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Worldwide Viral Vector & Plasmid DNA Manufacturing Market bits of knowledge spread qualities, development, and size, division, provincial retreats, serious scene, pieces of the pie, patterns, and plans. The qualities part of this catchphrase report characterizes and clarifies the development. The Viral Vector & Plasmid DNA Manufacturing showcase size office gives industry income, covering the verifiable development of this and foreseeing the since quite a while ago run. Viral Vector & Plasmid DNA Manufacturing Drivers and limitations with the factors influencing the development of this market. The division isolate the fundamental catchphrase sub-businesses that structure the market.

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Impact COVID-19 on Viral Vector & Plasmid DNA Manufacturing Market Along with Major Market Players | Merck, uniQure, The Cell and Gene Therapy...

Recommendation and review posted by Bethany Smith

Can melatonin make you as sleepy as this pup?

Sleep: We all want more. Most of us are in perpetual sleep debt, accruing lost hours every time we hit the hay. Waking up puffy-eyed and groggy is not ideal, yet many people accept it as their normal. The occasional late night at work or weekend of partying doesn't help our quest for more shut-eye.

If only there was a supplement that promised to improve your sleep cycle so you could bounce out of bed bright-eyed and bushy-tailed every morning.

Our Health & Wellness newsletter puts the best products, updates and advice in your inbox.

Melatonin, per various marketing claims, pill bottles and social media hype, could be that supplement. Is it really that easy, though? Can you just pop a sleep supplement before bed and quickly enter dreamland -- and stay there till sunrise?

If you're itching to grab a bottle of melatonin gummies next time you're at your local drugstore, first read up on the potential benefits and risks, plus how to supplement melatonin smartly and avoid dangerous drug interactions.

Read more: Collagen supplements promise smooth skin, but you should eat these foods instead

What is melatonin?

Melatonin is a hormone that animals, including humans, produce to regulate circadian rhythms. Melatonin may have some other functions, but its role in sleep-wake cycles is the most extensively studied and understood.

Read more: Caffeine: How bad is it really?

Now playing: Watch this: 9 sleep myths, busted by a sleep doctor

7:07

How does melatonin work?

Your body naturally produces melatonin in response to darkness and reduces production of melatonin in response to light. It's referred to as the "sleep hormone" because it essentially tells your body when to sleep and when to wake up.

Everyone has a circadian rhythm or "internal clock" that runs on a 24-hour cycle and is affected by your body's production of melatonin.

How it works: A certain area of your brain -- specifically thesuprachiasmatic nucleusin the hypothalamus -- controls this body clock, and it's primarily influenced by light and environment.

Your SCN processes that information and signals your body to produce melatonin accordingly. Various tissues in your body produce melatonin, but the main source is the pineal gland, a small gland inside your brain.

Melatonin production can be suppressed by constant exposure to light, which is primarily where all of the advice about shutting down screens an hour before bed comes from: Feeding your eyes bright light up until the point you shut your eyes can result in a wacky melatonin-production schedule, thus a messed up sleep schedule.

Melatonin supplementation is supposed to aid your body's natural production of melatonin -- if done correctly, this theoretically can help regulate your circadian rhythm and result in better sleep. While potentially beneficial if used properly, supplemental melatonin can be detrimental or, at best, useless, if not used with care.

Read more: Vitamin D is crucial for immune health -- make sure you're getting enough

Melatonin benefits

The obvious benefit is that melatonin can help you sleep more and sleep better, if used correctly (more on that later). However, melatonin can do much more than boost just one night of sleep -- it can also help you reset your circadian rhythm and result in a firmly established, healthy sleep cycle. You don't need a doctor to tell you that a healthy sleep cycle can help you be more alert, motivated and productive.

Basically, the benefits of melatonin mirror those of getting more sleep, and they can extend much further into your life than you may initially think. Sleep is the foundation of human function: Without it, we are at risk for an array of emotional and physical health problems, not to mention things like auto accidents and other dangerous mistakes.

Melatonin can also benefit people who have secondary sleep disorders, or a sleep disorder that's a symptom of a different condition or circumstance. This includes people whose jobs require shift work, poor sleep caused by jet lag and sleep-wake disorders in people who are blind.

Read more: Vitamin C: Why you need it and how to get enough of it

Melatonin risks and side effects

All supplements come with risks -- melatonin is no different.

Short-term side effects of melatonin are generally mild, but can still be frustrating or inconvenient. Side effects reported in clinical trials related to melatonin include:

Other than those listed, melatonin doesn't appear to induce any serious conditions, although some health organizations and practitioners worry that supplementing melatonin may mess with your body's natural production of the hormone. There's no evidence to currently support the idea that people build a tolerance to melatonin, though.

Certain people should use caution with melatonin to avoid any potential complications, including people who are pregnant or breastfeeding, people who are on dialysis treatment, people who have liver problems and people with autoimmune conditions.

Read more: Zinc and coronavirus: The supplement may help reduce severity of symptoms, but it's no cure

Is melatonin safe?

Melatonin is generally considered safe for short-term use, although some health agencies express concern about product quality and efficacy, as well as labels with misinformation. Here's the lowdown from some of the biggest health agencies:

As for the stance of the Food and Drug Administration on melatonin, there isn't really one. In the US, melatonin is classified as a dietary supplement, which means it is less strictly regulated than food ingredients or medications. The FDA has sent warning letters in the past to food and beverage companies who make questionable claims about melatonin in their products.

Melatonin is probably one of the most studied supplements currently available to consumers. Evidence in individual scientific studies sways both ways, but meta-analyses generally come to the same conclusion: Melatonin is generally safe and well-tolerated, even in the absence of sleep improvements.

Does melatonin actually work?

The scientific evidence on melatonin points in both directions: Many studies say it works, many say it doesn't. This could be because melatonin affects everyone differently (as do all supplements), so to find out if melatonin works for you, you'd have to try it yourself.

For argument's sake, here are some recent peer-reviewed studies on the efficacy of melatonin:

If you do decide to take melatonin, consider discussing potential benefits and risks with your doctor first, as well as proper dosing and timing guidelines, which are outlined below.

There are also many research studies on the efficacy of melatonin as it pertains to specific conditions, such as melatonin for sleep following a traumatic brain injury, melatonin for Parkinson's disease and melatonin for ADHD. If you have a health condition you think may benefit from melatonin, perusing studies can help you learn more, although you should definitely check with your doctor, too.

Is melatonin addictive?

There's no evidence that melatonin as a substance is addictive. No studies have reported that melatonin can cause people to build a dependence on or tolerance of the hormone, and it isn't known to cause symptoms of withdrawal.

What you may become "addicted" to, though, is the feeling of improved sleep. Once you know what it feels like to fall asleep quickly, stay asleep through the night and wake up energetic, it's tough to go back to the exact opposite. This may make it hard for you to fall asleep without the help of melatonin.

Even though melatonin isn't known to be addictive, if you have a history of addiction to any substance, it may be a good idea to discuss melatonin with your doctor before trying it.

Best time to take melatonin

Studies support taking melatonin between 30 minutes and two hours before bedtime. The range exists because everyone absorbs medications at different rates and your own body's melatonin production can affect how quickly supplemental melatonin works.

The most important thing is to avoid taking melatonin too late at night -- like way after your bedtime -- lest your sleep cycle get shifted and you have to drag yourself out of a cycle of late nights.

How much melatonin should you take?

There's no exact dosage of melatonin that everyone should take, as it can vary based on factors such as gender, age, health conditions, body size and more. According to the NIH, no effective dosing has been established, and dosing in studies has ranged from 0.1 up to 10 milligrams.

The National Sleep Foundation recommends a dose of 0.2 milligrams to 5 milligrams for adults, although it's not clear where that determination came from. If you plan to take melatonin, try starting with the smallest possible dose and working your way up to a dose that helps you fall asleep but doesn't cause any side effects.

Keep in mind that the FDA doesn't regulate melatonin, so what you see on the product label may not be what you get.

Can you take melatonin every night?

There's no evidence that warrants advising against taking melatonin every day, but keep in mind that the majority of clinical trials to date have only tested short-term use of melatonin (three months or less), and that more research is needed to determine if it's safe to take melatonin every day for a long time.

Should you take melatonin for insomnia?

If you have or think you have insomnia, you should chat with your doctor about melatonin as a potential treatment. Some major health agencies advise against using melatonin to treat insomnia and instead advocate for cognitive behavioral therapy or another drug-free intervention.

Your doctor may want you to try lifestyle modifications first, such as increasing your daily exercise, changing your eating habits or reducing alcohol consumption. Your provider will also want to rule out other conditions that can coexist with insomnia, such as anxiety or depression. Sometimes, when drug-free interventions don't suffice, prescription medication is needed to treat insomnia.

Can you take melatonin with...?

Before you take melatonin, check with your doctor if you have any existing health conditions. According to drugs.com, which is powered in part by theAmerican Society of Health-System Pharmacists, Harvard Health and Mayo Clinic, you should take caution -- and ask your doctor if you can take melatonin -- if you have any of the following health conditions:

You should also check with your doctor about melatonin drug interactions if you're currently on any other medications, including other sedatives.

Remember, when taking any dietary supplement, use it wisely.

The information contained in this article is for educational and informational purposes only and is not intended as health or medical advice. Always consult a physician or other qualified health provider regarding any questions you may have about a medical condition or health objectives.

View post:
Melatonin: Is it safe, does it work and other FAQs - CNET

Recommendation and review posted by Bethany Smith

Menopause is a natural phase of a womans life and is marked by the complete cessation of periods for one whole year. The average age at which Indian women undergo menopause is approximately 46 years. The main physiological change is that the ovaries stop producing the female reproductive hormone- estrogen.The years prior to menopause are called pre-menopause and they involve many changes such as irregular periods, vasomotor symptoms such as hot flashes(feeling hot suddenly for a few seconds to minutes especially in the face), cold sweats(i.e., sweating for no reason), mood disturbances including irritability, emotional lability and bouts of anger and crying etc. Other changes include urogenital symptoms such as urinary leakage, urgency and vaginal dryness and irritation; skin changes such as thinning, dryness, itching etc and loss and thinning of scalp hair. These symptoms can be variable in presentation and severity. About 80% women experience symptoms like hot flashes, which is the most common symptom.The health risks revolve around the effects of lack of estrogen such as bone loss leading to osteoporosis and associated fragility fractures, heart disease such as atherosclerosis, myocardial infarction, dementia, psychological disorders, certain cancers like breast, colon cancer etc.Being well-informed is the first step towards self-care. It is important that women in their premenopausal years undergo certain baseline tests to determine if there are any underlying diseases. Common disorders that may be pre-existing or new-onset are anaemia, hypocalcemia, vitamin D deficiency, osteoporosis, diabetes mellitus, hypertension and hypothyroidism, hypercholesterolemia and depression and anxiety. Also a baseline cancer screening is important and involves tests like Pap smear for cervical cancer, clinical breast examination and mammography and an ultrasound scan of the abdomen and pelvis.Lifestyle modification forms the fundamental preventive strategy at this age. Consistent moderate exercises such as weight bearing exercises, strength and balance exercises, yoga asanas and surya namaskar, regular walking or jogging go a long way in maintaining physical and emotional health. Nutrition at this stage is also important and should aim to get enough calcium, iron and other micronutrients along with soya based protein which is rich in phytoestrogens (plant based estrogen). Calcium supplements and vitamin D supplementation may be required to prevent weakening of bones. About one fifth of menopausal women may have severe symptoms for which various medications may need to be initiated. Menopausal hormone therapy can be given in selected individuals after a thorough evaluation, and helps alleviate symptoms substantially. Although, fertility rates drop substantially in perimenopause, women must use effective contraception until menopause is complete i.e., a year has passed since the last period.Regular follow up with physician, gynaecologist, urologist, psychiatrist, orthopaedician, ophthalmologist etc is vital to maintain health over the long term. Annual or more frequent health checks would help in identifying diseases earlier.Being fit at forty, strong at sixty and independent at eighty should be the motto for us women.May 25th 2020By Dr. Aruna Muralidhar, senior consultant obstetrician and gynaecologist, Fortis La Femme, Richmond Town, Bengaluru

Disclaimer: The views and opinions expressed by the doctors are their independent professional judgment and we do not take any responsibility for the accuracy of their views. This should not be considered as a substitute for physician's advice. Please consult your treating physician for more details.

