A year before the pandemic, I was diagnosed with a condition called mast cell activation syndrome (MCAS). A hallmark of the syndrome is hypersensitivities in more than one organ system: Food and other triggers can give me abdominal pain and severe diarrhea; my nose swells and I sneeze and wheeze. That sounds like allergies, but I've never tested positive on an allergy test.

Mast cells are among the immune system's first line of defense. They are abundant in the parts of the body that have close contact with the outside world, including the skin, airways, and intestines. Mast cells gone wrong cause allergic symptoms, secreting histamine and giving us itchy eyes, hives, and rashes. Less well understood is their role in modulating the responses of other immune cells. Before the pandemic, researchers had suggested that mast cell dysfunction could explain severe cases of the flu and highlighted the cells' role in shutting down inflammation in a variety of situations. In my case, probably because of a genetic peculiarity, my mast cells overreact.

I was fairly stable on my medication, and then I became sick with Covid-19. Months after the virus had passed and I no longer had pneumonia, I was still fighting fatigue and breathlessness. My symptoms also flared up erratically. On some mornings, for example, the oatmeal I had relied on for years could cause me abdominal pain. "Once the mast cell response is turned up, it doesn't wind down just because the infection is gone," explained my doctor, Leo Galland, a New York internist who specializes in difficult cases.

MCAS often seems to first emerge after a virus. Could it explain any of the symptoms of the growing group of patients with long Covid? Congress has now dedicated more than a billion dollars towards research into why so many post-Covid patients roughly a quarter, more often women still feel ill long after their infection. In Facebook groups and elsewhere, people with plausible symptoms for instance, severe lingering rashes and months of hives have been trading information about remedies for the disease. Severe fatigue after exercise suggested myalgic encephalomyelitis/chronic fatigue syndrome, which some say is linked to MCAS. Others became lightheaded when they stood up, which might mean they had postural orthostatic tachycardia syndrome (POTS). Spend an hour searching online, and you'll find papers saying POTS, too, may be a manifestation of MCAS.

But getting a workup for the syndrome can be a long ordeal. The full range of tests and treatments aren't routinely covered by insurance, leaving some patients to pay thousands of dollars out of pocket. Before you get there, you need to find a sympathetic doctor: Researchers don't agree on whether the illness is rare, or quite common.

I was lucky; Galland took me on in the 1980s. Long before the microbiome became a news item, he diagnosed me with intestinal dysbiosis a disturbed gut. We don't know why I got sick when I did, but when I showed up in Galland's office, I was a young woman on an absurdly limited diet with a myriad of fluctuating symptoms. On a trip to Tucson, as just one example, my face and arms ballooned, and then shrank on the plane home. I had been exposed to a fungus in the desert. My grandmother commiserated; when her face swelled up, her doctors in Antwerp, in the 1930s, pulled out all of her teeth. She had no explanation.

Interestingly, disturbances in the gut may be linked to severe Covid-19, and correcting them a possible path to health for long Covid sufferers. Mast cells may have a unique role in communicating with gut bacteria. In midlife, I fit the profile for irritable bowel syndrome (IBS), the abdominal pain, often accompanied by diarrhea or constipation, that afflicts as much as 20 percent of the population, and often sets in after a virus. Desperate, in 2018, I had just completed a trial of hypnotherapy for IBS when my digestion took an embarrassing turn, with accidents in taxis, and I could no longer eat outside my home.

A new dietician, Tamara Duker Freuman, author of "The Bloated Belly Whisperer," helped me identify the worst offenders: foods that are high in histamine, which can be found in everything from alcohol to avocados. After further testing, Galland put me on a regime: an arsenal of mast cell modulators and anti-histamines, including Pepcid, which also blocks histamine.

And I got better.

* * *

Mast cells were first named in 1878 by a German-Jewish Nobel Prize winner, Paul Ehrlich, a father of modern immunology who is most famous for discovering the cure for syphilis. At the turn of the century, scientists discovered anaphylaxis, the classic mast cell allergic reaction. The word comes from the Greek ana (against) and phylaxis (protection). The idea that an immune response could actually hurt us, rather than protect us, came as shock. Current research about the gut and immunity may change the paradigm again.

Five decades later, in 1949, scientists described a rare genetic disorder called mastocytosis, in which mast cells produce clones, building up in the skin, bones, and other organs. It wasn't until the 1980s that researchers began to notice that mast cells could become hyper-responsive or over-activated without cloning.

On a separate track, since the 1990s, researchers have explored mast cell activity in IBS. (A clinical trial of Pepcid and Zyrtec for difficult IBS cases is currently underway at the University of Cincinnati.) Kyle Staller, director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, now sometimes prescribes Pepcid if he sees other signs like hives, to patients who ask him to consider a histamine or MCAS issue. "I think anyone who's been following the science closely has to start wondering, 'How much could this be playing a role in that IBS patient who's in front of us on a given day?'" he told me.

Competing proposals for diagnostic criteria emerged after 2010. Both proposals say that doctors should rule out other explanations for a person's symptoms, and that symptoms should appear in a least two organ systems (in my case, it affects my gut, nose, and skin). Both proposals require lab tests but they disagree on which tests are necessary, and on the ranges that would indicate someone has MCAS, as well as other details. Because lab results are elusive, Galland and some other doctors rely on a medical history instead.

The disagreement has led to two camps. In camp one, the condition is rare; in camp two, it occurs in up to 17 percent of the adult population. Specialists in camp one say patients are misled: "More and more patients are informed that they may have [mast cell activation syndrome] without completing a thorough medical evaluation," an international group of 24 authors, led by Peter Valent, a hematologist and stem cell researcher at the Medical University of Vienna, wrote in April 2019 in the Journal of Allergy and Clinical Immunology.

A year later, a largely American group of 43 authors led by Lawrence Afrin, one of the earliest mast cell activation researchers, countered in the journal Diagnosis that patients are suffering and even dying from underdiagnosis. By then the pandemic had arrived, and Afrin suggested that some patients with long Covid might be experiencing MCAS.

Patients were seeing links as well. For example, the distinct POTS symptom of extreme lightheadedness, once often dismissed as a problem of anxious young women, emerged as one of the odder long Covid symptoms. POTS, which has been reported by patients who experienced Lyme and other infections, may involve histamine and several other chemicals released by mast cells. It is known to overlap with MCAS.

Last fall, when the Centers for Disease Control and Prevention reported on what it labeled multisystem inflammatory syndrome (MIS), the name rang bells: MCAS is clearly a multi-system inflammatory syndrome. Theoharis Theoharides, a professor of immunology at Tufts University who has studied mast cells for more than 40 years, wrote that MIS patients should be evaluated for MCAS.

Mariana Castells, director of the Mastocytosis Center at Brigham and Women's Hospital in Boston, told me in an email that she's seen no data showing that long Covid patients have the requisite diagnostic markers of MCAS.

Observers agree that the long Covid group probably includes people with different vulnerabilities. It would be marvelous indeed, if, one day, we found a single powerful concept to understand post-viral illness.

In the meantime, you might not need to fit either group's criteria for MCAS, a difficult and chronic illness, to experience your mast cells' betraying you sometimes. "Like many, many conditions, over time we [may] learn that there's a spectrum of disease," Staller said. "It's not an all or nothing phenomenon."

Even the group that sees MCAS as rare acknowledges the existence of a less severe form of mast cell activation that does not meet MCAS criteria. Theoharides has detailed several categories of the illness. He told me that he'd guess half of patients diagnosed with IBS might have mast cell activation of some kind.

If mast cell dysfunction is truly common, I trust the online buzz to help us find out. Crowdsourcing on patient forums is here to stay. And it's good, after all, that sick people shared information, found support, and made long Covid a "thing" with ontological status.

Growing up, I had wondered if my grandmother's multiple "allergies" were real. We didn't laugh, but we didn't exactly believe her. Then it happened to me.

* * *

Temma Ehrenfeld is a writer and ghostwriter in New York drawn to philosophy and psychiatry. Her most recent book is "Morgan: The Wizard of Kew Gardens."

This article was originally published on Undark. Read the original article.

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Immune system mutiny: mast cells and the mystery of long COVID - Salon

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An immunotherapy based on supercharging the immune system's natural killer cells has been effective in treating patients with recurrent leukemia and other difficult to treat blood cancers. Now, researchers at Washington University School of Medicine in St. Louis have shown in preclinical studies conducted in mice and human cells that this type of cell-based immunotherapy also could be effective against solid tumors, starting with melanoma, a type of skin cancer that can be deadly if not caught early.

The study is published June 29 inClinical Cancer Research, a journal of the American Association for Cancer Research.

In recent years, an immunotherapy called immune checkpoint inhibitors has revolutionized treatment for advanced melanoma. In one well-known example, this immunotherapy was successfully used to treat former President Jimmy Carter, whose melanoma had spread to his liver and brain.

But the therapy only works in about half of such patients. And even among those who respond well to the initial therapy, about half go on to develop resistance to it. Consequently, researchers have been seeking different ways to harness the immune system to attack melanoma cells. One possibility is to use natural killer (NK) cells, a part of the immune system's first line of defense against dangerous cells, whether cancer cells or invading bacteria.

Todd A. Fehniger, MD, PhD, a professor of medicine, and his team have had success in clinical trials treating recurrent leukemia with a patient's own natural killer cells or those from a donor. The NK cells are harvested from the patient's or a donor's blood and exposed to a set of chemical signals called cytokines that activate the cells and prime them to remember this activation. When these "cytokine-induced memory-like" NK cells are given to the patient, they are more potent in attacking the cancer because they already have been revved up, as Fehniger puts it.

"These 'revved-up' memory-like NK cells attack blood cancers quite well," said Fehniger, the study's co-senior author and an oncologist who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "But relatively little work has been done on whether these cells can be used against solid tumors. This is an unmet need in solid tumor oncology. Our study provides proof of principle that memory-like NK cells respond better than normal NK cells against melanoma, and it serves as a stepping stone to a first-in-human clinical trial of these cells in advanced melanoma."

Added co-senior author Ryan C. Fields, MD, the Kim and Tim Eberlein Distinguished Professor of Surgical Oncology: "We hope this is also a step toward harnessing NK cells against multiple solid tumors. Melanoma was a good place to start because we know it responds to immune therapy. But because many patients don't respond or develop resistance, we felt that targeting a different aspect of the immune system was a promising strategy to pursue."

The standard checkpoint inhibitor immunotherapy that works well in some melanoma patients targets T cells, another type of immune cell that also frequently is harnessed against different forms of cancer. According to the researchers, patients who don't respond well or stop responding to the T cell-based standard therapy and have no other options would be good candidates for NK cell therapy.

The researchers studied human NK cells from both healthy people and from patients with melanoma and found that the cytokine-induced memory-like NK cells could effectively treat mice harboring human melanoma tumors. Tumors shrank to the point of being almost undetectable in many of the mice, and the memory-like NK cells prevented the tumors from returning in most cases for the duration of the 21-day experiment. While normal NK cells also reduced and controlled melanoma tumors, they did not do so to the same degree.

"We are currently designing a clinical trial to evaluate these NK cells in patients with advanced melanoma who have exhausted all other treatment options," Fehniger said. "We would like to investigate NK cells from a donor and, separately, a patient's own NK cells to see if the cytokine-induced memory-like NK cells offer an effective treatment option for patients with this aggressive skin cancer."

The NK cell-based immunotherapy is potentially safer than other cell-based immunotherapies because the NK cells do not trigger a cytokine storm, as is seen sometimes in CAR-T cell therapy, which often is used for blood cancers, nor do the NK cells cause graft-versus-host disease, which sometimes follows a stem cell transplant.

"Even 10 years ago, we had no effective therapies for advanced melanoma -- much like the lack of therapies for glioblastoma or advanced pancreatic cancer today," said Fields, a surgeon who treats patients at Siteman. "Checkpoint immunotherapy has revolutionized melanoma treatment, but we're still not satisfied with the 50% response rate. We want to do better, and this NK cell therapy is a promising approach. And in the future, we may be able to combine an NK cell-based therapy with checkpoint inhibition for an even better response."

Fehniger and his colleagues have worked with Washington University's Office of Technology Management to license the cytokine-induced memory-like NK cell technology to a company called Wugen. Fehniger is a co-founder of Wugen and serves on its scientific advisory board.

Reference:Marin ND, Krasnick BA, Becker-Hapak M, et al. Memory-like differentiation enhances NK cell responses to melanoma. Clin Cancer Res. 2021. doi: 10.1158/1078-0432.CCR-21-0851

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Cell-Based Immunotherapy May Be Effective Against Melanoma - Technology Networks

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5 July 2021

It is becoming clear that our gene functions are influenced by a variety of epigeneticfactors throughout our lives and even before we are conceived. Environmental context may affect gene expression and which genes are 'activated' or not in children conceived via IVFmay be influenced by the dietary and lifestyle habits of an embryo's parents or grandparents, as well as by the culture medium in which eggs and embryos are kept in vitro. These findings have implications for the way we think about fertility, assisted reproduction, and genetic identity.

Epigenetics and bioethics of human embryonic development is a multidisciplinary project that spans disciplinary boundaries in order to better understand how scientists, clinicians, patients, and society should respond to these challenges. The project is funded by the University of Oslo Life Sciences, as part of its convergence environments initiative which has seeninterdisciplinary research groups formed to address major health and environmental challenges faced. The project started in 2017, and is now drawing towards its close. Here, three of our project members explain their work within the project.

Trine Skuland is a developmental biologist who works on epigenetic regulation of early embryo development.

When an egg and a sperm unite to form a zygote, numerous events need to be coordinated in order to achieve successful development. Out of the ~30,000 human genes, the right selection has to be switched on/off at the appropriate time point. No wonder these events are error-prone!

Upon fertilisation, extensive reprogramming happens in order to reset the epigenetic marks of the egg and the sperm DNA, and to set up a new pattern that is compatible with further embryo development. Epigenetic marks are chemical groups that are attached either to the DNA itself or to the proteins the DNA wraps around inside the cell nucleus. The pattern of these epigenetic marks will decide whether genes are activated or silenced.

When an embryo reaches the eight-cell stage, one of the most critical events takes place. This is when the first major set of genes is activated. My team is currently studying one specific epigenetic mark that we think is important for the embryonic genome activation and we hope our research will contribute in further characterisation of epigenetic factors involved in this crucial part of embryo development.

Our aim is to find another piece of the big genome activation puzzle in order to get a more complete picture of what is necessary for normal embryo development. This is as more than half of the embryos created during assisted reproduction develop abnormally and have to be discarded. Our ultimate goal is giving infertile people higher quality embryos to increase their chances of becoming parents.

Birgit Kvernflaten is a medical anthropologist who looks at prospective parents' experiences of assisted reproductive technologies.

My role in the project is to explore prospective parents' experiences and perspectives of practices and treatments used in assisted reproduction.It starts from the idea that their experiences do not take place in a vacuum, but are shaped within a particular socio-cultural and political context. The project further aims to explore and understand prospective parents' experiences and perceptions of the status of the embryo, embryo donation, research, and selection, in light of increased epigenetic knowledge.

This project has highlighted how prospective parents' experiences of infertility treatment are related to and shaped by social and cultural discourses on Norwegian family life.

In Norway, biological or genetic ties are considered central to people's understanding of kinship and identity, shaping couples' negotiations about gamete donation, family, relationships, and responsibilities. Yet people's understanding of genes is also ambiguous. As for the concept of epigenetics; it seems it has not yet entered the public's imagination.

Although the role of environmental factors in shaping who we are is acknowledged in Norwegian society, couples tend to view genetics in a rather deterministic way, in that they believe it shapes both looks, personality, and risk of disease. While difficult to truly grasp, the role of genetics is central to people's ideas about reproduction and parenthood. New epigenetic knowledge raises questions about the interface between nature and nurture, as well as opening up discussion related to the role mothers and their bodies play in determining the health of future offspring.

Joona Rsnenis a bioethicist who works on the philosophical and ethical implications of epigenetics.

Epigenetics raises challenging ethical issues throughout the human life cycle. Epigenetic transmission from one generation to the next may raise questions of moral responsibility of parents and grandparents. Epigenetics plays an important role in a range of chronic diseases, such as diabetes. Our lifestyle habits during pregnancy and even before, may influence whether our future children will live healthy lives or suffer from lifelong illness.

It is commonly known that we should eat healthily for our own sake, but these developments in our understanding of epigenetic could imply that we should eat healthily for the sake of our future children as well. Does this demand too much of future parents?

Epigenetics seems to put prospective parents under pressure since they would be partly responsible for their future child's health even before the child is conceived. Pregnant women are often advised to abstain from alcohol and tobacco, but maybe it is worth reminding them to eat healthily as well and this advice applies not only to future mothers, but to prospective fathers too, since epigenetic inheritance occurs through the male germline as well.

Conclusion

The interplay between science, anthropology, and philosophy in the context of epigenetics is complex.Skuland notes that a key aim for scientists working to unravel the epigenetic mechanisms involved in early embryo development, is to fulfil the needs of IVF patients to have their 'own' child. Dr Kvernflaten shows how genetics is central to patients' ideas about kinship and identity, yet epigenetics is still something unfamiliar to most prospective parents. Rsnen's example suggests that if parents did take on board some of the moral implications of epigenetics, they might find that the scope of their responsibility for future offspring is dramatically expanded.

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Epigenetics and bioethics of human embryonic development: a birds' eye perspective - BioNews

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Harappan seals, pottery, figurines and animal bones reveal many real and mythical animalsdog, tiger, birds, wild ass, unicorn, humped bull, elephant, rhinoceros, water buffalo, short-horned humpless bull, goat, antelope, crocodile and harebut not horse, one-humped camel or donkey. The horse appears in the subcontinent after the collapse of the Harappan Civilization. It likely arrived in numbers along with the Aryans from Central Asia, a horse-riding nomadicpastoralist people with perhaps some knowledge of crops. What also accompanied them was their language and religion: proto-Sanskrit, proto-Vedas and Vedic godsmostly male gods, such as Indra, Agni, Mitra, Varuna, Rudra and Surya, and a few female gods, such as Usha and Prithvi. They used iron, revered fire and the cow (though they also slaughtered it and ate beef), and preferred cremating the dead. By the time these Aryan herders entered the subcontinentin the middle centuries of the second millennium BCEurban Harappans had largely dissolved into rural life.

