones?

Premarin/Prempro

1.) Mixture of horse urine-based, chemicalized synthetic estrogens (equilin, equilinin, etc.) plus additives and coatings, which are also synthetic.

2). Can remain in the body for as long as 13 weeks.

3.) Potency of synthetic estrogen is approximately 200 times that of natural estrogen.

4.) Contains higher percentage of more aggressive types of estrogen.

5.) One-size-fits-all dosing.

Natural/Bioidentical HRT

1.) Bioidentical replaces instead of substituting an unfamiliar chemical.

2.) Eliminated from the body in a matter of hours, not weeks.

3.) Potency is same or even less than estrogen levels in ovulating women.

4.) Customized treatment program.

5.) Physiologic doses used.

6.) All of the bodys other hormones are evaluated and treated simultaneously, to keep natural balance intact (DHEA, cortisol, testosterone, progesterone, thyroid hormones, insulin, etc.)

7.) Diet /nutrition, exercise, stress control, digestion, and detox are equally important parts of treatment.

Latest Research

Its not the estrogen you take that causes breast cancer , but the estrogen you make. We now know that estrogen converts into other forms (metabolites), which determine the ultimate effects of estrogen on your body.

It appears to be the metabolites of estrogen that determine the risk of developing breast cancer. (Metabolite: The product of the chemical changes a substance undergoes in the tissues.)

There are three signifcant metabolites of estrogen that determine cancer risk:

The first is 2-hydroxy estrone (good for you). It does not stimulate cell division and it attaches to estrogen cell receptors and blocks attachment of more aggressive estrogens.

The second is 16-hydroxy estrone (bad for you). This one strongly attaches to receptors and stimulated DNA synthesis and cell replication. It binds permanently to receptors, while other estrogens attach briefly and are released.

The third metabolite is 4-hydroxy estrone (also bad). May directly damage DNA and can cause mutations that are carcinogenic.

Equine estrogens (Premarin, Prempro) promote metabolism of the 4-hydroxy estrones, causing mutagenic damage (cancer potential) five times more rapidly than human 4-hydroxy estrones.

Too high (or low) doses of ANY type of hormone (hormone imbalance) will cause undesirable sideeffects. Natural HRT is prescribed at the lowest effective doses, and treatment is followed with regular lab tests (blood, saliva, urine), uterine ultrasounds, breast exams, mammograms/thermograms, pap smears, and regular visits to the physicians office.

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Hormone Replacement Therapy | Born Clinic

Recommendation and review posted by sam

The Inaugural ISCT-ASBMT Cell Therapy Training Course One Scholars Experience

Beth Sage MBBS, PhD UCL Respiratory University College London, London, UK

Having been lucky enough to be selected as an international scholar for the inaugural Cell Therapy Training Course I was looking forward to leaving behind the rather disappointing British summer and heading towards the much warmer Houston fall. Having googled my destination and accommodation I boarded the plane with great excitement and hopes of enjoying the Texan heat whilst exploring the cosmopolitan offerings of Americas fourth largest city oh and learning something about cell therapy!

The course, chaired by Dave DiGiusto and John Barrett, was the first of its kind, a joint enterprise between the ISCT and the American Society of Blood and Marrow Transplantation. Following a competitive selection procedure 12 scholars from all over the world were invited to attend a 5 day intensive workshop with the primary objective of giving junior cell therapy researchers an insight into the process of taking their research project from bench to bedside, including processing, clinical trial design, regulatory requirements, commercialization and ethical research. Alongside didactic lecture based teaching there were tours of good manufacturing practice (GMP) facilities, both academic and commercial, and most anticipated by the scholars was the opportunity to participate in small group discussions, led by experts in the field, dissecting and improving the individual cell therapy projects.

To break the ice on the light first day each scholar gave a short presentation on their project. It was immediately clear that there is a great breadth of exciting, novel cell therapy projects under investigation throughout the world, from the use of modified T-cells in hematological malignancies to the development of a tissue-engineered oesophagus using amniotic fluid stem cells. Projects ranged from early pre-clinical to those embarking on a first in man clinical trial and every stage in between, making the session interesting and varied. Having fought the jet-lag, the session ended with an ice-breaker drinks and dinner before retiring to prepare for the days ahead.

Over the next few days we were exposed to a wealth of information with detailed talks on pre-clinical development of different cell therapies from CD34 cells to mesenchymal stromal cells, quality systems development and one of the most useful from my personal perspective, manufacturing and release testing of different products. We were able to visit different manufacturing facilities and to understand the processes involved in the production of a clinical grade therapy. It made us challenge the protocols we were developing in the lab as we gained an insight into how it would scale up into a commercially viable process a 26 day culture process of autologous cells requiring purification and multiple cytokine stimulations is significantly more challenging (and expensive) than allogeneic cells cultured for 14 days with no manipulation and simple media exchanges.

Once the process development sessions were complete, we switched gears to look at how to conduct cell therapy clinical trials, covering issues of producing products including normal donors that are used to treat multiple recipients, the challenges of pooling donor cells, how to run multicenter studies and most importantly (although I can say almost universally never thought about by the scholars) how to deal with a regulatory body audit. This really was a really informative session that opened our eyes to the challenges and complexities of working in the field of cell therapy trials.

Just when we were beginning to feel that our jobs over the next few years would be focused on clinical trial design, process validation and filling in an endless paper chain of regulatory documents we were brought back to where we all started the excitement of the translational science. This was, for me, a really interesting session on the importance of correlative studies not only to assess clinical trial performance but to provide mechanistic insights into the behavior of cells when delivered to patients with disease. As scientists we can design and perform many experiments to predict how manipulated cells will behave but the most important data of all comes from the patients themselves. For me, the importance of testing a novel therapy is not just to see if it works but how it works and, just as importantly, if it doesnt - why.

To end to course, our wise leaders Dave DiGiusto and John Barrett decided to test whether we had been listening, and each scholar had to deliver a detailed presentation on how their project had developed during the course. Each scholar had to address the potential pitfalls and specific challenges they faced in moving towards the clinic. Whilst many of us stayed up into the small hours worrying about aspects we were previously oblivious to, undoubtedly we found this one of the most rewarding moments. Despite the potential difficulties we were now aware of, we also felt better placed to solve them and could see a clearer path ahead.

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Cellular Therapy Training Course - ISCT

Recommendation and review posted by sam

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions.

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

Research currently conducted on horses, dogs, and cats can benefit the development of stem cell treatments in veterinary medicine and can target a wide range of injuries and diseases such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy both in large animals, as well as humans.[70][71][72][73] While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach.[74] Companion animals can serve as clinically relevant models that closely mimic human disease.[75][76]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

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Stem-cell therapy - Wikipedia

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When I was between five and six, I attended balletclasses. One day the ballet teacher was observing myarm positions and could not understand why my rightarm did not look the correct shape in certain positions.

The ballet teacher decided to ask my mum if I had anyproblems with it i.e. had I broken it at any time? My mumwas not aware of any problems and had not noticed it.

My mum and dad took me to our local GP, who afterlooking at my arm, decided to refer me to a bonespecialist at the Royal National Orthopaedic Hospital inLondon. I remember thinking it was fun, as I got to goon a train, a few x-rays were taken and afterwards Iwas diagnosed with Ollier disease (discondroplasia ofthe bone) this was managed by a yearly appointment tocheck things had not changed.

At around age of 11 to 12, they found that I also had itin my left ankle. We were told if they did not correct thetwisted ankle it would cause problems when I got olderwith walking.I went into hospital when I was 13 years old. This was ahard thing to deal with but luckily the hospital I went intoStanmore RNOH, Edgware was brilliant. My mum wasable to stay with me as there were parents housing onsite but it was hard on my sisters as my mum was awayfrom home a lot.

I was in hospital for nearly four months, as I caught amajor infection in the wound following surgery. It tookhold quickly. The plaster cast that they put on in theatresuddenly turned yellow; they took me into the treatmentroom, my dad came in and when they took the plaster offthey undone the stitches and the wound spilled infectioneverywhere; I remember my dad saying he could seethe bone beneath - it was bad!

I was put on IV antibiotics, but my veins kept collapsingwhich was very painful, and it would always happen lateat night. I had a fantastic friend; she sat with me everytime they needed to change the needle and she wassuch a wonderful person; she had gone through herown trauma by losing her leg due to cancer, but shewas such a strong person.

The nurses, doctors and domestic staff made my timein there enjoyable I made some good friends who I wishI had stayed in touch with but I was young and thoughtit did not matter.About a year or so after that surgery, I was back inhospital having my leg lengthened as the first surgeryhad left me with a 2 inch limp, so that I would notdevelop a back problem; they made the decision to lengthenit.

I went into surgery and had an external fixate attachedto my right tibia. I stayed in hospital for 3 months.Again, it was made fun but this time I was studying formy GCSEs so I had to do a lot more schooling, but itpassed the time as we had a giggle. We had some roughtimes too, but because most of the kids in there werenot poorly and as it was corrective surgery, we were allable bodied, so we would all take our wheelchairs downto the hospital shop; some would be on crutches, but wewere allowed our own space.

I saw a lot in my time in that hospital but it made methe person I am, because when you witness somebodyelses pain and it is greater than your own, you realisethat there is always someone worse off than yourself.I came home with the fixator still attached and went backto school; they were very supportive and my friendsthere were great, but I got a lot of attention as kids hadnot seen this device before, so they were curious butnever cruel.I lengthened it millimetre by millimetre, so it took alongtime, but once it was done I had no limp and things wereback to normal.

Once all that was finished with I then got on with myschooling; passed my GCSEs and left school. I thenmet my husband; I was age 16 and he lived in Harlow,Essex and I commuted to Harlow every weekend;during the week I worked in a bakery and went to nightcollege to learn cake decorating.

My consultant decided to lengthen my ulna bone as it wasshort. So once again I was in Stanmore hospital havinga fixator attached to my arm; once the lengthening wascomplete I had an op to take bone from my hip, as newbone had not grown between the gap; this was painfulas the removal of bone from the hip has to be chiselled.

Then, in early 1999 I was at work and my face suddenlystarted to tingle and went very red and numb in thespace of a couple of hours. I stayed at work and thoughtit was just an infection of some sort but as the daywent on I decided to go to my GP where by he gaveme antibiotics and said it could be the trigeminal nerve,I took them but the problem continued over the nextcouple of weeks and I was back and forward to my GP.When I was pregnant with my son (1997) I had to havea grommet fitted in my ear as it blocked up.

As the GP doc could not think what could be causingthe numbness, he sent me back to Dr OMalley at MiltonKeynes hospital; I went for the appointment and thedoctor decided to order an MRI scan. I had the scanand then went back to see Dr OMalley; I took my dadwith me and we were stunned by what we were beingshown - a tumour growing from the base of my skull thesize of an orange. It had grown up and into the opticnerve and damaged the nerves surrounding the rightside of my face; that is why I had numbness, rednessand a few painful headaches.

I was then referred from there to Oxford hospital where Isaw a Dr Kerr; they did not want to do a biopsy but theybrought in a specialist on tumours connected to Ollierdisease - a Dr Cadu Hudson. I was diagnosed witha chondrosarcoma, which is the rare form of maffuccisyndrome; these two diseases run side by side but itsrare to have both.

They talked us through the steps of how they weregoing to go about sorting the problem as the tumourwas very close to the carotid artery, so it was going tobe difficult to remove.The doctors thought it had been growing for about tenyears; as they are slow growing tumours they did not wantto rush in.

I had a Robbie Williams concert to go to in the September,Neil had brought me the tickets for Christmas; I loveRobbie and really wanted to go, so Dr Kerr said wewould hold off until after then as he knew the op wouldbe difficult - he implied I was to do and experience asmuch as I could. The only trouble was that the tumourwas not going to hold off, so in the May, I was rushed intoOxford hospital with a major headache. I was in over theweekend and Neil had gone home for the weekend asit was my mums 50th party and their 25th anniversary.It was hard for Neil and my family to celebrate it withoutme with them.

Over the weekend the headache got worse. ComeMonday morning, I had had a really bad night and theteam thought the tumour could have been bleeding!! Nopainkiller was working and I was given IV morphine. Iwas in so much pain in the morning, Dr Cadu Hudsonhad to come in as Dr Kerr was on holiday and theywanted to do surgery early that morning; Neil wascalled and he was on his way. They told me the risksthat were involved but I would not let them take medown to surgery until Neil arrived. My mum and dadwere not told how bad it was due to them being away,so I wanted him there to help me make some important decisions. I was so scared and confused; the consultantwas phoning Neil to find out how far away he was as itwas getting harder to hold off.

When Neil arrived, I then felt I could have the surgeryas I could relay things to him and say what I needed tosay to him and Ryan. I had the surgery; it went well butthe damage was already done to my eye, eye lid andface and I was in intensive care for three days - thesedays I dont remember. It took only ten days after that torecover and I went home to recover further.Once again, I had very good help and treatment atOxford from the nurses and doctors and I think theworld of Dr Cadu Hudson and Dr Kerr; they are veryclever people and special surgeons.I made it to the Robbie concert, three months aftersurgery and it was fantastic.I was kept a very close eye on at the clinic but theydecided a course of radiation would be needed to makesure that the tumour had stopped growing; but thething was, the radiation could not be done with normal radiation, I had to go to Paris for Proton and Photontherapy, at the IGR hospital Paris. The governmentwould pay for treatment but we had to fund the eightweek stay so family, friends, work friends and the localpaper helped find the money by fund raising, so I couldbe comfortable out there and that our son could belooked after while Neil was with me.

It was a hard time as we were away from our four yearold son, in a foreign country trying to communicate ourproblems when I did not speak French; Neil knew somebut only the kind of stuff for holiday visits, not hospitaltranslation. We had help from a lovely multilingual manin the hospital but it was very hard having radiation andnot being able to understand the instructions.Again the treatment and care we received was fantastic;we had two hospitals to visit- one that gave me theProton therapy at the IGR, and then we moved to thesecond hotel so I could have the second part of theradiation Photon therapy.

When I got back from Paris I was then referred to the endocrinology unit at the Churchill Radcliffe hospitalwhere I was kept a close eye on, as I was developingsymptoms of pituitary gland failure. They diagnosedhypopituitarism and I was gradually put on the relevanttablets for each part of pituitary shutdown.I am now on thyroxin, hydrocortisone, Premique HRTand growth hormone. I have a neck problem also due tothe radiation, so I am on pregabalin and ranitidine dueto the side effects of the pregabalin.Living with this pituitary problem is harder thandealing with the tumour itself and with my bonedisease put together, I am a different person. When Igot married to Neil six years ago, I was not well, butI weighed 10 stones 3lbs. Now I have no control overmy weight and I am 16 stones and 10lbs. You mightsay (and often I hear people say) But you are alive!!Yes I am, but its easy for them to say that as they are not inmy situation. It is a daily battle to remember to take mydrugs and to stay positive; deep depression, fatigue,keeping up with my son and not being able to get aboutdue to muscle fatigue. As I have low levels of growthhormone, this is being replaced slowly due to thepressure in my brain increasing the first time round.I am not a person to sit around and feel sorry for myself;I have continued to work with the help of my employerand friends, but have just been made redundant soam worried now if any employer will employ me. Mypositivity has come hugely from my husband Neil; hehas had to go through a lot of changes with me and stillhe is here supporting me.

I would like my story to be told as I feel I havebeen through a lot, but I still keep smiling, fundraising, working and generally staying positiveand as I said before There is always someonein more pain than you.If I can bring awareness and support, any research intoall of the diseases I have I will work to do that.

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Suzy's story - hypopituitarism | The Pituitary Foundation

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National Guideline Clearinghouse

The National Guideline Clearinghouse (NGC), an AHRQ initiative, is a publicly available database of evidence-based clinical practice guidelines and related documents. Updated weekly with new content, the NGC provides physicians and other health professionals, health care providers, health plans, integrated delivery systems, purchasers, and others an accessible mechanism for obtaining objective, detailed information on clinical practice guidelines and to further their dissemination, implementation, and use.

Created in 1984, the U.S. Preventive Services Task Force (USPSTF or Task Force) is an independent group of national experts in prevention and evidence-based medicine that works to improve the health of all Americans by making evidence-based recommendations about clinical preventive services such as screenings, counseling services, or preventive medications. The USPSTF is made up of 16 volunteer members who come from the fields of preventive medicine and primary care, including internal medicine, family medicine, pediatrics, behavioral health, obstetrics/gynecology, and nursing. All members volunteer their time to serve on the USPSTF, and most are practicing clinicians.

The Guide to Clinical Preventive Services includes U.S. Preventive Services Task Force (USPSTF) recommendations on screening, counseling, and preventive medication topics and includes clinical considerations for each topic. This new pocket guide is an authoritative source for making decisions about preventive services.

Between 1992 and 1996, the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) sponsored development of a series of 19 clinical practice guidelines. These guideline products are no longer viewed as guidance for current medical practice, and are provided for archival purposes only.

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Clinical Guidelines and Recommendations | Agency for ...

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Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cellsectoderm, endoderm and mesoderm (see induced pluripotent stem cells)but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

There are three known accessible sources of autologous adult stem cells in humans:

Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from one's own body, just as one may bank his or her own blood for elective surgical procedures.

Adult stem cells are frequently used in various medical therapies (e.g., bone marrow transplantation). Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic cell lines and autologous embryonic stem cells generated through somatic cell nuclear transfer or dedifferentiation have also been proposed as promising candidates for future therapies.[1] Research into stem cells grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s.[2][3]

The classical definition of a stem cell requires that it possess two properties:

Two mechanisms exist to ensure that a stem cell population is maintained:

Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.[4]

In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or hematopoietic stem cells (HSCs) is the ability to transplant the cells and save an individual without HSCs. This demonstrates that the cells can produce new blood cells over a long term. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.

Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, in which single cells are assessed for their ability to differentiate and self-renew.[7][8] Stem cells can also be isolated by their possession of a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells shall behave in a similar manner in vivo. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.[citation needed]

Embryonic stem (ES) cells are the cells of the inner cell mass of a blastocyst, an early-stage embryo.[9] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.

During embryonic development these inner cell mass cells continuously divide and become more specialized. For example, a portion of the ectoderm in the dorsal part of the embryo specializes as 'neurectoderm', which will become the future central nervous system.[10] Later in development, neurulation causes the neurectoderm to form the neural tube. At the neural tube stage, the anterior portion undergoes encephalization to generate or 'pattern' the basic form of the brain. At this stage of development, the principal cell type of the CNS is considered a neural stem cell. These neural stem cells are pluripotent, as they can generate a large diversity of many different neuron types, each with unique gene expression, morphological, and functional characteristics. The process of generating neurons from stem cells is called neurogenesis. One prominent example of a neural stem cell is the radial glial cell, so named because it has a distinctive bipolar morphology with highly elongated processes spanning the thickness of the neural tube wall, and because historically it shared some glial characteristics, most notably the expression of glial fibrillary acidic protein (GFAP).[11][12] The radial glial cell is the primary neural stem cell of the developing vertebrate CNS, and its cell body resides in the ventricular zone, adjacent to the developing ventricular system. Neural stem cells are committed to the neuronal lineages (neurons, astrocytes, and oligodendrocytes), and thus their potency is restricted.[10]

Nearly all research to date has made use of mouse embryonic stem cells (mES) or human embryonic stem cells (hES) derived from the early inner cell mass. Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin as an extracellular matrix (for support) and require the presence of leukemia inhibitory factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic fibroblast growth factor (bFGF or FGF-2).[13] Without optimal culture conditions or genetic manipulation,[14] embryonic stem cells will rapidly differentiate.

A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[15] The cell surface antigens most commonly used to identify hES cells are the glycolipids stage specific embryonic antigen 3 and 4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. By using human embryonic stem cells to produce specialized cells like nerve cells or heart cells in the lab, scientists can gain access to adult human cells without taking tissue from patients. They can then study these specialized adult cells in detail to try and catch complications of diseases, or to study cells reactions to potentially new drugs. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[16]

There are currently no approved treatments using embryonic stem cells. The first human trial was approved by the US Food and Drug Administration in January 2009.[17] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal cord injury research. On November 14, 2011 the company conducting the trial (Geron Corporation) announced that it will discontinue further development of its stem cell programs.[18] ES cells, being pluripotent cells, require specific signals for correct differentiationif injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[19] Due to ethical considerations, many nations currently have moratoria or limitations on either human ES cell research or the production of new human ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.

Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer

The primitive stem cells located in the organs of fetuses are referred to as fetal stem cells.[20] There are two types of fetal stem cells:

Adult stem cells, also called somatic (from Greek , "of the body") stem cells, are stem cells which maintain and repair the tissue in which they are found.[22] They can be found in children, as well as adults.[23]

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.[24] Bone marrow is a rich source of adult stem cells,[25] which have been used in treating several conditions including liver cirrhosis,[26] chronic limb ischemia [27] and endstage heart failure.[28] The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.[29] Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.[30] DNA damage accumulates with age in both stem cells and the cells that comprise the stem cell environment. This accumulation is considered to be responsible, at least in part, for increasing stem cell dysfunction with aging (see DNA damage theory of aging).[31]

Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, dental pulp stem cell, etc.).[32][33]

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[34] Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[35]

The use of adult stem cells in research and therapy is not as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, in instances where adult stem cells are obtained from the intended recipient (an autograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.[36]

Multipotent stem cells are also found in amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic. Amniotic stem cells are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.[37] Amniotic stem cells are a topic of active research.

Use of stem cells from amniotic fluid overcomes the ethical objections to using human embryos as a source of cells. Roman Catholic teaching forbids the use of embryonic stem cells in experimentation; accordingly, the Vatican newspaper "Osservatore Romano" called amniotic stem cells "the future of medicine".[38]

It is possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bank [39][40] was opened in 2009 in Medford, MA, by Biocell Center Corporation[41][42][43] and collaborates with various hospitals and universities all over the world.[44]

These are not adult stem cells, but rather adult cells (e.g. epithelial cells) reprogrammed to give rise to pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[45][46][47]Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4[45] in their experiments on human facial skin cells. Junying Yu, James Thomson, and their colleagues at the University of WisconsinMadison used a different set of factors, Oct4, Sox2, Nanog and Lin28,[45] and carried out their experiments using cells from human foreskin.

As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon somatic cell nuclear transfer as an avenue of research.[48]

Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.[49]

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.[50]

An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals decapentaplegic and adherens junctions that prevent germarium stem cells from differentiating.[51][52]

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplant is a form of stem cell therapy that has been used for many years without controversy. No stem cell therapies other than bone marrow transplant are widely used.[53][54]

Stem cell treatments may require immunosuppression because of a requirement for radiation before the transplant to remove the person's previous cells, or because the patient's immune system may target the stem cells. One approach to avoid the second possibility is to use stem cells from the same patient who is being treated.

Pluripotency in certain stem cells could also make it difficult to obtain a specific cell type. It is also difficult to obtain the exact cell type needed, because not all cells in a population differentiate uniformly. Undifferentiated cells can create tissues other than desired types.[55]

Some stem cells form tumors after transplantation;[56] pluripotency is linked to tumor formation especially in embryonic stem cells, fetal proper stem cells, induced pluripotent stem cells. Fetal proper stem cells form tumors despite multipotency.[citation needed]

Some of the fundamental patents covering human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF) they are patents 5,843,780, 6,200,806, and 7,029,913 invented by James A. Thomson. WARF does not enforce these patents against academic scientists, but does enforce them against companies.[57]

In 2006, a request for the US Patent and Trademark Office (USPTO) to re-examine the three patents was filed by the Public Patent Foundation on behalf of its client, the non-profit patent-watchdog group Consumer Watchdog (formerly the Foundation for Taxpayer and Consumer Rights).[57] In the re-examination process, which involves several rounds of discussion between the USTPO and the parties, the USPTO initially agreed with Consumer Watchdog and rejected all the claims in all three patents,[58] however in response, WARF amended the claims of all three patents to make them more narrow, and in 2008 the USPTO found the amended claims in all three patents to be patentable. The decision on one of the patents (7,029,913) was appealable, while the decisions on the other two were not.[59][60] Consumer Watchdog appealed the granting of the '913 patent to the USTPO's Board of Patent Appeals and Interferences (BPAI) which granted the appeal, and in 2010 the BPAI decided that the amended claims of the '913 patent were not patentable.[61] However, WARF was able to re-open prosecution of the case and did so, amending the claims of the '913 patent again to make them more narrow, and in January 2013 the amended claims were allowed.[62]

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the '913 patent to the US Court of Appeals for the Federal Circuit (CAFC), the federal appeals court that hears patent cases.[63] At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had legal standing to appeal; the case could not proceed until that issue was resolved.[64]

Diseases and conditions where stem cell treatment is being investigated include:

Research is underway to develop various sources for stem cells, and to apply stem cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.[80]

In more recent years, with the ability of scientists to isolate and culture embryonic stem cells, and with scientists' growing ability to create stem cells using somatic cell nuclear transfer and techniques to create induced pluripotent stem cells, controversy has crept in, both related to abortion politics and to human cloning.

Hepatotoxicity and drug-induced liver injury account for a substantial number of failures of new drugs in development and market withdrawal, highlighting the need for screening assays such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.[81]

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Recommendation and review posted by Bethany Smith

CCR5 Identifiers Aliases CCR5, CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5, CMKBR5, IDDM22, C-C motif chemokine receptor 5 (gene/pseudogene) External IDs OMIM: 601373 MGI: 107182 HomoloGene: 37325 GeneCards: CCR5 Targeted by Drug aplaviroc, cenicriviroc, maraviroc, vicriviroc[1] Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Chr 3: 46.37 46.38 Mb Chr 9: 124.12 124.15 Mb PubMed search [2] [3] Wikidata View/Edit Human View/Edit Mouse

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. This is the process by which T cells are attracted to specific tissue and organ targets. Many forms of HIV, the virus that causes AIDS, initially use CCR5 to enter and infect host cells. Certain individuals carry a mutation known as CCR5-32 in the CCR5 gene, protecting them against these strains of HIV.

In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[4][5][6][7][8][9]

The CCR5 protein belongs to the beta chemokine receptors family of integral membrane proteins.[10][11] It is a G proteincoupled receptor[10] which functions as a chemokine receptor in the CC chemokine group.

CCR5's cognate ligands include CCL3, CCL4 (also known as MIP 1 and 1, respectively), and CCL3L1.[12][13] CCR5 furthermore interacts with CCL5 (a chemotactic cytokine protein also known as RANTES).[12][14][15]

CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear. Regions of this protein are also crucial for chemokine ligand binding, functional response of the receptor, and HIV co-receptor activity.[16]

HIV-1 most commonly uses the chemokine receptors CCR5 and/or CXCR4 as co-receptors to enter target immunological cells.[17] These receptors are located on the surface of host immune cells whereby they provide a method of entry for the HIV-1 virus to infect the cell.[18] The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.[18] The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene: the Gp120 external subunit, and the Gp41 transmembrane subunit.[18] This envelope glycoprotein structure is arranged into a spike-like structure located on the surface of the virion and consists of a trimer of three Gp120-Gp41 hetero-dimers.[18] The Gp120 envelope protein is a chemokine mimic.[17] It lacks the unique structure of a chemokine, however it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.[17] During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell- forming a heterotrimeric complex.[17] The formation of this complex stimulates the release of a fusogenic peptide inducing the fusion of the viral membrane with the membrane of the target host cell.[17] Because binding to CD4 alone can sometimes result in gp120 shedding, gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine sulfated amino terminus of this co-receptor is the "essential determinant" of binding to the gp120 glycoprotein.[19] Co-receptor recognition also include the V1-V2 region of gp120, and the bridging sheet (an antiparallel, 4-stranded sheet that connects the inner and outer domains of gp120). The V1-V2 stem can influence "co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation." Unlike V1-V2 however, the V3 loop is highly variable and thus is the most important determinant of co-receptor specificity.[19] The normal ligands for this receptor, RANTES, MIP-1, and MIP-1, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[20] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This bind results in gp41, the other protein product of gp160, to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it hasn't been finalized as a proven theory yet, binding of gp120-CCR5 involves two crucial steps: 1) The tyrosine sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp120 (as stated previously) 2) Following step 1., there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains [19]

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus.[21] Knowledge of the mechanism by which this strain of HIV-1 mediates infection has prompted research into the development of therapeutic interventions to block CCR5 function.[22] A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with the associative binding between the Gp120 envelope protein and the HIV co-receptor CCR5.[21] These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). Maraviroc was approved for use by the FDA in August 2007.[21] It is the only one thus far approved by the FDA for clinical use, thus becoming the first CCR5 inhibitor.[19] A problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. However, because there is still another co-receptor available, this indicates that lacking the CCR5 gene doesn't make one immune to the virus; it simply implies that it would be more challenging for the individual to contract it. Also, the virus still has access to the CD4. Unlike CCR5, which the body apparently doesn't really need due to those still living healthy lives even with the lack of/or absence of the gene (as a result of the delta 32 mutation), CD4 is critical in the bodies defense system (fighting against infection).[23] Even without the availability of either co-receptors (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail), resulting in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.[24]

CCR5-32 (or CCR5-D32 or CCR5 delta 32) is an allele of CCR5.[25][26]

CCR5 32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor.[27][28] CCR5 is required for M-tropic HIV-1 virus entry.[29] Individuals homozygous for CCR5 32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures.[29] Individuals heterozygous for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface.[30] Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types.[27][29][31] Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment.[32] CCR5 32 has an (heterozygote) allele frequency of 10% in Europe, and a homozygote frequency of 1%.

The CCR5 32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution,[33] which together suggest that (a) it arose from a single mutation, and (b) it was historically subject to positive selection.

Two studies have used linkage analysis to estimate the age of the CCR5 32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 32 deletion would be proportional to the age of the deletion.[26][34] Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-32 deletion occurred 700 years ago (275-1875, 95% confidence interval). Another group, Libert et al. (1998), estimated the age of the CCR5 32 mutation is based on the microsatellite mutations to be 2100 years (700-4800, 95% confidence interval). On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years (900-4700, 95% confidence interval).[34] A third hypothesis relies on the on the north-to-south gradient of allele frequency in Europe which shows that the highest allele frequency occurred in Nordic regions such as Iceland, Norway and Sweden and lowest allele frequency in the south. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe was due to the Viking dispersal in the 8th to 10th century.[35] Vikings were later replaced by the Varangians in Russia, which migrated East which may have contributed to the observed east-to-west cline of allele frequency.[33][35]

HIV-1 was initially transmitted from chimpanzees (Pan troglodytes) to humans in the early 1900s in Southeast Cameroon, Africa,[36] through exposure to infected blood and body fluids while butchering bushmeat.[37] However, HIV-1 was effectively absent from Europe until the late 1980s.[38] Therefore, given the average age of roughly 1000 years for the CCR5-32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies.[33] Hence, other pathogens have been suggested agents of positive selection for CCR5 32. The first major one being bubonic plague (Yersinia pestis), and later, smallpox (Variola major). Other data suggest that the allele frequency resulted as a negative selection pressure as a result of pathogens that became more widespread during Roman expansion.[39] The idea that negative selection played a role in its low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.[40][41]

Several lines of evidence suggest that the CCR5 32 allele evolved only once.[33] First, CCR5 32 has a relatively high frequency in several different Caucasian populations but is comparatively absent in Asian, Middle Eastern and American Indian populations,[26] suggesting that a single mutation occurred after divergence of Caucasians from their African ancestor).[26][27][42] Second, genetic linkage analysis indicates that the mutation occurs on a homogenous genetic background, implying that inheritance of the mutation occurred from a common ancestor.[34] This was demonstrated by showing that the CCR5 32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele.[34] This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 32 alleles arose from a single mutational event. Finally, the CCR5 32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations (16%), and the lowest in Sardinia (4%).[34]

In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%.[26] Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.

It is estimated that HIV-1 entered the human population in Africa in the early 1900s,[36] symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 32 from zero to 10% in 2000 years. In 1998, Stephens et al. suggested that bubonic plague (Yersinia pestis) had exerted positive selective pressure on CCR5 32.[26] This hypothesis was based on the timing and severity of the Black Death pandemic, which killed 30% of the European population of all ages between 1346 and 1352.[43] After the Black Death, there were less severe, intermittent, epidemics. Individual cities experienced high mortality, but overall mortality in Europe was only a few percent.[43][44][45] In 1655-1656 a second pandemic called the "Great Plague" killed 15-20% of Europes population.[43][46] Importantly, the plague epidemics were intermittent. Bubonic plague is a zoonotic disease, primarily infecting rodents and spread by fleas and only occasionally infecting humans.[47] Human-to-human infection of bubonic plague does not occur, though it can occur in pneumonic plague, which infects the lungs.[48] Only when the density of rodents is low are infected fleas forced to feed on alternative hosts such as humans, and under these circumstances a human epidemic may occur.[47] Based on population genetic models, Galvani and Slatkin (2003) argue that the intermittent nature of plague epidemics did not generate a sufficiently strong selective force to drive the allele frequency of CCR5 32 to 10% in Europe.[25]

To test this hypothesis, Galvani and Slatkin (2003) modeled the historical selection pressures produced by plague and smallpox.[25] Plague was modeled according to historical accounts,[49][50] while age-specific smallpox mortality was gleaned from the age distribution of smallpox burials in York (England) between 1770 and 1812.[44] Smallpox preferentially infects young, pre-reproductive members of the population since they are the only individuals who are not immunized or dead from past infection. Because smallpox preferentially kills pre-reproductive members of a population, it generates stronger selective pressure than plague.[25] Unlike plague, smallpox does not have an animal reservoir and is only transmitted from human to human.[51][52] The authors calculated that if plague were selecting for CCR5 32, the frequency of the allele would still be less than 1%, while smallpox has exerted a selective force sufficient to reach 10%.

The hypothesis that smallpox exerted positive selection for CCR5 32 is also biologically plausible, since poxviruses, like HIV, are viruses that enter white blood cells by using chemokine receptors.[53] By contrast, Yersinia pestis is a bacterium with a very different biology.

Although Caucasians are the only population with a high frequency of CCR5 32, they are not the only population that has been subject to selection by smallpox, which had a worldwide distribution before it was declared eradicated in 1980. The earliest unmistakable descriptions of smallpox appear in the 5th century A.D. in China, the 7th century A.D. in India and the Mediterranean, and the 10th century A.D. in southwestern Asia.[52] By contrast, the CCR5 32 mutation is found only in European, West Asian, and North African populations.[54] The anomalously high frequency of CCR5 32 in these populations appears to require both a unique origin in Northern Europe and subsequent selection by smallpox.