See the original post here:
Menopause: How to prepare your body for it - Times of India

Recommendation and review posted by Bethany Smith

A month following surgery for thyroid cancer, a Hartford Hospital patients tumor grew to 10 inches. The case was presented to the hospitals tumor board, which involved 30 doctors from different specialties.

The gene mutation found to be controlling the patients tumor growth was already well-established as a driver of melanoma, the deadliest form of skin cancer, says Dr. Sope Olugbile, medical oncologist at Hartford HealthCare.Chemotherapy wouldnt work fast enough against the aggressive tumor. Tumor board members recommended a targeted therapy already treating patients with melanoma. Without that genetic information, we wouldnt have been able to come up with that therapy, he says. The treatment saved the patients life, so far. Our goal is to use more of the genetic information to drive the treatment of cancer patients.

This type of personalized care, known as precision medicine and its subset, genomic medicine, has been offered for years at world-renowned cancer-treatment hospitals such as Memorial Sloan Kettering Cancer Center in New York, Dana-Farber Cancer Institute in Boston and University of Texas MD Anderson Cancer Center in Houston. Its now the standard of care in Connecticuts Hartford HealthCare Cancer Institute, UConn Health Center in Farmington, Connecticut Childrens Medical Center in Hartford and Smilow Cancer Center at Yale New Haven Health.Cancer therapy has become precision therapy, says Dr. Roy Herbst, professor of medicinal oncology and pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital.

Dr. Roy Herbst, of Yale Cancer Center and Smilow Cancer Hospital, says that precision care is often used in cancer treatment these days.

While its most commonly used with cancer patients, precision medicine is also making inroads into other areas of health care including the treatment of some cardiac patients. Its also being studied and used on a limited basis to treat those with rare diseases. In the U.S., newborns are screened with a blood test for hearing loss and heart defects. If detected and treated early, this can prevent death and disability in some cases. For some doctors and researchers, precision medicine holds the promise of effective targeted diseases and chronic conditions, and, even more revolutionary, the chance to prevent illness before it arises. The race is on to gather as much data as possible in order to increase understanding of the connection between genes and overall health; here in Connecticut, Yales Center for Genetic Health last fall launched its Generations project to collect DNA from 100,000 volunteers (see sidebar below).

Precision medicine involves the study of human genes, called the genome. The human genome contains 23 pairs of chromosomes within all human cells, and each chromosome contains hundreds to thousands of genes. Using high-level computing and mathematics, genomics researchers analyze massive amounts of DNA-sequence data to find variations or mutations that affect health, disease or response to drugs, according to an online description by The Jackson Laboratory for Genomic Medicine in Farmington.

Researchers can sequence an entire tumor to look for markers or abnormalities that can be treated with a targeted medication that attacks that mutation, unlike traditional chemotherapy that kills healthy cells along with cancer cells, says Herbst, also associate director for translational science at the Yale School of Medicine.

These days, when Yales precision medicine tumor board meets weekly, they dont focus on where the tumor began, he says. They look at what errors occurred in the DNA of the tumor, because once they know whats driving the tumor, they can treat it.For example, lung cancer is the most common cancer in the world. When a nonsmoker gets lung cancer, doctors sequence the tumors DNA to see if it contains one of eight genes known to mutate.

Each cancer cell has about 18,000 to 20,000 genes, and there are some cancers where just one of those genes is directing the growth of the cancer, Olugbile says. We call that the driver gene. The other 17,999 are just following the lead of that driver gene, he says. That means if we tag just that one gene with the medication then we can actually shut down the growth of the entire cancer.

Traditional chemotherapy can only be given for 4-6 months because of the side effects, while targeted oral medications have very few side effects and patients remain on them for an average of two years, Olugbile says.

In the past five years, genetic testing has become standard of care for some cancers specifically colon, lung and melanoma because those types of cancers tend to have genetic mutations that have been known to respond to therapy, says Sara Patterson, manager of clinical analytics and curation at Jackson Labs, which works with UConn and Yale researchers.But targeted therapy is not a cure-all, and researchers are still a long way from using precision medicine to treat all cancer patients. Even if cancers have the same genomic change and mutation, theres no guarantee they will all respond to the same therapy, she says.Overall, precision medicine is only effective at stopping the spread of cancer in an average of 20 percent of cancer patients treated, Olugbile says, with variations by cancer. Sometimes the cancer returns because the tumor changes to resist the therapy, Patterson adds.

As doctors and researchers do more genomic sequencing, the data pool will grow and so will knowledge of what medications work most effectively against various tumor types.The more information we gather, the better well know how to treat specific patients, Patterson says.

Reimbursement from insurance companies can be a challenge. If precision treatment for a particular type of cancer hasnt been approved by the insurance industry, its difficult to get reimbursed for genomic testing, says Sue Mockus, director of product innovation and strategic commercialization at Jackson Labs.Its a catch-22. Even though a patient with pancreatic cancer could benefit from a targeted therapy, unless that patient is part of a clinical trial that would pay for the genomic testing, the patient would have to pay out of pocket, the annual cost of which can run into the hundreds of thousands of dollars. If you do have a mutation identified and your physician wants to give you the medication off label, you have to fight with the insurance company, Mockus says.

Experts have suggested a value-based approach to precision medicine, reports the International Journal of Public Health. This means policy decisions about reimbursement and investment in research and development will factor in how long patients lives are prolonged and the quality of those lives, the Journal reports.

Oncologists also offer cancer patients immunotherapy, another form of personalized medicine, Patterson says. Theyre using diagnostic tests on tumors, independent of genomic sequencing, to determine if their tumor profiles make them a good immunotherapy candidate. Immunotherapy is approved for multiple tumor types, as long as they have certain markers, she says.

Former President Jimmy Carter became cancer free after receiving radiation and immunotherapy to treat the melanoma that had spread to his brain and liver. While immunotherapy can cure cancer for some, its only effective about 20 percent of the time, Olugbile says. It varies a bit by cancer, with some cancers having a higher success rate, he adds.

Through a collaboration with Memorial Sloan Kettering, Hartford HealthCares Advanced Disease Clinic was scheduled to open this spring to give patients even more options, he says. If targeted therapies and immunotherapies dont work or are not a match for patients, doctors will look for suitable clinical trials that offer potential treatments, Olugbile says.Our goal is to create awareness on two fronts, one is among the doctors. Yes, we are available to help if patients have gone through standard of care who didnt respond, he says. Its also an option for patients who want to be treated with precision medicine closer to home. The goal is to make it available so they dont have to go to New York or Boston, he says. Its right here in Hartford and hopefully at other cancer centers over time.

From Yale, Herbst leads a clinical trial through the National Cancer Institute where he and his team are trying to match the right patient to the right drug.Every tumor is getting sequenced. Thats accelerating the field. The sequencing techniques have gotten cheaper and faster, so we can analyze them at the point of care, Herbst says. This is why clinical trials are so important. Whats a clinical trial today is standard of care tomorrow.

In a study published in the journal Science Translational Medicine, a multi-institutional research team including a Connecticut doctor developed an advanced method to analyze existing data from thousands of clinical trials, comparing which genes FDA-approved drugs work against to the genes active in pediatric brain tumor patients. This sped up the lengthy process of developing cancer drugs.

Dr. Ching Lau, head of the oncology-hematology division at Connecticut Childrens Medical Center and the pediatric oncology-hematology department at UConn School of Medicine, is accessing the World Community Grid, an IBM-funded program that allows researchers worldwide to perform tens of thousands of virtual experiments. Instead of screening thousands and thousands of compounds to try to find a potential drug, we found we could use genomics data already available and do a more systems-approach analysis to figure out the predominant pathways driving the tumor cells, Lau, professor at The Jackson Laboratory, says in an email. Then we asked if there were any existing FDA-approved drugs that could potentially modulate those pathways.

The researchers identified eight drugs that could potentially fight medulloblastoma (MB) tumors, the most common malignant brain tumor in children. One of the drugs showed an increased survival rate in mice with MB tumors, and a clinical trial is being pursued.

Personalized medicineand heart disease

Precision medicines applications have expanded beyond cancer care. At first, much heart disease research relied on a genetic analysis of whether someone was predisposed to a disease. Thanks to a growing database of patient information that is shared worldwide, researchers can mine huge data sets with hundreds of thousands of cases for patterns and abnormalities that lead to discoveries, says Beth Taylor, associate professor of kinesiology at UConn and director of exercise physiology research in cardiology at Hartford Hospital. Researchers and clinicians know that about half the people who have heart attacks dont have the typical risk factors such as high blood pressure, obesity and diabetes. To determine why physically active people with healthy diets have heart attacks, researchers are using precision medicine to comb through large studies to find small predictors, Taylor says. Often the influence of any one factor is hard to detect unless you have a big sample size, she says.

The National Institutes of Health requires grant recipients to share their data to a national registry so that researchers have access to big data, she says. (Personal information such as date of birth, name and address are removed from files used for research studies.)

When we first began to really measure genetic variations, it was believed that was going to be the big hope in treatment, Taylor says. But genes are complex and environmental factors modify genetics for multiple generations.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment, she says. Many of us would say that this concept of big data is as or more important than genetic risk. Genetic risks are not the whole picture.

For the first time ever, weve got wide-scale computing ability to analyze huge data points. This can better allow us to predict disease progression and optimize treatment.

Progress with diabetes

Precision medicine is not widely used in the treatment ofdiabetesin the U.S., except when it comes to a rare form of diabetes called neonatal diabetes mellitus. While type 1 and type 2 diabetes are controlled by two or more genesand additional genetic factors,neonatal diabetes mellitus involves a single gene and develops in babies under 6 months old.

Through genetic testing of babies with elevated blood sugar levels,researchers learnedthat about half the patients have gene mutations that respond well to a pill used to treat type 2 diabetes and they dont need to be on insulin for the rest of their lives like type 1 diabetics, says Karel Erion,director of research stewardship and communications for the American Diabetes Association.

When infants show signs of type 1 diabetes at Yale New Haven Childrens Hospital or Connecticut Childrens Medical Center, they are automatically tested for neonatal diabetes, hospital doctors say.

An example of precision medicine as a predictor of disease is the TrialNet database, which uses genetic testing to determine whether the relatives of those with type 1 diabetes have two or more of the five diabetes-related autoantibodies (proteins produced by the immune system directed against the persons own proteins) linked to increased risk of developing type 1 diabetes. Type 1 diabetics must take insulin for the rest of their lives to survive, and theres no known way to prevent the autoimmune disease. Type 1 diabetes, formerly called juvenile diabetes, typically strikes children and adolescents, causing the pancreas to stop producing insulin, a hormone needed to process sugar, or glucose, from food. Type 2 diabetes was formerly known as adult-onset diabetes, but the disorder is being seen in more children, thought to be the result of a rise in childhood obesity. Screening identifies the early stages of the disease years before any symptoms appear, according to the TrialNet website.

In a study published in the New England Journal of Medicine, researchers from the TrialNet Study Group, led by Yale Universitys Dr. Kevan Herold, found that an experimental medication delayed the onset of type 1 diabetes in high-risk participants by two years compared to the control group. The disease was diagnosed in 43 percent of the participants who received the medication, teplizumab, and 72 percent of those who received the placebo.

Alzheimers disease and dementia

Only 1 to 3 percent of the 5 million people living with Alzheimers disease have a genetic mutation that leads to whats called genetic or familial Alzheimers. But one in three older adults will eventually develop some form of dementia, says Rebecca Edelmayer, the Alzheimers Association director of scientific engagement.

Like other diseases that strike large segments of the population, researchers rely on big data to learn about Alzheimers and which genes play a role in who gets it.Researchers have learned that there are several risk factors that contribute to dementia, she says. Specifically, the presence of heart disease, high blood pressure, diabetes, social and cognitive isolation, poor nutrition and the level of education, can contribute to cognitive decline, she says.

Scientists from around the world share research data and draw from data in the Global Alzheimers Association Interactive Network, she says.The field has made some dramatic advances in understanding of how genetics play a role and how other underlying diseases play a role, Edelmayer says. We need to give doctors evidence-based recommendations.