Notably, the Vedic lore of the Aryans mentions defensive armour, weapons, chariots and warfare against dark-skinned foes named Dasas. But the Dasas were not Harappans, who no longer lived in fortified cities by the time the Aryans reached the Indus Valley. Based on the styles of Dasa forts described in the Rig Veda, Parpola and others have argued that the Dasas were proto-Sakas, a pastoralist group of the Central Asian steppes, and the major fights between the Aryans and the Dasas probably took place not in the Indus Valley but in the Indo-Iranian borderlands, en route to the Indus Valley. Nor does the description of the Saraswati River in the Rig Veda fit the Ghaggar-Hakra River that dried up c. 2000 BCE, and instead maps on to the river called Haraxvaiti (in Avestan) or Harahuvati (in Old Persian), which is very likely the Arghandab River, or less likely the Helmand River, both in modern Afghanistan.

After the arrival of the Aryans to the Indus Valley, the locals (rural descendants of the Harappans) probably saw them as an aggressive bunch and their encounters were likely not all peaceful. One indicator of this is the very skewed genetic footprint of the Aryan male in later populations, despite the fact that, like all migrating groups, they had come with entire families. According to a scientific study in 2017, Genetic influx from Central Asia in the Bronze Age was strongly male-driven, consistent with the patriarchal, patrilocal and patrilineal social structure attributed to the inferred pastoralist early Indo-European society. Further, while archaeologists havent found any telltale signs of war or invasion, its reasonable to expect that the locals would have initially resisted the imposition of the Aryan language, religion and culture, since thats how such encounters usually play out.

Also read: Indias native horses disappeared by 8000 BC. But Rig Veda mentions them more than the cow

The Aryans also brought with them a form of social hierarchy with priests at the topa proto-varna system without endogamy (i.e., marrying only within a specific social group). They had no linguistic script and the need for it was reduced due to the lack of an urban civilization. The priests may also have impeded the rise of a script that might have democratized their oral chants and deflated their esoteric powers. Notably, such instincts seem alien to the Harappan ethos, given the ubiquity of the artefacts with their script on them. For instance, their script often appears as graffiti-like scribbles on stone blocks in non-elite parts of Dholavira, and as messages stamped on pottery items used by ordinary people (possibly brand or ownership details?).

After a millennium of mixing and migration in the subcontinent, numerous sites arose in the Gangetic Plain, whose settlers had learnt to fire a more durable and sophisticated series of ceramics known as painted gray ware (PGW), writes historian Sudipta Sen. They evolved social formations in which clans, lineages, and tribes began to yield to new ruling councils and kings. From this came new urban life, hybrid cultures, languages, pantheons and religio-spiritual ideas that we now associate with mid-first millennium BCE India. These developments had strong contributions from both the Aryan and the Harappan substrates. New political and social conflicts en route also seem to have inspired many of the stories in the great epic Mahabharata.

Could the Harappan social hierarchy have included endogamy based on occupation, i.e., a proto-caste system? Did a hereditary group of manual scavengers clean the sullage jars of Dholavira homes? Current archaeology and genetics consider this unlikely (more ancient DNA analysis of Harappans may provide conclusive evidence). Scientists trace the earliest instances of endogamy to the first millennium BCE, probably more than a millennium after the Aryan migration into the subcontinent; mixing of populations was the norm until then. Thereafter, mixing coexisted with a few groups practicing endogamy, which eventually led to a more widely endogamous caste system.

But can we say which cultural substratethe Aryan or the Harappandrove the creation of the caste system? A strong clue comes from the fact that Aryan genes register far more strongly in the higher castes, who are also lighter skinned on average. Further, DNA evidence has shown that endogamy first appeared and became the norm among upper castes and Indo-European speakers. Indeed, as many scholars have long argued, the roots of the Indian caste system almost certainly trace back to the Aryan substrate.

Also read: Was Harappa wet or arid? Rhinos hold a clue

Further, patriarchal practices like Sati, too, appear to be a legacy of the Aryan substrate. Satis earliest noted occurrence in India dates to the fourth century BCE, as recorded by two first-century-BCE writers, Diodorus Siculus and Strabo. Though now mostly associated with India, sati also occurred back then in the Near East and Europe, among descendants of earlier migrants of the root proto-Indo-European culture, the Yamnayaalso the parent culture of the Indo-Aryans. In the fifth century BCE, Greek historian Herodotus wrote about a Thracian tribe where the most beloved wife of a dead husbanddeemed so by family and friends, and intended to be a coveted honourwas sacrificed and buried with him.

A century later, the Thracian wife of Philip II, father of Alexander the Great, was burned on her husbands funeral pyre, as per the custom of her people. In the first century CE, Roman historian Tacitus observed that in a Germanic tribe (descended from the Yamnaya), the wife refused to survive her husband, but killed herself in order to be burnt on the same funeral pyre as him. He noted that many other tribes disliked widow remarriage. In the tenth century CE, Arab historian Al Masudi noted sati among Slavic and Russian tribes (also descended from the Yamnaya) in the Caucasus region and in India. Such funerary customs have a distinctly patriarchal script. Theyre qualitatively different from those of ancient Egyptians, where servants were sometimes sacrificed and buried with an important man. Sati was likely alien to the Harappans, but in the mixed culture that arose later, it gained a foothold among the warrior elites and became part of the Indo- Aryan cultural legacy in the subcontinent.

In the last decades of the twentieth century, however, cultural chauvinism reared its ugly head in the scholarship of Indian prehistory. A host of Hindu nationalists and motivated scholars (almost entirely brown or white Hindu men) began championing an alternative view of the Aryan migration, arguing that there was no Aryan migration at all! That the Aryans and the Harappans were one people, both fully indigenous. They claimed that the proto-Indo-European language family, of which Sanskrit is a part, was created by these indigenous folks and taken to the westthe Out of India Theory (OIT). This also implied that the Harappans spoke proto-Sanskrit and codified it in their as-yet-undeciphered script, that they composed the Rig Veda, which describes their own fortified cities like Dholavira. Such bogus scholarship, as is now amply clear, has fed hordes of middlebrow Hindutva ideologues since the 1980s. Armed with little knowledge and misplaced pride, well-heeled urban Hindus began to confidently assert that the Aryan Migration Theory was discredited. Countless websites carry this fake news.

In fact, the controversy about Aryan migration was never an honest disagreement among scholars. Parpola, for instance, has long considered it impossible that the Vedic Aryans were indigenous to South Asia. The massive weight of evidence from linguistics, philology, and archaeologythough it had gaps that its rivals tried to exploit has long favoured whats now being proven or refined by population archaeogenetics, a field whose impact on ancient history may end up being as significant as radiocarbon dating (1949).

The OIT was motivated by bad politics rather than by good scholarship.

This excerpt from Indians: A Brief History Of A Civilization by Namit Arora has been published with permission from Penguin Random House India.

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CONSERVATIONISTS at Dudley Zoo and Castle are playing a major role in helping to secure the future of endangered black lemurs.

Senior figures at the Castle Hill attraction have been managing the European Endangered Species Programme for black lemurs for almost two decades, first overseen by zoo director Derek Grove before curator Richard Brown took over the reins in 2015.

But Richard is now not just the co-ordinator of the entire European captive population, but hes also overseeing the International Studbook and studying the genetic make-up of captive black lemurs as far afield as America and Japan.

He said: Its really exciting to have a bigger gene pool of the captive black lemur population to work with.

Im now overseeing 350 black lemurs in more than 75 collections worldwide, studying their genetics and making recommendations about which of these lemurs are suitable for exchanges or breeding.

Zoo registrar Nicola Wright has also been helping with the Studbook and collates details of all births, deaths and transfers within collections as well as identifying surplus animals.

Richard added: Its crucial for the survival of the species that we keep the gene pool viable, so we have to get the genetics right when matching pairs together.

We have to identify who is genetically closely related, to avoid in-breeding and prevent any defects.

Its a really interesting task and hopefully the new role may also open up the potential for us here at DZC working with Japanese zoos in the future.

Lemurs can live up to 30 years in captivity and, on average, they make between one and two moves throughout their lifetime.

The zoo has a breeding pair, Florence and Bryan, and their three-year-old offspring, Jimmy.

Ten-year-old Florence moved to Dudley in 2016 from Bioparc Fuengirola in Spain, while, Bryan, aged 15, relocated to the Midlands from Luxembourg in 2009 after originally being born in France.

The pairs first offspring, daughter Kimmy, who was born at DZC in 2017 and was the zoos first black lemur birth in a decade, was moved to Planckendael Zoo in Belgium in 2019 after Richard successfully matched her to a male there.

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Dudley Zoo staff are part of global effort to protect endangered black lemurs - Dudley News

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Multiple myeloma scientists at the Mayo Clinic are investigating a possible innovative chimeric antigen receptor-T cell treatment (CAR-T cell treatment) called antigen receptor therapy. Their results have been authored in the Lancet on June 24.

According to Yi Lin, M.D., a refer researcher at the Mayo Clinic, CAR-T cell treatment is a form of immunotherapeutic that harnesses the authority of an individuals own immune response by designing their T cells to recognise and kill the cancer cell.

Idecabtagenevicleucel, the first CAR-T cell therapy for numerous myeloma was first authorised by the Food and Drug Administration in March, according to Dr. Lin. In our ongoing work on a prospective CAR cell diagnosis for numerous myeloma Dr. Lin notes, Presently, we are going to work forward into some other prospective CAR cell therapy for numerous myeloma.

Dr. Lin says that CARTITUDE-1 research is a phase 1B/II clinical trial, the first of three enrollment trials. CAR-T cell treatment was evaluated in numerous myeloma patient populations who had done receive three or more lines of conventional drug treatment and who were still on proteasome inhibitors, immunostimulatory medications, and CD38 antibodies.

Cilta-cel is a singular injection created from the sufferers original T cells that were biologically modified explains Dr. Lin. According to Dr. Lin, the treatments total reaction percentage is 97 percent, with full remission & advancement life percentages of 67 percent & 77 percent, correspondingly. Ultimately, 89 percent of the people survived.

Notifications on the research are just given at American Society of Medical Oncology yearly conference, said Dr. Lin, this happened before our article is published in The Lancet. This ASCO report demonstrated that individuals getting this treatment had a continuing deeper responder, via an 80 percent full reaction frequency adds Dr. Lin. Those are outstanding findings in myeloma individuals who had previously had multiple rounds of treatment.

Dr. Lin believes that it would be critical in the future to fully comprehend the medical characteristics of individuals who have had sustained remissions on this medication, as well as the processes that cause individuals to revert.

Although official contrasts between 2 distinct study designs of ide-cel&cilta-cel cannot be made, Dr. Lin adds, the extremely overall responder rates and advancement patient survival administered with cilta-cel were extremely promising.

She warns, though, that turning this study into a therapeutic customised medicine would necessitate addressing a slew of technical problems particularly assuring that the transfer from study to retail venture is seamless.

The exorbitant expense of CAR T cell treatment is a major concern. The fact that CAR T cells must be custom-made for each patient is one of the key explanations for the increased cost. To overcome this problem, many scientists are currently attempting to generate off the shelf CAR T cells that are derived from donors and may be utilised to treat a wide range of sufferers. CAR T cells produced from allogeneic donors are one option.

Genome editing techniques can be used to remove the T cell receptors that may produce an allogeneic immune response. CAR T cells generated from iPS cells are another potential technique. Some studies have extensively successful in creating functioning T cells from iPS cells, which they are now attempting to employ as a source for CAR T cells.

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The Possibility Of New CAR-T Cell Therapy For Multiple Myeloma - Powdersvillepost.com

Recommendation and review posted by Bethany Smith

Introduction

Fragile X syndrome (FXS), OMIM # 300624, is a X-linked inherited genetic disease classified as a triplet repeat condition. FXS is the most common cause of inherited intellectual disability and autism in the world. It has a prevalence of 1 in 5000 men and 1 in 8000 women. Affected individuals are characterized by intellectual disability, autism, language deficit, typical facies, and macroorchidism.1,2

Alterations in the FMR1 gene with locus Xq27.3 are causative of Fragile X Syndrome and other disorders. This gene harbors a CGG repeat within the 5 untranslated region and, depending on the number of repetitions, 4 types of alleles are defined with different clinical manifestations:3 Normal alleles, which have up to 44 CGG repeats; grey zone or intermediate alleles that contain between 45 and 54 repeats; premutation (PM) alleles with between 55 and 200 repeats; and full mutation (FM) alleles, with more than 200 repeats. In most cases, this is due to an expansion of the CGG triplet from one generation to the next.4

The Fragile Mental Retardation Protein (FMRP) is coded by the FMR1 gene. The absence of FMRP expression is usually secondary to the methylation of the FMR1 gene that occurs when more than 200 CGG repeats are present in the 5UTR region; this can also be explained by a point mutation in the coding region for FMR1 or a deletion that includes this gene, but these changes have only been reported in a few cases. The absence of FMRP is related to the classic FXS phenotype.5,6

FMRP expression is slightly lower in the carriers of a PM allele. Lower levels of FMRP are found particularly in the upper premutation (PM) range however, they typically do not present the classic FXS syndrome phenotype.7 Furthermore, they have elevated FMR1 mRNA levels between 2 to 8 times normal levels, which also leads to RNA toxicity. These elevated levels of mRNA are a risk for a number of medical conditions that are not explained by decreased FMRP.2,4,8

FMRP has roles in chromatin dynamics, RNA binding, mRNA transport, and mRNA translation9,10 and for certain subgroups of cerebral transcripts.11

This protein is involved in the regulation of RNA stability, subcellular transport and translation of neural mRNAs that codify proteins involved in synapsis development, neural plasticity and brain development.8

In addition, FMRP interacts with at least 180 proteins expressed in the brain and connective tissue. This interactome comprises known FMRP-binding proteins, including the ribosomal proteins FXR1P, NUFIP2, Caprin-1, and other novel FMRP-interacting candidate proteins located in different subcellular compartments, including CARF, LARP1, LEO1, NOG2, G3BP1, NONO, NPM1, SKIP, SND1, SQSTM1 and TRIM28. This interactome suggests that, besides its known functions, FMRP is involved in transcription, RNA metabolism, ribonucleoprotein stress granule formation, translation, DNA damage response, chromatin dynamics, cell cycle regulation, ribosome biogenesis, miRNA biogenesis and mitochondrial organization.9

Several studies have shown that in the absence of FMRP, a wide range of neural mRNAs are affected, boosting neural protein synthesis, which results in dendritic spine dysmorphogenesis and glutamate/GABA imbalance, which in turn produce variations in neural excitation/inhibition, phenomena that are present in FXS. Dendritic spine dysmorphogenesis plays a role in the intellectual deficits and behavioral problems, due to the weak synaptic connections found in this syndrome.12,13

Fragile X syndrome (FXS) has incomplete penetrance and variable expressivity and biological sex is a decisive factor of the phenotype. Full mutation of the FMR1 gene has a 100% penetrance of intellectual disability in males and 60% in females. Other characteristics associated with FXS Appear with varying frequencies in affected individuals. Autism spectrum disorder (ASD) symptoms appear during early childhood in 50% to 60% of males and 20% of females with FXS.1417

Physical features include elongated face, large and prominent ears (7578% of affected males), mandibular prognathism (80% of adult men), hyperlaxity and macroorchidism (95% of adult men). Other characteristics also vary in their frequency of presentation: seizures (23%), strabismus (8%), and cardiac abnormalities such as abnormal aortic root dimensions (18%) and mitral valve prolapse (55%). In general, the female phenotype is less severe and less specific.4,18

The variation in the phenotype of monogenic diseases is common,19,20 it is explained by a combination of genetic, environmental, and lifestyle factors,21 and FXS is not an exception.

Here, we present a review of the knowledge about the molecular factors involved in the variable expressivity of FXS.

The presence of a full mutation in FMR1 is associated with the hypermethylation of a CpG island located in the promoter of the FMR1 gene. Methylation of DNA regions (mDNA) is one of the main epigenetic modifications related to transcription regulation.22 A CpG island is located proximal to the CGG repeat tract, which is expanded in FXS. Hypermethylation of the CpG island generates transcriptional silencing of the FMR1 gene.23 As a consequence, the Fragile Mental Retardation Protein (FMRP), codified by the FMR1 gene, is not produced24 and in turn, the absence or low expression of FMRP causes FXS.

CGG tract repetition expansion in the untranslated region (UTR) of exon 1 in the FMR1 gene generates instability of that region during the replication process, inducing size mosaicism, which is defined as the presence of premutation and mutation alleles in several cells.25

In males with FXS caused by full mutation, the detection of FMR1 mRNA levels in peripheral blood lymphocytes is common. This phenomenon is due to both size mosaicism and mDNA in the CpG island and nearby regions that vary between cells and tissues.26 Furthermore, longitudinal studies in women with FXS have shown that levels of mRNA transcribed from FMR1 decrease significantly with age.23 Complicating even more the behavior of mDNA and FXS, it has been found that in premutation alleles, a considerable number of cells have mDNA.27 The variation between methylation states of the CpG island and nearby regions among different cells and tissue of the same person is known as methylation mosaicism.28 It is estimated that around 50% of people with FXS have this type of mosaicism.29 In cells where mutated alleles are not methylated, they are transcriptionally active and can be expressed.30 However, in these cells there is no FMRP synthesis since mRNA with CGG expansion greater than 200 repeats is not translated efficiently in ribosomes.31,32

The absence or low levels of FMRP is a decisive factor for FXS development, as several studies have aimed to discover the relationship between protein levels and phenotypic characteristics of the patients. Since the late 1990s, correlations between FMRP levels and the neurological phenotype of FXS have been established.29,33,34 The first studies about this topic established the standard levels of FMRP in peripheral blood leucocytes through immunoblotting. When comparing protein levels with the allele type and the presence of size mosaicism, it was demonstrated that people with the lowest FMRP levels were males with FM. Males with size mosaicism and females with FM had slightly higher levels of FMRP than males with FM.33,35,36 Via multiple regression models, it was found that FMRP levels were significantly correlated with the intelligence quotient (IQ) of the patients in the study.33 However, studies did not identify the same relation between FMRP levels and behavioral symptoms.34,37 More recent evidence supports a partial overlap between the pathogenic mechanisms that lead to FXS and ASD.38 Lower FMRP levels have been documented in samples of individuals with FXS and ASD compared to patients with FXS only.29,34 The relation between FMRP levels and IQ in males and females with different expansions in CGG repeats was studied recently.39 This last study has two important advantages compared with previous studies: firstly, the use of fluorescence resonance energy transfer (FRET), which has a higher sensibility when measuring protein levels, and also FMRP levels were measured in dermal fibroblasts. Unlike leucocytes, fibroblasts derive from the ectoderm, the same germ layer from which nervous system cells originate. Researchers found a strong and positive relation between FMRP levels and cognitive skills in patients with levels below 30% of the standard levels in controls. Interestingly, above this level, there was a higher dependence between low FMRP levels and low IQ.39

In parallel with the aforementioned studies, researchers reported the incidence of size and methylation mosaicism in cognitive impairment severity.4042 The classic definition of premutation alleles behavior as non-methylated alleles, and mutated alleles as methylated or partially methylated ones in order to categorize premutation carriers and patients with FXS has been extended progressively to include a detailed classification that takes into account the existence of size and methylation mosaicisms.