Research has not yet revealed a cost of carrying the CCR5 null mutation that is as dramatic as the benefit conferred in the context of HIV-1 exposure. In general, research suggests that the CCR5 32 mutation protects against diseases caused by certain pathogens but may also play a deleterious role in postinfection inflammatory processes, which can injure tissue and create further pathology.[55] The best evidence for this proposed antagonistic pleiotropy is found in flavivirus infections. In general many viral infections are asymptomatic or produce only mild symptoms in the vast majority of the population. However, certain unlucky individuals experience a particularly destructive clinical course, which is otherwise unexplained but appears to be genetically mediated. Patients homozygous for CCR5 32 were found to be at higher risk for a neuroinvasive form of tick-borne encephalitis (a flavivirus).[56] In addition, functional CCR5 may be required to prevent symptomatic disease after infection with West Nile virus, another flavivirus; CCR5 32 was associated with early symptom development and more pronounced clinical manifestations after infection with West Nile virus.[57]

This finding in humans confirmed a previously-observed experiment in an animal model of CCR5 32 homozygosity. After infection with West Nile Virus, CCR5 32 mice had markedly increased viral titers in the central nervous system and had increased mortality[58] compared with that of wild-type mice, thus suggesting that CCR5 expression was necessary to mount a strong host defense against West Nile virus.

CCR5 32 can be beneficial to the host in some infections (e.g., HIV-1, possibly smallpox), but detrimental in others (e.g., tick-borne encephalitis, West Nile virus). Whether CCR5 function is helpful or harmful in the context of a given infection depends on a complex interplay between the immune system and the pathogen.

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals.[59] When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 eventually take over the culture, as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus resistant cell pool in infected individuals.[59]

This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However, the transplant was performed from a donor with 2 copies of CCR5-32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[5][60] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[5] However, this is consistent with the observation that cells expressing the CCR5-32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[61] After over six years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[6]

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified with a zinc finger nuclease to carry the CCR5-32 trait and then reintroduced into the body as a potential HIV treatment.[62][63] Results reported in 2014 were promising.[9]

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Recommendation and review posted by sam

BACKGROUND. Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia.

METHODS. We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (1018 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (3238 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin Dassociated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia.

RESULTS. Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.611.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD 30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.100.96). Differential expression of 348 vitamin Dassociated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin Dassociated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity.

CONCLUSIONS. Vitamin D supplementation initiated in weeks 1018 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin Dassociated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00920621.

FUNDING. Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Hooman Mirzakhani, Augusto A. Litonjua, Thomas F. McElrath, George OConnor, Aviva Lee-Parritz, Ronald Iverson, George Macones, Robert C. Strunk, Leonard B. Bacharier, Robert Zeiger, Bruce W. Hollis, Diane E. Handy, Amitabh Sharma, Nancy Laranjo, Vincent Carey, Weilliang Qiu, Marc Santolini, Shikang Liu, Divya Chhabra, Daniel A. Enquobahrie, Michelle A. Williams, Joseph Loscalzo, Scott T. Weiss

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Conference Series invites all the participants from all over the world to attend"8th European Immunology Conference, June 29-July 01, 2017 Madrid, Spain, includesprompt keynote presentations, Oral talks, Poster presentations and Exhibitions.

European ImmunologyConferenceis to gathering people in academia and society interested inimmunologyto share the latest trends and important issues relevant to our field/subject area.Immunology Conferencesbrings together the global leaders in Immunology and relevant fields to present their research at this exclusive scientific program. TheImmunology Conferencehosting presentations from editors of prominent refereed journals, renowned and active investigators and decision makers in the field of Immunology.European Immunology ConferenceOrganizing Committee also invites Young investigators at every career stage to submit abstracts reporting their latest scientific findings in oral and poster sessions.

Track:1Cellular Immunology

The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science ofimmunology. The immune system has been divided into a more primitive innate immune system and, in vertebrates, an acquired oradaptive immune system

The field concerning the interactions among cells and molecules of the immunesystem,and how such interactions contribute to the recognition and elimination of pathogens. Humans possess a range of non-specific mechanical and biochemical defences against routinely encountered bacteria, parasites, viruses, and fungi. The skin, for example, is an effective physical barrier to infection. Basic chemical defences are also present in blood, saliva, and tears, and on mucous membranes. True protection stems from the host's ability to mount responses targeted to specific organisms, and to retain a form of memory that results in a rapid, efficient response to a given organism upon a repeat encounter. This more formal sense of immunity, termed adaptive immunity, depends upon the coordinated activities of cells and molecules of the immune system.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland

Track: 2Inflammatory/Autoimmune Diseases

Autoimmune diseasescan affect almost any part of the body, including the heart, brain, nerves, muscles, skin, eyes, joints, lungs, kidneys, glands, the digestive tract, and blood vessels.

The classic sign of an autoimmune disease is inflammation, which can cause redness, heat, pain, and swelling. How an autoimmune disease affects you depends on what part of the body is targeted. If the disease affects the joints, as inrheumatoid arthritis, you might have joint pain, stiffness, and loss of function. If it affects the thyroid, as in Graves disease and thyroiditis, it might cause tiredness, weight gain, and muscle aches. If it attacks the skin, as it does in scleroderma/systemic sclerosis, vitiligo, andsystemic lupus erythematosus(SLE), it can cause rashes, blisters, and colour changes. Many autoimmune diseases dont restrict themselves to one part of the body. For example, SLE can affect the skin, joints, kidneys, heart, nerves, blood vessels, and more. Type 1 diabetes can affect your glands, eyes, kidneys, muscles, and more.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 3T-Cells and B-Cells

T cell: A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders. Immature T cells (termed T-stem cells) migrate to the thymus gland in the neck, where they mature and differentiate into various types of mature T cells and become active in the immune system in response to a hormone called thymosin and other factors. T-cells that are potentially activated against the body's own tissues are normally killed or changed ("down-regulated") during this maturational process.There are several different types of mature T cells. Not all of their functions are known. T cells can produce substances called cytokines such as the interleukins which further stimulate the immune response. T-cell activation is measured as a way to assess the health of patients withHIV/AIDSand less frequently in other disorders. T cell are also known as T lymphocytes. The "T" stands for "thymus" -- the organ in which these cells mature. As opposed to B cells which mature in the bone marrow.B cells, also known asBlymphocytes, are a type of white bloodcellof the lymphocyte subtype. They function in thehumoral immunitycomponent of the adaptive immune system by secreting antibodies. Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells. All of the plasma cells descended from a single B cell produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells "remember" the stimulus that led to their formation. The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow. The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production ofimmunoglobulins.It expresses immunoglobulins on its surface.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 4Cancer and Tumor Immunobiology

The tumour is an important aspect of cancer biology that contributes to tumour initiation, tumour progression and responses to therapy. Cells and molecules of the immune system are a fundamental component of the tumour microenvironment. Importantly,therapeutic strategies for cancer treatmentcan harness the immune system to specifically target tumour cells and this is particularly appealing owing to the possibility of inducing tumour-specific immunological memory, which might cause long-lasting regression and prevent relapse in cancer patients.The composition and characteristics of the tumour microenvironment vary widely and are important in determining the anti-tumour immune response.Immunotherapyis a new class ofcancer treatmentthat works to harness the innate powers of the immune system to fight cancer. Because of the immune system's unique properties, these therapies may hold greater potential than current treatment approaches to fight cancer more powerfully, to offer longer-term protection against the disease, to come with fewer side effects, and to benefit more patients with more cancer

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 5 Vaccines

A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. There are two basictypes of vaccines: live attenuated and inactivated. The characteristics of live and inactivatedvaccinesare different, and these characteristics determine how thevaccineis used. Liveattenuatedvaccinesare produced by modifying a disease-producing (wild) virus or bacteria in a laboratory.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology

Track: 6Immunotherapy

Immunotherapy,also called biologic therapy, is a type of cancer treatment designed to boost the body's natural defences to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. Immunotherapy is treatment that uses certain parts of a persons immune system to fight diseases such as cancer. This can be done in a couple of ways:1)Stimulating your own immune system to work harder or smarter to attack cancer cells2)Giving you immune system components, such as man-made immune system proteins. Some types of immunotherapy are also sometimes called biologic therapy or biotherapy.

In the last few decadesimmunotherapyhas become an important part of treating some types of cancer. Newer types of immune treatments are now being studied, and theyll impact how we treat cancer in the future. Immunotherapy includes treatments that work in different ways. Some boost the bodys immune system in a very general way. Others help train the immune system to attack cancer cells specifically. Immunotherapy works better for some types of cancer than for others. Its used by itself for some of these cancers, but for others it seems to work better when used with other types of treatment.

Many different types of immunotherapy are used to treat cancer. They include:Monoclonal antibodies,Adoptive cell transfer,Cytokines, Treatment Vaccines, BCG,

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 7Neuro Immunology

Neuroimmunology, a branch of immunologythat deals especially with the inter relationships of the nervous system and immune responses andautoimmune disorders. It deals with particularly fundamental and appliedneurobiology,meetings onneurology,neuropathology, neurochemistry,neurovirology, neuroendocrinology, neuromuscular research,neuropharmacologyand psychology, which involve either immunologic methodology (e.g. immunocytochemistry) or fundamental immunology (e.g. antibody and lymphocyte assays).

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 8Infectious Diseases and Immune System

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi; the diseases can be spread, directly or indirectly, from one person to another.Zoonotic diseasesare infectious diseases of animals that can cause disease when transmitted to humans. Some infectious diseases can be passed from person to person. Some are transmitted by bites from insects or animals. And others are acquired by ingesting contaminated food or water or being exposed to organisms in the environment. Signs and symptoms vary depending on the organism causing the infection, but often include fever and fatigue. Mild complaints may respond to rest and home remedies, while some life-threatening infections may require hospitalization.

Many infectious diseases, such as measles andchickenpox, can be prevented by vaccines. Frequent and thorough hand-washing also helps protect you from infectious diseases

There are four main kinds of germs:

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 9Reproductive Immunology,

Reproductive immunologyrefers to a field of medicine that studies interactions (or the absence of them) between the immune system and components related to thereproductivesystem, such as maternal immune tolerance towards the fetus, orimmunologicalinteractions across the blood-testis barrier. The immune system refers to all parts of the body that work to defend it against harmful enemies. In people with immunological fertility problems their body identifies part of reproductive function as an enemy and sendsNatural Killer (NK) cellsto attack. A healthy immune response would only identify an enemy correctly and attack only foreign invaders such as a virus, parasite, bacteria, ect.

The concept of reproductive immunology is not widely accepted by all physicians.Those patients who have had repeated miscarriages and multiple failed IVF's find themselves exploring it's possibilities as the reason. With an increased amount of success among treating any potential immunological factors, the idea of reproductive immunology can no longer be overlooked.The failure to conceive is often due to immunologic problems that can lead to very early rejection of the embryo, often before the pregnancy can be detected by even the most sensitive tests. Women can often produce perfectly healthy embryos that are lost through repeated "mini miscarriages." This most commonly occurs in women who have conditions such asendometriosis, an under-active thyroid gland or in cases of so called "unexplained infertility." It has been estimated that an immune factor may be involved in up to 20% of couples with otherwiseunexplained infertility. These are all conditions where abnormalities of the womans immune system may play an important role.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track:10Auto Immunity,

Autoimmunityis the system ofimmuneresponses of an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases. Autoimmune diseases occur when there is progression from benign autoimmunity to pathogenicautoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Autoimmune disorders

An autoimmune disorder occurs whenthe bodys immune systemattacks and destroys healthy body tissue by mistake. There are more than 80 types of autoimmune disorders.

Causes

The white blood cells in the bodys immune system help protect against harmful substances. Examples include bacteria, viruses,toxins,cancercells, and blood and tissue from outside the body. These substances contain antigens. The immune system producesantibodiesagainst these antigens that enable it to destroy these harmful substances. When you have an autoimmune disorder, your immune system does not distinguish between healthy tissue and antigens. As a result, the body sets off a reaction that destroys normal tissues. The exact cause of autoimmune disorders is unknown. One theory is that some microorganisms (such as bacteria or viruses) or drugs may trigger changes that confuse the immune system. This may happen more often in people who have genes that make them more prone toautoimmune disorders.

An autoimmune disorder may result in:

A person may have more than one autoimmune disorder at the same time. Common autoimmune disorders include:

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track: 11Costimmulatory pathways in multiple sclerosis

Costimulatory moleculescan be categorized based either on their functional attributes or on their structure. The costimulatory molecules discussed in this review will be divided into (1)positive costimulatory pathways:promoting T cell activation, survival and/or differentiation; (2)negative costimulatory pathways:antagonizing TCR signalling and suppressing T cell activation; (3) as third group we will discuss themembers of the TIM family, a rather new family of cell surface molecules involved in the regulation of T cell differentiation and Treg function.Costimulatory pathways have a critical role in the regulation of alloreactivity. A complex network of positive and negative pathways regulates T cell responses. Blocking costimulation improves allograft survival in rodents and non-human primates. The costimulation blocker belatacept is being developed asimmunosuppressivedruginrenal transplantation.

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3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 12Autoimmunity and Therapathies

Autoimmunityis the system ofimmuneresponsesof an organism against its own cells and tissues. Any disease that results from such an aberrantimmuneresponse is termed an autoimmune disease.

Autoimmunity is present to some extent in everyone and is usually harmless. However, autoimmunity can cause a broad range of human illnesses, known collectively as autoimmune diseases.Autoimmune diseasesoccur when there is progression from benign autoimmunity to pathogenic autoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies (antibodies directed against the person who produced them) and T cells that are reactive with host antigens.

Current treatments for allergic and autoimmune disease treat disease symptoms or depend on non-specific immune suppression. Treatment would be improved greatly by targeting the fundamental cause of the disease, that is the loss of tolerance to an otherwise innocuous antigen in allergy or self-antigen in autoimmune disease (AID). Much has been learned about the mechanisms of peripheral tolerance in recent years. We now appreciate that antigen presenting cells (APC) may be either immunogenic or tolerogenic, depending on their location, environmental cues and activation state

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3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 13DiagnosticImmunology

Diagnostic Immunology. Immunoassays are laboratory techniques based on the detection of antibody production in response to foreign antigens. Antibodies, part of the humoral immune response, are involved in pathogen detection and neutralization.

Diagnostic immunology has considerably advanced due to the development of automated methods.New technology takes into account saving samples, reagents, and reducing cost.The future of diagnosticimmunologyfaces challenges in the vaccination field for protection against HIV and asanti-cancer therapy. Modern immunology relies heavily on the use of antibodies as highly specific laboratory reagents. The diagnosis of infectious diseases, the successful outcome of transfusions and transplantations, and the availability of biochemical and hematologic assays with extraordinary specificity and sensitivity capabilities all attest to the value of antibody detection.Immunologic methods are used in the treatment and prevention ofinfectious diseasesand in the large number of immune-mediated diseases. Advances in diagnostic immunology are largely driven by instrumentation, automation, and the implementation of less complex and more standardized procedures.

Examples of such processes are as follows:

These methods have facilitated the performance of tests and have greatly expanded the information that can be developed by a clinical laboratory. The tests are now used for clinical diagnosis and the monitoring of therapies and patient responses. Immunology is a relatively young science and there is still so much to discover. Immunologists work in many different disease areas today that include allergy, autoimmunity, immunodeficiency, transplantation, and cancer.

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3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 14Allergy and Therapathies

Although medications available for allergy are usually very effective, they do not cure people of allergies. Allergenimmunotherapyis the closest thing we have for a "cure" for allergy, reducing the severity of symptoms and the need for medication for many allergy sufferers. Allergen immunotherapy involves the regular administration of gradually increasing doses of allergen extracts over a period of years. Immunotherapy can be given to patients as an injection or as drops or tablets under the tongue (sublingual).Allergen immunotherapy changes the way the immune system reacts to allergens, by switching off allergy. The end result is that you become immune to the allergens, so that you can tolerate them with fewer or no symptoms. Allergen immunotherapy is not, however, a quick fix form of treatment. Those agreeing to allergen immunotherapy need to be committed to 3-5 years of treatment for it to work, and to cooperate with your doctor to minimize the frequency of side effects.Allergen immunotherapyis usually recommended for the treatment of potentially life threatening allergic reactions to stinging insects. Published data on allergen immunotherapy injections shows that venom immunotherapy can reduce the risk of a severe reaction in adults from around 60 % per sting, down to less than 10%. In Australia and New Zealand,venom immunotherapyis currently available for bee and wasp allergy. Jack Jumper Ant immunotherapy is available in Tasmania for Tasmanian residents. Allergen immunotherapy is often recommended for treatment ofallergic rhinitis

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 15Technological Innovations inImmunology

Immunology is the branch of biomedical sciences concerned with all aspects of the immune system in all multicellular organisms. Immunology deals with physiological functioning of the immune system in states of both health and disease as well as malfunctions of the immune system in immunological disorders like allergies, hypersensitivities, immune deficiency, transplant rejection andautoimmune disorders.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track:16Antigen Processing

Antigen processingis an immunologicalprocessthat prepares antigensfor presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage ofantigenpresentation pathways. The process by which antigen-presenting cells digest proteins from inside or outside the cell and display the resulting antigenic peptide fragments on cell surface MHC molecules for recognition by T cells is central to the body's ability to detect signs of infection or abnormal cell growth. As such, understanding the processes and mechanisms of antigen processing and presentation provides us with crucial insights necessary for the design ofvaccines and therapeutic strategiesto bolster T-cell responses.

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3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 3rd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 2nd Autoimmunity Conference, Nov 9-10, 2017 Madrid, Spain; Integrating Metabolism and Immunity , May 29 - June 2, 2017 | Dublin, Ireland; American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting, March 03-06, 2017, Atlanta, Georgia

Track: 17Immunoinformatics and Systems Immunology

Immunoinformaticsis a branch ofbioinformaticsdealing with in silico analysis and modelling of immunological data and problems Immunoinformatics includes the study and design of algorithms for mapping potential B- andT-cell epitopes, which lessens the time and cost required for laboratory analysis of pathogen gene products. Using this information, an immunologist can explore the potential binding sites, which, in turn, leads to the development of newvaccines. This methodology is termed reversevaccinology and it analyses the pathogen genome to identify potential antigenic proteins.This is advantageous because conventional methods need to cultivate pathogen and then extract its antigenic proteins. Although pathogens grow fast, extraction of their proteins and then testing of those proteins on a large scale is expensive and time consuming. Immunoinformatics is capable of identifying virulence genes and surface-associated proteins.