Read more here:
For cancer treatment and more, genetic-based precision medicine holds a lot of promise - Connecticut Magazine

Recommendation and review posted by Bethany Smith

What makes the coronavirus pandemic unlike any other collective tragedy is that we can't commiserate together.

Post-layoff drinks at a dive bar near the office; embracing someone you haven't seen in months; pats on the back these are seemingly small comforts that have morphed into luxuries in the past few months.

While there are many things I miss about the Before, these touches of comfort are high on the list. As we round the corner into another month of social distancing I find myself thinking about touch constantly. One look at dating apps or porn sites and I know I'm not alone in that.

The phrase "touch starved" might once have sounded dramatic, evoking Victorian-era courting where couples couldn't even bear witness to each other's ankles. In a time where I haven't high-fived let alone hugged someone in months, though, it doesn't sound overdramatic at all.

While there's limited research on "touch starvation" itself, according to Dr. Natasha Bhuyan, MD, a practicing family physician in Phoenix, Arizona, there's emerging touch research that emphasizes its positive impact. "Physical touch activates brain neurotransmitters that can lift our mood, reduce stress, and even improve sleep quality," she said.

Dr. Lori Whatley, clinical psychologist and author of Connected and Engaged, reaffirmed those benefits. "As humans we are wired for connection, and connection also means touch," she said. "Touch with other humans is at the foundation of connection and an essential part of our being and forming healthy relationships."

Unfortunately, many are currently going without any physical connection for months on end. A lack of touch intensifies feelings of isolation, said Dr. Mitchell Hicks, core faculty in Walden University's PhD in Clinical Psychology program. When we can't touch anyone it leaves the impression that we lack that connection we're wired for, that we're truly alone.

"For many, touch from a loved and trusted person increases their visceral sense of connection and soothes them," said Hicks. "No amount of videoconferencing can really make up for that."

It's not just that touch gives the impression of connection, either. Touch actually has an impact on the brain. Humans deprived of connection experience a decrease in oxytocin a hormone known to increase positive feelings and a simultaneous increase in the stress hormone cortisol, explained Dr. Alexis Parcells, MD. High levels of cortisol can lead to a slew of physical and mental health problems, such as increased blood pressure.

"People suffering with touch deprivation report high rates of depression, anxiety, and insomnia," said Parcells.

"People suffering with touch deprivation report high rates of depression, anxiety, and insomnia."

Despite the consequences of lack of touch, there is good news. You can do something to help and I don't mean stopping social distancing. (Do not stop social distancing.) The benefit of touch has to do with moving the skin, said Dr. Tiffany Field, founder and director of the Touch Research Institute said in an interview with To the Best of Our Knowledge. Moving the skin stimulates the brain. This means that exercise, such as yoga or dance, can produce some of the benefits we see from touch.

Furthermore, it's okay to go months without touch if you're taking care of your mental health in other ways, according to Bhuyan. While there's no "real" substitute for human touch, there are activities you can do to give the same benefits.

While exercise can give you some of the physical benefits, it doesn't do much when it comes to creating that connection with your loved ones. Bhuyan suggests exercising with a friend over video while it seems silly, it can actually be beneficial. "The mutual body movement can create a powerful connection," said Bhuyan. "Its also important to invest in your own self-care and mindfulness."

Parcells suggested any virtual meetup, not just working out. While it's not the same as meeting in person, it still has a positive impact. Parcells said, "Research has shown that a virtual connection is about 80% as effective in increasing the release of oxytocin as seeing that same person face-to-face."

Whatley reiterated, "When we connect personally with others via FaceTime we can release oxytocin and lower stress." This is exactly the opposite of what occurs when we lack touch.

Another suggestion of Parcells has already been heeded by people across the United States: adopting a pet. "Time and time again," said Pacells, "Studies have shown pets to be therapeutic during a stressful time." Not only do they provide comfort, but they're a tactile substitute for human interaction.

As monks have demonstrated over millennia, we won't die from not having been touched in a while. There's no direct substitute from human touch, but through exercise and speaking to our loved ones even virtually we can maintain some of these benefits. Maybe we don't have to be touch starved; maybe we just need a little nosh.

Read the rest here:
The real impact of not having been touched in months - Mashable

Recommendation and review posted by Bethany Smith

Updated: May 26, 2020 7:57:00 pm

By Dr Shweta Goswami

In the past few decades, Polycystic ovary syndrome (PCOS) has emerged as one of the leading and most talked about health issues among women who are in their reproductive phase i.e. in the age group of 16 to 40 years. Speaking of the statistics, the problem affects 1 out of 10 women globally. If we talk about India alone, PCOS has a prevalence of nearly 20 per cent with one in five women being affected by it.

It is advisable that with the current lockdown, it is important to manage your PCOD or PCOS symptoms. PCOS is a problem triggered by elevated levels of the androgen hormones in a female body. Since androgen is mainly a male hormone that plays a vital role in the development of traits like facial and body hair growth, PCOS is likely to induce the same traits in women. Some of the common symptoms that indicate PCOS include:

*Irregular menstrual cycles with a gap of more than 35 to 40 days between two consecutive periods.*Acne-breakout on the face, chest and back.*Excessive hair loss and dandruff.*Dark patches in areas around the neck, groin and under the breasts.*Persistent mood swings and anxiety.*Unhealthy weight gain.

Read| How to get pregnant: A gynaecologists guide to boosting your fertility

To understand how PCOS affects your ability to conceive, it is very important to first understand these two terms fertility and ovulation. Fertility refers to the capability to reproduce i.e. to conceive a child naturally, whereas ovulation is a part of the mensuration cycle marked by the monthly release of an ovum (female gamete) from the ovaries. Regular and healthy ovulation is extremely important for female fertility.

Since PCOS interferes with the normal mensuration cycle, it is likely to disrupt the process of ovulation and negatively impact fertility. This happens because the ovaries are not able to release the ovum and even if they do, elevated levels of hormones like testosterone and estrogen affect the egg quality; thereby increasing the chances of infertility, miscarriage and stillbirth. PCOS can also prevent the uterine lining from developing properly, thereby hindering the implantation of the matured egg.

Read| How to calculate your pregnancy in weeks and months

This is a question that concerns almost every woman who has been detected with PCOS as it is one of the leading causes of female infertility. The problem can be easily tackled by adapting to healthy lifestyle modifications and simple medication.

So, the answer to this question is yes, it is possible to conceive a child even after being detected with PCOS, provided you opt for the treatment and stick to a healthy lifestyle.

Read| The challenges for fertility treatment in India

Here are a few tips that can help you to manage PCOS effectively during this current lockdown:

Keep your weight under check- The bond between obesity and PCOS is inseparable. Approximately 40 to 80 per cent of women suffering from PCOS are either obese or overweight. The reason behind this is that women with PCOS have an increased resistance to insulin owing to which they gain weight very easily and find it quite difficult to get rid of the same. Studies have shown that even 10 per cent weight loss can significantly improve ovulation and fertility. Here is what you need to do:

Whatever goes inside our body has a direct impact on our health. It is very important to have a balanced and healthy diet, making sure that you are not missing out on any important nutrients. You can easily get a personalized diet plan from a dietician which consists of all the haves and have nots. Diet management is very important. Since junk food is not easily available due to the lockdown use this as an opportunity to lose weight by shunning high-calorie foods and going for oats, dalia, and poha.

Take your medication on time- For women who find it rather difficult to lose weight naturally, certain medication may be prescribed for assisting in weight loss by decreasing insulin resistance. However, the medication alone will not be effective if you do not resort to healthy lifestyle changes.

Indulge in physical activities- A sedentary lifestyle promotes obesity. At least 150 minutes of exercise per week is required to keep your weight under check. You can join a gym or perform simple mat exercises at home depending upon your convenience.

Stress management A happy life is key to a healthy life. Excessive stress and strain can have a very negative impact on your reproductive health by releasing stress hormones as well as triggering problems like stress-eating which eventually lead to obesity.Maintain a balance between your work and personal life.

Here are some other tips to keep in mind:

*Indulge in activities that you love to do*Focus on self-love*Get enough sleep*Exercise regularly*Go out with family and friends

The mainstay of treatment in PCOS, after lifestyle modification is ovulation induction and follicular monitoring, to correct the problem of egg development. Your physician will be able to guide you on the treatment module depending upon the level of PCOD in your body. This is helpful for patients to understand their ovulation cycles before opting for other treatment options like IVF. It is important to note that in certain rare cases women might still find it difficult to conceive after the treatment. Such women can opt for assisted reproduction methods like IVF (In Vitro Fertilisation). The procedure is carried out by inducing artificial fertilization of male and female gametes using a combination of medicines, therapies and surgical procedures.

(The author is associate Director, fertility, Cloudnine Group of Hospitals, Noida.)

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Does PCOS affect your ability to conceive? - The Indian Express

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How myeloma promotes bone loss

Multiple myeloma can lead to bone loss by reducing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts. Using a combination of single-cell RNA sequencing, in vitro coculture, and experiments with human myeloma cells and MSCs in mice, Liu et al. demonstrated how direct contact between myeloma cells and MSCs shifted the balance of MSC differentiation to favor adipogenesis over osteoblastogenesis. Integrin 4 on the surface of myeloma cells activated the adhesion molecule VCAM1 on MSCs, leading to protein kinase C 1 (PKC1)dependent repression of the E3 ubiquitin ligase MURF1 and subsequent stabilization of the adipocyte transcription factor PPAR2. These findings suggest a possible avenue for preventing or treating myeloma-induced bone loss in patients.

The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the 4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule1 (VCAM1) on MSCs, leading to the activation of protein kinase C 1 (PKC1) signaling and repression of the muscle ring-finger protein-1 (MURF1)mediated ubiquitylation of peroxisome proliferatoractivated receptor 2 (PPAR2). Stabilized PPAR2 proteins enhanced adipogenesis and consequently reduced osteoblastogenesis from MSCs, thus suppressing bone formation in vitro and in vivo. These findings reveal that suppressed bone formation is a direct consequence of myeloma-MSC contact that promotes the differentiation of MSCs into adipocytes at the expense of osteoblasts. Thus, this study provides a potential strategy for treating bone resorption in patients with myeloma by counteracting tumor-MSC interactions.

More than 80% of patients with multiple myeloma suffer from bone destruction, which greatly reduces their quality of life and has a severe negative impact on survival (1). New bone formation, which usually occurs at sites of previously resorbed bone, is strongly suppressed in patients with myeloma, and bone destruction rarely heals in these patients (2). Therefore, prevention of bone disease is a priority in myeloma treatment, and understanding the mechanisms by which myeloma cells disturb the bone marrow (BM) is fundamental to myeloma-associated bone diseases.

Osteoblasts originate from mesenchymal stem cells (MSCs) and are responsible for bone formation. It has been reported that myeloma cells inhibit MSC differentiation into mature osteoblasts (35). Osteoblasts and adipocytes arise from a common MSC-derived progenitor and exhibit lineage plasticity, which further complicates the relationship between these two cell types in myeloma cellinfiltrated BM (6). Traditionally, initiation of adipogenesis and osteogenesis has been widely regarded as mutually exclusive, and factors that inhibit osteoblastogenesis activate adipogenesis and vice versa (7). Previous studies have demonstrated that MSCs differentiate into either adipocytes or osteoblasts depending on the stimulator (8), and adipocytes transdifferentiate into osteoblasts in patients with several benign diseases (9). However, the underlying effects of myeloma cells on the activation of adipogenic transcriptional factors and the molecular mechanisms involved are still obscure.

Peroxisome proliferatoractivated receptor 2 (PPAR2) is a key transcription factor for the regulation of fatty acid storage and glucose metabolism (10), and it activates genes important for adipocyte differentiation and function (11). Previous findings have demonstrated that PPAR2 plays important roles not only in the activation of adipogenesis but also in the suppression of osteoblastogenesis (12, 13). In vitro coculture of MSCs from multiple myeloma patients with malignant plasma cell lines enhances adipocyte differentiation of the MSCs due to increased PPAR2 in the MSCs (14), suggesting that PPAR2 mediates myeloma-induced adipogenesis. However, the mechanism by which myeloma cells activate PPAR2 in MSCs, thereby causing MSCs to differentiate into adipocytes rather than osteoblasts, remains unclear.