Regarding size mosaicisms, different combinations have been described, including patients with some FM cells and other cells with PM. Indeed, patients with FM, PM, grey zone alleles and even alleles with normal size have been reported.40 The presence of size mosaicisms with PM and FM alleles is related with a less severe phenotype and a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS).43

When exploring the possible relation between size mosaicisms and the intellectual functioning of patients with FXS disregarding sex, it was found that patients with FM/PM had better intellectual functioning and less maladaptive behavior, compared with FM-affected individuals.42 Interestingly, the same study found that ASD features and maladaptive behaviors were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. A limitation of this study is that they used venous blood and real time PCR and Southern blot analysis to quantify the level of methylation.

Recently, methylation mosaicism has been taken into account as an important variable in phenotype traits. The most frequent mosaicism found in males is the presence of FM-methylated alleles and non-methylated FM and PM alleles (combination of size and methylation mosaicism).25,44 However, in patients with FM and not PM mosaicisms, methylated alleles do not express mRNA, while non-methylated alleles do. An aspect that highlights the importance of detecting the presence of this kind of mosaicism is the influence on phenotype severity. Additionally, according to some case reports, the presence of synthesized mRNA from PM and FM alleles increases the odds of developing the FXTAS phenotype.45,46 The final consequence of methylation mosaicism is the cells reduced ability to express FMR1 mRNA, measure mRNA and determine if there is a relation with phenotypic traits. When analyzing mRNA levels between males and females, it was found that females had higher levels. Also, in females, higher levels of FMR1 mRNA were related positively with age but not with intellectual functioning and autistic features. Males with FM that express FMR1 mRNA had significantly higher ADOS calibrated severity scores, when compared with males with fully methylated FM. Interestingly, no differences were found regarding intellectual functioning.41 Likewise, when contrasting FMR1 mRNA levels and scores on the Aberrant Behavior Checklist-Community-FXS version (ABC-CfX) it was found that in males with FM, higher values of FMR1 mRNA were related with elevated irritability and lower health-related quality of life scores.47 This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations, it is essential to take into consideration not only sex but also size and methylation mosaicism.

Recent investigations explored simultaneously how FMR1 mRNA levels of FMRP are related to phenotypic alterations in males with PM and FM.48 In a study composed of 14 cases of patients with PM or PM and FM mosaicism and mental illnesses such as bipolar disorder, schizophrenia and psychosis, among others, low levels of FMRP and increased FMR1 mRNA were evident in these patients. This combination of characteristics in patients with FM, decreased FMRP, PM and increased FMR1 mRNA represents a dual mechanism of clinical significance that may generate characteristics of both FXS and FXTAS.48 In a clinic-based ascertained group of patients with FXS of both gender, a significant difference was found between FXS with ASD and low levels of FMRP when comparing concentrations of the protein in patients with FXS without ASD.29 They found that the mean full scale IQ and adaptive skills composite scores were significantly lower in males than in females (p = 0.016 and p = 0.001, respectively, MannWhitney). Additionally, all individuals with moderate or severe ID were males. Not surprisingly, ASD was present more frequently in males with FXS (46% vs 20% females). This association was not found in males with PM/FM, suggesting that for improved genotype/phenotype associations is essential to take into consideration not only sex but size and methylation mosaicism.29

There is a small proportion of FXS patients without expansions in the CGG-repeat tract. In this group, the condition is caused by missense or nonsense mutations,5,16 or deletions in FMR1.1,6 Patients with these mutations have similar physical, cognitive and behavioral characteristics to FXS patients. With the increasing availability of diagnostic methods based on next-generation sequencing and comparative genomic hybridization, a higher rate of diagnosis of mutations causing FMR1 function loss is expected. This will allow a clear delimitation of the phenotype caused by the loss of the protein in the absence of CGG tract expansions.

For many monogenic diseases it is known that, besides the allelic variance, the effect of modifier genes has an important role in incomplete penetrance and variable expressivity. The identification of modifier genes that affect the phenotype in monogenic diseases has many challenges that complicate their description. A genetic variant can modify the effect in the phenotype of another variant in many ways, including epistasis and genetic interactions.49,50

In studies using FXS murine models, important new evidence was acquired in order to establish the importance of potential modifier genes and their impact on FXS phenotype development. The knockout mouse model for FXS was generated in the last decade of the XX century. Fmr1 KO mice had learning deficits, abnormal synaptic connections, seizures, hyperactivity and macroorchidism.51,52 When describing the mouse phenotype in detail, it was evident that abnormal phenotypic characteristics depend, at least in some proportion, on their genetic background.53

During the identification of modifier genes in the FXS phenotype, a large proportion of the research has aimed towards the susceptibility to developing certain clinical behavioral characteristics, such as aggression, ASD and seizures.34,5459 All of the studies use a similar methodological design: they arrange groups of people with or without a specific phenotypic trait and establish the frequency of specific variants in modifier gene candidates.

The possibility that Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype in FXS patients has also been investigated. The replacement of a methionine for a valine in the 66th position of the BDNF protein interferes with normal intracellular traffic and BDNF dependent secretory activity in cortical neurons.60 This polymorphism has been related to cerebral anatomy alterations61 and neuropsychiatric disorders.62,63 In a sample of 27 males with FXS from Finland, it was found that all the patients with epilepsy (15%) had the Met66 allele, whereas the prevalence of this allele is 20% in the normal population. Research suggests that the Met66 allele in BDNF interacting with FM in FMR1 may partially explain the higher incidence of seizures in patients with FXS.56 In a more recent study with a higher number of males with FXS (77 patients), the results were not replicated and there was no association between seizures and Val66Met polymorphism.58 These results show the importance of validating studies about modifier genes in different populations.

In research about genes that affect mood and aggression, such as the serotonin transporter (5-HTTLPR), the monoamine oxidase A (MAOA-VNTR) and COMT, conflicting results were found. All of those genes are involved in regulatory pathways for different neurotransmitters, and their variants have been associated with the development of behavioral phenotypes in different contexts other than FXS. In one group of 50 males with FXS, the relationship of 5-HTTLPR and MAOA-VNTR polymorphisms with the frequency/severity of aggressive/destructive, self-injurious and stereotypic behaviors was studied. It was found that the high-transcribing long (L/L) genotype in 5-HTTLPR was related with a higher frequency of aggressive/destructive and stereotypic behavior, while patients with the short (S/S) genotype had less aggression. The MAOA-VNTR genotype had no effect on behavior.55 On the other hand, in a study of 64 males with FXS where the COMT gene was also included, the results of the previous study were not replicated. There was no association between behavioral characteristics and either 5-HTTL PR (serotonin) or MAOA genotypes. Nevertheless, the A/A genotype in COMT that modifies dopamine levels was associated with greater interest and pleasure in the environment, and with less risk of property destruction, stereotyped behavior and compulsive behavior.54 The authors of the study suggest that the non-reproducibility of the results regarding MAOA-VNTR can be explained by differences in the prevalence of aggressive and stereotyped behavior among the studied populations or by differences in the measurements used to characterize each behavior.

The importance of identifying potential modifier genes was explored in a clinical trial. The researchers investigated the relation between polymorphisms in several genes and the response of sertraline in 51 children. They found that BDNF, MAOA, 5-HTTLPR, Cytochrome P450 2C19 and 2D6 polymorphisms had significant correlations with treatment response.64

Currently the knowledge about molecular causes of the variable phenotype in patients with FXS include characteristics associated with the FMR1 gene itself and to secondary, modifying gene effects.

Regarding FMR1, when the diagnosis is established, the type of mutation causing FXS is identified: CGG repeat tract expansion vs pathological variant causing loss of function in FMR1.

When the CGG is identified, is it expected that about half of the patients have size or methylation mosaicism or both.29 The presence of any of those mosaicisms determines the expression or not of FMR1 mRNA and FMRP. The quantity of FMRP is directly related with IQ.34,37,39 While the presence of size mosaicism is related with better intellectual functioning and less maladaptive behavior,29,42 elevated concentrations of FMR1 mRNA in patients with FM have been associated with a higher risk of developing FXTAS45,46,48 and with the severity of behavioral symptoms.47

The search for modifier genes affecting the phenotype has been carried out using the candidate genes strategy. Because high impact clinical manifestations in FXS are related with neurologic phenotypes, the studied candidate genes are involved in CNS development and the appearance of seizures (BNDF)56,6062 and associated with mood and aggression (5-HTTLPR, MAOA-VNTR y COMT).54,55 Recent research has been done with small groups of patients and there are no conclusive results about the importance of these variants in modifier genes.

Scientific and clinical evidence about molecular causes of variable expressivity in FXS is growing quickly. It is evident that aspects of the mutation type in FMR1 and the behavior of the CGG repeat tract are relevant in the presentation of the condition. Research about modifier genes is still emerging. There are important limitations such as sample size and comparability of different studies, mainly due to smaller groups of selected patients and the use of different tools for measuring the phenotypes.

Independent cohorts of patients with FXS across different continents have shown evidence that mosaicism, FMR1 mRNA or FMRP quantification are associated with the severity of the phenotype. However, this information cannot currently be used effectively in the integral management of patients. When intervention strategies become available in order to prevent the development of FXTAS, or when certain molecules can regulate levels of FMRP expression to measure FMR1 mRNA and FMRP, they could be crucial for selecting patients and identifying the best therapeutic intervention.

In clinical trials there is an important window of opportunity. Identifying mosaicism, measuring transcription/translation activity of FMR1 and stratifying patients by modifier genotypes29,65 will permit the identification of subgroups of patients with greater potential to respond to specific treatments.

The authors report no conflicts of interest in this work.

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51. Mineur YS, Sluyter F, De Wit S, Oostra BA, Crusio WE. Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse. Hippocampus. 2002;12(1):3946. doi:10.1002/hipo.10005

52. Bakker CE, Verheij C; The Dutch-Belgian Fragile X Consorthium, et al. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell. 1994. doi:10.1016/0092-8674(94)90569-X

53. Errijgers V, Kooy RF. Genetic modifiers in mice: the example of the fragile X mouse model. Cytogenet Genome Res. 2004;105(24):448454. doi:10.1159/000078218

54. Crawford H, Scerif G, Wilde L, et al. Genetic modifiers in rare disorders: the case of fragile X syndrome. Eur J Hum Genet. 2021;29(1):173183. doi:10.1038/s41431-020-00711-x

55. Hessl D, Tassone F, Cordeiro L, et al. Brief report: aggression and stereotypic behavior in males with fragile X syndrome - Moderating secondary genes in a single gene disorder. J Autism Dev Disord. 2008;38(1):184189. doi:10.1007/s10803-007-0365-5

56. Louhivuori V, Arvio M, Soronen P, Oksanen V, Paunio T, Castrn ML. The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome. Epilepsy Res. 2009;85(1):114117. doi:10.1016/j.eplepsyres.2009.01.005

57. Stepniak B, Kstner A, Poggi G, et al. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes. EMBO Mol Med. 2015;7(12):15651579. doi:10.15252/emmm.201505696

58. Tondo M, Poo P, Naud M, et al. Predisposition to epilepsy in fragile X syndrome: does the Val66Met polymorphism in the BDNF gene play a role? Epilepsy Behav. 2011;22(3):581583. doi:10.1016/j.yebeh.2011.08.003

59. Wassink TH, Hazlett HC, Davis LK, Reiss AL, Piven J. Testing for association of the monoamine oxidase a promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome. J Neurodev Disord. 2014;6(1). doi:10.1186/1866-1955-6-6

60. Chen ZY, Patel PD, Sant G, et al. Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24(18):44014411. doi:10.1523/JNEUROSCI.0348-04.2004

61. Szeszko PR, Lipsky R, Mentschel C, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10(7):631636. doi:10.1038/sj.mp.4001656

62. Chen ZY, Jing D, Bath KG, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science (80-). 2006;314(5796):140143. doi:10.1126/science.1129663

63. Gratacs M, Gonzlez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61(7):911922. doi:10.1016/j.biopsych.2006.08.025

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Genetic mapping of subsets of patients with fragile X syndro | TACG - Dove Medical Press

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Michelle Angs Omega joins the Star Wars universe in the latest Disney+ television series from Lucasfilm, Star Wars: The Bad Batch. With voice actor veteran, Dee Bradley Baker, back as the titular Bad Batch, Angs character is stirring up some big questions for Star Wars fans namely, who is Omega in The Bad Batch?

Here is your guide to the new female clone in the Star Wars universe.

The Bad Batch premiere launched on Star Wars Day (May 4) and tells the story of a group of defective, genetically modified clones called Clone Force 99, or the Bad Batch. Made up of five mutated clone troopers Hunter, Tech, Echo, Crosshair, and Wrecker the squad partakes in numerous mercenary missions on behalf of the Republic, and are quickly becoming some of the best characters in the galaxy.

Dave Filonis (Star Wars Rebels, Star Wars Resistance) new animated series crosses over the events of Star Wars: The Clone Wars and Star Wars: Episode III Revenge of the Sith (2005) in the time before the original trilogy began. The season began with a feature-length episode titled, Aftermath, highlighting the historic moment of the Galactic Empires rise to power. Despite The Bad Batch controversy early on, the new series seems to have already built its fandom like many of the other Star Wars spinoffs.

When Chancellor Palpatine executed Order 66, overriding the Clone Armys programming to turn on their Jedi generals, Clone Force 99 was seemingly unaffected due to their enhancements. Although, as time wore on, some of the squad members did succumb to the Order 66 protocol before being saved by their brothers.

Omega, like the member of Clone Force 99, is a genetically enhanced clone. Essentially made from the DNA of bounty hunter Jango Fett, Omegas existence at least at first was seemingly unknown, but as the series progresses more and more is coming to light about the new character.

In the ninth episode of The Bad Batch, Bounty Lost, Omega was revealed to be a direct replica of Jango Fett, at least in terms of genetics. Only one other clone has this same link the bounty hunter, Boba Fett.

Arguably the new Grogu of Star Wars, Omega was introduced as a wide-eyed child intent on seeking a more adventurous life. Raised under the guidance of the Kaminoans on Kamino, Omegas first appearance came when the elite soldiers of Clone Force 99 returned to Kamino following the execution of Order 66. She was the medical assistant to Nala Se.

Hunter had just saved the Padawan Caleb Dume Kanan Jarrus in Star Wars Rebels after the murder of Jedi Master Depa Billaba, and upon returning to Kamino stumbled upon Omega. When Admiral Tarkin arrived on Kamino, Omega bonded with Hunter and the rest of Clone Force 99 before escaping the planet with them after Crosshairs chip activated, making him turn on his squad.

Many theories point to Omega being Force-sensitive. Her skill targeting a weapon in the premiere episode of the Star Wars animation, and more recently her ability to win every opponent at a game of dejarik, suggests there may be more than meets the eye with this honorary Bad Batch member.

What Star Wars fans do know, however, is that Omega is the daughter of Jango Fett and sister to Boba Fett. In Bounty Lost, after a near-death situation with the notorious Cad Bane and Fennec Shand, Tech revealed that Omegas genetic makeup is a direct replication of Jango Fetts. While the clone trooper armys genetics were slightly modified to grow quicker, Omega and Boba Fett were left completely untouched.

While Star Wars fans dont know much else other than this familial connection to two of the galaxys most notorious bounty hunters, her relationship to Boba Fett provides the most interesting detail, and not just for Filonis The Bad Batch. With only six episodes left of the first season, her backstory could point to the animated reprisal of Boba Fett or likewise the live-action debut of Omega in a Star Wars series down the line like Robert Rodriguezs The Book of Boba Fett.

Back to The Bad Batch though, we know the Kaminoans have hired bounty hunters to capture and protect Omega reasons unknown so her existence in the animated series suggests that trouble isnt far away for Clone Force 99.

As well as discovering what she is, Omega is slowly building a life outside of Kamino. Still under the shadow of those who made her, Omegas burgeoning connection to the members of the Bad Batch is how she seems to be writing her own history. The character is always one to dive into adventure, and even though this causes despair for Hunter and the gang, she is proving herself to be a valuable part of this formidable crew.

From helping in the mission on Corellia to find and secure a tactical droid to being present for the removal of the clones inhibitor chips on Bracca, Omegas Star Wars story has only just begun.

Omega is sharp-minded and headstrong. Sometimes a little nave, the character often heads into trouble with the right intentions but not the military skill to back it up. However, her way to find good in everyone as well as passing no judgments on what Clone Force 99 has had to do to stay alive makes her one of the galaxys warmest hearts.

Omegas personality has been shaped by those around her. The individual members of the unique squad, all of which have their own personalities seem to have rubbed off on the young clone. It is in her difference now to when she first met Clone Force 99, that fans can get an idea of how sheltered her life was back on Kamino. Much like how Grogu was in hiding for so long in The Mandalorian, Omegas entry into the big wide galaxy is a point of much character exploration.