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9thworld congress & expo on Immunology, Oct 02-04, 2017, Toronto, Canada; 3rdAntibodies and Bio Therapeutics Congress, November 02-03, 2017 Las Vegas, USA; Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18th International Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; British Society for Immunology Congress, Dec 06-09, 2016, Liverpool, United Kingdom; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology (C7), March 19 - 23, 2017, Whistler, British Columbia, Canada

Track: 18Rheumatology

Rheumatology represents a subspecialty in internal medicine and pediatrics, which is devoted to adequate diagnosis andtherapy of rheumatic diseases(including clinical problems in joints, soft tissues, heritable connective tissue disorders, vasculitis and autoimmune diseases). This field is multidisciplinary in nature, which means it relies on close relationships with other medical specialties.The specialty of rheumatology has undergone a myriad of noteworthy advances in recent years, especially if we consider the development of state-of-the-art biological drugs with novel targets, made possible by rapid advances in the basic science of musculoskeletal diseases and improved imaging techniques.

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Molecular Immunology & Immunogenetics Congress, March 20-21, 2017 Rome, Italy; 3nd International Congress on Neuroimmunology and Therapeutics, September 18-19, 2017 Philadelphia, USA; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand; Annual Meeting on Immunology and Immunologist, July 03-05, 2017 Malyasia, Kuala lumpur; 19thInternational Conference on Immunology (ICI) Sept 14-17, 2017, Berlin, Germany; Modelling Viral Infections and Immunity (E1) , May 1 - 4, 2017 | Estes Park, Colorado, USA; 7thInternational Conference on Allergy, Asthma and Clinical Immunology; 18thInternational Conference on Immunology (ICI) Dec 12-13, 2016, Bangkok, Thailand

Track: 19Nutritional Immunology

Nutritional immunologyis an emerging discipline that evolved with the study of the detrimental effect of malnutrition on the immune system. The clinical and public health importance of nutritional immunology is also receiving attention. Immune system dysfunctions that result from malnutrition are, in fact, NutritionallyAcquired Immune Deficiency Syndromes(NAIDS). NAIDS afflicts millions of people in the Third World, as well as thousands in modern centers, i.e., patients with cachexia secondary to serious disease, neoplasia or trauma. The human immune system functions to protect the body against foreign pathogens and thereby preventing infection and disease. Optimal functioning of the immune system, both innate and adaptive immunity, is strongly influenced by an individuals nutritional status, with malnutrition being the most common cause of immunodeficiency in the world. Nutrient deficiencies result in immunosuppression and dysregulation of the immune response including impairment of phagocyte function and cytokine production, as well as adversely affecting aspects of humoral and cell-mediated immunity. Such alterations in immune function and the resulting inflammation are not only associated with infection, but also with the development of chronic diseases including cancer, autoimmune disease, osteoporosis, disorders of the endocrine system andcardiovascular disease.

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See the original post:
8 - OMICS International Conference

Recommendation and review posted by Bethany Smith

Some of the promise of stem cell therapy has been realized. A prime example is bone marrow transplantation. Even here, however, manyproblems remain to be solved.

Challenges facing stem cell therapy include the following:

Adult stem cells Tissue-specific stem cells in adult individuals tend to be rare. Furthermore, while they can regenerate themselves in an animal or person they are generally very difficult to grow and to expand in the laboratory. Because of this, it is difficult to obtain sufficient numbers of many adult stem cell types for study and clinical use. Hematopoietic or blood-forming stem cells in the bone marrow, for example, only make up one in a hundred thousand cells of the bone marrow. They can be isolated, but can only be expanded a very limited amount in the laboratory. Fortunately, large numbers of whole bone marrow cells can be isolated and administered for the treatment for a variety of diseases of the blood. Skin stem cells can be expanded however, and are used to treat burns. For other types of stem cells, such as mesenchymal stem cells, some success has been achieved in expanding the cellsin vitro, but application in animals has been difficult. One major problem is the mode of administration. Bone marrow cells can be infused in the blood stream, and will find their way to the bone marrow. For other stem cells, such as muscle stem cells, mesenchymal stem cells and neural stem cells, the route of administration in humans is more problematic. It is believed, however, that once healthy stem cells find their niche, they will start repairing the tissue. In another approach, attempts are made to differentiate stem cells into functional tissue, which is then transplanted. A final problem is rejection. If stem cells from the patients are used, rejection by the immune system is not a problem. However, with donor stem cells, the immune system of the recipient will reject the cells, unless the immune system is suppressed by drugs. In the case of bone marrow transplantation, another problem arises. The bone marrow contains immune cells from the donor. These will attack the tissues of the recipient, causing the sometimes deadly graft-versus-host disease.

Pluripotent stem cells All embryonic stem cell lines are derived from very early stage embryos, and will therefore be genetically different from any patient. Hence, immune rejection will be major issue. For this reason, iPS cells, which are generated from the cells of the patient through a process of reprogramming, are a major breakthrough, since these will not be rejected. A problem however is that many iPS cell lines are generated by insertion of genes using viruses, carrying the risk of transformation into cancer cells. Furthermore, undifferentiated embryonic stem cells or iPS cells form tumors when transplanted into mice. Therefore, cells derived from embryonic stem cells or iPS cells have to be devoid of the original stem cells to avoid tumor formation. This is a major safety concern.

A second major challenge is differentiation of pluripotent cells into cells or tissues that are functional in an adult patient and that meet the standards that are required for 'transplantation grade' tissues and cells.

A major advantage of pluripotent cells is that they can be grown and expanded indefinitely in the laboratory. Therefore, in contrast to adult stem cells, cell number will be less of a limiting factor. Another advantage is that given their very broad potential, several cell types that are present in an organ might be generated. Sophisticated tissue engineering approaches are therefore being developed to reconstruct organs in the lab.

While results from animal models are promising, the research on stem cells and their applications to treat various human diseases is still at a preliminary stage. As with any medical treatment, a rigorous research and testing process must be followed to ensure long-term efficacy and safety.

See the article here:
Stem Cell FAQ

Recommendation and review posted by simmons

1. Introduction

Hematopoietic stem cell transplantation (HSCT) has a half-century history. It is currently an indispensable treatment for not only incurable blood diseases such as aplastic anemia and severe hemolytic anemia, but also malignant hematological diseases such as leukemia and lymphoma. Although allergenic HSCT is also used to treat hereditary diseases, its indications are restricted because of critical complications including regimen-related toxicities involving conditioning, infection, and graft-versus-host disease.

Studies in recent decades have shown that HSCT can have a long-term effect in the treatment of hereditary diseases involving a responsible gene in hematogenous cells. Although the first successful gene therapy using lymphocytes or bone marrow cells for a patient with adenosine deaminase (ADA) deficiency inspired great hope in the future of gene therapy [1-3], subsequent gene therapy using HSCs for patients with X-linked severe combined immunodeficiency (SCID-X1) resulted in tumorigenesis [4]. In addition to the self-renewal and multilineage differentiation capacities of tissue stem cells, HSCs exhibit cell-cycle dormancy, which complicates their use in gene therapy.

However, as technological advances have increased the safety and efficiency of introducing genes into HSCs, gene therapy with HSCs is attracting attention again. In this chapter, advances in the technology of HSC gene therapy, e.g., vector design to avoid genotoxicity and increase transgenic efficiency by taking advantage of the special characteristics of HSCs, are reviewed. In addition, recent studies on HSC gene therapy for various hereditary diseases, such as thalassemia, Fanconi anemia, hemophilia, primary immunodeficiency, mucopolysaccharidosis, Gaucher disease, and X-linked adrenoleukodystrophy (X-ALD) are discussed.

The concept of the HSC was introduced by Till and McCulloch in 1961 [5]. Although a healthy adult produces approximately 1 trillion blood cells each day, they are considered to originate from a single HSC which can potentially be transplanted into a mouse [6, 7]. Generally stem cells are defined as cells capable of self-renewal and multilineage differentiation. In addition to these two characteristics, HSCs have the capability of cell-cycle dormancy, i.e. to enter a state of dormancy (G0 phase) in the cell cycle and can continue blood cell production over a lifetime while protecting themselves from various kinds of stress [8].

Fig. 1 shows HSC surface markers and the typical cytokines regulating HSCs. Stem cell factor (SCF) and thrombopoietin (TPO) are important direct cytokine regulators of HSCs. Although SCF promotes the proliferation and differentiation of hematopoietic progenitor cells, it is thought to not be essential for the initiation of hematopoiesis and HSC self-renewal [9]. TPO and its receptor, c-Mpl, are thought to play important roles in early hematopoiesis from HSCs. In contrast to the CD34+CD38-c-Mpl- population, CD34+CD38-c-Mpl+ cells show significantly better HSC engraftment [10]. Mice lacking either TPO or c-Mpl have deficiencies in progenitor cells of multiple hematopoietic lineages [11]. TPO-mediated signal transduction for the self-renewal of HSCs is negatively regulated by the intracellular scaffold protein Lnk [12, 13]. A signal from angiopoietin-1 via Tie2 regulates HSC dormancy by promoting the adhesion of HSCs to osteoblasts in the bone marrow niche and maintains long-term repopulating activity [14]. Although cytokine-induced lipid raft clustering of the HSC membrane is essential for HSC re-entry into the cell cycle, transforming growth factor- (TGF-) inhibits lipid raft clustering and induces p57Kip2 expression, leading to HSC dormancy [15, 16]. Recently, the hypoxic niche of HSCs has been demonstrated. It, along with the osteoblastic and vascular niches, are important for HSC dormancy [17-19]. They are targets in HSC gene therapy [20].

Hematopoietic stem cell (HSC) surface markers and typical cytokines that regulate HSCs. Stem cell factor (SCF) promotes the proliferation and differentiation of HSCs. Thrombopoietin (TPO) and its receptor, c-Mpl, play important roles in early hematopoiesis, especially self-renewal. Signals from angiotensin-1 via Tie2 and transforming growth factor - via its receptors regulate HSC dormancy. (This figure is based on the illustration by BioLegend, Inc. San Diego, CA, U.S.A. http://www.biolegend.com/cell_markers)

While making a HSC with few opportunities for cell division into a transgenic target, it is important to design a safe and efficient vector for inserting a gene into the host chromosome. Furthermore, since a hematogenous cell also has many cells which exhibit its function in the specialization process to a mature effector cell, it is also important to select differentiation-specific or non-specific promoters or enhancers during the vector design process.

Vectors derived from the Retroviridae family, RNA viruses with reverse transcriptase activity, are widely used for inserting genes in host chromosomes. Although adeno-associated virus (AAV) vectors can also insert genes into host chromosomes, this process is inefficient and partial. Gammaretroviruses and lentiviruses are members of the Retroviridae family that are commonly used as vectors in HSC gene therapy. Generally, the former is called simply a retroviral vector and the latter is called a lentiviral vector. When a gene is inserted in the chromosome of an HSC with a Retroviridae vector, genotoxicity can occur.

Retroviral vectors are commonly constructed from the Moloney murine leukemia virus (MoMLV) genome. Retroviral genomes have a gag/pol gene that codes for viral structure proteins, protease and reverse transcriptase, an env gene that codes for the envelope glycoprotein and the packaging signal. These genes are flanked by long terminal repeats (LTR) which contain enhancers and promoters. A retroviral vector consists of a packaging plasmid that does not have the packaging signal but does include the gag/pol gene, a transfer vector with the packaging signal, and the target gene cDNA. After transfection of these plasmids into producer cells (e.g., 297T cells, NIH3T3 cell, etc.), a target vector is obtained by collecting the culture solution.

Expression of a target gene can be inhibited by mechanisms such as methylation of CpG islands in the promoter region, insertion of a negative control region (NCR) into the LTR, and the presence of a repressor binding site (RBS) downstream of the 5 LTR. Other vectors, such as the murine stem cell virus (MSCV) vector [21], the myeloproliferative sarcoma virus vector, the negative control region deleted (MND) vector [22], and the MFG-S vector [23] were developed to improve the efficiency of transgene expression; they are widely used in clinical applications of gene therapy involving HSCs.

Since the retroviral viral genome cannot cross the nuclear membrane, it can be incorporated into a chromosome only during the phase of mitosis when the nuclear membrane has disassembled. Since many HSCs are thought to exist in a dormant phase, insertions into the HSC genome with a retroviral vector require a proliferation stimulus by cytokines. Although various combinations of cytokines to suppress the decrease in HSC self-renewal have been studied, stem cell factor (SCF), fms-related tyrosine kinase-3 (Flt-3) ligand, interleukin-3 (IL-3), TPO, among others, are commonly used [24, 25].

Human immunodeficiency virus type 1 (HIV-1), the representative lentivirus, differs from gammaretroviruses in that it can be incorporated during a non-mitotic phase. This is one advantage of lentiviral vectors in HSC gene therapy.

Both lentiviruses and gammaretroviruses have gag, pol, and env genes sandwiched between LTRs with promoter activity at both ends. In addition, lentiviruses have accessory genes (vif, vpr, vpu, nef) and regulatory genes (tat, rev). Double-stranded cDNA produced from the viral genome enters the cell, and a pre-integration complex is formed with a host protein. This complex can pass through the pores of the nuclear membrane during non-mitotic phases, allowing the viral genome to be inserted into the host cell chromosome.

HIV provirus (A) and the four plasmids of a third-generation lentiviral vector (B). The viral long terminal repeats (LTRs), reading frames of the viral genes, splice donor site (SD), splicing acceptor site (SA), packaging signal (), and rev-responsive element (RRE) are indicated. The packaging plasmid contains the gag and pol genes under the influence of the CMV promoter, intervening sequences, and the polyadenylation site (polyA) of the human -globin gene. As the transcripts of the gag and pol genes contain cis-repressive sequences, they are expressed only if rev promotes their nuclear export by binding to the RRE. All tat and rev exons have been deleted, and the viral sequences upstream of the gag gene have been replaced. The rev plasmid expresses rev cDNA. The SIN vector plasmid contains HIV-1 cis-acting sequences and an expression cassette for the transgene. It is the only portion transferred to the target cells and does not contain wild-type copies of the HIV LTR. The 5 LTR is chimeric, with the RSV enhancer and promoter replacing the U3 region to rescue transcriptional dependence on tat. The 3 LTR has an almost completely deleted U3 region, which includes the TATA box. As the latter is the template used to generate both copies of the LTR in the integrated provirus, transduction of this vector results in transcriptional inactivation of both LTRs; thus, it is a self-inactivating (SIN) vector. The envelope plasmid encodes a heterologous envelope to pseudotype the vector, here shown coding for vesicular stomatitis virus (VSV)-G. Only the relevant parts of the constructs are shown (Reproduced with modifications from [26]).

Although first-generation lentiviral vectors included modification genes, they were removed in the second generation because it was discovered that the modification genes are not required for infection during non-mitotic phases. In the third generation, further modifications included the deletion of tat, use of multiple vector plasmids, and introduction of self-inactivating (SIN) vectors. The structure of HIV-1 and a typical third-generation lentiviral vector system are shown in Fig. 2 [26]. Approximately one-third of the HIV-1 genome has been deleted, and the vector system has been divided into four plasmids, namely, the packaging plasmid, rev plasmid, SIN vector plasmid and envelope plasmid. To prevent production of wild type HIV-1, tat, a regulatory gene indispensable to viral reproduction was deleted, and the rev gene was moved to a separate plasmid. Moreover, since the HIV-1 LTR promoter is weak in the absence of tat, it was replaced with the cytomegalovirus (CMV) promoter in the packaging plasmid. Since an envelope plasmid can only infect CD4 positive cells with a HIV-1 envelope, the envelope gene was replaced with the vesicular stomatitis virus G glycoprotein (VSV-G) envelope. The SIN vector further improved safety by replacing the enhancer / promoter portion of the LTR, suppressing the activation of unnecessary genes with the integrated gene (Fig. 3) [27].

Mechanism of gene activation induced by vector insertion. The genomic integration site of an MLV-based retroviral vector is depicted. With this MLV vector design, the enhancer and promoter within the U3 region (blue rectangle) of the long terminal repeat (LTR) drive transcription of the transgene (indicated by the parallel arrow arising from the blue rectangle). Vector integration near Gene X is shown in the top panel. The enhancer elements located in the U3 region (blue rectangle) of the vector can interact with the regulatory elements upstream of Gene X to increase its basal transcription rate to inappropriately high levels, potentially altering the growth of the cell. Two alternatives for eliminating the use of the powerful enhancer in the U3 region include (1) middle panel: use of a self-inactivating (SIN) MLV-based vector in which the U3 region has been deleted. An internal cellular promoter is used to drive transgene expression and (2) bottom panel: use of a SIN lentiviral vector in which U3 (yellow rectangle) has been eliminated. This system also uses an internal cellular promoter to drive transgene expression (Reproduced with modification from [27]).

To improve the gene transfer into HSCs, Verhoeyen and colleagues designed lentiviral vectors displaying early-acting cytokines such as TPO and SCF. This vector can promote survival of CD34 positive HSCs and achieve selective transduction of long-term repopulating cells in a humanized mouse model (Fig. 4) [28, 29].