In the present study, we demonstrated that myeloma cells enhanced the differentiation of human MSCs into adipocytes rather than osteoblasts by stabilizing PPAR2 protein through an integrin 4protein kinase C 1 (PKC1)muscle ring-finger protein-1 (MURF1) signaling pathway in MSCs. Our study thus provides a potential therapeutic strategy for myeloma-associated bone disease.

To determine whether myeloma cells affect MSC fate, we characterized the heterogeneity of human BMderived MSCs after exposure to myeloma cells. We cultured MSCs alone (controls) or cocultured them with myeloma cells in a 1:1 mixture of adipocyte:osteoblast (1:1 AD:OB) medium (Fig. 1A). An aliquot of cells was cultured for 48 hours and then subjected to single-cell RNA sequencing (scRNA-seq). We cultured another aliquot of cells for 2 weeks, removed the myeloma cells, and assessed the ability of the MSCs to differentiate into mature osteoblasts or adipocytes using Alizarin red-S, which stains calcium deposits, and Oil red O, which stains lipids (Fig. 1A). Trajectory analysis indicated the dynamic cellular transition processes of MSCs in vitro, in line with the in vivo MSC fates, reported by Wolock et al. (15). We observed a fate shift in MSC differentiation when MSCs were cocultured with myeloma cells (Fig. 1B). T-distributed stochastic neighbor embedding cluster analysis based on the entire transcriptome gene signature showed that both control and cocultured MSCs had specific transcriptome characteristics (Fig. 1C). After identification of genes with highly variable expression across the dataset, clusters were identified in each of the control and coculture groups (Fig. 1C). Enrichment analysis demonstrated that the adipokine signaling pathway and the mineral absorption pathway were among the 20 pathways most significantly changed in MSCs cocultured with myeloma cells (Fig. 1D). We identified clusters 0, 1, 6, and 8 in the MSCs cocultured with myeloma cells as being of adipogenic lineage because their expression of the specific markers of adipogenesis, the ADD1 and PPAR genes, were markedly higher than that of other clusters (Fig. 1E). These results demonstrated that myeloma cells at least partially increase MSC transformation into adipocytes.

(A) System for coculturing of human MSCs with the human multiple myeloma cell (MM) line MM.1S in a 1:1 mixture of adipocyte (AD) and osteoblast (OB) medium. Cells were cocultured for 48 hours and then MSC-derived cells were subjected to single-cell RNA sequencing (scRNA-seq). As a control, scRNA-seq was also performed on MSCs cultured alone in 1:1 AD:OB medium. (B) The single-cell trajectory reconstructed by Monocle in the control (Ctrl) and coculture (Coculture) groups. Each point represents a cell, and colors indicate their respective group. n = 2 independent experiments. The trajectory constructed by Monocle is in black. (C) T-distributed stochastic neighbor embedding (t-SNE) plot depicting clusters of MSCs cultured alone (Ctrl) or cocultured with MM cells. The first two dimensions are shown. Each cluster represents individual cells with similar transcriptional profiles of MSCs or different MSC lineages, with total of 10 clusters from aggregated samples of two biologically independent experiments. (D) Enrichment analysis showing the 20 most significantly changed pathways in the MSCs cocultured with MM cells. Red indicates activated pathways, and green indicates repressed pathways. (E) Distributions of unique transcripts per cell and PPARG and CEBPB gene expression in all cell clusters. The red frame shows the highest expression among the clusters. TGF-, transforming growth factor.

The coculture of MSCs and myeloma cells resulted in lower Alizarin red-S staining and higher Oil red O staining in MSCs, indicating an increase in the generation of adipocytes, compared to culture of MSCs alone (Fig. 2A). We further labeled cocultured MSCs with antibodies recognizing the osteoblast marker osteocalcin or the adipocyte marker fatty acid binding protein 4 (FABP4) and analyzed them using flow cytometry. We observed that culturing MSCs in osteoblast medium increased the osteocalcin+ population and that coculturing MSCs with myeloma cells inhibited this increase. Also, culturing MSCs in adipocyte medium increased the FABP4+ population, and coculturing them with myeloma cells further increased it. When we cultured MSCs alone in the 1:1 AD:OB medium, both the osteocalcin+ and FABP4+ populations increased, whereas coculturing MSCs with myeloma cells reduced the osteocalcin+ population but increased the FABP4+ population (Fig. 2, B and C). We obtained similar effects on osteoblastogenesis (Fig. 2D) and adipogenesis (Fig. 2E) when we cocultured MSCs with six other myeloma cell lines or with CD138+ primary myeloma cells isolated from BM aspirates from five patients with myeloma, but not with plasma cells from healthy donors (Fig. 2, F and G). Real-time polymerase chain reaction (PCR) analysis further showed lower expression of the osteoblast differentiationassociated genes alkaline phosphatase (ALP), secreted phosphoprotein 1 (SPP1), collagen type I alpha 1 chain (COL1A1), and bone gamma-carboxyglutamate protein (BGLAP; Fig. 2H) and higher expression of the adipocyte differentiationassociated genes delta-like noncanonical Notch ligand 1 (DLK1), diacylglycerol O-acyltransferase 1 (DGAT1), FABP4, and fatty acid synthase (FASN; Fig. 2I) in MSCs cocultured with ARP-1 or MM.1S myeloma cells than in MSCs cultured alone. These results demonstrate that myeloma cells directed the differentiation of MSCs preferentially toward adipocytes than to osteoblasts.

(A) Representative images of Alizarin red-S and Oil red O staining (whole wells and enlarged views) of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cell lines in MSC medium, adipocyte (AD) medium, osteoblast (OB) medium, or mixed 1:1 AD:OB medium as indicated. n = 3 independent experiments. Scale bars, 5 mm (whole wells) and 20 m (enlargements). (B and C) Flow cytometric analysis showing the percentage of osteocalcin+ (B) and FABP4+ (C) cells in cultures of MSCs alone or in direct contact with ARP-1 cells in the indicated medium. Data are representative of three independent experiments with each sample analyzed in triplicate. (D and E) Quantification of Alizarin red-S (D) and Oil red O (E) staining of MSCs cultured alone (No MM) or cocultured with the six indicated myeloma cell lines. Combined data are from three biologically independent experiments. (F and G) Quantification of Alizarin red-S (F) and Oil red O (G) staining of MSCs cultured alone or cocultured with primary myeloma cells isolated from BM aspirates of five patients with myeloma (P1 to P5) or normal plasma cells from the BM of two healthy donors (PC1 and PC2). Combined data are from n = 3 experiments using the same donor source material. (H and I) Quantitative reverse transcription PCR showing the expression of the osteoblast differentiationassociated genes ALP, SPP1, COL1A1, and BGLAP (H) and the adipocyte differentiationassociated genes DLK1, DGAT1, FABP4, and FASN (I) in cells generated by coculture of MSCs with myeloma cells relative to expression of each gene in MSCs cultured alone. Combined data are from n = 3 independent experiments. All data are means SD. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

We next investigated the mechanism of myeloma-induced shifting of MSCs from osteoblastogenesis to adipogenesis. We focused on PPAR2 because it is a key transcriptional factor for the activation of adipogenesis. scRNA-seq showed higher PPAR2 mRNA expression in MSCs cocultured with myeloma cells compared to MSCs cultured alone (Fig. 1E). Using the coculture system with MSCs and myeloma cells in a 1:1 mixture of adipocyte and osteoblast medium, we again observed the transformation of osteoblastogenesis into adipogenesis in MSCs cocultured with myeloma cells (Fig. 3A), as well as an increase in the abundance of PPAR2 in MSCs cultured with myeloma cells (Fig. 3B and fig. S1). To determine the importance of PPAR2 in MSC transformation, we added the PPAR2 antagonist G3335 to cocultures. G3335 inhibited the myeloma cellinduced increase in PPAR2 protein (Fig. 3B and fig. S1). Consistent with the Western blot results, G3335 treatment decreased Oil red O staining (Fig. 3C) and adipocyte gene expression (Fig. 3D) and increased Alizarin red-S staining (Fig. 3E) and osteoblast gene expression (Fig. 3F). These results suggest that PPAR2 mediated myeloma-induced MSC transformation into adipocytes.

(A) Representative images of Oil red O or Alizarin red-S staining of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in 1:1 OB:AD medium and treated with the PPAR2 antagonist G3335 as indicated. Scale bar, 5 mm. (B) Representative Western blot for PPAR2 in cells treated as in (A). Quantitation is presented in fig. S1. Actin is a loading control. (C to F) Quantitative analysis of Oil red O staining (C), adipocyte differentiationassociated gene expression (D), Alizarin red-S staining (E), and osteoblast differentiationassociated gene expression (F) in cells treated as in (A). Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using Students t test for paired samples (D and F) and one-way ANOVA with Tukeys multiple comparisons test (C and E).

To determine whether myeloma cells distort MSC transformation through myeloma-secreted soluble factors or cell-to-cell contact, we cocultured MSCs with ARP-1 or MM.1S myeloma cells in 1:1 AD:OB medium either together or separated by transwell inserts. We observed that the transwell coculture had a slight effect on increased Oil red O staining, whereas cell-to-cell contact coculture in the mixed medium produced much more significant boost of this staining, suggesting that direct interaction between MSCs and myeloma cells was needed for enhancing adipogenesis from MSCs (Fig. 4A). When we added supernatants collected from 24-hour cultures of ARP-1 or MM.1S cells to MSC cultures, we obtained results similar to those for the transwell coculture (Fig. 4A), reaffirming the importance of direct contact of MSCs with myeloma cells.

(A) Oil red O staining in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S myeloma cells in 1:1 AD:OB medium directly (cell-cell) or separated by transwell inserts (Trans) or in myeloma cell culture media (sup). Staining was quantified relative to the No MM condition. Representative data are from three independent experiments. (B to D) Relative Oil red O staining (B) and the relative expression of the indicated osteoblast (C) and adipocyte (D) marker genes in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S cells with or without neutralizing antibodies against integrin subunits 4, 5, V, or L. Combined data are from three independent experiments. (E) Western blot showing integrin 4 and integrin 1 in ARP-1 and MM.1S cells expressing shRNA targeting integrin 4 (4 KD) or nontargeted control shRNAs (NT Ctrl). Actin is a loading control. (Blot is a representative of three independent experiments, and blot quantitation data are presented in fig. S2C. (F to J) PPAR2 protein (F), Alizarin red-S staining (G), Oil red O staining (H), osteoblast marker gene expression (I), and adipocyte marker gene expression (J) in MSCs cultured alone or cocultured with ARP-1 or MM.1S cells expressing NT Ctrl or 4 KD shRNA. Blots in (E) and (F) are representative of three independent experiments, and blot quantitation is presented in fig. S2 (A and D). Data in (G) to (J) are means SD from n = 3 independent experiments using MSCs derived from BM aspirates of three healthy donors. Data are **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

To identify the specific molecules involved in adipocyte differentiation, we tested the effect of blocking antibodies against various integrins, which are highly expressed in myeloma cells, in cocultures of MSCs with ARP-1 or MM.1S cells in 1:1 AD:OB medium. The addition of an antibody against integrin 4but not antibodies against integrins 5, V, or L or a control immunoglobulin G (IgG)markedly reduced Oil red O staining in cocultures with both myeloma cell lines (Fig. 4B). The addition of the antibody recognizing integrin 4 to cocultures of MSCs and ARP-1 cells in the mixed medium also increased osteoblast gene expression (Fig. 4C) and decreased adipocyte gene expression (Fig. 4D) substantially more than did the addition of the control IgG. To determine whether integrin 4 affected PPAR2 production in MSCs, we infected ARP-1 and MM.1S cells with a lentivirus carrying short hairpin RNAs (shRNAs) targeting integrin 4 (fig. S2A). Integrin 4 knockdown (4 KD) reduced integrin 4 production without changing the cell viability or proliferation, whereas integrin 1 remained unchanged in ARP-1 and MM.1S cells (Fig. 4E and fig. S2, A to C). We also cocultured MSCs with control or 4 KD myeloma cells in the mixed medium. Western blot analysis demonstrated that 4 KD in myeloma cells reduced PPAR2 protein production in MSCs more than did myeloma cells expressing a nontargeting control shRNA (Fig. 4F and fig. S2D). In addition, coculture of MSCs with 4 KD myeloma cells induced higher Alizarin red-S staining (Fig. 4G) and osteoblast gene expression (Fig. 4H) but lower Oil red O staining (Fig. 4I) and adipocyte gene expression (Fig. 4J) compared to MSCs cocultured with myeloma cells expressing the control shRNA.