From the Bad Batch, she learned about teamwork and survival, and even from characters like Cid (Rhea Perlman) has Omega developed new traits for this example, it seems Cids abrupt nature and aloofness has given Omega some new street smarts if her dejarik winning streak is anything to go by.

While Omega is the one Clone Force 99 protects most of the time, her calmness and quality to not see everything from a military perspective has aided the group on many occasions. Her competitive kinship with Rafa and Trace Martez on Corellia helped bring the sisters and the Bad Batch together to battle the army of police droids.

Omegas caring nature and inability to leave those she loves also highlight how the young clone is adding something new to the squad. Even after Wrecker set out to kill her after his inhibitor chip activated, Omega stayed by his side following the chip removal surgery and wouldnt rest until her squadmate woke up.

Omega has learned much since joining Clone Force 99. On Bracca, Wrecker taught her how to disarm explosives while on Ord Mantell, she acquired a Zygerrian energy bow. Although at first a novice in combat, Omega has quickly learned new skills in order to survive the attacks of Crosshair and the Galactic Empire as well as the relentless confrontations with the galaxys most nefarious bounty hunters.

Omega picked up her energy bow on Ord Mantell and has become an adept user at handling the weapon, although she still needs much practice to use it confidently. As StarWars.com describes:

Firing sizzling laser bolts instead of arrows, a Zygerrian energy bow is a formidable weapon in a firefight if you have a sharp eye and strong arms to lend the weapon unwavering accuracy.

It is perhaps the mystery surrounding the possibility of Omega being Force-sensitive that is most interesting in her skillset. Some might say its beginners luck or youthful charm, but the way she successfully aimed, possibly the first weapon she has ever wielded, in the premiere episode or managed to win numerous back-to-back games of dejarik, alludes to the fact that Omega may not be any regular clone.

Whether she is connected to the Force or not, Omegas skills at negotiating with her team members and other allies, as well as her ability to quickly pick up military talents make her more than suitable to take up the opening Crosshair left in Clone Force 99 and become one of the new rebels of the galaxy.

With more yet to discover, Omega is perhaps one of Star Wars most interesting new characters, and with many more upcoming projects, fans might not have to wait long for some answers.

What is your favorite thing about Omega? Let us know in the comments!

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'Star Wars: The Bad Batch' Who Is Omega? Inside the Magic - Inside the Magic

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There are many different types of hair, including straight, curly, wavy, and coily.

Depending on a persons hair type, they may need to follow different care instructions.

This article will provide some general information about hair types and detail some specific care instructions.

Hair type typically refers to the shape of a persons hair. Hair can be straight, wavy, curly, or coily.

According to one 2020 article, hair consists of two structures: the strand of hair itself, or the hair shaft, and the hair follicle.

The hair shaft consists of different layers, including the cortex, the surrounding cells, and, in thicker hair, a central medulla.

A 2017 study notes that the shape of the hair follicle determines the shape of a persons hair. For example, the hair follicles for curly hair are in the shape of an S.

Genetic factors play a role in deciding the shape of a persons hair follicle.

Learn more about what determines hair shape here.

Hair shape refers to the degree of curliness of a persons hair.

One review article notes that different researchers have used different hair shape categorization systems in their research about hair. For example, some have used use labels such as:

Some hairstylists like to distinguish hair shapes into four categories. However, scientists do not use this categorization system in medicine or scientific research.

Hairstylists use the following categorization system:

Hair density refers to the number of hairs that a person has on their head. The more hairs a person has, the higher that persons hair density.

Hair structure refers to the thickness of the strands of hair. A persons hair can be:

According to the World Trichology Society (WTS), hair thickness varies depending on the person. Some people have finer hairs than others. The WTS also notes that the hair fibers become shorter and finer as a person ages.

Hair porosity is a measure of the amount of moisture that a persons hair can absorb.

Hair porosity depends on how many gaps or tears are present in the cuticle layer. The cuticle is the outer layer of the hair, which protects it from wear and tear.

According to one 2015 article, hair is naturally porous. However, hair that has sustained damaged due to bleaching or chemical treatments is more porous than untreated hair.

People may find it helpful to avoid strong chemical and high heat treatments to let their hair recover.

According to the American Academy of Dermatology (AAD), people can try the following when caring for their hair:

People should select their shampoo and conditioner based on their hair type.

If possible, they should try to limit:

There is some evidence to suggest that straight hair carries sebum more easily than curly hair. Sebum is a waxy, oily substance that a persons skin produces. This means that people with straight hair may be more likely to get oily hair than those with curlier hair.

For this reason, people with straighter hair may wish to avoid the excessive use of certain hair products. These include:

People with straight hair may also wish to wash their hair more frequently.

According to a 2015 article, a person with straight hair may need to use a more gentle approach to caring for their hair. This may involve:

Over-brushing can damage curl definition. Therefore, people with curly hair may need to experiment to find the right amount of brushing for their hair.

Some other care tips for curly hair include:

Some people may also wish to use hair mousses and gels that are intended for curly hair to maintain curl definition.

The AAD suggests the following tips for Black hair:

Additionally, people may wish to take care when using weaves or extensions. To prevent hair damage, they may wish to try:

Tight hairstyles can also lead to traction alopecia, which results in hair loss. People may wish to consider giving the hair a break after 23 months of wearing a weave or extension.

Learn more about Black hair care tips here.

People with thick hair may find it helpful to use denser hair products, such as:

Additionally, people with greater hair density may find it beneficial to use brushes that are designed for thick hair. These brushes have fewer spokes than others, which helps people remove knots without breaking the hairs.

There is anecdotal evidence to suggest that denser hair products, such as oils and butters, can weigh down thinner hair. For this reason, people with thin hair may wish to avoid these products.

People with thinner hairs may also benefit from:

The WTS notes that people shed approximately 50150 hairs per day. This can occur through hair washing, brushing, and combing. However, some people lose more hair than they can grow.

This can happen for various reasons. One common cause is androgenetic alopecia. This is a genetically predetermined condition that affects around 50% of people. In males, hair loss occurs at the temples and the top of the head. In females, hair loss can affect the crown.

Hair loss can also occur in females due to other health conditions, including:

A person should contact a doctor if they:

Some anecdotal evidence suggests that people can use certain shampoos, essential oils, and dietary supplements to thicken the hair. However, there is no scientific evidence to prove that hair care can prevent thinning hair.

That said, a person can take measures to help prevent some causes of hair loss, such as traction alopecia.

Learn more about stopping hair loss here.

Everyones hair is slightly different. A persons hair can be straight, curly, coily, or wavy, and each type benefits from different methods of care.

Although some hair loss is common, a person should contact a healthcare professional if they are concerned.

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Hair: Types and care instructions - Medical News Today

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Check out what laws go into effect on July 1, 2021.

Dozens of Mississippi laws will go into effect on Thursday, July 1, 2021. Take a look at some of the most talked about bills of the 2021 session and how these new or revised laws could impact you.

Teacher Pay Raise

Probably one of the most talked about bill that passed from the House of Representatives was a raise for teachers and teaching assistants. HB 852, which had a nearly identical companion bill in the Senate, provided for a $1,000 raise for teachers at the start of the 2021-2022 school year and $1,100 for assistant teachers.

A teacher pay raise was on everyones mind entering the 2021 session and COVID-19 made it particularly important to lawmakers to see these funds diverted to teachers. In total, the raise made up an additional $50 million to education in the FY2022 budget.

Occupational Licensing Recognition

Workers in Mississippi and those who would like to come to the state but are licensed in other states, just got a helping hand. HB 1263, authored by Rep. Becky Currie, instated the Universal Recognition of Occupational Licensing Act. This bill allows individuals who work in other states and have a license that is in good standing with that agency to transfer for work to Mississippi with no additional loopholes.

RELATED: Governor Reeves on Universal Occupational Licensing Act: Mississippi is open for business

Just days before going into law, Governor Tate Reeves commented that this bill would allow workforce development to continue and labor shortages from the pandemic to decrease. He also said that it will reduce the red tape many professionals have to go through in order to work in Mississippi. That will include teachers coming from out of state to work here.

Election Qualifying

Planning to run for office in Mississippi? Well, take note of this bill lawmakers passed this session. HB 1048 effectively changes the qualification deadline to February 1 for some statewide, state district, county and county district offices.

Previously the deadline was not until March 1. This will bump the decision up for candidates considering a run for elected office by one month.

Appropriations bills

Mississippis budget was set during the 2021 session. The bills that pertain to appropriations for state agencies and such will all go into effect July 1, 2021. This marks the start of a new fiscal year in the state.

You can read more of those bills from the Senate and House here.

Alcohol Delivery

Many Mississippians have been pushing for more accessible ways to get their alcohol. The Legislature listened with HB 1135. This bill will allow the delivery of a particular wine, spirit or beer from a licensed retailer to a consumer. The retailer must also have a delivery service permit to participate in this service.

Those delivering can be current employees or contracted individuals who are at least 21 years old and receive proper training consistent with current programs. To place an order, you must be at least 21 years old.

Executive Sessions for Public Bodies

Speaker of the House Philip Gunn authored a bill, HB 1323, that will allow any public body to enter into executive session in order to develop a strategic plan to combat, eliminate, reduce or respond to human trafficking or the commercial sexual exploitation of children.

The reason these meetings would be necessary is to address a particular trafficking issue and attempt to provide an immediate solution.

MAEP Calculations

Over in the Senate, many lawmakers set their sights on improving education as well as helping the Mississippi Department of Education operate in unprecedented times.

SB 2149, which was authored by Sen. Dennis DeBar, provided that typical daily attendance rolls would not count against schools from the 2020-2021 school year.

Mississippis MAEP funding formula is calculated in part by daily attendance. Due to the unprecedented nature of the pandemic and virtual learning, daily attendance was unpredictable and, for many schools, impossible in-person during portions of the last year.

Teacher License Reciprocity

Similar to the removal of red tape for all occupational licensing, SB 2267 will allow reciprocity for teachers.

This bill will apply to any teacher coming from another state who already possess a teacher license and can pass a background check. Under the law, the Department of Education can grant a one-year extension to June 2022 to allow for that teacher to meet requirements in Mississippi.

The bill also implements the creation of a licensing and certification committee that will assist in streamlining the process for teacher certification in the state.

Earned Parole Eligibility

Possibly one of the most talked about pieces of legislation in general this year centered around the criminal justice system in Mississippi. SB 2795, or the Earned Parole Eligibility Act, was offered by Sen. Juan Barnett. He brought forward a similar bill in 2020 but it was vetoed by Governor Reeves.

Barnett said he took those critiques and perfected the language in order to have an agreement.

The Earned Parole Eligibility Act allows for particular non-violent, and some violent offenders, to be eligible for parole after a certain amount of their sentence has been served. The hesitation in 2020 centered around murderers being considered in the eligibility category, a move Barnet said was removed in the 2021 bill.

RELATED: Senate passes Mississippi Earned Parole Eligibility Act

Those not eligible include sex offenders, human traffickers, murderers, capitol, and habitual offenders. It is important to note that the bill does not grant any offenders parole; it only allows the possibility of parole in the event the individual has met the proper criteria for consideration.

The bill passed in both chambers and was later signed into law by Governor Reeves.

Medicaid Tech Bill

Every three years lawmakers are tasked with reconfiguring the guidelines for the Mississippi Division of Medicaid. This year it almost looked as if lawmakers would leave the 2021 session without a Medicaid Tech bill. However, at the final hour they were able to come to an agreement on the program with SB 2799.

RELATED: Medicaid will live on in the Governors office and with a budget

Though some attempts were made to remove the Division of Medicaid from under the Governors office, it remained housed there in the 2021 legislation. But the House did remove language that would have provided 12 months of postpartum care for mothers who receive the benefits.

Sen. Kevin Blackwell, Chairman of Medicaid, said the final bill included a 5% reimbursement for some providers, restored crossover claims for hospitals, nursing home and immediate care facility reimbursement days, and provided an additional 5% bump for dentists in 2022-2024 to cover preventative services.

RELATED: Senate passes bill to increase TANF benefits for Mississippians

Dept. of Public Safety

Many changes were made in regard to law enforcement and the Department of Public Safety. Perhaps the largest of note was the transfer of the Capitol Police from the Department of Finance and Administration to the Department of Public Safety. The law came by way of SB 2434.

The duties and abilities of the Capitol Police did not change with the bill, only the overseeing agency. The bill was offered by Sen. Brice Wiggins, Sen. Angela Hill and Sen. John Horhn.

Capitol Police monitor the Capitol Complex in Jackson.

Mississippi Fairness Act

Mississippi gained national attention with the passage of SB 2536, entitled the Fairness Act. The legislation, offered by Sen. Angela Hill, would prevent biologically male individuals from competing in female sports. This law will apply to K-12 schools as well as institutions of higher learning.

When defending her bill to those who claimed it was non-inclusive to transgendered athletes, Hill said those who were born physically a male have an advantage over female athletes simply due to genetics.

RELATED: Mississippi Governor signs Fairness Act into law barring biological men participating in women, girls sports

The bill was up in the air until the last minutes of the session when it was passed. Sen. Hill said the legislation was necessary in order to protect girls sports in the state under the current federal position toward transgendered persons competing among athletes that do not share their at-birth genetic makeup.

Name, Image, Likeness

Another bill that could impact Mississippi athletes is SB 2313. This bill will allow Mississippi collegiate athletes to receive compensation if their image, name or likeness is used in advertising.

RELATED: Reeves signs bill to allow college athletes compensation when their name, image or likeness is used

Mississippi lawmakers believe passing this legislation will keep Mississippi schools competitive in the event the U.S. Supreme Court rules in current court cases to allow for the compensation.

Weight Limits

Senator Jennifer Branning presented SB 2825, the Mississippi Infrastructure Act of 2021 which tackled several road, bridge and transportation issues the state faces.

Probably the most considerable change was that of the harvest weight limits being raised from 84,000 pounds to 88,000 pounds. The bill goes into effect July 1, 2021, but the harvest permit increase does not take effect until July 1, 2023. These weight limits would only apply to commercial truckers carrying a harvest permit.

The bill was argued by many in the Senate as it moved through the process.

While this story only highlights some of the more impactful bills going into effect on July 1, you can access information on all bills passed from the 2021 session, and when they will take effect you can visit the Mississippi Legislatures website HERE.

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Lawmakers will officially head back to the Capitol in January for the 2022 session.

Read more:
New laws hit the books in Mississippi on Thursday - Yall Politics

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This article is branded content for Seifert Belmont Reds

Profit-making genetics are readily apparent in the 90 bulls and 10 PTIC heifers' that husband and wife team Ian Stark and Jeanne Seifert, have selected for their third annual Seifert Belmont Reds Sale.

Seifert Belmont Reds is the largest breeder of purebred registered Breedplan recorded Belmont Reds in Australia. Their aggregation of five properties totals approximately 10,000ha and is a mix of ticky and clean country from marginal iron bark breeder country to brigalow backgrounding country.

Mrs Seifert is particularly proud of their females who continue to naturally rebreed, even on the back of two of the driest years on record.

"Our genetics are produced from a tough, unpampered cow herd where females are managed under a single sire mating program, using Belmont Red bulls at 1 per cent - 2 per cent, for a nine or a twelve-week joining period.

"Our cattle are never ever treated for tick or fly, are rarely handled, and every female must wean a calf every year, off native pasture, without any special care," she said.

"Under this regime and dry years, our wet cows and heifers returned from 93.2 per cent to 98.5 per cent pregnancy rates this year."

Early puberty bulls are also used from 14 months old to produce higher fertility daughters and sons. These stringent 'survival of the fittest' breeding principles, ensure that the young bulls catalogued for the 2021 sale will provide valuable heritable traits including phenomenal fertility, excellent growth and carcase attributes, genuine docility, and the highest levels of environmental adaptation.

Of the 90 bulls, 44 are Homozygous Polls (PP) and offer phenomenal fertility, truetropical adaptation and parasite resistance, with muscling and marbling.

"To top it off , 44 bulls of the 90 bulls are homozygous (PP) polls, and an impressive 73 per cent of them are at or above the 50th percentile for the Breedplan export $index."

Mr Stark said their emphasis on real fitness for purpose, and their ability to reliably meet volume demand, plus JBAS 7 status, ensures Seifert Belmont Reds can sell Australia-wide including into the Northern Territory and Western Australia.

"The reputation for our bulls to deliver consistent lines of calves, stems from many decades of breeding, where our pedigrees can be traced back to the original CSIRO Africander cross breeding trials of 1954," Mr Stark said.

"I'm especially pleased with the progress our herd has made with respect to type, muscling, and eye muscle area.

"IVF (invitro fertilization), ET (embryo transfer), AI (artificial insemination) and cloning are used to create optimum genetic combinations and accelerate genetic progress."

The demand for tropically adapted Bos Taurus Seifert Belmont Red genetics is emphasised by their exportation to Papua New Guinea, New Caledonia, the Philippines, and South America.

In 2020 the stud also established a satellite purebred Belmont Red herd with partners in Paraguay.

"Our focus on personal and professional integrity, combined with trustworthy data, provides peace of mind to our buyers," he said.

"We have every confidence in this draft, and we're sure they will make a valuable contribution to your herd and your profitability."

The demand for tropically adapted Bos Taurus Seifert Belmont Red genetics is emphasised by their exportation to Papua New Guinea, New Caledonia, the Philippines, and South America.

The catalogue is available now on http://www.seifertbelmontreds.com with hardcopies mailed on request. Inspections are welcome at any time, on any day - call, text or email Ian 0439 632 113 or Jeanne 0427 632 113, jeanne@seifertbelmontreds.com.

Click here for sale catalogue.

Videos will be on the website and AuctionsPlus two weeks before the sale. The sale will be on AuctionsPlus and by Helmsman auction, from 12 noon Monday, August 2, on property at 'Wonga' Jandowae. Attendees are welcome from 7am with complimentary morning tea and lunch.

Free delivery to Charters Towers, Rockhampton, Roma and Dalby saleyards will be available. Outside agents welcome, contact Elders Michael Smith 0428 541 711 or Anthony Ball 0428 275 499.