Lentiviral vector particles (HIV-1) display recombinant membrane envelope proteins such as stem cell factor (SCF), thrombopoietin (TPO), and vesicular stomatitis virus G glycoprotein (VSV-G). This vector can specifically target vector particles to hematopoietic stem cells (HSCs) expressing c-kit and c-mpl receptors for SCF and TPO, respectively. VSV-G envelope protein can bind to phospholipids in the HSC cell membrane. (Karlsson S, Gene therapy: efficient targeting of hematopoietic stem cells. Blood. 2005;106(10):3333)

The most serious problem with using viral vectors to incorporate a gene into a chromosome is the potential development of clonal proliferative diseases such as leukemia, which was observed in clinical trials involving gene therapy for SCID-X1 and chronic granulomatous disease (CGD). Although this problem of genotoxicity represents a great hurdle in the development of clinical applications for gene therapy, there is promising ongoing research on the mechanisms underlying genotoxicity and how to avoid it.

The mechanisms of retrovirus-induced oncogenesis are shown in Fig. 5 [30]. In oncogene capture, an acute transforming replication-competent retrovirus captures a cellular proto-oncogene and mediates transformation. This mechanism does not occur in replication-incompetent vectors. Second, the provirus 3 LTR can trigger increased transcription of a cellular proto-oncogene. Third, enhancers in the provirus LTRs can activate transcription from nearby cellular proto-oncogene promoters. Fourth, a novel isoform can be expressed when transcription from the provirus 5 LTR creates a novel truncated isoform of a cellular proto-oncogene via splicing. Fifth, an inserted provirus can disrupt transcription by causing premature polyadenylation. The same mechanisms can occur in cellular oncogenesis when a gene is inserted by a retroviral vector [30].

Retroviral mechanisms of oncogenesis. The detailed mechanisms are shown in the text. The integrated provirus is indicated by two LTRs. Cellular proto-oncogene promoter and exons are indicated by black and grey boxes respectively (Reproduced from [30]).

Even if a gene is inserted into a HSC similarly, it is also known that there are diseases which may develop a tumor, and diseases a tumor is not accepted to be. Each type of virus has a unique integration profile, and the following observations have been made [30]: (a) Different retroviral vectors have distinct integration profiles. (b) The route of entry does not appear to strongly affect distribution of integration sites. VSV-Gpseudotyped HIV vectors have an integration profile similar to HIV virions with the native HIV envelope despite differences in the route of entry. (c) The integration profile is largely independent of the target cell type, although the transcriptional program and epigenetic status of the target cell can influence integration site selection. (d) For lentiviruses, which can integrate independently of mitosis, the cell-cycle status of the target cell has only a modest effect on the distribution of integration sites.

In order to avoid genotoxicity, various SIN vectors have been developed and improved. In general, lentiviral vectors are considered to have a lower risk of oncogenesis than retroviral vectors [31]. However, when a HSC is the target cell, more attention should be required because tumorigenesis can occur when the cell with the inserted gene undergoes differentiation.

Diseases in which gene therapy using HSCs are being studied are shown in Table 1. They are roughly divided into hematological disorders, immunodeficiencies, and metabolic diseases. Most are congenital or hereditary diseases. The characteristic clinical features and recent basic science or clinical studies on HSC gene therapy for each disease are discussed below.

Clinical applications of hematopoietic stem cell gene therapy.

Hemoglobin A (HbA), comprising 98% of adult human hemoglobin, is a tetramer with two -globin and two -globin chains combined with a heme group. -thalassemia is an autosomal hemoglobin disorder caused by decreased -globin chain synthesis. Although individuals with -thalassemia minor (heterozygote) may be asymptomatic or have mild to moderate microcytic anemia, -thalassemia major (homozygote) progresses to serious anemia by one or two years of age, and hemosiderosis, iron overload caused by transfusion or increased iron absorption, develops. Since most patients develop life-threatening complications such as heart failure by adolescence, HSCT has been performed in patients with advanced disease [32]. In recent years, gene therapy using a lentiviral vector containing a functional -globin gene has been performed in an HbE/ -thalassemia (E/ 0) transfusion-dependent adult male, who subsequently did not require transfusions for over 21 months [33].

The human -globin locus is located in a large 70kb area which also contains some -like globulin genes (, G, A, , ). Gene switching takes place according to the development stage, and the -globin gene is transcribed and expressed specifically after birth. A powerful enhancer called the LCR (locus control region) exists on the 5 side of the promoter. The LCR contains five DNase I hypersensitive sites, referred to as HS5 to HS1 starting from the 5 side. Furthermore, HS5 contains CCCTC-binding factor (CTCF)-dependent insulator.

The structure of the lentiviral SIN vector used in gene therapy for -thalassemia is shown in Fig. 6. To improve safety, two stop codons were inserted into the packaging signal () of GAG, the HS5 portion with insulator activity was deleted, and two copies of the 250 base pair (bp) core of the cHS4 chromatin insulators (chicken -globin insulators) were inserted in the U3 region of the HIV 3 LTR. Furthermore, the amino acid at the 87th position of -globin was changed from threonine to glutamine. This altered -globin can be distinguished from normal adult -globin by high performance liquid chromatography (HPLC) analysis in individuals receiving red blood cell transfusion and +-thalassemia patients [33].

Diagram of the human -globin gene in a lentiviral vector. HIV LTR, human immunodeficiency type-1 virus long terminal repeat; +, packaging signal; cPPT/flap, central polypurine tract/DNA flap; RRE, rev-responsive element; p, human -globin promoter; ppt, polypurine tract; HS, DNase I Hypersensitive Sites (Reproduced with color modification from [33])

A clinical study using this vector was performed in two -thalassemia patients. As with autologous bone marrow transplantation, some of the patients marrow cells were cryopreserved as a backup. The lentiviral vector particles containing a functional -globin were introduced into the remaining cells. After the transfected cells were cultured for one week ex vivo, some were also cryopreserved. The patients were conditioned with intravenous busulfan (3.2 mg/kg/day for four days) without the addition of cyclophosphamide, before transplantation using the autologous gene-modified cryopreserved cells (Fig. 7) [34].

The first patient failed to engraft because the HSCs had been compromised by how they were handled, not because of any issues with the gene therapy vector, and ultimately used backup bone marrow. The second patient, as described previously, achieved long-term -globin production; one-third of the patients hemoglobin was produced by the genetically modified cells [33].

Furthermore, the detailed examination of the transgenic cells showed significantly increased expression of high mobility group AT-hook 2 (HMGA2), which interacts with transcription factors to regulate gene expression, in the clones where gene insertion occurred in the HMGA2 gene. The proportion of the HMGA2 overexpressing clones increased with time, to over 50% of transgenic cells at 20 months after gene therapy. In this patient, the HMGA2 overexpressing cells were only 5% of all circulating hematopoietic cells and there was no evidence of malignant transformation. However, researchers point out that there was expressive production of a truncated form of the HMGA2 protein. Since truncated or overexpressed HMGA2 is observed with some blood cancers and non-malignant expansions of blood cells, caution is recommended with this therapy [34].

Gene-therapy procedure for patient with b-thalassemia. a. Hematopoietic stem cells (HSCs) are collected from the bone marrow of a patient with -thalassemia and maintained them in culture. b, Lentiviral-vector particles containing a functional -globin gene were then introduced into the cells and allowed them to expand further in culture. c. To eradicate the patients remaining HSCs and make room for the geneticaaly modified cells, the patient underwent chemotherapy. d. The genetically modified HSCs were then transplanted into the patient (Reproduced from [34]).

Recently, researchers generated a LCR-free SIN lentiviral vector that combines two hereditary persistence of fetal hemoglobin (HPFH)-activating elements, resulting in therapeutic levels of A-globin protein produced by erythroid progenitors derived from thalassemic HSCs [35]. Both lentiviral-mediated -globin gene addition and genetic reactivation of endogenous -globin genes are considered potentially capable of providing therapeutic levels of hemoglobin F to patients with -globin deficiency [36]. In addition, a trial of -globin induction with -globin production using mithramycin, an inducer of -globin expression, to remove excess -globin proteins in -thalassemic erythroid progenitor cells was reported [37].

Fanconi anemia is a hereditary disease characterized by cellular hypersensitivity to DNA crosslinking agents. It leads to bone marrow failure, such as aplastic anemia, by approximately eight years of age. Since there is a high risk of developing malignancy, HSCT has been performed as a curative treatment for bone marrow insufficiency. Although the ten-year probability of survival after transplant from an Human leukocyte antigen (HLA) -identical donor is over 80%, results with other donors are not satisfactory. HSC gene therapy is considered an alternative in cases where there is no HLA-identical donor available [38-40].

There are currently 13 discovered Fanconi anemia complement groups and 13 distinct genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN) have been cloned. Mutations in FANCB are associated with an X-linked form of Fanconi anemia; mutations in the other genes are associated with autosomal recessive transmission. Although frequencies vary by geographical region, FANCA gene abnormalities are found in more than half of all Fanconi anemia patients [41]. Although one of the major hurdles in the development of gene therapy for Fanconi anemia is the increased sensitivity of Fanconi anemia stem cells to free radical-induced DNA damage during ex vivo culture and manipulation, retroviral and lentiviral vectors have been successfully employed to deliver complementing Fanconi anemia cDNA to HSCs with targeted disruptions of the FANCA and FANCC genes [20, 42-44]. In a phase I trial of FANCA gene therapy, gene transfer was performed with patient bone marrow-derived CD34+ cells and the MSCV retroviral vector [38]. Whether sufficient HSCs can be obtained is a potential problem in Fanconi anemia patients due to possible bone marrow insufficiency, but in this study, sufficient target CD34+ cells were obtained from most patients. Two patients had FANCA-transduced cells successfully infused. The procedure was safe, well tolerated, and resulted in transient improvements in hemoglobin and platelet counts [39]. However, transduced cell products were not obtained in one patient who required cryopreserved bone marrow. The first clinical study of FANCC gene therapy using a retroviral vector involved four patients. Although functional FANCC gene expression was observed in peripheral blood and bone marrow cells, the results were transient [43].

Engraftment efficiency of FANCA-modified cells using a lentiviral vector was studied in a mouse model. Rapid transduction with four hours of culture using only SCF and megakaryocyte growth and development factor and minimal differentiation of gene-induced cells is better than standard 96-hour culture using a variety of cytokines, including SCF, interleukin-11, Flt-3 ligand, and IL-3 [44]. Moreover, a recent trial demonstrated enhanced viability and engraftment of gene-corrected cells in patients with FANCA abnormalities with short transduction (overnight), low oxidative stress (5% oxygen), and the anti-oxidant N-acetyl-L-cysteine [20]. Lentiviral transduction of unselected Fanconi anemia bone marrow cells mediates efficient phenotypic correction of hematopoietic progenitor cells and CD34- mesenchymal stromal cells, with increased efficacy in hematopoietic engraftment [45]. In Fancg -/- mice, the wild-type mesenchymal stem and progenitor cells play important roles in the reconstitution of exogenous HSCs in vitro [46]. Recently, a new approach that directly injects lentiviral vector particles into the femur for FANCC gene transfer in mice was able to successfully introduce the FANCC gene to HSCs. This result provides evidence that targeting the HSCs directly in their native environment enables efficient and long-term correction of bone marrow defects in Fanconi anemia [47].

In recent years, the design of lentiviral vectors used for gene therapy in Fanconi anemia has improved. Although the vav and phosphoglycerate kinase (PGK) promoters are relatively weak, physiological levels of FANCA gene expression can be obtained in lymphoblastoid cells. CMV and spleen focus-forming virus (SFFV) promoters result in overexpression of FANCA. The PGK-FANCA lentiviral vectors with either a wild-type woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) or a mutated WPRE in the 3 region have higher levels of FANCA gene expression. In conclusion, lentiviral vectors with a mutated WPRE and a PGK promoter are considered the most suitable with respect to safety and efficiency for Fanconi anemia gene therapy [48].

There was a recent interesting report on the use of induced pluripotent stem cells (iPS cell). Instead of introducing a repaired gene into the HSCs of a patient with a FANCA gene abnormality, the modified gene was introduced into more stable somatic cells, e.g. fibroblasts, and iPS cells were derived from the genetically modified somatic cells. If HSCs can be produced from genetically modified iPS cells, hematological function can be efficiently reconstructed in patients with hematologic disorders [49].

Hemophilia is a common congenital coagulopathy caused by coagulation factor VIII (hemophilia A) or IX (hemophilia B) deficiency. Although the genes encoding both factor VIII (Xq28) and factor IX (Xq27) are located on the X chromosome and most cases are X-linked, many sporadic variations have been reported. Factor substitution therapies have been used to treat hemophilia for many years. However, there is great hope for gene therapy with hemophilia because coagulation factors have short half-lives (factor VIII, 8 to 12 hours; factor IX, 18 to 24 hours), and an inhibitor is produced in many cases. Furthermore, it is possible for gene therapy to suppress immunogenicity by introducing a mutant protein that lacks the domain with which the inhibitor interacts. Since both coagulation factors are usually produced in the liver, there are few studies involving HSCs. In addition to hepatocytes, trials introducing the modified gene directly into splenic cells, endothelial cells, myoblasts, fibroblasts, etc. have been reported [50-52]. Since the factor IX gene (34 kb) is smaller than the factor VIII gene (186 kb), hemophilia B gene therapy can be possible with an adenovirus vector or an AAV vector. Therefore, hemophilia B is progressing more as a field of gene therapy research even through there are five times more patients with hemophilia A [51-53].

Recently, human factor VIII variant genes were successfully introduced into the HSCs of a mouse with hemophilia A resulting in therapeutic levels of factor VIII variant protein expression. This variant factor VIII has changes in the B and A2 domain in addition to the A1 domain for improved secretion and reduced immunogenicity (wild-type factor VIII has six domains, A1, A2, B, A3, C1, and C2) [54]. To ameliorate the symptoms of hemophilia A, partial replacement of the mutated liver cells by healthy cells in hemophilia A mice was challenged with allogeneic bone marrow progenitor cell transplantation. In this study, the bone marrow progenitor cell-derived hepatocytes and sinusoidal endothelial cells synthesized factor VIII, showing that autologous gene-modified bone marrow progenitor cells have the potential to treat hemophilia [55].

Although HSCT has been widely performed as curative treatment for primary immunodeficiencies, gene therapy has been considered when there is no HLA-identical donor available. As previously shown, the first successful gene therapy was performed in a patient with ADA deficiency in the U.S. in 1990. Since the gene was introduced into T lymphocytes, frequent treatment was required. However, this treatment was associated with an unacceptable level of toxicity. Since transfected vector and normal ADA gene expression in T lymphocytes continued for two years after the cessation of treatment [1], gene therapy attracted attention. With advances in HSC gene-transfer technology, gene therapy for many primary immunodeficiencies can now be considered [56].

SCID-X1 is an X-linked disease caused by deficiency of the common (c) chain in the IL-2 receptor. Because the c chain is common to the IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, in SCID-X1 patients, there are defects in T and natural killer (NK) cells, and B cell dysfunction are usually observed [57]. Patients begin suffering from various infections starting several weeks after birth. Without curative treatment, such as HSCT, patients die in infancy.

In SCID-X1, since T cells are lacking, engraftment of the gene-transduced cells can be achieved without pre-conditioning therapy. In the clinical studies of SCID-X1 patients in France and the U.K., the MFG retroviral vector was used with HSCs obtained from the patient. After gene therapy, many patients had improvements in immune function. However, since the genes regulating lymphocyte proliferation, such as LIM domain only 2 (LMO2), Bmi1, cyclin D2 (CCND2) are near the gene insertion region, there was a high frequency of T-cell leukemia after treatment. Furthermore, in the patients who developed leukemia, additional chromosomal changes, including activating mutations of Notch1, changes in the T cell receptor region, and deletion of tumor suppressor genes, e.g. cyclin-dependent kinase-2A (CDKN2A) were observed [58]. Almost gene integration sites by the retroviral vector were inside or near genes that are highly expressed in CD34 positive stem cells. Furthermore, the activity of protein kinases or transferases coded by these activated genes was stronger in CD3 positive T cells than CD34 positive cells [59]. Thus, gene integration mediated by a retrovirus influences the target cells dormant capacity for survival, engraftment, and proliferation.

Although continuous T cell production was founded in many cases, there was little reconstruction of myeloid cells and B cells, and some patients required continuous immunoglobulin substitution therapy. The use of conditioning therapy is also related to immunological reconstruction after c chain gene therapy. There is decreased NK cell reconstruction without conditioning therapy, so conditioning chemotherapy is required for the engraftment of undifferentiated stem cells [58]. A trial of SCID-X1 gene therapy in the U.S. involved three patients ranging from 10 to 14 years of age. They had poor immunological recovery after allergenic HSCT and T cell recovery was only observed in the youngest patient, suggesting there is a limit to the recovery of the function of the thymus in older children [60].

To study whether activation of genes near the region of gene insertion or inserted c chain gene expression itself induces oncogenicity during SCID-X1 gene therapy, a study of the human c chain gene being expressed under the control of the human CD2 promoter and LTR (CD2- c chain gene) was performed in mice. When the CD2- c chain gene was expressed in transgenic mice, a few abnormalities involving T cells were observed, but tumorigenesis was not observed and T and B cell functions were recovered in c chain-gene deficient mice. This study demonstrated that when the c c chain gene is expressed externally, SCID-X1 may be treated safely [61].

Although SIN vectors were developed from earlier retroviral [62] or lentiviral vectors [63] to reduce the risk of oncogenicity in SCID-X1 gene therapy, genotoxicity unrelated to mutations in gene insertion regions or c chain gene overexpression have been reported with lentiviral vectors in recent years, and it seems that more sophisticated vector development is required [64].