Because vascular cell adhesion molecule1 (VCAM1) is a major ligand of integrin 4, we investigated whether it mediated myeloma-induced MSC transformation by adding a blocking antibody against VCAM1 or control IgG to MSC and myeloma cell cocultures. Addition of the antibody, but not IgG, increased Alizarin red-S staining (Fig. 5A) and osteoblast gene expression (Fig. 5B) but decreased Oil red O staining (Fig. 5C) and adipocyte gene expression (Fig. 5D) in MSCs. To determine whether binding of integrin 4 to VCAM1 induced an increase in PPAR2, we constructed MSCs with reduced expression of VCAM1 using a lentivirus carrying VCAM1 shRNAs (VCAM1 KD) (Fig. 5E and fig. S3A) and cocultured myeloma cells with control or VCAM1 KD MSCs. Western blot analysis showed that cocultured VCAM1 KD MSCs had reduced PPAR2 protein production compared to cocultured MSCs expressing nontargeting control shRNA (Fig. 5F and fig. S3B). We also found that VCAM1 KD in MSCs considerably abrogated myeloma-induced suppression of osteoblastogenesis and activation of adipogenesis, because Oil red O staining and adipocyte gene expression decreased significantly (Fig. 5, G and H), whereas Alizarin red-S staining and osteoblast gene expression both increased (Fig. 5, I and J).

(A to D) Alizarin red-S staining (A), Oil red O staining (B), and real-time PCR analysis of the expression of osteoblast (C) and adipocyte (D) marker genes in MSCs cultured alone (No MM) or cocultured with ARP-1 or MM.1S myeloma cells in the presence of a neutralizing antibody against VCAM1 or IgG (control). Data are from n = 3 independent experiments. (E) Western blotting analysis showing VCAM1 in the MSCs infected with a lentivirus carrying nontargeted control shRNAs (NT Ctrl-MSCs) or human VCAM1 shRNAs (VCAM1 KD-MSCs). Actin is a loading control. Blot is a representative of three independent experiments, and blot quantitation is presented in fig. S3A. (F to J) PPAR2 protein (F), adipocyte gene expression (G), Oil red O staining (H), Alizarin red-S staining (I), and osteoblast gene expression (J) in MSCs expressing NT Ctrl or VCAM1 shRNAs cocultured with ARP-1 or MM.1S cells in 1:1 OB:AD medium. Blot in (F) is a representative of three independent experiments, and blot quantitation is presented in fig. S3B. Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test except in (G) and (J), where Students t test for paired samples were used.

Because VCAM1 stimulates intracellular signaling that results in the activation of protein kinase C (PKC), we examined PKC activation in cocultures. Coculture of myeloma cells and MSCs enhanced the phosphorylation of PKC1 but did not affect phosphorylation of the PKC isoforms PKC, PKC, or PKC/ or the abundance of total PKC and reduced the phosphorylation of PKC and PKC (Fig. 6, A and B). Addition of the PKC inhibitor Go6976 to the cocultures markedly reduced PKC1 phosphorylation and PPAR2 protein in MSC cells cocultured with ARP-1 or MM.1S cells (Fig. 6C and fig. S4). Functionally, treatment of cocultures with Go6976 reduced Oil red O staining and increased Alizarin red-S staining (Fig. 6, D to F). Together, these results demonstrate that myeloma cells activated PPAR2 in MSCs and induced MSC differentiation into adipocytes rather than osteoblasts through the integrin 4-VCAM1-PKC1 pathway.

(A) Western blotting for all phosphorylated PKCs (p-PKC pan), the indicated phosphorylated PKC isoforms, and total PKC in MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells. The abundances of total PKC served as protein loading controls. (B) Quantification of the phosphorylation of PKC isoforms in MSCs cocultured with myeloma cells in (A) relative to the MSC-only control. The cutoff values are fold change more than twofold or less than 0.5-fold. (C) Western blotting for phosphorylated PKC1, total PKC, and PPAR2 in MSCs cocultured with ARP-1 or MM.1S cells in the presence of the PKC inhibitor Go6976 or DMSO (control). Actin is a loading control. Blot is a representative of three independent experiments, and blot quantitation is presented in fig. S4. (D) Representative images of Oil red O staining and Alizarin red-S staining of MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in the presence of the PKC inhibitor Go6976 or DMSO (control). Scale bar, 5 mm. (E and F) Quantification of Oil red O staining (E) and Alizarin red-S staining (F), in cells treated as in (D). Data are means SD from n = 3 independent experiments. *P 0.05 and **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test.

Because a key mechanism of regulation of PPAR2 is its ubiquitylation-dependent proteasome-mediated degradation (16), we added the proteasome inhibitor MG132 to cultures of MSCs. We found that treatment with MG132 increased the presence of PPAR2 protein in MSCs in a time- and dose-dependent manner (Fig. 7A and fig. S5A). MG132 treatment causes the accumulation of ubiquitylated PPAR2 in MSCs, and coculturing these cells with myeloma cells reduced PPAR2 ubiquitylation (Fig. 7B and fig. S5B). However, the addition of a neutralizing antibody against VCAM1 to the cocultures restored ubiquitylation of PPAR2 (Fig. 7C and fig. S5C). These results suggested that myeloma cells activate PPAR2 in MSCs through inhibition of its ubiquitylation.

(A) Western blotting analysis for PPAR2 in MSCs cultured in 1:1 OB:AD medium and treated with the proteasome inhibitor MG132 for the indicated amounts of time. Actin is a loading control. (B) Immunoblotting (IB) for ubiquitin in PPAR2 immunoprecipitates (IP) from MSCs cultured alone or cocultured with ARP-1 or MM.1S myeloma cells in the presence of MG132. (C) Western blotting for ubiquitin in PPAR2 immunoprecipitates from MSCs cocultured with ARP-1 or MM.1S cells in the presence of MG132 and an antibody against VCAM1 or IgG (control). (D) Expression of the E3 ligaseencoding genes USP7, MURF1, MKRN1, CRBN, CRL4B, and TRIM23 in MSCs cocultured with myeloma cells relative to the expression in MSCs cultured alone (No MM). Data are means SD from n = 3 independent experiments. **P 0.01. P values were determined using one-way ANOVA with Tukeys multiple comparisons test. (E) Western blotting for USP7, MURF1, and MKRN1 in MSCs cultured alone or cocultured with myeloma cells. (F) Western blotting for MURF1 in MSCs cocultured with ARP-1 or MM.1S myeloma cells and treated with Go6976 or DMSO (control) as indicated. (G) Immunoblotting for MURF1 or PPAR2 in PPAR2 or MURF1 immunoprecipitates, respectively, from MSCs. IgG immunoprecipitates and whole-cell lysate (input) were used as controls. (H) Immunoblotting for ubiquitin in PPAR2 immunoprecipitates from MSCs expressing nontarget control (NT Ctrl) or MURF1 shRNAs in the presence of MG132. Each blot is representative of n = 3 independent experiments, and blot quantitation is presented in fig. S5.

To investigate the mechanism by which myeloma cells inhibited PPAR2 ubiquitylation, we examined the E3 ubiquitin ligases known to induce ubiquitylation of PPARs (17). Among the tested ligases, we found that MURF1 mRNA (Fig. 7D) and MURF1 protein (Fig. 7E and fig. S5D) were reduced in MSCs cocultured with myeloma cells. Addition of the PKC inhibitor Go6976 to the cocultures increased MURF1 protein in MSCs (Fig. 7F and fig. S5E), indicating that myeloma cells inhibited MURF1 production in MSCs through the PKC signaling pathway. Because the effects of MURF1 on PPAR2 ubiquitylation are unclear, we examined the interaction of these two proteins in MSCs. Co-immunoprecipitation of PPAR2 from MSCs demonstrated an interaction between MURF1 and PPAR2 (Fig. 7G), and knockdown of MURF1 in MSCs reduced the ubiquitylation of PPAR2 (Fig. 7H and fig. S5, F and G). These results demonstrate that myeloma cells activated PPAR2 in MSCs by reducing MURF1-mediated ubiquitylation of PPAR2.

To test the influence of myeloma cells on MSC differentiation in vivo, we established an extramedullary bone formation model in mice. Matrigel containing MSCs and Matrigel containing MSCs plus -irradiated ARP-1 cells were subcutaneously implanted into the right and left flanks of nonobese diabetic/severe combined immunodeficiency/interleukin-2rnull mice, respectively (Fig. 8A). Each sample also included human endothelial colony-forming cells (ECFCs) to stimulate blood vessel formation in the implant. In line with results of a previous study (18), we observed lower bone density in the extramedullary bones that formed in the left flanks, which were implanted with MSCs plus irradiated myeloma cells, compared to the extramedullary bones that formed on the right side, which were implanted with MSCs alone (Fig. 8A). Furthermore, we examined subcutaneous tissues on both sides of mice using histologic or immunohistochemical staining with antibodies against the mature osteoblast marker osteocalcin, the adipocyte marker perilipin, the myeloma marker CD138, and human MURF1. We observed lower numbers of new bones and osteocalcin+ osteoblasts and higher numbers of perilipin+ adipocytes in tissues on the sides of mice implanted with both MSCs and myeloma cells, reduction of MURF1 abundance in tissues on the sides of mice implanted with MSCs alone, and CD138+ cells only in tissues on the sides of mice implanted with myeloma cells (Fig. 8B).

(A) Representative images of subcutaneous tissues and bone density in mice implanted with human MSCs plus ECFCs in the right flank and MSCs plus ECFCs mixed with ARP-1 myeloma cells in the left flank. The arrows indicate bone formation in subcutaneous tissue, and the bars indicate bone density. (B) Representative hematoxylin and eosin (H&E) and immunohistochemical staining for the osteoblast marker osteocalcin, the adipocyte marker perilipin, the myeloma cell marker CD138+, and MURF1 of the subcutaneous tissues from (A). Scale bar, 20 m. Data represent n = 3 independent experiments with five mice each. (C) Expression of MURF1 in MSCs from BM aspirates from 12 patients with myeloma and 12 age-matched healthy donors relative to expression in a randomly selected sample from healthy donor. Data are from n = 3 experiments using the same donor source material. *P 0.05. P values were determined using Students t test. (D and E) Western blotting for MURF1 and PPAR2 (D) and Alizarin red-S and Oil red O staining (E) in MSCs from BM aspirates from three healthy donors and three patients with myeloma. Blots and images are representative of three experiments using the same donor materials, and blot quantitation is presented in fig. S6. Scale bars, 5 mm (whole wells) and 100 m (enlargements). (F) Quantitation of Alizarin red-S and Oil red O staining in the cultures of MSCs from BM aspirates from healthy donors and patients with myeloma in (C). Data are from n = 3 experiments using the same donor source material. P values were determined using Students t test. OD490, optical density at 490 nm.

We also isolated MSCs from the BM of 12 healthy human donors and 12 age-matched patients with myeloma and found markedly lower MURF1 mRNA expression in patient-derived MSCs compared to healthy donor MSCs (Fig. 8C). Western blotting validated the negative correlation between MURF1 and PPAR2 at the protein level in MSCs isolated from 3 of 12 samples in both groups (Fig. 8D and fig. S6). When we cultured these primary MSCs in 1:1 AD:OB medium, we found lower Alizarin red-S staining and higher Oil red O staining in cultures of patient-derived MSCs than in cultures of healthy donor MSCs (Fig. 8, E and F). These findings demonstrate that myeloma cells reduced MURF1 in MSCs and skewed MSC differentiation to favor adipogenesis, resulting in the suppression of osteoblast-mediated new bone formation in myeloma-bearing mice and in cells from patients with myeloma.