This article is branded content for Seifert Belmont Reds

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PATHWAY to Northern PROFITABILITY with Seifert Belmont Reds - Queensland Country Life

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Imagine being able to reverse blindness, cure multiple sclerosis (MS), or rebuild your heart muscles after a heart attack. For the past few decades, research into stem cells, the building blocks of tissues and organs, has raised the prospect of medical advances of this kind yet it has produced relatively few approved treatments. But that could be about to change, says Robin Ali, professor of human molecular genetics of Kings College London. Just as gene therapy went from being a fantasy with little practical value to becoming a major area of treatment, stem cells are within a few years of reaching the medical mainstream. Whats more, developments in synthetic biology, the process of engineering and re-engineering cells, could make stem cells even more effective.

Stem cells are essentially the bodys raw material: basic cells from which all other cells with particular functions are generated. They are found in various organs and tissues, including the brain, blood, bone marrow and skin. The primary promise of adult stem cells lies in regenerative medicine, says Professor Ali.

Stem cells go through several rounds of division in order to produce specialist cells; a blood stem cell can be used to produce blood cells and skin stem cells can be used to produce skin cells. So in theory you can take adult stem cells from one person and transplant them into another person in order to promote the growth of new cells and tissue.

In practice, however, things have proved more complicated, since the number of stem cells in a persons body is relatively limited and they are hard to access. Scientists were also previously restricted by the fact that adult stem cells could only produce one specific type of cell (so blood stem cells couldnt produce skin cells, for instance).

In their quest for a universal stem cell, some scientists initially focused on stem cells from human embryos, but that remains a controversial method, not only because harvesting stem cells involves destroying the embryo, but also because there is a much higher risk of rejection of embryonic stem cells by the recipients immune system.

The good news is that in 2006 Japanese scientist Shinya Yamanaka of Kyoto University and his team discovered a technique for creating what they call induced pluripotent stem cells (iPSC). The research, for which they won a Nobel Prize in 2012, showed that you can rewind adult stem cells development process so that they became embryo-like stem cells. These cells can then be repurposed into any type of stem cells. So you could turn skin stem cells into iPSCs, which could in turn be turned into blood stem cells.

This major breakthrough has two main benefits. Firstly, because iPSCs are derived from adults, they dont come with the ethical problems associated with embryonic stem cells. Whats more, the risk of the body rejecting the cells is much lower as they come from another adult or are produced by the patient. In recent years scientists have refined this technique to the extent that we now have a recipe for making all types of cells, as well as a growing ability to multiply the number of stem cells, says Professor Ali.

Having the blueprint for manufacturing stem cells isnt quite enough on its own and several barriers remain, admits Professor Ali. For example, we still need to be able to manufacture large numbers of stem cells at a reasonable cost. Ensuring that the stem cells, once they are in the recipient, carry out their function of making new cells and tissue remains a work in progress. Finally, regulators are currently taking a hard line towards the technology, insisting on exhaustive testing and slowing research down.

The good news, Professor Ali believes, is that all these problems are not insurmountable as scientists get better at re-engineering adult cells (a process known as synthetic biology). The costs of manufacturing large numbers of stem cells are falling and this can only speed up as more companies invest in the area. There are also a finite number of different human antigens (the parts of the immune system that lead a body to reject a cell), so it should be possible to produce a bank of iPSC cells for the most popular antigen types.

While the attitude of regulators is harder to predict, Professor Ali is confident that it needs only one major breakthrough for the entire sector to secure a large amount of research from the top drug and biotech firms. Indeed, he believes that effective applications are likely in the next few years in areas where there are already established transplant procedures, such as blood transfusion, cartilage and corneas. The breakthrough may come in ophthalmology (the treatment of eye disorders) as you only need to stimulate the development of a relatively small number of cells to restore someones eyesight.

In addition to helping the body repair its own tissues and organs by creating new cells, adult stem cells can also indirectly aid regeneration by delivering other molecules and proteins to parts of the body where they are needed, says Ralph Kern, president and chief medical officer of biotechnology company BrainStorm Cell Therapeutics.

For example, BrainStorm has developed NurOwn, a cellular technology using peoples own cells to deliver neurotrophic factors (NTFs), proteins that can promote the repair of tissue in the nervous system. NurOwn works by modifying so-called Mesenchymal stem cells (MSCs) from a persons bone marrow. The re-transplanted mesenchymal stem cells can then deliver higher quantities of NTFs and other repair molecules.

At present BrainStorm is using its stem-cell therapy to focus on diseases of the brain and nervous system, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrigs disease), MS and Huntingtons disease. The data from a recent final-stage trial suggests that the treatment may be able to halt the progression of ALS in those who have the early stage of the disease. Phase-two trial (the second of three stages of clinical trials) of the technique in MS patients also showed that those who underwent the treatment experienced an improvement in the functioning of their body.

Kern notes that MSCs are a particularly promising area of research. They are considered relatively safe, with few side effects, and can be frozen, which improves efficiency and drastically cuts down the amount of bone marrow that needs to be extracted from each patient.

Because the manufacture of MSC cells has become so efficient, NurOwn can be used to get years of therapy in one blood draw. Whats more, the cells can be reintroduced into patients bodies via a simple lumbar puncture into the spine, which can be done as an outpatient procedure, with no need for an overnight stay in hospital.

Kern emphasises that the rapid progress in our ability to modify cells is opening up new opportunities for using stem cells as a molecular delivery platform. Through taking advantage of the latest advances in the science of cellular therapies, BrainStorm is developing a technique to vary the molecules that its stem cells deliver so they can be more closely targeted to the particular condition being treated. BrainStorm is also trying to use smaller fragments of the modified cells, known as exosomes, in the hope that these can be more easily delivered and absorbed by the body and further improve its ability to avoid immune-system reactions to unrelated donors. One of BrainStorms most interesting projects is to use exosomes to repair the long-term lung damage from Covid-19, a particular problem for those with long Covid-19. Early preclinical trials show that modified exosomes delivered into the lungs of animals led to remarkable improvements in their condition. This included increasing the lungs oxygen capacity, reducing inflammation, and decreasing clotting.

Overall, while Kern admits that you cant say that stem cells are a cure for every condition, there is a lot of evidence that in many specific cases they have the potential to be the best option, with fewer side effects. With Americas Food and Drug Administration recently deciding to approve Biogens Alzheimers drug, Kern thinks that they have become much more open to approving products in diseases that are currently considered untreatable. As a result, he thinks that a significant number of adult stem-cell treatments will be approved within the next five to ten years.

Adult stem cells and synthetic biology arent just useful in treatments, says Dr Mark Kotter, CEO and founder of Bit Bio, a company spun out of Cambridge University. They are also set to revolutionise drug discovery. At present, companies start out by testing large numbers of different drug combinations in animals, before finding one that seems to be most effective. They then start a process of clinical trials with humans to test whether the drug is safe, followed by an analysis to see whether it has any effects.

Not only is this process extremely lengthy, but it is also inefficient, because human and animal biology, while similar in many respects, can differ greatly for many conditions. Many drugs that seem promising in animals end up being rejected when they are used on humans. This leads to a high failure rate. Indeed, when you take the failures into account, it has been estimated that it may cost as much to around $2bn to develop the typical drug.

As a result, pharma companies are now realising that you have to insert the human element at a pre-clinical stage by at least using human tissues, says Kotter. The problem is that until recently such tissues were scarce, since they were only available from biopsies or surgery. However, by using synthetic biology to transform adult stem cells from the skin or other parts of the body into other types of stem cells, researchers can potentially grow their own cells, or even whole tissues, in the laboratory, allowing them to integrate the human element at a much earlier stage.

Kotter has direct experience of this himself. He originally spent several decades studying the brain. However, because he had to rely on animal tissue for much of his research he became frustrated that he was turning into a rat doctor.

And when it came to the brain, the differences between human and rat biology were particularly stark. In fact, some human conditions, such as Alzheimers, dont even naturally appear in rodents, so researchers typically use mice and rats engineered to develop something that looks like Alzheimers. But even this isnt a completely accurate representation of what happens in humans.

As a result of his frustration, Kotter sought a way to create human tissues. It initially took six months. However, his company, Bit Bio, managed to cut costs and greatly accelerate the process. The companys technology now allows it to grow tissues in the laboratory in a matter of days, on an industrial scale. Whats more, the tissues can also be designed not just for particular conditions, such as dementia and Huntingdons disease, but also for particular sub-types of diseases.

Kotter and Bit Bio are currently working with Charles River Laboratories, a global company that has been involved in around 80% of drugs approved by the US Food and Drug Administration over the last three years, to commercialise this product. They have already attracted interest from some of the ten largest drug companies in the world, who believe that it will not only reduce the chances of failure, but also speed up development. Early estimates suggest that the process could double the chance of a successful trial, effectively cutting the cost of each approved drug by around 50% from $2bn to just $1bn. This in turn could increase the number of successful drugs on the market.

Two years ago my colleague Dr Mike Tubbs tipped Fate Therapeutics (Nasdaq: FATE). Since then, the share price has soared by 280%, thanks to growing interest from other drug companies (such as Janssen Biotech and ONO Pharmaceutical) in its cancer treatments involving genetically modified iPSCs.

Fate has no fewer than seven iPSC-derived treatments undergoing trials, with several more in the pre-clinical stage. While it is still losing money, it has over $790m cash on hand, which should be more than enough to support it while it develops its drugs.

As mentioned in the main story, the American-Israeli biotechnology company BrainStorm Cell Therapeutics (Nasdaq: BCLI) is developing treatments that aim to use stem cells as a delivery mechanism for proteins. While the phase-three trial (the final stage of clinical trials) of its proprietary NurOwn system for treatment of Amyotrophic lateral sclerosis (ALS, or Lou Gehrigs disease) did not fully succeed, promising results for those in the early stages of the disease mean that the company is thinking about running a new trial aimed at those patients. It also has an ongoing phase-two trial for those with MS, a phase-one trial in Alzheimers patients, as well as various preclinical programmes aimed at Parkinsons, Huntingtons, autistic spectrum disorder and peripheral nerve injury. Like Fate Therapeutics, BrainStorm is currently unprofitable.

Australian biotechnology company Mesoblast (Nasdaq: MESO) takes mesenchymal stem cells from the patient and modifies them so that they can absorb proteins that promote tissue repair and regeneration. At present Mesoblast is working with larger drug and biotech companies, including Novartis, to develop this technique for conditions ranging from heart disease to Covid-19. Several of these projects are close to being completed.

While the US Food and Drug Administration (FDA) controversially rejected Mesoblasts treatment remestemcel-L for use in children who have suffered from reactions to bone-marrow transplants against the advice of the Food and Drug Administrations own advisory committee the firm is confident that the FDA will eventually change its mind.

One stem-cell company that has already reached profitability is Vericel (Nasdaq: VCEL). Vericels flagship MACI products use adult stem cells taken from the patient to grow replacement cartilage, which can then be re-transplanted into the patient, speeding up their recovery from knee injuries. It has also developed a skin replacement based on skin stem cells.

While earnings remain relatively small, Vericel expects profitability to soar fivefold over the next year alone as the company starts to benefit from economies of scale and runs further trials to expand the range of patients who can benefit.

British micro-cap biotech ReNeuron (Aim: RENE) is developing adult stem-cell treatments for several conditions. It is currently carrying out clinical trials for patients with retinal degeneration and those recovering from the effects of having a stroke. ReNeuron has also developed its own induced pluripotent stem cell (iPSC) platform for research purposes and is seeking collaborations with other drug and biotech companies.

Like other small biotech firms in this area, it is not making any money, so it is an extremely risky investment although the rewards could be huge if any of its treatments show positive results from their clinical trials.

Read more from the original source:
Investing in stem cells, the building blocks of the body - MoneyWeek

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Corning HYPERStack 36-layer and 12-layer cell culture vessels

Mesenchymal stem cells (MSCs) are used frequently for cell therapy applications. As multipotent cells, they can differentiate into other lineages such as adipocytes, osteocytes, and chondrocytes. Additionally, they are known to secrete trophic factors that can play important roles in immunoregulation. Although MSCs can be isolated from several different tissue sources, those derived from bone marrow commonly are studied because they are easy to access in quantities large enough for therapeutic dosing (2 106 cells/kg of body weight). Still, that equates to 140 million cells for a 150-pound individual. And the process of expanding MSCs to achieve such quantities can introduce risks for heterogeneity-induced quality failures. Chances of clinical success can improve with a manufacturing process that maintains a homogeneous MSC population after expansion to meet required critical quality attributes (CQAs).

Once cells are scaled up, they need to be cryopreserved for stability and transport. Cryoprotectants such as dimethyl sulfoxide (DMSO) often are added to freezing media to reduce ice formation and increase cell survival after thawing. However, because DMSO can be cytotoxic, its final concentration in a drug product must be minimized. Tools from Corning Life Sciences can help scientists and drug developers meet growing demand for bone-marrowderived MSC therapies.

Figure 1:Expansion of human mesenchymal stem cells (MSCs) in a Corning HYPERStack-36 vessel; MSC densities ranging from 4.4 104 to 5.2 104 cells/cm2 were achieved after five days of culture. Across three studies, total MSC yield averaged 8.7 108 cells per HYPERStack-36 vessel, with >90% average MSC viability.

Mesenchymal Cell Scale-UpMSCs are adherent cells that are sensitive to manufacturing process changes. That sensitivity can complicate scale-up to large quantities. When cultured under suboptimal conditions, MSCs can lose their multipotency. Corning HYPERStack 36-layer cell culture vessels offer a solution. A HYPERStack unit uses proprietary technology to provide a large surface area in a compact footprint. That technology relies on an ultrathin, gas-permeable film to facilitate gas exchange in each layer of the vessel. Each HYPERStack module comprises 12 individual chambers featuring Corning CellBIND surface treatment for optimal cell attachment. One module provides 6,000 cm2 of surface area; three modules can connect to form a HYPERStack 36-layer vessel, totaling 18,000 cm2 of growth surface area.

When human bone-marrowderived MSCs are cultured in a HYPERStack 36-layer vessel, yields of >800 million viable cells can be achieved (Figure 1). Harvested cells show high viability and expression of markers demonstrating MSC multipotency (Figure 2). Such results show that large-scale expansion of MSCs in a HYPERStack vessel generates a homogeneous population of cells that maintain necessary CQAs.

Figure 2: Mesenchymal stem cells (MSCs) recovered from a Corning HYPERStack 36-layer cell culture vessels show >99% expression of CD90, CD105, and CD73 markers while expressing <0.5% of differentiation markers (CD45, CD34, CD11b, CD19, and HLA-DR).

Corning cryopreservation bags remain flexible at ultralow temperatures(e.g., 196 C).

Large-Scale CryopreservationCryopreservation of large quantities of cells has become an important strategy for simplifying cell therapy workflows because it increases product shelf life, allows time for quality testing, and lengthens the period of potential administration. Cryopreservation bags are designed for single-use storage, preservation, and transfer of large volumes of cells. Cornings cryopreservation bags are novel bag-film containers that can remain flexible at ultralow temperatures (196 C) because they are made from a proprietary polyolefinethyl vinyl acetate blend. Corning produces the bags in four sizes covering fill volumes between 20 mL and 190 mL, with demonstrated performance for storage of bone-marrowderived MSCs.

The Corning X-WASH system performs DMSO removal in a closed, sterile format.

DMSO RemovalDMSO can serve as a cryoprotectant for a wide range of cell types. It often accounts for 510% of a freezing solution to reduce ice formation and maintain cell viability. But because of its cytotoxic effects, DMSO must be removed as much as possible from a final cell therapy product. That can be accomplished by centrifugation and buffer exchange.

The Corning X-WASH system can perform those steps in sterile, closed conditions (Figure 3). The X-WASH system also uses highly sensitive infrared sensors and software to transfer process data from the X-WASH control module to a database. That feature supports good manufacturing practice (GMP) data processing, monitoring, and reporting. Ultimately, the X-WASH system is designed to wash, resuspend, and condense cell suspensions without compromising product quality.

Corning has used the X-WASH system to reduce the DMSO concentration from a bone-marrowderived MSC product. About 70 million human MSCs were processed into Corning cryopreservation bags containing 10 mL of a 90% fetal bovine serum (FBS) and 10% DMSO solution. MSCs were thawed into 200 mL of phosphate-buffered saline containing 2% human serum albumin and 5% glucose. Cells were added to X-WASH cartridges for processing, then analyzed for recovery (Figure 4), viability (Figure 5), and multipotency (Figure 6). Ultraperformance liquid chromatography (UPLC) was used to quantify DMSO reduction. UPLC analysis showed that 200-mL dilution followed by a 200-mL wash in an X-WASH system reduced the final DMSO concentration by at least40 fold.

Figure 3:Corning X-WASH system workflow to remove dimethyl sulfoxide (DMSO)

Figure 4:Recovery of human mesenchymal stem cells (MSCs) after washing with a Corning X-WASH system; the bars below represent MSC density, and cell viability levels are represented as dots.

Considerations for Closed Systems and Custom MediaClosed-system cell-culture products help reduce contamination risks during drug development and manufacturing. Thus, they should be considered when planning for cell-culture operations. Ordering multiple components and assembling tubing sets in house can add complexity and time to cell therapy processes. To aid in the development of such processes, Corning offers preassembled closed systems and aseptic-transfer caps that are compatible with many Corning cell culture vessels.

Figure 5:Human MSC multipotency as represented by average marker expression after processing with a Corning X-WASH system (with standard deviation, n = 3)

Corning closed-system solutions arrive at your facility sterile and ready to use. They mitigate contamination risks, reduce the time and expense of sourcing and assembly, and improve overall productivity. Moreover, Cornings extensive library of fully validated filters, connectors, tubing, and clamps enables customized design of a closed-system solution for a specific application.

In cell-based therapies, cultured cells are the final product, requiring different manufacturing processes from those used for conventional biologics production. Major considerations in cell therapy scale-up include culture vessels and media as well as cells themselves. Inadequate attention to culture equipment and raw materials not only can diminish a therapys efficacy, but also can result in regulatory challenges that might delay a candidates progress through development. Because culture media are linked to cell growth and productivity, they rank among the most critical aspects of process development during scale-up.