ADA is an enzyme that catalyzes the conversion of purine metabolism products adenosine and deoxyadenosine into inosine or deoxyinosine. ADA-SCID is an autosomal recessive disease that results in the accumulation of adenosine, deoxyadenosine, and deoxyadenosinetriphosphate (dATP). Accumulated phosphorylated purine metabolism products act on the thymus and cause the maturational or functional disorder of lymphocytes. Because ADA-SCID patients have both T and B cell production fail, patients have a severe combined immunodeficiency disease with a clinical presentation similar to SCID-X1 results, but unlike SCID-X1, many patients have a low level of T cells. Although enzyme replacement therapy with polyethylene glycolmodified bovine ADA (PEG-ADA) was developed to treat ADA-SCID, it is limited by the development of neutralizing antibodies and the cost of lifelong treatment.

In ADA-SCID, since T cell counts are increased by PEG-ADA, gene therapy to increase peripheral T cell counts was attempted during the early stages of gene therapy. Although adverse events were not observed and continuous expression of ADA was achieved in many patients, reconstruction of immune function was not obtained and substitution therapy with PEG-ADA remained necessary. Therefore, HSCs were no longer the target of gene therapy for ADA-SCID. Since ADA-SCID patients have T cells, nonmyeloablative conditioning was performed to achieve gene-transduced HSC engraftment [25, 65].

In a joint Italian-Israeli study started in 2000, ten ADA-SCID children were infused with CD34 positive cells transduced with a MoMLV retroviral vector containing the ADA gene after nonmyeloablative conditioning with busulfan (2mg/kg/day for two days). T cell counts or function were improved in nine out of the ten patients, and PEG-ADA was discontinued in eight. Many patients also had improvements in B or NK cell function, and immunoglobulin substitution therapy was discontinued in five patients. Although some patients had serious adverse events including prolonged neutropenia, hypertension, Epstein-Barr virus infection, and autoimmune hepatitis, there were no cases of treatment-induced leukemia [25].

As with SCID-X1, the retroviral vector gene insertion region is also near genes that control cell proliferation or self-duplication, such as LMO2, or proto-oncogenes [66]. In clinical studies performed in France, the U.S., and the U.K., none of the ADA-SCID patients had adverse events related to insertional mutagenesis, such as leukemia [67, 68]. Thus, HSC gene therapy for ADA-SCID using a lentiviral vector [69] is expected to become the alternative therapy in cases without a suitable donor for HSCT [70]. As an alternative to HSC-based gene therapy, a study using an AAV vector has reported ADA gene expression in various tissues, including heart, skeletal muscle, and kidney [71].

CGD is a disease caused by an abnormality in nicotinamide dinucleotide phosphate (NADPH) oxidase expressed in phagocytes, resulting in failure to produce reactive oxygen species and decreased ability to kill bacteria or fungi after phagocytosis. NADPH oxidase consists of gp91phox (Nox2) and p22 phox which together constitute the membrane-spanning component flavocytochrome b558 (CYBB), and the cytosolic components p47phox, p67phox, p40phox, and Rac. CGD is caused by a functional abnormality in any of these components. Mutations in gp91phox on the X chromosome account for approximately 70% of CGD cases. CGD patients are afflicted with recurrent opportunistic bacterial and fungal infections, leading to the formation of chronic granulomas. Although lifelong antibiotic prophylaxis reduces the incidence of infections, the overall annual mortality rate remains high (2%5%) and the success rate of HSCT is limited by graft-versus-host-disease and inflammatory flare-ups at infected sites [56].

In the initial trials of CGD gene therapy without any conditioning therapy, p47phox or gp91phox gene was inserted using a retroviral vector. The inserted gene was expressed in peripheral blood granulocytes three to six weeks after re-infusion and mobilization by granulocyte colony-stimulating factor (G-CSF), but there was no clinical effect within six months [72-74].

In a German study where gp91phox was inserted with busulfan conditioning (8mg/kg), there were fewer infections after gene therapy. Gene expression was observed in 20% of leukocytes in the first month, rising to 80% at one year. However, in the gene insertion region there are genes related to myeloid cell proliferation, such as myelodysplastic syndrome 1-ecotropic virus integration site 1 (MDS1/EVI1), PR domain containing protein 16 (PRDM16), SET binding protein 1 (SETBP1). Two patients developed myelodysplasia [75]. These two patients had monosomy 7, considered to be related to EVI1 activation. One died of severe sepsis 27 months after gene therapy. Although the gene-inserted cells remained expressed in this patient, methylation of the CpG site in the LTR of the viral vector was observed and the expression of the inserted gp91phox gene was decreased. Interestingly, methylation was restricted to the promoter region of the LTR; the enhancer region was not methylated. Therefore, although gp91phox gene expression was decreased, the activation of EVI1 near the inserted region occurred, leading to clonal proliferation [76]. Since there is a possibility that the transcription activity of genes related to myeloid cell proliferation near the gene insertion site will be increased, there remains a concern about tumorigenesis with peripheral stem cells mobilization by G-CSF in CGD patients, as with X-SCID [74].

Recently, next-generation gene therapy for CGD using lineage- and stage-restricted lentiviral vectors to avoid tumorigenesis [77] and novel approaches involving iPSs derived from CGD patients using zinc finger nuclease (ZFN)-mediated gene targeting were studied [78]. Specific gene targeting can be performed in human iPSs using ZFNs to induce sequence-specific double-strand DNA breaks that enhance site-specific homologous recombination. A single-copy of gp91phox was targeted into one allele of the "safe harbor" AAVS1 locus in iPSs [79].

WAS is a severe X-linked immunodeficiency caused by mutations in the gene encoding the WAS protein (WASP), a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WAS gene result in a wide spectrum of clinical manifestations ranging from relatively mild X-linked thrombocytopenia to the classic WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, high susceptibility to developing tumors, and autoimmune manifestations [80]. Preclinical and clinical evidence suggest that WASP-expressing cells have a proliferative or survival advantage over WASP-deficient cells, supporting the development of gene therapy [56]. Furthermore, up to 11% of WAS patients have somatic mosaicism due to spontaneous in vivo reversion to the normal genotype, and in WAS patients, accumulation of normal T-cell precursors are sometimes seen [81].

In one preclinical study introducing the WAS gene into human T and B cells or mouse HSCs using a retroviral vector, recovery of T cell function and immune reactions to infection were observed [82, 83]. The first clinical study of WAS using HSCs involved two young boys in Germany. The WASP-expressing retroviral vector was transfected into CD34 positive cells obtained by apheresis of peripheral blood. Busulfan was used for conditioning therapy (4mg/kg/day for two days). Over two years, WASP gene expression by HSCs, lymphoid and myeloid cells, and platelets was sustained, and the number and function of monocytes, T, B, and NK cells normalized. Clinically, hemorrhagic diathesis, eczema, autoimmunity, and the predisposition to severe infections were diminished. Since comprehensive insertion-site analysis showed vector integration near multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis, careful monitoring for tumorigenesis is necessary, as with SCID-X1 and CGD [84, 85].

SIN lentiviral vectors using the minimal domain of the WAS promoter or other ubiquitous promoters, such as the PGK promoter, are currently being developed for WAS gene therapy. Preclinical studies using the HSCs obtained from mice or human patients have yield good results in terms of gene expression and genotoxicity [86-90].

Since a study using human embryonic stem cells (hESCs) and WAS-promoterdriven lentiviral vectors labeled by green fluorescent protein (GFP) showed highly specific gene expression in hESCs-derived HSCs, the WAS promoter will be used specifically in the generation of hESC-derived HSCs [91].

JAK3 deficiency is characterized by the absence of T and NK cells and impaired function of B cells, similar to SCID-X1. Treatment consists of HSCT with an HLA-identical or HLA-haplo-identical donor, often the parents of the patient, with T cell depletion. Engraftment is successful in most cases.

Although the recovery of T cell function is usually observed after HSCT, there are usually no improvements in B or NK cell function [92]. One case report involved introduction of JAK3 into the patients bone marrow CD34 positive cells using the MSCV retroviral vector. In this study, immunological recovery was not achieved although gene expression was observed for seven months [93]. Since JAK activation can cause T-cell lymphoma, tumorigenesis remains a concern with JAK gene therapy [92].

PNP metabolizes adenosine into adenine, inosine into hypoxanthine, and guanosine into guanine. PNP deficiency is an autosomal recessive metabolic disorder characterized by lethal T cell defects resulting from the accumulation of products from purine metabolism.

In PNP-deficient mice, transplantation of bone marrow cells transduced with a lentiviral vector containing human PNP resulted in human PNP expression, improved thymocyte maturation, increased weight gain, and extended survival. However, 12 weeks after transplant, the benefit of PNP-transduced cells and the percentage of engrafted cells decreased [94].

LAD-1 is a primary immunodeficiency disease caused by abnormalities in the leukocyte integrin CD11/CD18 heterodimer due to mutations in the CD18 gene. It is similar to canine leukocyte adhesion deficiency (CLAD). LAD-1 patients begin experiencing repeated serious bacterial infections immediately after birth.

In order to suppress gene activation near the gene insertion region in CLAD and to obtain the sufficient expression of the CD18 gene, researches have used various promoters with a lentiviral vector or foamy virus, a retroviral vector. In vivo animal experiments using a PGK or an elongation factor 1 promoter did not lead to symptom improvement [95-97], but improvement was seen with CD11b and CD18 promoters, respectively, with a SIN lentiviral vector in one animal study [98].

MPS is a general term for diseases characterized by glycosaminoglycan (GAG) accumulation into lysosomes as a result of deficiencies in lysosomal enzymes that degrade GAG. Although there are more than ten enzymes that are known to degrade GAG, MPS is divided into seven types: type I (-L-iduronidase deficiency, Hurler syndrome, Sheie syndrome, Hurler-Sheie syndrome), type II (iduronate sulfatase deficiency, Hunter syndrome), type III (heparan N-sulfatase deficiency, -N-acetylglucosaminidase deficiency, -glucosaminidase acetyltransferase deficiency, N-acetylglucosamine 6-sulfatase deficiency, Sanfilippo syndrome), type IV (galactose 6-sulfatase deficiency, Morquio syndrome), type VI (N-acetylgalactosamine 4-sulfatase deficiency, Maroteaux-Lamy syndrome), type VII (-glucuronidase deficiency, Sly syndrome), and type IX (hyaluronidase deficiency). Type II is X-linked; the other types are autosomal recessive. Although lysosomes are found in almost all cells, MPS mainly affects internal organs such as the brain, heart, bones, joints, eyes, liver, and spleen. The extent of disease, including mental retardation, varies with MPS type.

In types I, II, and VI, enzyme replacement therapy is performed. HSCT is performed in types I, II, IV, and VII. Gene therapy for types I, II, III, and VII type have been investigated. There are trials using an AAV or adenovirus vector to insert the modified gene into various cell types, including hepatocytes, muscle cells, myoblasts, and fibroblasts [99].

The first study of HSC gene therapy for MPS using a retroviral vector was performed on type VII mice in 1992, resulting in decreased accumulation of GAG in the liver and spleen but not in the brain and eyes [100]. Subsequent studies in type I and III animal models showed decreases in GAG accumulation in the kidneys and brain. Introductory efficiency and immunological reactions are considered challenges in HSC gene therapy for MPS [99].

Restoring or preserving central nervous system (CNS) function is one of the major challenges in the treatment of MPS. Since replaced enzymes easily cannot pass the blood-brain barrier (BBB), a high dose of enzyme is needed to improve CNS function. Gene therapy faces the same challenge. Even with high expression of enzyme by, for example, hepatocytes, the BBB prevents efficient delivery into the CNS. When a lentiviral vector is directly injected into the body, gene expression in brain tissue is observed, although the underlying mechanism is unknown. There are also trials where AAV vectors are directly injected into the CNS of mice or dogs and gene expression was observed in brain tissue [99].

Recently, a lentiviral vector using an ankyrin-1-based erythroid-specific hybrid promoter/enhancer (IHK) was used with HSCs to obtain gene expression only in erythroblasts for type I MPS. This approach resulted in decreased accumulation of GAG in the liver, spleen, heart, and CNS via enzyme expression in erythroblasts [101].

Gaucher disease is the most common lysosomal storage disorder. It is caused by deficiency of glucocerebroside-cleaving enzyme (-glucocerebrosidase), resulting in the accumulation of glucocerebroside in the reticuloendothelial system [102]. This autosomal recessive disease presents with hepatosplenomegaly, anemia, thrombocytopenia, and convulsions with or without mental retardation. It is classified into three types based on the clinical course or existence of neurological symptoms: type I (non-neuropathic, adult type), type II (acute neuropathic, infantile type), and type III (chronic neuropathic, juvenile type). Enzyme replacement therapy has been established in type I. As with MPS, since it is difficult to improve CNS symptoms with enzyme replacement therapy, HSCT is used, especially with type III. Gene therapy is considered in cases with little improvement with enzyme replacement therapy [103].

For Gaucher disease without CNS symptoms, a animal model using an AAV vector to produce enzyme in hepatocytes yielded good results [103]. HSC gene therapy using a retroviral vector was attempted in type I mice. The treated cells had higher -glucocerebrosidase activity than the HSCs from wild-type mice. Glucocerebroside levels normalized five to six months after treatment and no infiltration of Gaucher cells could be observed in the bone marrow, spleen, and liver [104]. In recent years, development of lentiviral vectors including the human glucocerebrosidase gene [105] and low-risk HSCT with nonmyeloablative doses of busulfan (25mg/kg) and no radiation therapy have been attempted in mice [106].

X-ALD is a peroxisomal disease in which a lipid metabolism abnormality causes demyelination of CNS tissues and dysfunction of the adrenal gland. It results from mutations in the ATP-binding cassette sub-family D (ABCD1) gene that codes for the adrenoleukodystrophy (ALD) protein. Behavioral disorders, mental retardation, or both occur by the age of five or six. Once symptoms appear, they progress to gait disorder and visual impairment within several months and the prognosis is poor. Increased levels of very long chain fatty acids (VLCFA), such as C25:0 or C26:0, are observed in the CNS, plasma, erythrocytes, leucocytes, etc. If the neurological defects are not severe, arrest of or improvement in symptoms can be obtained with HSCT [107].

One study has reported the introduction of wild-type ABCD1 using a lentiviral vector into peripheral blood CD34 positive cells of two patients with no HLA-identical donor. The patients received a transfusion of autologous gene-modified cells after myeloablative conditioning therapy. At three years of follow-up, ALD proteins were expressed in approximately 714% of neutrophils, monocytes, and T cells. Clinically, cerebral demyelination stopped 14 and 16 months after gene therapy, respectively, similar to results with allergenic HSCT [108, 109].

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Human[1] Temporal range: 0.1950Ma Middle Pleistocene Recent An adult human male (left) and female (right) in Northern Thailand. Scientific classification Kingdom: Animalia Phylum: Chordata Class: Mammalia Order: Primates Suborder: Haplorhini Family: Hominidae Genus: Homo Species: H.sapiens Binomial name Homo sapiens Linnaeus, 1758 Subspecies

Homo sapiens idaltu White et al., 2003 Homo sapiens sapiens

Modern humans (Homo sapiens, primarily ssp. Homo sapiens sapiens) are the only extant members of Hominina clade (or human clade), a branch of the taxonomical tribe Hominini belonging to the family of great apes. They are characterized by erect posture and bipedal locomotion; manual dexterity and increased tool use, compared to other animals; and a general trend toward larger, more complex brains and societies.[3][4]

Early homininsparticularly the australopithecines, whose brains and anatomy are in many ways more similar to ancestral non-human apesare less often referred to as "human" than hominins of the genus Homo.[5] Several of these hominins used fire, occupied much of Eurasia, and gave rise to anatomically modern Homo sapiens in Africa about 200,000 years ago.[6][7] They began to exhibit evidence of behavioral modernity around 50,000 years ago. In several waves of migration, anatomically modern humans ventured out of Africa and populated most of the world.[8]

The spread of humans and their large and increasing population has had a profound impact on large areas of the environment and millions of native species worldwide. Advantages that explain this evolutionary success include a relatively larger brain with a particularly well-developed neocortex, prefrontal cortex and temporal lobes, which enable high levels of abstract reasoning, language, problem solving, sociality, and culture through social learning. Humans use tools to a much higher degree than any other animal, are the only extant species known to build fires and cook their food, and are the only extant species to clothe themselves and create and use numerous other technologies and arts.

Humans are uniquely adept at utilizing systems of symbolic communication (such as language and art) for self-expression and the exchange of ideas, and for organizing themselves into purposeful groups. Humans create complex social structures composed of many cooperating and competing groups, from families and kinship networks to political states. Social interactions between humans have established an extremely wide variety of values,[9]social norms, and rituals, which together form the basis of human society. Curiosity and the human desire to understand and influence the environment and to explain and manipulate phenomena (or events) has provided the foundation for developing science, philosophy, mythology, religion, anthropology, and numerous other fields of knowledge.

Though most of human existence has been sustained by hunting and gathering in band societies,[10] increasing numbers of human societies began to practice sedentary agriculture approximately some 10,000 years ago,[11] domesticating plants and animals, thus allowing for the growth of civilization. These human societies subsequently expanded in size, establishing various forms of government, religion, and culture around the world, unifying people within regions to form states and empires. The rapid advancement of scientific and medical understanding in the 19th and 20th centuries led to the development of fuel-driven technologies and increased lifespans, causing the human population to rise exponentially. By February 2016, the global human population had exceeded 7.3 billion.[12]

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In common usage, the word "human" generally refers to the only extant species of the genus Homo anatomically and behaviorally modern Homo sapiens.

In scientific terms, the meanings of "hominid" and "hominin" have changed during the recent decades with advances in the discovery and study of the fossil ancestors of modern humans. The previously clear boundary between humans and apes has blurred, resulting in now acknowledging the hominids as encompassing multiple species, and Homo and close relatives since the split from chimpanzees as the only hominins. There is also a distinction between anatomically modern humans and Archaic Homo sapiens, the earliest fossil members of the species.