Using scRNA-seq, an in vitro coculture system, and mouse models, we demonstrated that myeloma cells shift the differentiation of MSCs into adipocytes rather than osteoblasts. Mechanistic studies revealed that integrin 4 on myeloma cells bound to VCAM1 on MSCs and inhibited ubiquitylation of PPAR2 through PKC-MURF1 signaling. The resulting increase in PPAR2 enhanced adipogenesis and suppressed osteoblastogenesis from MSCs. Thus, our study elucidates a previously unknown mechanism underlying myeloma-induced suppression of osteoblast-mediated bone formation and provides a potential approach for treating bone resorption in patients with myeloma.

Suppressed differentiation of osteoblasts is well known to be a key reason for bone loss and skeleton-related events in patients with myeloma (19). The molecules and pathways involved in myeloma-induced suppression of osteoblastogenesis include the Wnt signaling inhibitor Dickkopf-related protein 1 (DKK-1) (2, 20). However, antibody-mediated blocking of DKK-1 function cannot restore new bone formation completely or heal myeloma-induced resorbed bone, suggesting that additional factors expressed by myeloma cells critically affect bone formation. In the present study, we demonstrated that the 4 subunit of integrin, which is highly abundant in myeloma cells, promoted MSC differentiation into adipocytes, demonstrating that adhesion moleculesbut not soluble factorsproduced by myeloma cells primarily mediated the shift from osteoblastogenesis to adipogenesis. Integrin 41, also known as very late antigen-4, is a cell surface heterodimer present on malignant cells in patients with many types of cancer, including myeloma (21). It is a key adhesion molecule that acts as a receptor for the extracellular matrix protein fibronectin and the cellular receptor VCAM1. Interaction between integrin 41 and VCAM1 can activate mature osteoclast formation in patients with bone-metastatic breast cancer (22). In patients with multiple myeloma, this interaction promotes the secretion of interleukin-7 by tumor cells, which inhibits the expression of RUNX-2, which encodes a transcription factor that is essential for osteoblast differentiation, and RUNX-2 transcriptional regulatory activity in MSCs (23). This interaction also increases DKK-1 secretion by myeloma cells. Adding to these known mechanisms, we revealed that binding of myeloma cell integrin 41 to VCAM1 on the MSC surface activated the PKC signaling pathway. We also identified activation of PKC1, suppression of the downstream mediator MURF1, and the fundamental roles of such signaling pathways in the promotion of the MSC-derived adipocyte lineage. PKCs are also reportedly associated with Jagged-Notch signaling pathways, and they can regulate the transition of embryonic stem cells differentiating into postmitotic neurons (24). Some immunomodulatory drugs, such as lenalidomide, may affect osteoblast differentiation through this pathway (25), indicating the important role of Jagged-Notch in osteoblast differentiation from MSCs. We may further investigate their impacts and mechanisms on myeloma-induced the shift of MSC fates in our next studies.

BM adipocytes are recognized as important regulators of bone remodeling rather than just being inert filler cells (26, 27). Normal BM adipocytes have been shown to be reprogrammed by myeloma cells and gain the ability to resorb bone in myeloma patients in remission (13). Focusing on the determination of MSC fate in this study, we investigated the molecular mechanism underlying the shift from osteoblastogenesis to adipogenesis induced by myeloma cells. Lineage-tracing experiments have revealed that adipocytes can also originate from osterix-positive cells and are closely related to osteoblasts (28). Chan et al. (29) reported that BM adipocytes were derived from a progenitor cell that was also the progenitor for osteoblasts. In addition, Gao et al. (30) reported plasticity between BM adipocytes and osteoblasts and potential transdifferentiation and transformation between these two identities after initiating differentiation. Despite this new knowledge about the balance between osteoblastogenesis and adipogenesis, how myeloma cells regulate this balance and transformation of MSCs is still unclear.

scRNA-seq can identify subpopulations using the transcriptome to avoid the complicated isolation procedures after cell-cell contact culture (15). We found that MSCs could be naturally divided into two populations by transcriptomic data, and at least one cluster of MSCs cocultured with myeloma cells highly expressed adipocyte marker genes. Coculture of myeloma cells pushed MSC differentiation toward adipocytes rather than osteoblasts, resulting in the suppression of bone formation in the in vivo extramedullary bone assay. Because MSCs are pluripotent stem cells capable of differentiation into other cell types, such as chondrocytes and skeletal muscle cells (31), whether myeloma cells affect MSC transformation into these cell types instead of osteoblasts remains unclear. It is possible that the observed differentiation from MSC to adipocyte in the presence of myeloma cells might have been rather the result of a differentiation of MSCs into osteoblasts followed by a transdifferentiation from osteoblast into adipocyte. Further investigation is needed to address this possibility.

Like other transcription factors and coregulators, PPAR2 can undergo posttranslational modifications, such as phosphorylation, acetylation, and SUMOylation (32). Researchers have identified the key enzymes and target amino acid sites involved in these modifications, but modification of PPAR2 by ubiquitylation, especially that induced by myeloma cells, is still unclear. Many E3 ligases, such as MURF1 and makorin ring finger protein 1 (MKRN1), are reported to be regulators of ubiquitylation of PPAR proteins (17, 3335), whereas investigators have identified only polyubiquitylation at Lys184 and Lys185 (K184/185) mediated by MKRN1 (16). In the present study, we demonstrated that the E3 ligase MURF1 contributed to PPAR2 ubiquitylation, and inhibition of MURF1 by myeloma cells reduced PPAR2 ubiquitylation, leading to enhanced protein stability in MSCs. MURF1 contains a canonical N-terminal RING-containing E3 ligase that is required for its ubiquitin ligase activity (36). Others have reported dysregulation of MURF1 in experimental models of fasting, diabetes, cancer, denervation, and immobilization (37). However, none have reported the substrate proteins, such as PPAR2, that are targeted for proteasomal degradation by MURF1 in patients with myeloma bone disease. Although the amino acids in PPAR2 that MURF1 targets remain to be identified, we demonstrated that the reduced MURF1 production in MSCs induced by myeloma cells was critical for the inhibition of PPAR2 ubiquitylation and thus stabilization of the PPAR2 protein. Other posttranslational modifications may also regulate PPAR2 protein, especially SUMOylation, which was not addressed in the current study. For example, the transcriptional activity of PPAR2 can be inhibited by SUMOylation at Lys107 to regulate insulin sensitivity (38), and growth differentiation factor 11 promotes osteoblastogenesis through enhancement of PPAR2 SUMOylation (39). A logical next step could be the investigation of the role of SUMOylation in myeloma-induced MSC transformation and how it interplays with the mechanisms described here.

In summary, our results shed light on the cross-talk between myeloma cells and MSCs and the impact of this interaction on the determination of the MSC-derived adipocyte lineage and the suppression of osteoblastogenesis from MSCs. Myeloma cell integrin 4 promoted phosphorylation of PKC1 through VCAM1, and the activated PKC1 reduced the production of MURF1 in MSCs, leading to reduced PPAR2 ubiquitylation. Therefore, counteracting 4-VCAM1-MURF1mediated adipogenesis from MSCs may be a promising strategy to heal myeloma-induced bone resorption.

Myeloma cell lines ARP-1 and ARK were provided by University of Arkansas for Medical Sciences (Little Rock, AR, USA), and others were purchased from American Type Culture Collection. Primary myeloma cells or normal plasma cells were isolated from the BM aspirates of patients with myeloma or healthy donors using antibody-coated magnetic beads against CD138, respectively (Miltenyi Biotec Inc.) (40). The cells were maintained in RPMI 1640 medium with 10% fetal bovine serum (FBS). MSCs from BM of healthy donors or patients with myeloma were maintained and augmented in Dulbeccos modified Eagles medium (DMEM) with 10% FBS (13). Information of healthy donors and patients were listed in table S1. The study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center.

Human MSCs were generated from BM mononuclear cells from fetal bones of healthy human donors, characterized using flow cytometry, and labeled with antibodies against MSC markers (CD44, CD90, and CD166) (41). Mature adipocytes were generated from MSCs using an adipocyte medium, which was formulated of DMEM medium with 10% FBS, 1 M dexamethasone, 0.2 mM indomethacin, insulin (10 g/ml), and 0.5 mM 3-isobutyl-l-methylxanthine (41). Mature adipocytes were fixed with 4% paraformaldehyde, stained with Oil red O for 1 hour, and observed under a light microscope. Mature osteoblasts were generated from MSCs using an osteoblast medium, which was formulated of alpha MEM medium with 10% FBS, 100 nM dexamethasone, 10 mM -glycerophosphate, and 0.05 mM l-ascorbic acid 2-phosphate (42). The bone-forming activity of osteoblasts was determined using Alizarin red-S staining (43, 44). Human MSCs were cultured alone or cocultured with myeloma cells at a ratio of 5:1 in MSC medium, osteoblast medium, adipocyte medium, or 1:1 mixed of osteoblast and adipocyte medium with or without inhibitors (G3335 or Go6976) or neutralizing antibodies for 2 weeks. Addition of dimethyl sulfoxide (DMSO) served as vehicle control for inhibitor-treatment experiments, and addition of IgG served as control for antibody-neutralizing experiments. In the transwell nondirect contact model, adipocytes were seeded onto the bottom of culture wells and cocultured with the myeloma cells on the insert. In direct contact coculture system, MSCs were seeded together with the myeloma cells in the culture wells to allow direct cell-cell contact. Supernatants collected from 24-hour cultures of myeloma cells were added to the MSCs in mixed osteoblast and adipocyte medium at a ratio of 1:5. In the experiments with primary cells, MSCs were cultured in the mixed medium for a week (45) and then cocultured with primary myeloma cells isolated from BM aspirates from patients with myeloma or normal plasma cells from BM of healthy donors for another week. Medium, inhibitors, and antibodies were refreshed every 3 days. After culture, the myeloma cells were removed, and the residual cells were stained with Alizarin red-S to assess osteoblast differentiation and with Oil red O to assess adipocyte differentiation. Culture of MSCs alone served as a control.

Single-cell preparation, complementary DNA (cDNA) library synthesis, RNA sequencing, and data analysis were performed by Gene Denovo Inc. Briefly, 1 106 MSCs were plated for 6 hours, 5 106 myeloma cells were added to the MSCs directly, and the cells were cocultured in mixed culture media for 48 hours; control MSC cells were cultured alone at the same media and then mixed with myeloma cells at the same ratio just before preparation for analysis. After removal of dead cells, the cells in these groups were counted using a Countess II Automated Cell Counter, and the concentration was adjusted to 1000 cells/l. The single-cell suspensions were bar-coded labeled and reverse-transcribed into scRNA-seq library using the Chromium Single Cell 3 GEM, Library and Gel Bead Kit (10X Genomics). The cDNA libraries from two independent experiments were sequenced on the Illumina HiSeq X-Ten platform, and data were pooled for the analysis. Myeloma cells were excluded using CD138 markers. The raw scRNA-seq data were aligned, filtered, and normalized using Cell Ranger (10X Genomics) software (tables S2 to S6). The cell subpopulation was grouped by graph-based clustering based on the gene expression profile of each cells in Seurat (tables S7 and S8). Subsequent data analysis including standardization, cell subpopulation, difference of gene expression, and marker gene screening were achieved by Seurat software.

MSCs were cultured alone or cocultured with myeloma cells with or without G3335 or neutralizing antibodies for 48 hours. In some experiments, MG132 was added to the cultures 6 hours before the cell collection. Addition of DMSO served as vehicle control for inhibitor experiment; addition of IgG served as neutralizing antibody control.

Quantitative real-time PCR was performed as described (46). The primers are listed in table S9. For Western blotting, cells were lysed with 1 lysis buffer (Cell Signaling Technology), subjected to 4 to 20% gradient gel electrophoresis, transferred to, and immunoblotted with antibodies against integrin 4 (R&D Systems), integrin 1, VCAM1, PKC, MURF1, and phosphorylated isoforms of PKC along with p-PKC-pan (Cell Signaling Technology) and PPAR2 (Santa Cruz Biotechnology). The membrane was stripped and reprobed with an antibody against -actin to ensure equal protein loading, and last, signals were detected using peroxidase-conjugated secondary antibody followed by enhanced chemiluminescence system (Millipore) in the MiniChem system (Saizhi Biotech), and quantitative analysis of blots were performed using the Fiji-based ImageJ software (version 1.51n, National Institutes of Health, Bethesda, MA, USA).