Figure 6:Dimethyl sulfoxide (DMSO) concentration in final product after 200-mL dilution followed by 200-mL wash in a Corning X-WASH system (data from three independent runs)

Although off-the-shelf media can provide fast and efficient solutions during early stages, they can have trouble meeting specific scale-up conditions later on. Moving from small-scale, small-volume, static cultures into large-scale, large-volume vessels can trigger a host of additional requirements that cannot be addressed easily using an off-the-shelf solution. Customization by a media manufacturer is an attractive solution to concerns associated with large production scales, including media stability, packaging, handling, and storage. Custom media solutions also help to derisk processing. Cornings high-quality custom development and manufacturing services can produce tailored media and reagents to meet cell therapy production needs.

Simplifying Cell Therapy WorkflowsAddressing the growing demand for cell-based therapies requires optimization of scale-up, cryopreservation, and DMSO removal. With some human MSC therapies requiring as many as one billion cells per dose, cell therapy companies need efficient ways to scale up production of homogeneous MSCs that meet CQAs. Additionally, large quantities of MSCs will need to be cryopreserved to simplify cell therapy workflows. Before product administration, DMSO and other reagents used during the manufacturing process will need to be reduced. Corning offers solutions to simplify the complete range of cell therapy workflows.

Hilary Sherman is senior scientist, and Chris Suarez is field applications manager at Corning Life Sciences, 836 North Street, Tewksbury, MA 01876; ScientificSupport@Corning.com; 1-800-492-1110.

CellBIND, HYPERStack, and X-WASH all are registered trademarks of Corning Incorporated.

Read more:
Cell Therapy Workflows Using Corning HYPERStack: MSC Production - BioProcess Insider

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The research report presents a comprehensive assessment of the Bone Marrow-Derived Stem Cells (BMSCS) Market and contains thoughtful insights, facts, historical data, and statistically supported and industry-validated market data. Bone Marrow-Derived Stem Cells (BMSCS) with 100+ market data Tables, Pie Chat, Graphs & Figures spread through Pages and easy to understand detailed analysis. Bone Marrow-Derived Stem Cells (BMSCS) market future, competitive analysis by Bone Marrow-Derived Stem Cells (BMSCS) Market Players, Deployment Models, Opportunities, Future Roadmap, Value Chain, Major Player Profiles.

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Bone Marrow-Derived Stem Cells (BMSCS) Market Global Briefing and Future Outlook 2020 to 2027 The Courier - The Courier

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The Global Rheumatoid Arthritis Stem Cell Therapy Market Research Report 2020-2026, offers an in-depth evaluation of each crucial aspect of the Global Rheumatoid Arthritis Stem Cell Therapy industry that relates to market size, share, revenue, demand, sales volume, and development in the market. The report analyzes the Rheumatoid Arthritis Stem Cell Therapy market related to the time period, historical pricing structure, and volume trends that make it easy to predict growth momentum and precisely estimate forthcoming opportunities in the Rheumatoid Arthritis Stem Cell Therapy Market. The report explores the current outlook in global and key regions (North America, Europe, Asia-Pacific, and Latin America) from the perspective of players, countries (U.S., Canada, Germany, France, U.K., Italy, Russia, China, Japan, South Korea, Taiwan, Southeast Asia, Mexico, and Brazil, etc.), product types, and end use segments. This report provides the COVID-19 (Corona Virus) impact analysis (historic and present) in major regions and countries, also provides a futuristic analysis considering COVID-19.

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Rheumatoid Arthritis Stem Cell Therapy Market Size, Status and Precise Outlook During 2020 to 2026 The Manomet Current - The Manomet Current

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Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Patients with blood cancers are particularly vulnerable to COVID-19, and there has been concern that such patients mount poor responses to COVID vaccination.

Perhaps surprising, then, is a new study showing good responses in a subgroup of these patients who underwent intensive treatment with allogeneic hematopoietic stem cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy

These patients had relatively good responses to COVID-19 vaccination with the mRNA vaccine, with overall cellular and humoral responses that were near to or over 80%.

"I was actually surprised by the fact patients who underwent allogeneic HCT and are currently treated with immunosuppression medications had a such high response to the vaccine," first author Ron Ram, MD, director of the Bone Marrow Transplantation Unit, Division of Hematology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel, told Medscape Medical News.

"In other seasonal vaccines, we usually see much lower responses," he noted. "The problem is that we are not sure how long this response lasts, and this should be further investigated."

The results show that among immunocompromised patients, "the vaccine is safe and efficacious," he concluded.

However, "5% of patients developed transient severe low counts and graft-vs-host disease [GVHD] exacerbation. Therefore, close monitoring of these patients is mandatory.

"COVID-19 is a very dangerous infection to our allogeneic and CAR-T patients, and all patients should be vaccinated as soon as possible," he added.

The study was presented at the European Hematology Association (EHA) 2021 Annual Meeting. It involved 79 eligible patients who received hematopoietic cell transplant (n = 66) and CAR T-cell therapy (n = 14) at the Tel Aviv Sourasky Medical Center.

The patients in the study were being treated for acute myeloid leukemia (46%), myelodysplastic syndromes (9%), acute lymphocytic leukemia (10%), diffuse large B-cell lymphoma (15%); and others.

All patients were vaccinated with the Pfizer/BioNTech BNT162b2 COVID-19 vaccine, which yielded a protection rate of 94.6% in a phase 3 study in healthy patients and is recommended for immunosuppressed patients.

The median age of the patients was 65 years, and the median time from infusion of cells to vaccination was 32 months in the allogeneic HCT group and 9 months in the CAR T-cell therapy group.

Of the allogeneic HCT patients, 62% had active chronic GVHD, and 58% were receiving immune suppressive therapy, mostly calcineurin inhibitors.

In addition, 11% of the patients overall had complete B-cell aplasia.

An evaluation of humoral immune responses to the vaccines at 7 to 14 days after the second vaccine dose, as determined on the basis of serology, showed that 82% of those in the allogeneic HCT group developed immunogenicity. However, the humoral response rate was only 36% in the CAR T-cell group.

When including the results cellular responses, assessed with the ELISpot assay, the tables were nearly turned, with the antibody titer response rate of 46% in the allogeneic HCT group and 79% in the CAR T-cell group.

Combined, the overall antibody responses were 86% of allogeneic HCT patients and 79% of CAR T-cell patients, Ram reported.

A multivariate analysis showed that factors associated with a positive humoral response included increased amount of time from the infusion of cells (P = .032), female sex (P = .028), and a higher number of CD19-positive cells (P = .047).

Age, active GVHD, and the intensity of concomitant immunosuppressive therapy were not predictive of results.

Ram noted that higher numbers of CD19-positive cells and CD4 cells were predictive of positive ELISpot cellular response (P = 0.49 and P = .041, respectively).

Two patients developed SARS-CoV-2 infection after receiving the first dose of the vaccine, although they did not require hospitalization. After fully recovering, both patients received a second dose.

The vaccine was well tolerated among patients in general. Side effects were similar to those observed in the nontransplant population.

Of the patients overall, 5% experienced GVHD exacerbation after each vaccine dose.

A low blood count was observed in about 10% of patients; in 5%, the cytopenia was severe.

Adverse events that were of grade 3 or higher occurred in 4.6% and 7% of the two groups, respectively. Although the adverse events resolved quickly in most cases, one secondary graft rejection occurred; that case is being investigated.

The European Society for Blood and Marrow Transplantation (EBMT) recommends vaccination starting at least 3 months after allogeneic HCT, and Ram said the recommendation "makes sense."

"We did see a nice response in the allogeneic HCT patients 3 months after the transplant," he said.

Exceptions were patients receiving anti-CD19 therapy in the CAR T-cell group and those with B-cell aplasia. "Those patients did not respond well to the vaccine, so this is something to take into consideration," Ram said.

"We certainly need more data about durability of the vaccine and methods in patients who do not have sufficient response to the vaccine."

The EBMT's recommendation on the timing of vaccination is endorsed by the National Comprehensive Cancer Network, which recommends that COVID-19 vaccination be delayed for at least 3 months for patients with allogeneic HCT or those undergoing CAR-T therapy.

In commenting on the study during a press conference, Elizabeth Macintyre, MD, said the new findings were encouraging.

"It's very precious to see consensus recommendations regarding who should be vaccinated and when, and the end result seems to be that it's better to be vaccinated than not," she said.

In a separate talk at the meeting, Evangelos Terpos, MD, PhD, reported finding lower response rates to COVID-19 vaccination among older patients with hematologic malignancies in general, consistent with findings from other studies.

Reporting on responses up to day 50 post vaccination among 48 patients with multiple myeloma (median age, 83 years), 40% of patients did not achieve antibody titers above the level of 30% considered to represent positivity.

Among the 49% who did achieve antibody responses above levels of 50%, representing clinically relevant inhibition, the treatment factors that were associated with the higher response included treatment with lenalidomide. Treatment with daratumumab or anti-BCMA conjugates was associated with very low antibody responses.

He noted other research of 58 older patients with Waldenstrom macroglobulinemia or other low-grade lymphomas showed similarly low responses, particularly among those receiving anti-CD20 treatment, compared with healthy individuals.

"We found that patients with hematological malignancies or solid tumors have lower responses [to the COVID-19 mRNA vaccine], especially those under immunotherapy or targeted therapies, including anti-CD20, anti-CD38, anti-BCMA, Bruton kinase inhibitors, PDL-1 or PD-1 inhibitors," said Terpos, a professor of hematology at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece.

Ram has disclosed no relevant financial relationships. Terpos has relationships with Janssen, Genesis/Celgene, Amgen, Novartis, Sanofi, and Takeda.

European Hematology Association (EHA) 2021 Annual Meeting: Abstract S285. Presented June 11, 2021.

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Good Response to COVID-19 Vaccine After HSCT and CAR T-cell Tx Medscape - Medscape

Recommendation and review posted by Bethany Smith

Data Bridge Market Research has recently added a concise research on theGlobal Stem Cell Manufacturing Market to depict valuable insights related to significant market trends driving the industry. The report features analysis based on key opportunities and challenges confronted by market leaders while highlighting their competitive setting and corporate strategies for the estimated timeline. The development plans, market risks, opportunities and development threats are explained in detail. The CAGR value, technological development, new product launches and Industry competitive structure is elaborated. As per study key players of this market are Thermo Fisher Scientific. Merck Group, Becton, Dickinson and Company. Holostem Advanced Therapies, JCR Pharmaceuticals, Organogenesis Inc and more.

The Global Stem Cell manufacturing Market is expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to account to USD 18.59 billion by 2027 growing at a CAGR of 6.42% in the above-mentioned forecast period. The growing awareness towards diseases like cancer, hematopoietic disorders and degenerative disorders is going to drive the growth of the stem cell manufacturing market.

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Global Stem Cell Manufacturing Market, By Product (Stem Cell Line, Instruments, Culture Media, Consumables), Application (Research Applications, Clinical Applications, Cell and Tissue Banking), End Users (Hospitals and Surgical Centers, Pharmaceutical and Biotechnology Companies, Clinics, Community Healthcare, Others), Country (U.S., Canada, Mexico, Germany, Italy, U.K., France, Spain, Netherland, Belgium, Switzerland, Turkey, Russia, Rest of Europe, Japan, China, India, South Korea, Australia, Singapore, Malaysia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific, Brazil, Argentina, Rest of South America, South Africa, Saudi Arabia, UAE, Egypt, Israel, Rest of Middle East & Africa) Industry Trends and Forecast to 2027

Healthcare Infrastructure growth Installed base and New Technology Penetration

Stem cell manufacturing market also provides you with detailed market analysis for every country growth in healthcare expenditure for capital equipment, installed base of different kind of products for stem cell manufacturing market, impact of technology using life line curves and changes in healthcare regulatory scenarios and their impact on the stem cell manufacturing market. The data is available for historic period 2010 to 2018.

The Global Stem Cell Manufacturing Market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of stem cell manufacturing market for global, Europe, North America, Asia Pacific and South America.

Global Stem Cell Manufacturing Market Scope and Market Size

Stem cell manufacturing market is segmented on the basis of product, application and end users. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

Major Market competitors/players:Global Stem Cell manufacturing Market

Some of the major players operating in the stem cell manufacturing market are Thermo Fisher Scientific. Merck Group, Becton, Dickinson and Company. Holostem Advanced Therapies, JCR Pharmaceuticals, Organogenesis Inc, Osiris Therapeutics, Osiris Therapeutics, Vericel Corporation, AbbVie, American CryoStem, AM-Pharma, Anterogen.Co.,Ltd, Astellas Pharma, Bristol-Myers Squibb, Apceth Biopharma, Cellular Dynamics International, Rheacell, Takeda Pharmaceutical, Teva Pharmaceutical Industries Ltd. ViaCyte, VistaGen Therapeutics Inc, Translational Biosciences, GlaxoSmithKline plc, Daiichi Sankyo Company, Limited, among others.

Market Definition:

This market report defines the market trends and forecast the upcoming opportunities and threats of the stem cell manufacturing market in the next 8 years. Stem cell manufacturing is a process of extracting the cells either from bone marrow or peripheral blood cells and culturing the cells in the culture dish containing nutrient media. Stem cells can be isolated from umbilical cord blood, placenta, amniotic sac, amniotic fluid, adipose tissue and menstrual blood. Stem cell manufacturing is used in the cell therapy as well as in gene therapy. Stem cell therapy is under research for many diseases like degenerative diseases and hematopoietic disorders like sickle cell anemia, storage disorders. Now stem cells are also used in making the cell and tissue bank. Some of the cell culture banks are National Institute of Biomedical Innovation, Health and Nutrition and World Federation for Culture Collections.

Key Insights in the report:

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Data Bridge Market Research set forth itself as an unconventional and neoteric Market research and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best market opportunities and foster efficient information for your business to thrive in the market. Data Bridge endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process.

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Stem Cell manufacturing Market All-Inclusive Research Report (20212027) : Includes Impact of COVID-19 The Manomet Current - The Manomet Current

Recommendation and review posted by Bethany Smith

Dublin, June 18, 2021 (GLOBE NEWSWIRE) -- The "Global Cell Isolation Market By Product (Consumables and Instruments), By Cell Type (Human Cells and Animal Cells), By Source, By Technique, By Application, By End-User, By Region, Competition Forecast & Opportunities, 2026" report has been added to ResearchAndMarkets.com's offering.

The Global Cell Isolation Market was valued at USD7013.71 million in 2020 and is anticipated to reach USD15529.45 million by 2026 by registering a CAGR of 15.25% until 2026.

Cell isolation is a technique of isolating cells for diagnosis and analysis of a particular type of cell. The market growth can be attributed to the rising demand for drugs, vaccines and other related products, as they are manufactured with the assistance of cell isolation technique. Increasing popularity of precision medicines is also working in the favor of the market growth.

The Global Cell Isolation Market has been segmented into product, cell type, source, technique, application, end-user, company and region. Based on technique, the market is further fragmented into centrifugation-based cell isolation, surface-marker based cell isolation and filtration-based cell isolation, amongst which, centrifugation-based cell isolation segment occupied the largest market share in 2020 as it finds extensive applications in various end-user sectors such as academic institutes, research laboratories, etc.

Based on application, the market is further divided into biomolecule isolation, cancer research, stem cell research, in vitro diagnostics and others. Among these, cancer research and stem cell research are projected to be the lucrative segments of the market in the forecast period. Increase in the research activities by biopharma companies and laboratory is the key factor for the growth of the segments.

Based on regional analysis, Asia-Pacific is expected to grow at the highest CAGR during the forecast period. The high CAGR of the region can be attributed to the relaxation in the stringent rules and regulations laid down by the government for drug development. Another factor that can be held responsible for the fastest growth of the region is the availability of competent researchers and personnel who can carry out cell isolation techniques along with a wide genome pool.

The market players are focusing on research and development activities in order to enhance their product portfolios and strengthen their position across the global market. For instance, the major pharmaceutical companies worldwide are making substantial investments in R&D to introduce new drugs in the market.

Such investments are expected to increase the demand for cell isolation products over the coming years. In addition to this, new product developments help vendors to expand their product portfolio and gain maximum share in the sector. For example, Thermo Scientific's Medifuge is a benchtop centrifuge which is having a unique hybrid rotor as well as an interchangeable swing-out buckets and fixed-angle rotors to facilitate rapid & convenient applications on a single platform.

Moreover, collaborations, mergers & acquisitions and regional expansions are some of the other strategic initiatives taken by major companies for serving the unmet needs of their customers.

Major players operating in the Global Cell Isolation Market include

Years considered for this report:

Objective of the Study:

Key Target Audience:

Report Scope:

Global Cell Isolation Market, By Product:

Global Cell Isolation Market, By Cell Type:

Global Cell Isolation Market, By Source:

Global Cell Isolation Market, By Technique:

Global Cell Isolation Market, By Application:

Global Cell Isolation Market, By End-User:

Global Cell Isolation Market, By Region:

Competitive Landscape

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Global $15.52 Bn Cell Isolation (Human Cells and Animal Cells) - GlobeNewswire

Recommendation and review posted by Bethany Smith

DALLAS June 21, 2021 Jean D. Wilson, M.D., an internationally known endocrinologist whose scientific discoveries led to profound insights into the mechanisms underlying sexual differentiation and led to now widely used treatments for prostate disease, died June 13. He was 88.

Wilson, seen here in 1962, graduated from UTSouthwestern Medical School in 1955 and joined the faculty in 1960, where he began his studies of testosterone.

Wilson, professor emeritus of internal medicine at UTSouthwestern, was largely responsible for current understanding of the mechanisms by which steroid hormones induce male sexual differentiation. He also was instrumental in identifying the scientific underpinnings of a widely prescribed class of drugs known as 5-alpha-reductase inhibitors which include finasteride (Proscar, Propecia) and dutasteride (Avodart) to treat enlarged prostate and balding in men.

Wilsons discovery of 5-alpha-reductase and the identification of dihydrotestosterone as the primary hormone associated with the growth of the prostate transformed our understanding of prostate gland growth and paved the way for new effective treatment of prostate disease, says Daniel K. Podolsky, M.D., president of UTSouthwestern. His findings led to the first medical therapy for benign prostatic hyperplasia, and also provided the basis for understanding of the mechanism underlying the differentiation of male and female genital development. His legacy will be found in the legions of patients who have benefited from the therapy made possible by his discoveries.