The English adjective human is a Middle English loanword from Old French humain, ultimately from Latin hmnus, the adjective form of hom "man." The word's use as a noun (with a plural: humans) dates to the 16th century.[13] The native English term man can refer to the species generally (a synonym for humanity), and could formerly refer to specific individuals of either sex, though this latter use is now obsolete.[14]

The species binomial Homo sapiens was coined by Carl Linnaeus in his 18th century work Systema Naturae.[15] The generic name Homo is a learned 18th century derivation from Latin hom "man," ultimately "earthly being" (Old Latin hem a cognate to Old English guma "man," from PIE demon-, meaning "earth" or "ground").[16] The species-name sapiens means "wise" or "sapient." Note that the Latin word homo refers to humans of either gender, and that sapiens is the singular form (while there is no such word as sapien).[17]

The genus Homo evolved and diverged from other hominins in Africa, after the human clade split from the chimpanzee lineage of the hominids (great apes) branch of the primates. Modern humans, defined as the species Homo sapiens or specifically to the single extant subspecies Homo sapiens sapiens, proceeded to colonize all the continents and larger islands, arriving in Eurasia 125,00060,000 years ago,[18][19]Australia around 40,000 years ago, the Americas around 15,000 years ago, and remote islands such as Hawaii, Easter Island, Madagascar, and New Zealand between the years 300 and 1280.[20][21]

The closest living relatives of humans are chimpanzees (genus Pan) and gorillas (genus Gorilla).[22] With the sequencing of both the human and chimpanzee genome, current estimates of similarity between human and chimpanzee DNA sequences range between 95% and 99%.[22][23][24] By using the technique called a molecular clock which estimates the time required for the number of divergent mutations to accumulate between two lineages, the approximate date for the split between lineages can be calculated. The gibbons (Hylobatidae) and orangutans (genus Pongo) were the first groups to split from the line leading to the humans, then gorillas (genus Gorilla) followed by the chimpanzees (genus Pan). The splitting date between human and chimpanzee lineages is placed around 48 million years ago during the late Miocene epoch.[25][26] During this split, chromosome 2 was formed from two other chromosomes, leaving humans with only 23 pairs of chromosomes, compared to 24 for the other apes.[27][28]

There is little fossil evidence for the divergence of the gorilla, chimpanzee and hominin lineages.[29][30] The earliest fossils that have been proposed as members of the hominin lineage are Sahelanthropus tchadensis dating from 7 million years ago, Orrorin tugenensis dating from 5.7 million years ago, and Ardipithecus kadabba dating to 5.6 million years ago. Each of these species has been argued to be a bipedal ancestor of later hominins, but all such claims are contested. It is also possible that any one of the three is an ancestor of another branch of African apes, or is an ancestor shared between hominins and other African Hominoidea (apes). The question of the relation between these early fossil species and the hominin lineage is still to be resolved. From these early species the australopithecines arose around 4 million years ago diverged into robust (also called Paranthropus) and gracile branches, possibly one of which (such as A. garhi, dating to 2.5 million years ago) is a direct ancestor of the genus Homo.[citation needed]

The earliest members of the genus Homo are Homo habilis which evolved around 2.8 million years ago.[31]Homo habilis has been considered the first species for which there is clear evidence of the use of stone tools. More recently, however, in 2015, stone tools, perhaps predating Homo habilis, have been discovered in northwestern Kenya that have been dated to 3.3 million years old.[32] Nonetheless, the brains of Homo habilis were about the same size as that of a chimpanzee, and their main adaptation was bipedalism as an adaptation to terrestrial living. During the next million years a process of encephalization began, and with the arrival of Homo erectus in the fossil record, cranial capacity had doubled. Homo erectus were the first of the hominina to leave Africa, and these species spread through Africa, Asia, and Europe between 1.3to1.8 million years ago. One population of H. erectus, also sometimes classified as a separate species Homo ergaster, stayed in Africa and evolved into Homo sapiens. It is believed that these species were the first to use fire and complex tools. The earliest transitional fossils between H. ergaster/erectus and archaic humans are from Africa such as Homo rhodesiensis, but seemingly transitional forms are also found at Dmanisi, Georgia. These descendants of African H. erectus spread through Eurasia from ca. 500,000 years ago evolving into H. antecessor, H. heidelbergensis and H. neanderthalensis. The earliest fossils of anatomically modern humans are from the Middle Paleolithic, about 200,000 years ago such as the Omo remains of Ethiopia and the fossils of Herto sometimes classified as Homo sapiens idaltu.[33] Later fossils of archaic Homo sapiens from Skhul in Israel and Southern Europe begin around 90,000 years ago.[34]

Human evolution is characterized by a number of morphological, developmental, physiological, and behavioral changes that have taken place since the split between the last common ancestor of humans and chimpanzees. The most significant of these adaptations are 1. bipedalism, 2. increased brain size, 3. lengthened ontogeny (gestation and infancy), 4. decreased sexual dimorphism (neoteny). The relationship between all these changes is the subject of ongoing debate.[35] Other significant morphological changes included the evolution of a power and precision grip, a change first occurring in H. erectus.[36]

Bipedalism is the basic adaption of the hominin line, and it is considered the main cause behind a suite of skeletal changes shared by all bipedal hominins. The earliest bipedal hominin is considered to be either Sahelanthropus[37] or Orrorin, with Ardipithecus, a full bipedal, coming somewhat later.[citation needed] The knuckle walkers, the gorilla and chimpanzee, diverged around the same time, and either Sahelanthropus or Orrorin may be humans' last shared ancestor with those animals.[citation needed] The early bipedals eventually evolved into the australopithecines and later the genus Homo.[citation needed] There are several theories of the adaptational value of bipedalism. It is possible that bipedalism was favored because it freed up the hands for reaching and carrying food, because it saved energy during locomotion, because it enabled long distance running and hunting, or as a strategy for avoiding hyperthermia by reducing the surface exposed to direct sun.[citation needed]

The human species developed a much larger brain than that of other primates typically 1,330 cm3 in modern humans, over twice the size of that of a chimpanzee or gorilla.[38] The pattern of encephalization started with Homo habilis which at approximately 600cm3 had a brain slightly larger than chimpanzees, and continued with Homo erectus (8001100cm3), and reached a maximum in Neanderthals with an average size of 12001900cm3, larger even than Homo sapiens (but less encephalized).[39] The pattern of human postnatal brain growth differs from that of other apes (heterochrony), and allows for extended periods of social learning and language acquisition in juvenile humans. However, the differences between the structure of human brains and those of other apes may be even more significant than differences in size.[40][41][42][43] The increase in volume over time has affected different areas within the brain unequally the temporal lobes, which contain centers for language processing have increased disproportionately, as has the prefrontal cortex which has been related to complex decision making and moderating social behavior.[38] Encephalization has been tied to an increasing emphasis on meat in the diet,[44][45] or with the development of cooking,[46] and it has been proposed [47] that intelligence increased as a response to an increased necessity for solving social problems as human society became more complex.

The reduced degree of sexual dimorphism is primarily visible in the reduction of the male canine tooth relative to other ape species (except gibbons). Another important physiological change related to sexuality in humans was the evolution of hidden estrus. Humans are the only ape in which the female is fertile year round, and in which no special signals of fertility are produced by the body (such as genital swelling during estrus). Nonetheless humans retain a degree of sexual dimorphism in the distribution of body hair and subcutaneous fat, and in the overall size, males being around 25% larger than females. These changes taken together have been interpreted as a result of an increased emphasis on pair bonding as a possible solution to the requirement for increased parental investment due to the prolonged infancy of offspring.[citation needed]

By the beginning of the Upper Paleolithic period (50,000 BP), full behavioral modernity, including language, music and other cultural universals had developed.[48][49] As modern humans spread out from Africa they encountered other hominids such as Homo neanderthalensis and the so-called Denisovans. The nature of interaction between early humans and these sister species has been a long-standing source of controversy, the question being whether humans replaced these earlier species or whether they were in fact similar enough to interbreed, in which case these earlier populations may have contributed genetic material to modern humans.[50] Recent studies of the human and Neanderthal genomes suggest gene flow between archaic Homo sapiens and Neanderthals and Denisovans.[51][52][53] In March 2016, studies were published that suggest that modern humans bred with hominins, including Denisovans and Neanderthals, on multiple occasions.[54]

This dispersal out of Africa is estimated to have begun about 70,000 years BP from Northeast Africa. Current evidence suggests that there was only one such dispersal and that it only involved a few hundred individuals. The vast majority of humans stayed in Africa and adapted to a diverse array of environments.[55] Modern humans subsequently spread globally, replacing earlier hominins (either through competition or hybridization). They inhabited Eurasia and Oceania by 40,000 years BP, and the Americas at least 14,500 years BP.[56][57]

Until about 10,000 years ago, humans lived as hunter-gatherers. They gradually gained domination over much of the natural environment. They generally lived in small nomadic groups known as band societies, often in caves. The advent of agriculture prompted the Neolithic Revolution, when access to food surplus led to the formation of permanent human settlements, the domestication of animals and the use of metal tools for the first time in history. Agriculture encouraged trade and cooperation, and led to complex society.[citation needed]

The early civilizations of Mesopotamia, Egypt, India, China, Maya, Greece and Rome were some of the cradles of civilization.[58][59][60] The Late Middle Ages and the Early Modern Period saw the rise of revolutionary ideas and technologies. Over the next 500 years, exploration and European colonialism brought great parts of the world under European control, leading to later struggles for independence. The concept of the modern world as distinct from an ancient world is based on a rapid change progress in a brief period of time in many areas.[citation needed] Advances in all areas of human activity prompted new theories such as evolution and psychoanalysis, which changed humanity's views of itself.[citation needed] The Scientific Revolution, Technological Revolution and the Industrial Revolution up until the 19th century resulted in independent discoveries such as imaging technology, major innovations in transport, such as the airplane and automobile; energy development, such as coal and electricity.[61] This correlates with population growth (especially in America)[62] and higher life expectancy, the World population rapidly increased numerous times in the 19th and 20th centuries as nearly 10% of the 100 billion people lived in the past century.[63]

With the advent of the Information Age at the end of the 20th century, modern humans live in a world that has become increasingly globalized and interconnected. As of 2010, almost 2billion humans are able to communicate with each other via the Internet,[64] and 3.3 billion by mobile phone subscriptions.[65] Although interconnection between humans has encouraged the growth of science, art, discussion, and technology, it has also led to culture clashes and the development and use of weapons of mass destruction.[citation needed] Human civilization has led to environmental destruction and pollution significantly contributing to the ongoing mass extinction of other forms of life called the Holocene extinction event,[66] which may be further accelerated by global warming in the future.[67]

Early human settlements were dependent on proximity to water and, depending on the lifestyle, other natural resources used for subsistence, such as populations of animal prey for hunting and arable land for growing crops and grazing livestock. But humans have a great capacity for altering their habitats by means of technology, through irrigation, urban planning, construction, transport, manufacturing goods, deforestation and desertification. Deliberate habitat alteration is often done with the goals of increasing material wealth, increasing thermal comfort, improving the amount of food available, improving aesthetics, or improving ease of access to resources or other human settlements. With the advent of large-scale trade and transport infrastructure, proximity to these resources has become unnecessary, and in many places, these factors are no longer a driving force behind the growth and decline of a population. Nonetheless, the manner in which a habitat is altered is often a major determinant in population change.[citation needed]

Technology has allowed humans to colonize all of the continents and adapt to virtually all climates. Within the last century, humans have explored Antarctica, the ocean depths, and outer space, although large-scale colonization of these environments is not yet feasible. With a population of over seven billion, humans are among the most numerous of the large mammals. Most humans (61%) live in Asia. The remainder live in the Americas (14%), Africa (14%), Europe (11%), and Oceania (0.5%).[68]

Human habitation within closed ecological systems in hostile environments, such as Antarctica and outer space, is expensive, typically limited in duration, and restricted to scientific, military, or industrial expeditions. Life in space has been very sporadic, with no more than thirteen humans in space at any given time.[69] Between 1969 and 1972, two humans at a time spent brief intervals on the Moon. As of November 2016, no other celestial body has been visited by humans, although there has been a continuous human presence in space since the launch of the initial crew to inhabit the International Space Station on October 31, 2000.[70] However, other celestial bodies have been visited by human-made objects.[71][72][73]

Since 1800, the human population has increased from one billion[74] to over seven billion,[75] In 2004, some 2.5 billion out of 6.3 billion people (39.7%) lived in urban areas. In February 2008, the U.N. estimated that half the world's population would live in urban areas by the end of the year.[76] Problems for humans living in cities include various forms of pollution and crime,[77] especially in inner city and suburban slums. Both overall population numbers and the proportion residing in cities are expected to increase significantly in the coming decades.[78]

Humans have had a dramatic effect on the environment. Humans are apex predators, being rarely preyed upon by other species.[79] Currently, through land development, combustion of fossil fuels, and pollution, humans are thought to be the main contributor to global climate change.[80] If this continues at its current rate it is predicted that climate change will wipe out half of all plant and animal species over the next century.[81][82]

Most aspects of human physiology are closely homologous to corresponding aspects of animal physiology. The human body consists of the legs, the torso, the arms, the neck, and the head. An adult human body consists of about 100 trillion (1014) cells. The most commonly defined body systems in humans are the nervous, the cardiovascular, the circulatory, the digestive, the endocrine, the immune, the integumentary, the lymphatic, the muscoskeletal, the reproductive, the respiratory, and the urinary system.[83][84]

Humans, like most of the other apes, lack external tails, have several blood type systems, have opposable thumbs, and are sexually dimorphic. The comparatively minor anatomical differences between humans and chimpanzees are a result of human bipedalism. One difference is that humans have a far faster and more accurate throw than other animals. Humans are also among the best long-distance runners in the animal kingdom, but slower over short distances.[85][86] Humans' thinner body hair and more productive sweat glands help avoid heat exhaustion while running for long distances.[87]

As a consequence of bipedalism, human females have narrower birth canals. The construction of the human pelvis differs from other primates, as do the toes. A trade-off for these advantages of the modern human pelvis is that childbirth is more difficult and dangerous than in most mammals, especially given the larger head size of human babies compared to other primates. This means that human babies must turn around as they pass through the birth canal, which other primates do not do, and it makes humans the only species where females require help from their conspecifics[clarification needed] to reduce the risks of birthing. As a partial evolutionary solution, human fetuses are born less developed and more vulnerable. Chimpanzee babies are cognitively more developed than human babies until the age of six months, when the rapid development of human brains surpasses chimpanzees. Another difference between women and chimpanzee females is that women go through the menopause and become unfertile decades before the end of their lives. All species of non-human apes are capable of giving birth until death. Menopause probably developed as it has provided an evolutionary advantage (more caring time) to young relatives.[86]

Apart from bipedalism, humans differ from chimpanzees mostly in smelling, hearing, digesting proteins, brain size, and the ability of language. Humans' brains are about three times bigger than in chimpanzees. More importantly, the brain to body ratio is much higher in humans than in chimpanzees, and humans have a significantly more developed cerebral cortex, with a larger number of neurons. The mental abilities of humans are remarkable compared to other apes. Humans' ability of speech is unique among primates. Humans are able to create new and complex ideas, and to develop technology, which is unprecedented among other organisms on Earth.[86]

It is estimated that the worldwide average height for an adult human male is about 172cm (5ft 712in),[citation needed] while the worldwide average height for adult human females is about 158cm (5ft 2in).[citation needed] Shrinkage of stature may begin in middle age in some individuals, but tends to be typical in the extremely aged.[88] Through history human populations have universally become taller, probably as a consequence of better nutrition, healthcare, and living conditions.[89] The average mass of an adult human is 5464kg (120140lb) for females and 7683kg (168183lb) for males.[90] Like many other conditions, body weight and body type is influenced by both genetic susceptibility and environment and varies greatly among individuals. (see obesity)[91][92]

Although humans appear hairless compared to other primates, with notable hair growth occurring chiefly on the top of the head, underarms and pubic area, the average human has more hair follicles on his or her body than the average chimpanzee. The main distinction is that human hairs are shorter, finer, and less heavily pigmented than the average chimpanzee's, thus making them harder to see.[93] Humans have about 2 million sweat glands spread over their entire bodies, many more than chimpanzees, whose sweat glands are scarce and are mainly located on the palm of the hand and on the soles of the feet.[94]

The dental formula of humans is: 2.1.2.32.1.2.3. Humans have proportionately shorter palates and much smaller teeth than other primates. They are the only primates to have short, relatively flush canine teeth. Humans have characteristically crowded teeth, with gaps from lost teeth usually closing up quickly in young individuals. Humans are gradually losing their wisdom teeth, with some individuals having them congenitally absent.[95]

Like all mammals, humans are a diploid eukaryotic species. Each somatic cell has two sets of 23 chromosomes, each set received from one parent; gametes have only one set of chromosomes, which is a mixture of the two parental sets. Among the 23 pairs of chromosomes there are 22 pairs of autosomes and one pair of sex chromosomes. Like other mammals, humans have an XY sex-determination system, so that females have the sex chromosomes XX and males have XY.[96]

One human genome was sequenced in full in 2003, and currently efforts are being made to achieve a sample of the genetic diversity of the species (see International HapMap Project). By present estimates, humans have approximately 22,000 genes.[97] The variation in human DNA is very small compared to other species, possibly suggesting a population bottleneck during the Late Pleistocene (around 100,000 years ago), in which the human population was reduced to a small number of breeding pairs.[98][99]Nucleotide diversity is based on single mutations called single nucleotide polymorphisms (SNPs). The nucleotide diversity between humans is about 0.1%, i.e. 1 difference per 1,000 base pairs.[100][101] A difference of 1 in 1,000 nucleotides between two humans chosen at random amounts to about 3 million nucleotide differences, since the human genome has about 3 billion nucleotides. Most of these single nucleotide polymorphisms (SNPs) are neutral but some (about 3 to 5%) are functional and influence phenotypic differences between humans through alleles.[citation needed]

By comparing the parts of the genome that are not under natural selection and which therefore accumulate mutations at a fairly steady rate, it is possible to reconstruct a genetic tree incorporating the entire human species since the last shared ancestor. Each time a certain mutation (SNP) appears in an individual and is passed on to his or her descendants, a haplogroup is formed including all of the descendants of the individual who will also carry that mutation. By comparing mitochondrial DNA, which is inherited only from the mother, geneticists have concluded that the last female common ancestor whose genetic marker is found in all modern humans, the so-called mitochondrial Eve, must have lived around 90,000 to 200,000 years ago.[102][103][104]

Human accelerated regions, first described in August 2006,[105][106] are a set of 49 segments of the human genome that are conserved throughout vertebrate evolution but are strikingly different in humans. They are named according to their degree of difference between humans and their nearest animal relative (chimpanzees) (HAR1 showing the largest degree of human-chimpanzee differences). Found by scanning through genomic databases of multiple species, some of these highly mutated areas may contribute to human-specific traits.[citation needed]

The forces of natural selection have continued to operate on human populations, with evidence that certain regions of the genome display directional selection in the past 15,000 years.[107]

As with other mammals, human reproduction takes place as internal fertilization by sexual intercourse. During this process, the male inserts his erect penis into the female's vagina and ejaculates semen, which contains sperm. The sperm travels through the vagina and cervix into the uterus or Fallopian tubes for fertilization of the ovum. Upon fertilization and implantation, gestation then occurs within the female's uterus.