Viral particles were produced by human embryonic kidney 293T cells transfected with PMD2G and PSPAX2 packaging plasmids (Addgene) together with lentivirus-expressing shRNA vectors targeting 4, MURF1, or VCAM1 (Sigma-Aldrich). Nontargeted shRNA control (Sigma-Aldrich) was used as control. Sequences for knocking down specific genes are the following: 4, 5-CCGGGCTCCGTGTTATCAAGATTATCTCGAGATAATCTTGATAACACGGAGCTTTTT-3; VCAM1, 5-CCGGGGAATTAATTATCCAAGTTACCTCGAGGTAACTTGGATAATTAATTCCTTTTTTG-3; MURF1, 5-CCGGGAAGAGGAAGAGTCCACAGAACTCGAGTTCTGTGGACTCTTCCTCTTCTTTTTG-3 or 5-CCGGGTATAATAATGCCTGGTCATTCTCGAGAATGACCAGGCATTATTATACTTTTTG-3. Supernatants carrying the viral particles were harvested 48 hours later and concentrated to a 100 volume using polyethylene glycol 8000 (Sigma-Aldrich). MSCs (1 106 cells) were seeded 6 hours before the infection. Concentrated viral particles were added to MSCs or myeloma cells, respectively, in the presence of polybrene (8 g/ml) for 12 hours. The medium was then changed, and cells were cultured for another 48 hours until further management.

Cells were harvested and lysed using NP-40 lysis buffer supplemented with complete protease inhibitors, and the supernatant was precleaned with protein G beads (Thermo Fisher Scientific) and incubated with a mouse antibody against MURF1 (Santa Cruz Biotechnology) or monoclonal rabbit antibody against PPAR2 antibody (Santa Cruz Biotechnology) at 4C overnight with protein A/G agarose beads (Thermo Fisher Scientific). The next day, the pellet was washed four times with lysis buffer and then subjected to Western blot analysis using the antibodies against PPAR2 or MURF1. IgG was used as a control and total cell lysates (5%) were used as input controls.

For a ubiquitylation assay, diluted lysates were incubated with an antibody against PPAR2 at 4C overnight after precleaning with protein G beads (Thermo Fisher Scientific). Protein G beads were added to the washed lysate/antibody mixture at 4C for 4 hours. The resin was washed and applied to Western blot analysis using an antibody against ubiquitin.

MSCs were cultured alone or cocultured with myeloma cells for 2 weeks. Abundance of FABP4 and osteocalcin was assessed by immunofluorescence using fluorescein isothiocyanate or allophycocyanin-conjugated antibodies (BD Biosciences). After staining, cells were resuspended in phosphate-buffered saline with 1% FBS and analyzed using a BD LSR Fortessa flow cytometer.

The animal experiments in the present study were approved by the MD Anderson Institutional Animal Care and Use Committee. In vivo extramedullary bone formation in nonobese diabetic/severe combined immunodeficiency/interleukin-2rnull mice was established and examined (18). Briefly, MSCs alone or a mixture of human MSCs (1.5 106) and human ECFCs (1.5 106) in 0.2 ml of Matrigel (Corning Inc.) was subcutaneously injected into the right flanks of mice. This mixture and an additional 2 105 -irradiated (5000 centigrays) myeloma cells were injected into the left flanks of the mice. At 8 weeks after implantation, subcutaneous tissues were established, and the mice were intraperitoneally injected with OsteoSense 750 to assess new bone formation in those tissues. The subcutaneous tissues were collected after the mice were sacrificed and subjected to hematoxylin and eosin or immunohistochemical staining of cells labeled with an antibody against osteocalcin (a marker of mature osteoblasts), an antibody against perilipin (a marker of mature adipocytes), or an antibody against CD138 (a marker of myeloma cells).

The subcutaneous tissues were extracted from the mice and then formalin-fixed and paraffin-embedded. Tissue sections were deparaffinized with xylene and rehydrated to water through a graded alcohol series. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide. The presence of CD138 (R&D Systems), osteocalcin, perilipin, and MURF1 (Abcam) in tissues was detected using specific antibodies. Signals were detected using secondary biotinylated antibodies and streptavidin/horseradish peroxidase. Chromagen 3,3-diaminobenzidine/H2O2 (Dako) was used, and slides were counterstained with hematoxylin. All slides were observed under a light microscope, and images were captured using a SPOT RT camera (Diagnostic Instruments).

Experimental values were expressed as means SD unless indicated otherwise. Statistical significance was analyzed using the GraphPad Prism v7.0 with two-tailed unpaired Students t tests for comparison of two groups and one-way analysis of variance (ANOVA) with Tukeys multiple comparisons test for comparison of more than two groups. P values less than 0.05 were considered statistically significant. All results were reproduced in at least three independent experiments.

stke.sciencemag.org/cgi/content/full/13/633/eaay8203/DC1

Fig. S1. G3335 inhibits PPAR2 accumulation in MSCs cocultured with myeloma cells.

Fig. S2. 4 KD in myeloma cells.

Fig. S3. VCAM1 knockdown in MSCs.

Fig. S4. PKC inhibition reduces PKC1 phosphorylation and PPAR2 abundance in MSCs cocultured with myeloma cells.

Fig. S5. Coculture with myeloma cells reduces ubiquitylation of PPAR2 in MSCs.

Fig. S6. MSCs from patients with myeloma show decreased MURF1 and increased PPAR2.

Table S1. Characteristics of patients with myeloma and healthy donors.

Table S2. Read quality control of the samples for scRNA-seq.

Table S3. Mapping quality control of aligned scRNA-seq data.

Table S4. Basic information of the aggregated samples for scRNA-seq before and after normalization.

Table S5. Information of each sample after aggregation.

Table S6. Cell quality control showing the cell numbers before and after the filtration.

Table S7. Number of cells in each subpopulation.

Table S8. Number of cells in each subpopulation of control and cocultured samples.

Table S9. Primers used in the quantitative reverse transcription PCR analysis.

Data file S1. scRNA-seq data from control sample.

Data file S2. scRNA-seq data from coculture sample.

Acknowledgments: We thank M. J. Li from Department of Genetics, Tianjin Medical University for the evaluation of our statistical analysis. Funding: This work was supported by R01 grants from NCI (CA190863 and CA193362 to J.Y.) and by the Research Scholar Grant from the American Cancer Society (127337-RSG-15-069-01-TBG to J.Y.). It was also supported by NIH/NCI (Core Labs at UT MD Anderson Cancer Center, P30CA016672) for the Small Animal Imaging and Research Histopathology Facilities. Author contributions: Z.L. and J.Y. designed all experiments and wrote the manuscript. H.L., Z.L., and J.H performed all experiments and statistical analysis. P.L. provided and interpreted patient samples. Q.T. provided critical suggestions. Conflict of interests: The authors declare that they have no competing interests. Data and materials availability: All of the data needed to evaluate the conclusions in the paper are provided in the main text or the Supplementary Materials. Stable cell lines carrying targeted shRNA are available with a materials transfer agreement between Houston Methodist Research Institute and the requesting institution.

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Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells - Science

Recommendation and review posted by Bethany Smith

IN A stark hospital room, Damian Cross waits for his 14-year-old daughter to save his life.

Shauna is less than 10km away at the Queensland Children's Hospital having her bone marrow extracted.

Despite only being a half match for her father, it was the best solution during a time when full match bone marrow was difficult to come by due to COVID-19 travel restrictions.

The family are a long way from their Coraki home where for a year Damian has been in remission from leukaemia after five rounds of chemotherapy.

"Leukaemia has come back and my only hope for cure now is my 14-year-old daughter," he said.

At Royal Brisbane Hospital with his partner Amy Rolfe by his side, the 33-year-old was under sedation for a bone marrow biopsy.

Shauna's bone marrow will be collected through a needle in her neck.

"Shauna has a fear of needles but hasn't batted an eye at the catheter in her neck," Amy said.

Coraki's Damian Cross in hospital in Brisbane waiting for a bone marrow transplant from his 14 year old daughter. PIC: AMY ROLFE Amy Rolfe

In preparation to receive his daughter's bone marrow, Damian will undergo three days of chemotherapy and four days of radiation to wipe out his cells.

"Then he gets her cells," Amy said.

Donor cells, especially when they are a half match, could attack Damian's cells.

"He'll be here for 100 days after the transplant," Amy said.

"Three to four weeks in hospital and then we have to stay in Brisbane for three months."

Damian will be on anti-rejection drugs and the procedure can fail within a three-year period.

The family is hopeful though and urge Australians to consider registering for bone marrow donation through the Australian Bone Marrow Donor Registry.

The World Marrow Donor Association operates a global database to find the best stem cell

source with a database of 36,214,535 donors from 98 different registries in 53 different countries.

Amy said Germany had the best bone marrow donor rate.

The WMDA said COVID-19 infection had the potential to impact and interfere with the timely provision of cells across international borders.

It is currently uncertain whether COVID-19 is transmissible parenterally, and it seems prudent to defer donors from countries with a high rate of COVID-19 infection, WMDA said.

Support the family through their crowdfunding campaign.

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14-year-old girl is only chance to save dad's life - Chinchilla News

Recommendation and review posted by Bethany Smith

Key points:

NEW YORK, May 25, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in cellular medicines for inflammatory diseases, today announced that clinical outcomes of its allogeneic mesenchymal stem cell (MSC) medicine RYONCIL (remestemcel-L) in children and adults with steroid-refractory acute graft versus host disease (GVHD) have been published in three peer-reviewed articles and an accompanying editorial in the May issue of Biology of Blood and Marrow Transplantation, the official publication of the American Society for Transplantation and Cellular Therapy.

Mesoblast Chief Medical Officer Dr Fred Grossman said: Results from these three trials show a consistent pattern of safety and efficacy for RYONCIL (remestemcel-L) in patients with the greatest levels of inflammation and the most severe grades of acute GVHD. These clinical outcomes provide a compelling rationale for use of remestemcel-L in children and adults with other conditions associated with severe inflammation and cytokine release, including acute respiratory distress syndrome (ARDS) and systemic vascular manifestations of COVID-19 infection.

In the accompanying editorial, Dr Jacques Galipeau, Professor and Assistant Dean of Medicine at the Stem Cell & Regenerative Medicine Center at the University of WisconsinMadison and Chair of the International Society of Cell and Gene Therapy (ISCT) MSC Committee, concluded that after more than a decade of clinical study involving three distinct advanced trials, it appears that remestemcel-L might well have finally met the regulatory requirements for marketing approval in the United States for steroid refractory acute GVHD in children, and it is to be determined whether this industrial MSC product will find utility for adults afflicted by acute GVHD or other indications.

The trials highlighted in the three articles all evaluated the same treatment regimen of RYONCIL, with patients receiving twice weekly intravenous infusions of 2 million cells per kg body weight over a four-week period. RYONCIL was well-tolerated in all studies with no identified safety concerns. The three trials were:

1. Study 275: An Expanded Access Program in 241 children across 50 centers in eight countries where RYONCIL was used as salvage therapy for steroid-refractory acute GVHD in patients who failed to respond to steroid therapy as well as multiple other agents.

2. Study GVHD001/002: A Phase 3 single-arm trial in 55 children across 20 centers in the United States where RYONCIL was used as the first line of treatment for children who failed to respond to steroids for acute GVHD.

3. Study 280: A Phase 3 randomized placebo-controlled trial in 260 patients, including 28 children, across 72 centers in seven countries where RYONCIL or placebo were added to second line therapy in patients with steroid-refractory acute GVHD who failed to respond to steroid treatment.

About Acute Graft Versus Host DiseaseAcute GVHD occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT). Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, and these numbers are increasing.1 In patients with the most severe form of acute GVHD (Grade C/D or III/IV) mortality is as high as 90% despite optimal institutional standard of care.2,3 There are currently no FDA-approved treatments in the United States for children under 12 with steroid-refractory acute GVHD.