Wilson, seen in 1978, was a popular and highly sought-after attending physician on the wards of Parkland Memorial Hospital, valued for his vast expertise in endocrinology and medicine in general.

Jean Wilson was one of the most critical and helpful sources of information concerning the development of two important drugs we were developing at Merck the statins, for control of LDL cholesterol, and Proscar, for treatment of benign prostate enlargement. Wilson was always available to wrestle with problems that often arise in drug development. I needed expert friends in those early days, and probably still do, says P. Roy Vagelos, M.D., former chairman, president, and chief executive officer of Merck & Co. and now chair of the board of Regeneron Pharmaceuticals.

Wilsons research included the study of cholesterol metabolism and steroid hormone action. The UTSouthwestern Medical School graduate and former National Institutes of Health (NIH) researcher earned international prominence for his investigations of testosterone including its formation from cholesterol as well as its metabolism and action. His efforts elucidated disorders resulting from genetic defects that lead to disruption in sex hormone biosynthesis with corresponding alteration in development.

Collaborations at UTSouthwestern with David Russell, Ph.D., professor of molecular genetics, led to the cloning of the 5-alpha-reductase (5AR) gene, development of animal models for 5AR deficiency, and eventually the finding that a 5AR inhibitor blocked prostate growth, which resulted in clinical trials led by Claus Roehrborn, M.D., chair of urology. The human androgen receptor later was cloned in 1989, allowing Wilson and colleagues to identify the receptor as a transcription factor that could regulate both the receptor and 5AR expression in prostate cancer. Other scientists at UTSouthwestern expanded upon his research, identifying androgen involvement in virtually all aspects of prostate development, alternate mechanisms of androgen synthesis, and other forms of androgens related to castrate-resistant prostate cancer.

Among his numerous awards, Wilson received the Kober Medal from the Association of American Physicians (1999); the Fred Conrad Koch Award from The Endocrine Society (1993); Gregory Pincus Award from the Worcester Foundation for Experimental Biology (1992); Henry Dale Medal from the Society for Endocrinology (1991); Amory Prize from the American Academy of Arts and Sciences (1977); and the Eugene Fuller Award from the American Urological Association. He was elected as a member of the American Academy of Arts and Sciences (1982), the National Academy of Sciences (1983), and the National Academy of Medicine (1994) as well as the American Philosophical Society and served as president of the Endocrine Society, the American Society for Clinical Investigation, and the Association of American Physicians.

Wilson, seen in 1992, was elected as a member of the American Academy of Arts and Sciences (1982), the National Academy of Sciences (1983), and the National Academy of Medicine (1994).

Wilson, who had held the Charles Cameron Sprague Distinguished Chair of Biomedical Research, was known as a collaborative colleague and empathetic adviser to students and fellows. His approach with students and trainees was threefold find out what they want to do, encourage them to do it, and develop pathways to fulfill their goals, he said in an interview with The Journal of Clinical Investigation. He also noted that some of the most difficult students to counsel turned out to be late bloomers who really were worth an investment of time and effort.

At UTSouthwestern, he served as the first director of the Medical Scientist Training Program, and it was recently announced that the Physician Scientist Training Program in Internal Medicine would be known as the Jean Wilson Society. The Jean D. Wilson Center for Biomedical Research and The Jean D. Wilson, M.D. Award, which honor excellence in scientific research mentorship, are named in his honor. The center was established with support from Dr. Wilson and his sister, the late Dr. Margaret Sitton, to promote research in endocrinology, developmental biology, and genetics, along with the J.D. and Maggie E. Wilson Distinguished Chair in Biomedical Research. In addition, he served among editors of two landmark medical textbooks Williams Textbook of Endocrinology and Harrisons Principles of Internal Medicine and as editor for The Journal of Clinical Investigation, among other journals. He authored The Memoir of a Fortunate Man, which chronicles his life growing up in the Texas Panhandle through his rise to pioneering academic physician and researcher.

Jean was a popular and highly sought-after attending physician on the wards of Parkland Memorial Hospital, valued for his vast expertise in endocrinology and medicine in general, say Nobel Laureates Joseph Goldstein, M.D, chair of molecular genetics, and Michael Brown, M.D., director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease. He founded a diabetic foot clinic at Parkland and spent hours each week clipping toenails and treating ulcers on the feet of elderly diabetic patients. After long days on the wards, he would retire to his modest laboratory where he would spend half the night meticulously dissecting rabbit fetuses. Often, when we were just starting our careers, we would sit by his side while he dissected, receiving sage advice about our careers as physician-scientists and life in general. Later, he extended his fatherly role to generations of M.D./Ph.D. students when he became the founding director of our M.D./Ph.D. program.

He had a rich life outside of the Medical Center as well. An avid opera buff, Wilson collected antique gramophones that could play every type of recording that had ever been produced. His extensive collection of 3,500 old 78-rpm operatic recordings included a 1917 disc of Enrico Caruso singing songs of Irving Berlin the only record that Caruso ever recorded in English, they note.

An avid opera buff, Wilson, seen in 2019, collected antique gramophones. His extensive collection of 3,500 old 78-rpm operatic recordings included a 1917 disc of Enrico Caruso singing songs of Irving Berlin the only record that Caruso ever recorded in English.

He took memorable trips to places like the North Pole, Antarctica, the Galapagos Islands, and the Easter Islands. He often incorporated science into his trips, visiting the Kangaroo Island in Australia to study sexual development in wallabies, and to Kenya to biopsy the phallus of the spotted hyena. Fearless in the pursuit of knowledge, he performed a rectal examination on a lion to estimate the size of the prostate, Goldstein and Brown say. A dedicated bird watcher, he traveled the world to many exotic places, hoping to spot that rare bird. But in the end, the rarest of that rare bird was Jean Wilson himself.

Born in Wellington, Texas, in 1932, Wilson obtained an undergraduate degree in chemistry from UT Austin and graduated from UTSouthwestern Medical School in 1955. As a student, he studied the control of urinary acid secretion by adrenal hormones, and as a resident, he investigated cholesterol metabolism. After residency, he spent two years at the NIH, where he studied ethanolamine biosynthesis. He joined the UTSouthwestern faculty in 1960 where he began his studies of testosterone, and worked in 1970 at Cambridge University. In all, he spent 60 years at UTSouthwestern and was named professor emeritus of UTSouthwesterns storied internal medicine department in 2011.

Jean Wilson leaves us with a remarkable legacy a quintessential physician-scientist whose scholarship both inspires and continues to serve as a foundation for new advances, says Podolsky, also professor of internal medicine.

In a career spanning six decades at UTSouthwestern, Dr. Jean Wilsons discoveries included:

Cholesterol metabolism

Dr. Wilson developed methods for quantifying cholesterol synthesis, absorption, degradation, and excretion in lab animals. Together, these analytical methods served as tools for understanding the feedback control of cholesterol synthesis and turnover. In addition, Dr. Wilson demonstrated that plasma cholesterol is synthesized in the intestinal wall and liver, findings that helped researchers define the contributions of diet and endogenous synthesis to cholesterol turnover in humans and other primates.

Male androgens

Concurrently, Dr. Wilson studied the action of male androgens, focusing on testosterone and its metabolite, dihydrotestosterone. Starting with a collaboration with his postdoctoral fellow, Nicholas Bruchovsky, in 1966, the researchers discovered that testosterone is converted inside prostate cells into dihydrotestosterone, a more potent androgen that is responsible for most of male sexual maturation and male sexual function. Dr. Wilson and his colleagues later showed that mutations that impair either the synthesis of testosterone, the conversion of testosterone to dihydrotestosterone, or the function of this metabolites receptor protein are the most common cause of birth defects associated with incomplete development of the male urogenital tract, affecting about four in every 1,000 boys. Cloning these responsible genes eventually allowed researchers to identify asymptomatic carriers of these mutations.

Dihydrotestosterone

Dr. Wilson also discovered that excess dihydrotestosterone is responsible for benign prostatic hyperplasia (BPH), or prostate enlargement, a condition that affects about 210 million men worldwide. Dihydrotestosterone is responsible for prostate growth in all male mammals, but in humans and dogs, prostate growth continues throughout life. Wilson and his colleagues showed that local excess of this potent androgen leads to prostate overgrowth. By curbing its production by inhibiting 5a-reductase, the enzyme that converts testosterone to dihydrotestosterone, they were able to prevent BPH in dog models of this condition. These findings have been developed into multiple 5a-reductase-inhibiting pharmaceuticals to treat this condition in human patients.

Brown, a Regental professor and director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease, holds The W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research, and the Paul J. Thomas Chair in Medicine.

Goldstein, a Regental professor and chair of molecular genetics, holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research, and the Paul J. Thomas Chair in Medicine.

Podolsky holds the Philip OBryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration, and the Doris and Bryan Wildenthal Distinguished Chair in Medical Science.

Russell holds the Eugene McDermott Distinguished Chair in Molecular Genetics.

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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In Memoriam: Jean Wilson, M.D., made scientific discoveries that led to effective prostate treatments, insights into sexual differentiation - UT...

Recommendation and review posted by Bethany Smith

About 5.8 million Americans in 2020 were living with the disease, according to CDC data.2

Estimates show that this number will nearly triple to about 14 million people by the year 2060. Although the disease occurs mostly in older individuals, symptoms sometimes also occur in younger patients.

AD is the sixth-leading cause of death in the United States and the third-leading cause of death for patients older than age 65 years.

The disease is named after physician Alois Alzheimer, MD, who in 1906 discovered changes in the brain of a female patient who had died of mental illness. This patient suffered from language problems, memory loss, and unusual behavior. While examining her brain, Alzheimer found a few abnormal clumps, also known as amyloid plaques, and tangled bundles of fibers called neurofibrillary tangles.

An early symptom of AD is forgetfulness. As the disease advances, the individual may develop more severe memory impairment and can become more debilitated, causing then to struggle with completing everyday tasks. Symptoms are typically noticed by close family members who interact with the individual frequently, and they may become severe to the point that the patients forget relationships and even sometimes the names of loved relatives. Changes in the brains of these patients can also affect their behavior and mood and include aggressiveness, delusions, depression, irritability, more distrust of others, and social withdrawal.

Causes of AD may be related to brain proteins that fail to function normally, causing neurons to not be able to perform their duties. This impairment can be caused by environment, genetics, and lifestyle. The damage starts earlier than the point that the symptoms start to show, and in late stages, the brain shrinks significantly from its normal size.

The proteins involved include beta-amyloid plaques, which when clumped together cause toxic effects on neurons and disrupt the cell-to-cell connection. Meanwhile, Tau proteins help carry essential minerals and nutrients to the brain, and in patients with AD, these proteins change shape and become entangled. This disrupts the nutrient transport system, affecting brain cell function.

Genetics play a role in a patient developing AD, specifically for those with first-degree relatives diagnosed with the disease. Gender also plays a role, with women diagnosed more often than men, though this may also be related to the fact that women tend to live longer.1

One genetic factor known to cause the disease is Apolipoprotein E gene, which with the e4 variation, increases the risk of AD exponentially. Additionally, patients with Down syndrome are more likely to develop AD than others. This is likely related to 3 copies of the chromosome 21, which connect with the creation of beta-amyloid.

Diagnosing AD may include neuropsychological testing and brain imaging, using amyloid positron emission tomography (PET), computer tomography, magnetic resonance imaging, PET scan, or Tau PET imaging.

Medications used to great AD include those that help with memory symptoms and treat cognitive changes. Two major types of the drugs available on the market for these patients include cholinesterase inhibitors and memantine. Cholinesterase inhibitors may help treat agitation and depression and commonly include donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon). Memantine (Namenda) and the combination of memantine and donepezil (Namzaric) combine a cholinesterase inhibitor with memantine to help with medication compliance and help slow the progression of disease symptoms.

On June 8, 2021, the FDA approved aducanumab injection (Aduhelm), an amyloid beta-directed antibody indicated for the treatment of AD. Aduhelm comes in 2 dosages of 170mg/1.7ml and 300mg/3ml solution. The recommended dosage for this drug is 10mg/kg as an intravenous infusion for more than 60 minutes every 4 weeks.

Aduhelm provides new hope for patients diagnosed with AD to have more treatment options available to them after many years of waiting for an FDA approval. The future for research in this area is promising and holds the key to more discoveries, including a cure for AD.

References

Read more:
Aduhelm Is A New Option to Treat Alzheimer Disease - Pharmacy Times

Recommendation and review posted by Bethany Smith

Kiwi trans woman weightlifter Laurel Hubbard has reignited debates on transgender participation in sports following the announcement that she would be allowed to compete in the womens category at the Summer Olympics in Tokyo this year.

The landmark decision is the first since the International Olympic Committee modified its guidelines in 2015 to allow trans woman athletes to participate if they showed testosterone levels of less than 10 nanomoles per liter for at least one year prior to competition.

Needless to say, allowing Hubbard to participate in the womens weightlifting category has sparked both praise and criticism, with one side commending its inclusivity, while the other side draws attention to an uneven playing field created, with concerns that trans women may have an advantage over their peers and competitors due to their physical abilities.

Malta is equally divided on the subject, with some activists on one side of the fence and sports professionals on the other.

Laurel Hubbard is the first trans woman to compete in an Olympic Games

When you look at a female-born athlete at a high level, they are competing at around three nanomoles per liter of testosterone which already indicates that the level of testosterone of a female athlete is three times lower than that of a transgender woman that has undergone hormone replacement therapy, renowned strength and conditioning coach Nigel McCarthy told Lovin Malta.

Amongst the benefits of having higher testosterone levels are increased muscle mass, bone density, decreased fat percentage and recovery time.

Apart from the latter, performance does not reflect what happened the previous year but is an accumulation of years of building, he continued. The blood, hormones and cell production in your body are all signaled by previous years of training.

Despite having to undergo hormone replacement therapy, a body of research indicates that trans women are still at a biological advantage when compared to other female athletes, McCarthy argued.

Not all the advantages are diminished and still a large overwhelming benefit remains from being male years prior when it comes to biological advantages of strength and power, he said.

This is clearly shown by the results of transgender athletes when competing in female categories winning by large distances and not just the mere half a second or a centimeter.

In 2019, transgender athlete Rachel McKinnon set a world record time in sprint cycling with a timing of 11.649 seconds. Her opponent, Dawn Owrick, came in second with a time of 12.063.

Those on the other side of the fence argue that the decision to allow Hubbard to compete in the womens category of the Olympic Games promotes inclusivity and that it is skill, rather than genetics, that determines a champion.

Unfortunately, we think of sports as being fair which in reality is not, it is all a natural genetic lottery you do not choose to be tall, have higher testosterone levels or respond to training as well as others, McCarthy said.

While acknowledging that sports should be accessible to all, the S&C coach also believes in preserving the right of fairness for those who are also competing.

More studies need to be done to test baseline level before and after therapies for transgender athletes, he continued. There also needs to be a better understanding of the biological differences between males and females which determines athletic ability.

Hubbard will be competing in the womens 87kg weightlifting category. Though she has the backing of the New Zealand government and Olympic Committee, the decision on her participation hasnt been welcomed by some of her peers, including Belgian weightlifter Anna Vanbellinghen, who claimed that this particular situation is unfair to the sport and to the athletes.

As things stand, an out-of-proportion and unfair biological athletic advantage is occurring at the expense of born female athletes when competing against transgender athletes, McCarthy continued.

Hubbard had competed in mens weightlifting competitions prior to coming out as transgender in 2013.

The current total weightlifting record for men competing in the 89kg category is 387kg consisting of a combination of clean & jerk and snatch.

Meanwhile, the total female world record for athletes competing in the 87kg category stands at 294kg.

On a personal note, this should really be discussed by female athletes and not by myself or by any outsider not knowledgeable or impacted by the decisions, McCarthy said.

Females are having their hard work and opportunities lost to transgender athletes who evidently have an unfair athletic biological advantage, he ended.

What do you make of this? Let us know below

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'Unfair Biological Athletic Advantage', Maltese S&C Coach Weighs In On Trans Weightlifter Competing At The Olympics - Lovin Malta

Recommendation and review posted by Bethany Smith

Meet Raja, the newest resident of the Point Defiance Zoo & Aquarium. The 2-year-old critically endangered Sumatran tiger was revealed to the public last weekend (June 19-20) and could hold the key to protecting the Sumatran tiger species.

Rajas definitely not in Kansas anymore, but Tacoma welcomes the tiger with open arms and the possibility he brings.

Raja moved from Topeka Zoo & Conservation Center to Point Defiance Zoo in an attempt to boost breeding and ensure the future survival of the big cat species. With roughly 400 remaining, zoos joined the Species Survival Plan for Sumatran tigers to protect the critically endangered species from disappearing entirely because of habitat loss, poaching, lack of prey, and tiger-human conflict. Point Defiance Zoo has become a leader in Sumatran tiger conservation efforts, along with a list of other endangered species.

We are proud to be part of the conservation community working to ensure this species is around for future generations, Dr. Karen Goodrowe Beck, the general curator and Species Survival Plan coordinator for all tiger species at the Association of Zoos & Aquariums, said in a press release.

Rajas valuable genetics are vital to the survival of his species, Dr. Goodrowe Beck said. In the future, Raja will likely father the cubs of the three female Sumatran tigers housed at the zoo: Kali, Kirana, and/or Indah.

Visit Raja in the Asian Forest Sanctuary section of Point Defiance Zoo and stay tuned for news of Sumatran tiger cubs in the future.

Read more here:
Lions, More Tigers, and Bears, Oh My! Meet PDZA's Newest Resident Tiger - southsoundmag.com

Recommendation and review posted by Bethany Smith

Cancer treatments are improving as scientists are finding ways to develop new techniques and treatments. One of which is precision medicine, where they have focused on improving patients health using personalized solutions.

RELATED: Oxfords Genomics Pushing the Boundaries of Personalized Medicine

Precision medicine, in the simplest definition, is the way a patient is treated, diagnosed, or prevent disease by checking his/her genetics, environment, or lifestyle.

This type of treatment is related to pharmacogenomics. Where pharmacogenomics is the study of how a persons gene affects his/her response to a drug, it is used to treat a person through effective and safe medication tailored to their genes.