The zygote divides inside the female's uterus to become an embryo, which over a period of 38 weeks (9 months) of gestation becomes a fetus. After this span of time, the fully grown fetus is birthed from the woman's body and breathes independently as an infant for the first time. At this point, most modern cultures recognize the baby as a person entitled to the full protection of the law, though some jurisdictions extend various levels of personhood earlier to human fetuses while they remain in the uterus.

Compared with other species, human childbirth is dangerous. Painful labors lasting 24 hours or more are not uncommon and sometimes lead to the death of the mother, the child or both.[108] This is because of both the relatively large fetal head circumference and the mother's relatively narrow pelvis.[109][110] The chances of a successful labor increased significantly during the 20th century in wealthier countries with the advent of new medical technologies. In contrast, pregnancy and natural childbirth remain hazardous ordeals in developing regions of the world, with maternal death rates approximately 100 times greater than in developed countries.[111]

In developed countries, infants are typically 34kg (69pounds) in weight and 5060cm (2024inches) in height at birth.[112][not in citation given] However, low birth weight is common in developing countries, and contributes to the high levels of infant mortality in these regions.[113] Helpless at birth, humans continue to grow for some years, typically reaching sexual maturity at 12 to 15years of age. Females continue to develop physically until around the age of 18, whereas male development continues until around age 21. The human life span can be split into a number of stages: infancy, childhood, adolescence, young adulthood, adulthood and old age. The lengths of these stages, however, have varied across cultures and time periods. Compared to other primates, humans experience an unusually rapid growth spurt during adolescence, where the body grows 25% in size. Chimpanzees, for example, grow only 14%, with no pronounced spurt.[114] The presence of the growth spurt is probably necessary to keep children physically small until they are psychologically mature. Humans are one of the few species in which females undergo menopause. It has been proposed that menopause increases a woman's overall reproductive success by allowing her to invest more time and resources in her existing offspring, and in turn their children (the grandmother hypothesis), rather than by continuing to bear children into old age.[115][116]

For various reasons, including biological/genetic causes,[117] women live on average about four years longer than menas of 2013 the global average life expectancy at birth of a girl is estimated at 70.2 years compared to 66.1 for a boy.[118] There are significant geographical variations in human life expectancy, mostly correlated with economic developmentfor example life expectancy at birth in Hong Kong is 84.8years for girls and 78.9 for boys, while in Swaziland, primarily because of AIDS, it is 31.3years for both sexes.[119] The developed world is generally aging, with the median age around 40years. In the developing world the median age is between 15 and 20years. While one in five Europeans is 60years of age or older, only one in twenty Africans is 60years of age or older.[120] The number of centenarians (humans of age 100years or older) in the world was estimated by the United Nations at 210,000 in 2002.[121] At least one person, Jeanne Calment, is known to have reached the age of 122years;[122] higher ages have been claimed but they are not well substantiated.

Humans are omnivorous, capable of consuming a wide variety of plant and animal material.[123][124] Varying with available food sources in regions of habitation, and also varying with cultural and religious norms, human groups have adopted a range of diets, from purely vegetarian to primarily carnivorous. In some cases, dietary restrictions in humans can lead to deficiency diseases; however, stable human groups have adapted to many dietary patterns through both genetic specialization and cultural conventions to use nutritionally balanced food sources.[125] The human diet is prominently reflected in human culture, and has led to the development of food science.

Until the development of agriculture approximately 10,000 years ago, Homo sapiens employed a hunter-gatherer method as their sole means of food collection. This involved combining stationary food sources (such as fruits, grains, tubers, and mushrooms, insect larvae and aquatic mollusks) with wild game, which must be hunted and killed in order to be consumed.[126] It has been proposed that humans have used fire to prepare and cook food since the time of Homo erectus.[127] Around ten thousand years ago, humans developed agriculture,[128] which substantially altered their diet. This change in diet may also have altered human biology; with the spread of dairy farming providing a new and rich source of food, leading to the evolution of the ability to digest lactose in some adults.[129][130] Agriculture led to increased populations, the development of cities, and because of increased population density, the wider spread of infectious diseases. The types of food consumed, and the way in which they are prepared, have varied widely by time, location, and culture.

In general, humans can survive for two to eight weeks without food, depending on stored body fat. Survival without water is usually limited to three or four days. About 36 million humans die every year from causes directly or indirectly related to starvation.[131] Childhood malnutrition is also common and contributes to the global burden of disease.[132] However global food distribution is not even, and obesity among some human populations has increased rapidly, leading to health complications and increased mortality in some developed, and a few developing countries. Worldwide over one billion people are obese,[133] while in the United States 35% of people are obese, leading to this being described as an "obesity epidemic."[134] Obesity is caused by consuming more calories than are expended, so excessive weight gain is usually caused by an energy-dense diet.[133]

No two humansnot even monozygotic twinsare genetically identical. Genes and environment influence human biological variation from visible characteristics to physiology to disease susceptibly to mental abilities. The exact influence of genes and environment on certain traits is not well understood.[135][136]

Most current genetic and archaeological evidence supports a recent single origin of modern humans in East Africa,[137] with first migrations placed at 60,000 years ago. Compared to the great apes, human gene sequenceseven among African populationsare remarkably homogeneous.[138] On average, genetic similarity between any two humans is 99.9%.[139][140] There is about 23 times more genetic diversity within the wild chimpanzee population, than in the entire human gene pool.[141][142][143]

The human body's ability to adapt to different environmental stresses is remarkable, allowing humans to acclimatize to a wide variety of temperatures, humidity, and altitudes. As a result, humans are a cosmopolitan species found in almost all regions of the world, including tropical rainforests, arid desert, extremely cold arctic regions, and heavily polluted cities. Most other species are confined to a few geographical areas by their limited adaptability.[144]

There is biological variation in the human specieswith traits such as blood type, cranial features, eye color, hair color and type, height and build, and skin color varying across the globe. Human body types vary substantially. The typical height of an adult human is between 1.4m and 1.9m (4ft 7 in and 6ft 3 in), although this varies significantly depending, among other things, on sex and ethnic origin.[145][146] Body size is partly determined by genes and is also significantly influenced by environmental factors such as diet, exercise, and sleep patterns, especially as an influence in childhood. Adult height for each sex in a particular ethnic group approximately follows a normal distribution. Those aspects of genetic variation that give clues to human evolutionary history, or are relevant to medical research, have received particular attention. For example, the genes that allow adult humans to digest lactose are present in high frequencies in populations that have long histories of cattle domestication, suggesting natural selection having favored that gene in populations that depend on cow milk. Some hereditary diseases such as sickle cell anemia are frequent in populations where malaria has been endemic throughout historyit is believed that the same gene gives increased resistance to malaria among those who are unaffected carriers of the gene. Similarly, populations that have for a long time inhabited specific climates, such as arctic or tropical regions or high altitudes, tend to have developed specific phenotypes that are beneficial for conserving energy in those environmentsshort stature and stocky build in cold regions, tall and lanky in hot regions, and with high lung capacities at high altitudes. Similarly, skin color varies clinally with darker skin around the equatorwhere the added protection from the sun's ultraviolet radiation is thought to give an evolutionary advantageand lighter skin tones closer to the poles.[147][148][149][150]

The hue of human skin and hair is determined by the presence of pigments called melanins. Human skin color can range from darkest brown to lightest peach, or even nearly white or colorless in cases of albinism.[143] Human hair ranges in color from white to red to blond to brown to black, which is most frequent.[151] Hair color depends on the amount of melanin (an effective sun blocking pigment) in the skin and hair, with hair melanin concentrations in hair fading with increased age, leading to grey or even white hair. Most researchers believe that skin darkening is an adaptation that evolved as protection against ultraviolet solar radiation, which also helps balancing folate, which is destroyed by ultraviolet radiation. Light skin pigmentation protects against depletion of vitamin D, which requires sunlight to make.[152] Skin pigmentation of contemporary humans is clinally distributed across the planet, and in general correlates with the level of ultraviolet radiation in a particular geographic area. Human skin also has a capacity to darken (tan) in response to exposure to ultraviolet radiation.[153][154][155]

Within the human species, the greatest degree of genetic variation exists between males and females. While the nucleotide genetic variation of individuals of the same sex across global populations is no greater than 0.1%, the genetic difference between males and females is between 1% and 2%. Although different in nature[clarification needed], this approaches the genetic differentiation between men and male chimpanzees or women and female chimpanzees. The genetic difference between sexes contributes to anatomical, hormonal, neural, and physiological differences between men and women, although the exact degree and nature of social and environmental influences on sexes are not completely understood. Males on average are 15% heavier and 15cm taller than females. There is a difference between body types, body organs and systems, hormonal levels, sensory systems, and muscle mass between sexes. On average, there is a difference of about 4050% in upper body strength and 2030% in lower body strength between men and women. Women generally have a higher body fat percentage than men. Women have lighter skin than men of the same population; this has been explained by a higher need for vitamin D (which is synthesized by sunlight) in females during pregnancy and lactation. As there are chromosomal differences between females and males, some X and Y chromosome related conditions and disorders only affect either men or women. Other conditional differences between males and females are not related to sex chromosomes. Even after allowing for body weight and volume, the male voice is usually an octave deeper than the female voice. Women have a longer life span in almost every population around the world.[157][158][159][160][161][162][163][164][165]

Males typically have larger tracheae and branching bronchi, with about 30% greater lung volume per unit body mass. They have larger hearts, 10% higher red blood cell count, and higher hemoglobin, hence greater oxygen-carrying capacity. They also have higher circulating clotting factors (vitamin K, prothrombin and platelets). These differences lead to faster healing of wounds and higher peripheral pain tolerance.[166] Females typically have more white blood cells (stored and circulating), more granulocytes and B and T lymphocytes. Additionally, they produce more antibodies at a faster rate than males. Hence they develop fewer infectious diseases and these continue for shorter periods.[166]Ethologists argue that females, interacting with other females and multiple offspring in social groups, have experienced such traits as a selective advantage.[167][168][169][170][171] According to Daly and Wilson, "The sexes differ more in human beings than in monogamous mammals, but much less than in extremely polygamous mammals."[172] But given that sexual dimorphism in the closest relatives of humans is much greater than among humans, the human clade must be considered to be characterized by decreasing sexual dimorphism, probably due to less competitive mating patterns. One proposed explanation is that human sexuality has developed more in common with its close relative the bonobo, which exhibits similar sexual dimorphism, is polygynandrous and uses recreational sex to reinforce social bonds and reduce aggression.[173]

Humans of the same sex are 99.9% genetically identical. There is extremely little variation between human geographical populations, and most of the variation that does occur is at the personal level within local areas, and not between populations.[143][174][175] Of the 0.1% of human genetic differentiation, 85% exists within any randomly chosen local population, be they Italians, Koreans, or Kurds. Two randomly chosen Koreans may be genetically as different as a Korean and an Italian. Any ethnic group contains 85% of the human genetic diversity of the world. Genetic data shows that no matter how population groups are defined, two people from the same population group are about as different from each other as two people from any two different population groups.[143][176][177][178]

Current genetic research has demonstrated that humans on the African continent are the most genetically diverse.[179] There is more human genetic diversity in Africa than anywhere else on Earth. The genetic structure of Africans was traced to 14 ancestral population clusters. Human genetic diversity decreases in native populations with migratory distance from Africa and this is thought to be the result of bottlenecks during human migration.[180][181] Humans have lived in Africa for the longest time, which has allowed accumulation of a higher diversity of genetic mutations in these populations. Only part of Africa's population migrated out of the continent, bringing just part of the original African genetic variety with them. African populations harbor genetic alleles that are not found in other places of the world. All the common alleles found in populations outside of Africa are found on the African continent.[143]

Geographical distribution of human variation is complex and constantly shifts through time which reflects complicated human evolutionary history. Most human biological variation is clinally distributed and blends gradually from one area to the next. Groups of people around the world have different frequencies of polymorphic genes. Furthermore, different traits are non-concordant and each have different clinal distribution. Adaptability varies both from person to person and from population to population. The most efficient adaptive responses are found in geographical populations where the environmental stimuli are the strongest (e.g. Tibetans are highly adapted to high altitudes). The clinal geographic genetic variation is further complicated by the migration and mixing between human populations which has been occurring since prehistoric times.[143][182][183][184][185][186]

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From the Departments of Physiology (H.O., K.Y., Y.O., O.T., S.N., K.M.) and Orthopedic Surgery (M.N., O.T., S.N.) and Kanrinmaru Project (K.Y., Y.O.), School of Medicine, Keio University, Tokyo, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan (E.I.); Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (S.Y.); and Genomic Science Laboratory, Dainippon Sumitomo Pharma, Osaka, Japan (K.Y.).

Satoshi Nori

From the Departments of Physiology (H.O., K.Y., Y.O., O.T., S.N., K.M.) and Orthopedic Surgery (M.N., O.T., S.N.) and Kanrinmaru Project (K.Y., Y.O.), School of Medicine, Keio University, Tokyo, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan (E.I.); Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (S.Y.); and Genomic Science Laboratory, Dainippon Sumitomo Pharma, Osaka, Japan (K.Y.).

Eiji Ikeda

From the Departments of Physiology (H.O., K.Y., Y.O., O.T., S.N., K.M.) and Orthopedic Surgery (M.N., O.T., S.N.) and Kanrinmaru Project (K.Y., Y.O.), School of Medicine, Keio University, Tokyo, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan (E.I.); Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (S.Y.); and Genomic Science Laboratory, Dainippon Sumitomo Pharma, Osaka, Japan (K.Y.).

Shinya Yamanaka

From the Departments of Physiology (H.O., K.Y., Y.O., O.T., S.N., K.M.) and Orthopedic Surgery (M.N., O.T., S.N.) and Kanrinmaru Project (K.Y., Y.O.), School of Medicine, Keio University, Tokyo, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan (E.I.); Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (S.Y.); and Genomic Science Laboratory, Dainippon Sumitomo Pharma, Osaka, Japan (K.Y.).

Kyoko Miura

From the Departments of Physiology (H.O., K.Y., Y.O., O.T., S.N., K.M.) and Orthopedic Surgery (M.N., O.T., S.N.) and Kanrinmaru Project (K.Y., Y.O.), School of Medicine, Keio University, Tokyo, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan (E.I.); Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (S.Y.); and Genomic Science Laboratory, Dainippon Sumitomo Pharma, Osaka, Japan (K.Y.).

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Steps Toward Safe Cell Therapy Using Induced Pluripotent ...

Recommendation and review posted by sam

SIGNIFICANCE:

Heart disease is the primary cause of death in the industrialized world. Cardiac failure is dictated by an uncompensated reduction in the number of viable and fully functional cardiomyocytes. While current pharmacological therapies alleviate the symptoms associated with cardiac deterioration, heart transplantation remains the only therapy for advanced heart failure. Therefore, there is a pressing need for novel therapeutic modalities. Cell-based therapies involving cardiac stem cells (CSCs) constitute a promising emerging approach for the replenishment of the lost tissue and the restoration of cardiac contractility.

CSCs reside in the adult heart and govern myocardial homeostasis and repair after injury by producing new cardiomyocytes and vascular structures. In the last decade, different classes of immature cells expressing distinct stem cell markers have been identified and characterized in terms of their growth properties, differentiation potential, and regenerative ability. Phase I clinical trials, employing autologous CSCs in patients with ischemic cardiomyopathy, are being completed with encouraging results.

Accumulating evidence concerning the role of CSCs in heart regeneration imposes a reconsideration of the mechanisms of cardiac aging and the etiology of heart failure. Deciphering the molecular pathways that prevent activation of CSCs in their environment and understanding the processes that affect CSC survival and regenerative function with cardiac pathologies, commonly accompanied by alterations in redox conditions, are of great clinical importance.

Further investigations of CSC biology may be translated into highly effective and novel therapeutic strategies aiming at the enhancement of the endogenous healing capacity of the diseased heart.

Follow this link:
Cardiac stem cells: biology and clinical applications.

Recommendation and review posted by Bethany Smith