Precision medicine is now commonly used on patients treated with pancreatic cancer, lung cancer, melanoma/skin cancer, and colon cancer. It is also used to detect and treat HIV and cystic fibrosis.

Slowly, it is also seen in treatments for heart diseases, Alzheimers disease, rheumatoid arthritis, and multiple sclerosis.

In cancer patients, most medical facilities treat every patient the same way. However, studies suggest that not everyone responds to treatments the same way. One persons body may react differently with medicines as compared to another person.

Genetics plays a role in treating tumors, and precision medicine promise to tailor treatments based on a persons genes. It is seeing how a tumor would react to certain treatments that may work for other people.

Precision medicine can be used in the prevention and prediction of disease and management and treatment. Here are some examples of how it is used to treat, prevent, or treat people in a practical setting.

Checking your familys history of diseases and illnesses can somehow determine what you are capable of acquiring. If a family member has a history of cancer, heart diseases, diabetes, high blood pressure, or other chronic diseases, there is a high chance of you getting it.

With this data and information, a doctor can create treatment plans to prevent these from happening to you.

For example, when the doctor finds out that any of your family members had breast cancer, then the chances of you having it is likely. The doctor will then decide for you to have regular mammograms to check for any signs.

Newborns (usually right after theyre conceived) are screened where blood samples are taken. This test will check if they have any pre-existing conditions acquired from their parents, check hearing capabilities or heart defects, among others.

This way, the baby will be treated accordingly if any crucial or life-threatening conditions are seen.

For example, the newborn screening shows Baby Mary has severe combined immunodeficiency (SCID), she will receive a bone marrow transplant immediately to battle her condition. SCID is life-threatening to babies since its responsible for fighting off infections.

Personal trackers such as smartwatches or other mobile devices that check on your health can be lifesavers and be tools for precision medicine.

For example, a person is notified by his smart device that he is experiencing abnormal heart rates even if he has no family history of any heart condition. He then goes to see a doctor because of this and has been diagnosed with atrial fibrillation. This device could have saved his life because that condition can lead to a stroke. Now, he can treat his condition before it worsens.

Genomic sequencing can be used to control and track-out infectious diseases. Similar to whats been used to track COVID-19, this approach shows a DNA of a germ or virus where scientists have the opportunity to learn more about it and find a treatment a cure for it.

An example of this is the COVID-19, where scientists were able to extract samples from those infected with the virus and learn about it and find vaccines and cures for it, which is now slowly happening to us.

As a treatment, tumor profiling is genetic testing of a tumor. It is a way for doctors to choose which kind of treatment they would use for a condition. They would know from this process if cancer will return or would need radiation or chemotherapy.

For example, Jennys breast cancer returned and is diagnosed again. But her tumor profiling reveals she has triple-negative breast cancer. Her approach to this, along with her doctors, is a more aggressive one, including chemotherapy, radiation, and mastectomy.

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As mentioned above, pharmacogenomics studies how a person reacts to a certain treatment based on their genes. Doctors using this treatment can gauge if a certain medicine can be effective or not based on a patients history. They can also determine if the patient will experience any serious side effects.

For example, John needs to undergo Fluorouracil (5-FU), which is a type of chemotherapy. But if John has a low level of an enzyme called dihydropyrimidine dehydrogenase (DPD), which helps metabolize fluorouracil in the body, the doctors would need to check on him using pharmacogenomics. If he has a low dose of fluorouracil, an oncologist will decrease the dosage in the chemotherapy to prevent any serious side effects.

With these examples revealed, some facilities and companies provide precision medicine to improve the living conditions of patients treated with different diseases.

ExactCure is a French start-up that combines artificial intelligence with precision medicine to create flawless software for the use of drugs to be used by patients depending on their kidney status, genotype, gender, or age.

Patients use this service by inputting their data, and ExactCure will give the necessary medications based on the information provided.

Tepthera is a Swiss start-up that focuses on cancer immunotherapy, infectious and auto-immune diseases.

Their focus concerning precision medicine is on identifying T cell antigens for better and personalized therapies and treatment.

Caris Life Sciences is a molecular science company that focuses on precision medicine in oncology. They are working on the development of innovative therapeutics and advance potential treatments for cancer in the clinic.

They develop profiling assays for oncology that scan DNA, RNA and proteins to reveal a molecular blueprint to help physicians determine the best course of treatment for cancer patients.

Precigen is a Maryland-based company that is advancing its UltraCAR-T cell therapy approach to treating cancer.

They are now developing next-generation gene and cell therapies that can change the treatment paradigm in immuno-oncology, autoimmune disorders and infectious diseases.

There are numerous ways to treat diseases and medical conditions with the use of precision medicine. Scientists are continually finding out ways to improve patients lives by using their traits.

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Precision Medicine: Improving Health With Personalized Solutions - BioSpace

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COVID appears to be in retreat in the U.S. and other nations that have widespread access to vaccines. But some developing countries with high infection rates have become hotspots for viral variants that may be more transmissible or resistant to vaccinesand these variants can quickly cross national borders. For example, the B.1.167.2 variant (now dubbed Delta) that was first detected in India has spread to more than 70 countries and regions, including the U.S.

Much of the developing world lacks the capacity for viral surveillanceefforts to monitor the spread and evolution of new variants. This process requires expensive genomic-sequencing technology and trained workforces that many nations do not have. Nepal, for instance, has sequenced just 0.01 percent of the more than 600,000 cases reported in the country so far. New variants could undo hard-won progress in curbing the pandemic, according to Alina Chan, a postdoctoral fellow specializing in gene therapy and cell engineering at the Broad Institute of the Massachusetts Institute of Technology and Harvard University. Variants that evolve to be able to reinfect previously infected people are likely to also reduce the efficacy of vaccines, she says.

Scientists and organizations around the world are now working to build capacity to hunt for variants in developing countries. They are mobilizing to deliver funds, training and equipment to where these resources are needed most, with aspirations of creating a lasting viral surveillance infrastructure. COVID is the catalyst, says Jairo Mendez-Rico, a microbiologist and adviser on viral diseases at the Pan American Health Organization (PAHO), headquartered in Washington, D.C. But we also need to survey for other pathogens that for sure will come in the future.

In India, 27 laboratories have now banded together to create the Indian SARS-CoV-2 Genomics Consortium (INSACOG). The group plans to sequence 5 percent of all positive COVID cases in the country (the current rate is only 0.09 percent). Shahid Jameel, a virologist and director of the Trivedi School of Biosciences at Indias Ashoka University, says that bringing existing surveillance capacity under a single umbrella could, in principle, make that a feasible goal. But there are not enough trained field-workers, he says, and the laboratories have acute shortages of chemical reagents needed for genomic analyses.

International experts are now stepping in to help. Recently, a nonprofit volunteer group called INDIA COVID SOS formed to assist with the pandemic response in the country. It aims to scale genomic surveillance across India, as well among neighboring South Asian nations. Aditi Hazra, an epidemiologist at Harvard Medical School, co-leads the groups sequencing team, which meets regularly on video conference calls with the directors of Indias sequencing consortium. She says a key objective is to extend viral surveillance to more people in rural areas, where much of the population lives.

Rural surveillance is a priority in Africa as well. Millions of people on the continent live in remote areas that are also hot spots for disease outbreaks, says Akaninyene Otu, a medical doctor and a senior lecturer at the University of Calabar in Nigeria. Several new partnerships aim to boost sequencing in African countries. Otu highlights the Africa Pathogen Genomics Initiative (Africa PGI), which launched last year with support from international donor organizations and private companies. Most of the sequencing capacity in Africa is concentrated in South Africa, Kenya, Nigeria, Morocco and Egypt. The Africa PGI, which is headed by the Africa Centers for Disease Control and Prevention, is setting out to create a pan-African network of sequencing centers to serve the continents 54 countries.

In Latin American countrieswhich are currently reporting some of the highest COVID infection rates in the worldPAHO is spearheading the COVID-19 Genomic Surveillance Regional Network. Some countries in the region already have fairly strong sequencing capabilities, but the network is leading efforts to build surveillance capacity where it does not exist at all, which is the case throughout much of Central America. In the interim, two large reference labsone in Brazil and one in Chileare sequencing samples sent by other countries at PAHO's expense, Mendez-Rico says.

In addition to building partnerships and networks, scientists are also exploring low-cost sequencing technologies that could be deployed easily in the field. Nearly all of the SARS-CoV-2 cases sequenced so far have relied on large, expensive instruments housed in climate-controlled lab facilities. As an alternative, INDIA COVID SOS is encouraging wider use of a handheld sequencing device made by Oxford Nanopore Technologies in England. The device, called the MinION, can run on a battery pack, processes 96 samples at a time and uses software to generate whole genome sequences that can be stored on a laptop. We're looking for technologies that are cheap, efficient, scalable and portable, and this is an example, Hazra says.

Keith Robison, a computational biologist at Ginkgo Bioworks, a Boston-based biotechnology company, agrees that the MinION is a practical option for developing nationsespecially in rural settings. The portable technology was widely used during the recent Ebola outbreaks in the Democratic Republic of the Congo and other West African countries. You can generate sequences with it from anywhere, he says. The MinION has its drawbacks: the quality of the data is not as good as what the lab-based instruments provide, Robison notes. However, that can also be computationally corrected if you have many copies of the same sequence, he says.

Tue Sparholt Jrgensen, a postdoctoral researcher in microbiology at the Technical University of Denmark, argues that whole-genome sequences may not always be needed. All the important SARS-CoV-2 mutations identified so far, he says, sit on the same stretch of genome encoding the microbes well-known spike protein. Jrgensen says scientists can simply target this piece of the viral geome with an alternative method called Sanger sequencing. This method, which was used as part of the effort that led to the sequencing of the complete human genome back in 2003, is still employed by labs all over the world. Unlike whole-genome methods that sequence millions of genetic fragments simultaneously, the Sanger method sequences one fragment at a time. Sanger can't replace whole-genome sequencing, but you can use it for targeted analyses at a fraction of the cost, Jrgensen says. People have been using it in small labs for decades. Id use it to monitor for known variants, [to] qualify samples for whole genome sequencing and for contact tracing [of infected people] in hospitals.

Jrgensen and his colleagues are now working with health officials in Rwanda on plans to expand Sanger-based COVID surveillance in the country. If a new variant emerges in Rwanda and starts spreading [elsewhere] in Africa, then we want to know about it, he says.

Read this article:
New Coronavirus Variants Are Urgently Being Tracked around the World - Scientific American

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Each year, an estimated 1.8 million people in the United States are affected by cancer most commonly cancers of the breast, lung, prostate, and blood cancers such as leukemia. While not everyone overcomes the disease, thanks to science, more people are surviving and for longer than ever before in history.

We asked three people whose lives have been impacted by cancer to share their stories how their lives were changed by the disease, and how they're using that experience to change the future of cancer treatments with the hope that ultimately, in the fight against cancer, science will win. Here's what they had to say.

Photo courtesy of Celine Ryan

In September 2013, Celine Ryan woke up from a colonoscopy to some traumatic news. Her gastroenterologist showed her a picture of the cancerous mass they found during the procedure.

Ryan and her husband, Patrick, had scheduled a colonoscopy after discovering some unusual bleeding, so the suspicion she could have cancer was already there. Neither of them, however, were quite prepared for the results to be positive -- or for the treatment to begin so soon. Just two days after learning the news, Ryan had surgery to remove the tumor, part of her bladder, and 17 cancerous lymph nodes. Chemotherapy and radiation soon followed.

Ryan's treatment was rigorous but in December 2014, she got the devastating news that the cancer, once confined to her colon, had spread to her lungs. Her prognosis, they said, was likely terminal.

But rather than give up hope, Ryan sought support from online research, fellow cancer patients and survivors, and her medical team. When she brought up immunotherapy to her oncologist, he quickly agreed it was the best course of action. Ryan's cancer, like a majority of colon and pancreatic cancers, had been caused by a defect on the gene KRAS, which can result in a very aggressive cancer that is virtually "undruggable." According to the medical literature, the relatively smooth protein structure of the KRAS gene meant that designing inhibitors to bind to surface grooves and treat the cancer has been historically difficult. Through her support systems, Ryan discovered an experimental immunotherapy trial at the National Institutes of Health (NIH) in Bethesda, MD., and called them immediately to see if she was eligible. After months of trying to determine whether she was a suitable candidate for the experimental treatment, Ryan was finally accepted.

The treatment, known as tumor-infiltrating lymphocyte therapy, or TIL, is a testament to how far modern science has evolved. With this therapy, doctors remove a tumor and harvest special immune cells that are found naturally in the tumor. Doctors then grow the cells in a lab over the next several weeks with a protein that promotes rapid TIL growth and once the cells number into the billions, they are infused back into the patient's body to fight the cancer. On April 1, 2015, Ryan had her tumor removed at the NIH. Two months later, she went inpatient for four weeks to have the team "wash out" her immune system with chemotherapy and infuse the cells all 148 billion of them back into her body.

Six weeks after the infusion, Ryan and Patrick went back for a follow-up appointment and the news they got was stunning: Not only had no new tumors developed, but the six existing tumors in her lungs had shrunk significantly. Less than a year after her cell infusion, in April 2016, the doctors told Ryan news that would have been impossible just a decade earlier: Thanks to the cell infusion, Ryan was now considered NED no evaluable disease. Her body was cancer-free.

Ryan is still NED today and continuing annual follow-up appointments at the NIH, experiencing things she never dreamed she'd be able to live to see, such as her children's high school and college graduations. She's also donating her blood and cells to the NIH to help them research other potential cancer treatments. "It was an honor to do so," Ryan said of her experience. "I'm just thrilled, and I hope my experience can help a lot more people."

Photo courtesy of Patrice Lee

Patrice Lee got into scientific research in an unconventional way through the late ocean explorer Jacques Cousteau.

Lee never met Cousteau but her dreams of working with him one day led her to pursue a career in science. Initially, Lee completed an undergraduate degree in marine biology; eventually, her interests changed and she decided to get a dual doctoral degree in physiology and toxicology at Duke University. She now works at Pfizer's R&D site in Boulder, CO (formerly Array BioPharma), leading a group of scientists who determine the safety and efficacy of new oncology drugs.

"Scientists focused on drug discovery and development in the pharmaceutical industry are deeply committed to inventing new therapies to meet unmet needs," Lee says, describing her field of work. "We're driven to achieve new medicines and vaccines as quickly as possible without sacrificing safety."

Among the drugs Lee has helped develop during her career, including cancer therapies, she says around a dozen are currently in development, while nine have received FDA approval an incredible accomplishment as many scientists spend their careers without seeing their drug make it to market. Lee's team is particularly interested in therapies for brain metastases something that Lee says is a largely unmet need in cancer research, and something her team is working on from a variety of angles. "Now that we've had rapid success with mRNA vaccine technology, we hope to explore what the future holds when applying this technology to cancers," Lee says.

But while evaluating potential cancer therapies is a professional passion of Lee's, it's also a mission that's deeply personal. "I'm also a breast cancer survivor," she says. "So I've been on the other side of things and have participated in a clinical trial."

However, seeing how melanoma therapies that she helped develop have affected other real-life cancer patients, she says, has been a highlight of her career. "We had one therapy that was approved for patients with BRAF-mutant metastatic melanoma," Lee recalls. "Our team in Boulder was graced by a visit from a patient that had benefited from these drugs that we developed. It was a very special moment for the entire team."

None of these therapies would be available, Lee says without rigorous science behind it: "Facts come from good science. Facts will drive the development of new drugs, and that's what will help patients."

Photo courtesy of Cynthia Kuk

Cynthia Kuk was just 10 years old when they had a conversation that would change their life forever.

"My mother, who worked as a translator for the government at the time, had been diagnosed with breast cancer, and after her chemotherapy treatments she would get really sick," Kuk, who uses they/them pronouns, recalls. "When I asked my dad why mom was puking so much, he said it was because of the medicine she was taking that would help her get better."

Kuk's response was immediate: "That's so stupid! Why would a medicine make you feel worse instead of better? When I'm older, I want to create medicine that won't make people sick like that."

Nine years later, Kuk traveled from their native Hong Kong to the United States to do exactly that. Kuk enrolled in a small, liberal arts college for their Bachelor's degree, and then four years later started a PhD program in cancer research. Although Kuk's mother was in remission from her cancer at the time, Kuk's goal was the same as it had been as a 10-year-old watching her suffer through chemotherapy: to design a better cancer treatment, and change the landscape of cancer research forever.

Since then, Kuk's mission has changed slightly.

"My mom's cancer relapsed in 2008, and she ended up passing away about five years after that," Kuk says. "After my mom died, I started having this sense of urgency. Cancer research is such that you work for twenty years, and at the end of it you might have a fancy medication that could help people, but I wanted to help people now." With their mother still at the forefront of their mind, Kuk decided to quit their PhD program and enter medical school.

Now, Kuk plans to pursue a career in emergency medicine not only because they are drawn to the excitement of the emergency room, but because the ER is a place where the most marginalized people tend to seek care.

"I have a special interest in the LGBTQ+ population, as I identify as queer and nonbinary," says Kuk. "A lot of people in this community and other marginalized communities access care through the ER and also tend to avoid medical care since there is a history of mistreatment and judgement from healthcare workers. How you carry yourself as a doctor, your compassion, that can make a huge difference in someone's care."

In addition to making a difference in the lives of LGBTQ+ patients, Kuk wants to make a difference in the lives of patients with cancer as well, like their mother had.

"We've diagnosed patients in the Emergency Department with cancer before," Kuk says. "I can't make cancer good news but how you deliver bad news and the compassion you show could make a world of difference to that patient and their family."

During their training, Kuk advocates for patients by delivering compassionate and inclusive care, whether they happen to have cancer or not. In addition to emphasizing their patient's pronouns and chosen names, they ask for inclusive social and sexual histories as well as using gender neutral language. In doing this, they hope to make medicine as a whole more accessible for people who have been historically pushed aside.

"I'm just one person, and I can't force everyone to respect you, if you're marginalized," Kuk says. "But I do want to push for a culture where people appreciate others who are different from them."

More here:
Early-onset Alzheimer's stole the memory of his marriage. Then he proposed again. - Upworthy

Recommendation and review posted by Bethany Smith