About RYONCILTMMesoblasts lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. RYONCIL is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in SR-aGVHD by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

References1. Niederwieser D, Baldomero H, Szer J. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.Bone Marrow Transplant 2016; 51(6):778-85.2. Westin, J., Saliba, RM., Lima, M. (2011) Steroid-refractory acute GVHD: predictors and outcomes. Advances in Hematology 2011;2011:601953.3. Axt L, Naumann A, Toennies J (2019) Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 2019;54(11):1805-1814.

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About MesoblastMesoblast Limited (Nasdaq:MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblasts Biologics License Application to seek approval of its product candidate RYONCIL (remestemcel-L) for pediatric steroid-refractory acute graft versus host disease (acute GVHD) has been accepted for priority review by the United States Food and Drug Administration (FDA), and if approved, product launch in the United States is expected in 2020. Remestemcel-L is also being developed for other inflammatory diseases in children and adults including moderate to severe acute respiratory distress syndrome. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. This IP position is expected to provide the Company with substantial commercial advantages as it develops its product candidates for these conditions.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws.Forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblast and its collaborators clinical studies; Mesoblast and its collaborators ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblasts product candidates, if approved;the potential benefits of strategic collaboration agreements and Mesoblasts ability to maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology.You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

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Clinical Outcomes Using RYONCIL (remestemcel-L) in Children and Adults With Severe Inflammatory Graft Versus Host Disease Published in Three Articles...

Recommendation and review posted by Bethany Smith

In the current situation of restricted movement and reduced workforce, (due to COVID-19 Pandemic) new technologies have been developed to provide end-to-end automation in different sectors such as food processing. Automated systems are hired by the companies to ensure continued supply and manufacturing of products with the least manual interference

The advent of Health Information Technology (HIT) components such as electronic health records (EHR), hospital information systems (HIS), picture archiving and communication systems (PACS), and vendor neutral archives (VNA) has had just as transformational an impact on the overall healthcare sector as the concerns regarding security and privacy. Data theft, undue access to personal health records, and cyber-attacks are very real threats that the healthcare sector faces today.

Myelofibrosis or osteomyelofibrosis is a myeloproliferative disorder which is characterized by proliferation of abnormal clone of hematopoietic stem cells. Myelofibrosis is a rare type of chronic leukemia which affects the blood forming function of the bone marrow tissue. National Institute of Health (NIH) has listed it as a rare disease as the prevalence of myelofibrosis in UK is as low as 0.5 cases per 100,000 population. The cause of myelofibrosis is the genetic mutation in bone marrow stem cells. The disorder is found to occur mainly in the people of age 50 or more and shows no symptoms at an early stage. The common symptoms associated with myelofibrosis include weakness, fatigue, anemia, splenomegaly (spleen enlargement) and gout. However, the disease progresses very slowly and 10% of the patients eventually develop acute myeloid leukemia. Treatment options for myelofibrosis are mainly to prevent the complications associated with low blood count and splenomegaly.

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The global market for myelofibrosis treatment is expected to grow moderately due to low incidence of a disease. However, increasing incidence of genetic disorders, lifestyle up-gradation and rise in smoking population are the factors which can boost the growth of global myelofibrosis treatment market. The high cost of therapy will the growth of global myelofibrosis treatment market.

The global market for myelofibrosis treatment is segmented on basis of treatment type, end user and geography:

As myelofibrosis is considered as non-curable disease treatment options mainly depend on visible symptoms of a disease. Primary stages of the myelofibrosis are treated with supportive therapies such as chemotherapy and radiation therapy. However, there are serious unmet needs in myelofibrosis treatment market due to lack of disease modifying agents. Approval of JAK1/JAK2 inhibitor Ruxolitinib in 2011 is considered as a breakthrough in myelofibrosis treatment. Stem cell transplantation for the treatment of myelofibrosis also holds tremendous potential for market growth but high cost of therapy is foreseen to limits the growth of the segment.

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On the basis of treatment type, the global myelofibrosis treatment market has been segmented into blood transfusion, chemotherapy, androgen therapy and stem cell or bone marrow transplantation. Chemotherapy segment is expected to contribute major share due to easy availability of chemotherapeutic agents. Ruxolitinib is the only chemotherapeutic agent approved by the USFDA specifically for the treatment of myelofibrosis, which will drive the global myelofibrosis treatment market over the forecast period.

Geographically, global myelofibrosis treatment market is segmented into five regions viz. North America, Latin America, Europe, Asia Pacific and Middle East & Africa. Northe America is anticipated to lead the global myelofibrosis treatment market due to comparatively high prevalence of the disease in the region.

Some of the key market players in the global myelofibrosis treatment market are Incyte Corporation, Novartis AG, Celgene Corporation, Mylan Pharmaceuticals Ulc., Bristol-Myers Squibb Company, Eli Lilly and Company, Taro Pharmaceuticals Inc., AllCells LLC, Lonza Group Ltd., ATCC Inc. and others.

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Our unmatched research methodologies set us apart from our competitors. Heres why:PMRs set of research methodologies adhere to the latest industry standards and are based on sound surveys.We are committed to preserving the objectivity of our research.Our analysts customize the research methodology according to the market in question in order to take into account the unique dynamics that shape the industry.Our proprietary research methodologies are designed to accurately predict the trajectory of a particular market based on past and present data.PMRs typical operational model comprises elements such as distribution model, forecast of market trends, contracting and expanding technology applications, pricing and transaction model, market segmentation, and vendor business and revenue model.

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Global Myelofibrosis Treatment Market to Register Growth in Incremental Opportunity During the Forecast Period 2016 2022 - Cole of Duty

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ZUG, Switzerland and CAMBRIDGE, Mass., May 26, 2020 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, today announced that members of its senior management team are scheduled to participate virtually in the following investor conferences in June:

Jefferies Global Healthcare ConferenceDate:Tuesday, June 2, 2020Fireside chat: 1:30 p.m. ET

Goldman Sachs 41st Annual Global Healthcare ConferenceDate:Tuesday, June 9, 2020Fireside chat: 9:40 a.m. ET

A live webcast of these events will be available on the "Events & Presentations" page in the Investors section of the Company's website athttps://crisprtx.com/events. A replay of the webcast will be archived on the Company's website for 14 days following the presentation.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic partnerships with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

Investor Contact:Susan Kim+1 617-307-7503susan.kim@crisprtx.com

Media Contact:Rachel EidesWCG on behalf of CRISPR+1 617-337-4167reides@wcgworld.com

Read more:
CRISPR Therapeutics to Participate in Upcoming Investor Conferences - GlobeNewswire

Recommendation and review posted by Bethany Smith

By Piyush K. Jain6 minute Read

A desperately needed tool to curb the COVID-19 pandemic is an inexpensive home-based rapid testing kit that can detect the coronavirus without needing to go to the hospital.

The Food and Drug Administration has approved a few home sample collection kits but a number of researchers, including myself, are using the gene-editing technique known as CRISPR to make home tests. If they work, these tests could be very accurate and give people an answer in about an hour.

I am a biomolecular scientist with training in pharmaceutical sciences and biomedical engineering, and my lab focuses on developing next-generation of technologies for detecting and treating cancer, genetic, and infectious diseases.

The COVID-19 disease is caused by a coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unlike humans which carry their genetic material encoded in DNA, the coronavirus encodes theirs in a related molecule called RNA.

My research group recently engineered a sensitive CRISPR-based technology, that we named CRISPR-ENHANCE, and used it to create a rapid test for SARS-CoV-2 RNA. Our assay works like a pregnancy test and shows two purple-colored lines if the sample is positive for the virus. Using our technology, I envision developing a test kit that would allow rapid detection of SARS-CoV-2 RNA in saliva within 45 to 60 minutes at home without needing any expensive equipment.

The FDA recently gave a green light to a couple of sample collection kits from LabCorp and Everywell under the Emergency Use Authorization (EUA) that would allow people to ship out the nasal swab samples for analysis. Patients can take a swab of their nose, ship the samples to a lab, and wait for a few days to get the results back.

Although not an at-home testing kit, the test allows the samples to be shipped directly to a lab for detecting SARS-CoV-2 RNA. There they use a technique called reverse transcription-polymerase chain reaction (RT-PCR), which converts the viral RNA into DNA so that it can be easily multiplied and detected.

Although most FDA-approved tests are based on detecting SARS-CoV-2 RNA at an early stage, before symptoms even appear, such tests can only be performed in a laboratory setting with expensive equipment and can take multiple days to get the results.

Several antibody testing kits have been approved by the FDA that use a paper-based lateral flow strip, also similar to an at-home pregnancy testing strip, for detecting antibodies called IgM and IgG. Almost all SARS-CoV-2-infected patients make antibodies within 19 days of onset of symptoms and then the body continues to make detectable antibodies for several weeks to months even after symptoms fade away. Therefore, the Centers for Disease Control and Prevention recommends using antibody tests for detecting past infections.

However, the coronavirus is usually very active and contagious in the first week of infection and peaks on the day of onset of symptoms. Therefore, to prevent the spread of the coronavirus, it is extremely important to detect the coronavirus early to block the spread.

The antibody testing can be great for detecting past infections but they cannot reliably detect current or early infections. The delayed appearance and patient-to-patient variability of antibodies in a blood test further complicates the COVID-19 diagnosis with antibody testing kits.

In addition, the variability between different antibody testing methods has raised doubts about the reliability of these test kits.

Therefore, the National Institutes of Health recently announced a Rapid Acceleration of Diagnostics (RADx), which offers up to U.S.$500 million in funding for ramping up the technologies that detect the SARS-CoV-2 virus.

Most people know of CRISPR/Cas systems as a famous gene-editing technology that can precisely edit DNA. Researchers engineer a guide RNA molecule with a target genetic sequence that serves like a GPS and zooms in on a location on the DNA where a Cas protein, a pair of molecular scissors, can cut at the desired location.

Scientists in the labs of Feng Zhang at MIT, Jennifer Doudna at UC Berkeley, and others discovered several newer versions of CRISPR/Cas systems, including ones using the proteins Cas12a and Cas13a-d, which get crazy cutting once they find their match.

My colleagues and I have used this Cas12a-based CRISPR technique to detect the coronavirus.

The coronavirus RNA activates CRISPR/Cas, transforming a pair of controlled molecular scissors into an unstoppable chainsaw. When the the CRISPR/Cas enzyme activates, we know that the genetic sequence of the coronavirus is present in the saliva sample. To make the signal of the coronavirus stronger in the testing kit, we add millions of synthetic reporter molecules, which are also chopped up by the CRISPR/Cas mechanism. This means that within minutes we can detect detect the presence of coronavirus.

Under EAU, the FDA recently approved the first CRISPR-based SARS-CoV-2 RNA testing kit from Sherlock Biosciences for testing nasal swabs in a lab. Although not yet approved for at-home testing, this is a big leap toward the development of CRISPR-based diagnostics.

While similar CRISPR-based test kits are in development, including one from Mammoth Biosciences and others, our CRISPR-ENHANCE technology relies on engineered CRISPR RNAs that increases the speed of Cas12a chainsaw by between three- and fourfold.

This technique dramatically enhances the sensitivity of detection. Our system can detect fewer virus in a clinical sample faster with a clear visual readout. We are in the process of clinically validating the CRISPR-ENHANCE technology for SARS-CoV-2 RNA detection.

Standard collection method for detecting respiratory viruses in the clinic is the nasal swab. However, coronaviruses have been detected at comparable levels in saliva, so some researchers are now turning to saliva for diagnostic testing.

Collecting saliva is not only less invasive than the nasal swabs but also contains more virus, which makes it easier to detect with RT-PCR. In fact, an at-home saliva collection kit just received a green light by the FDA on May 8, 2020. In our validation study we will be internally comparing our test between the nasal swabs and saliva for FDA approval.

We are developing a six-step procedure for home-based testing for saliva along with the nasal swabs. Here is how it would work with saliva.

Spit into a sample collection tube that contains dry chemical reagents that will begin to react with your saliva when you drop the closed tube into the warm water for 30 minutes.

The heat helps the chemicals break up the virus particle and expose the viruss genetic materialRNA. The RT-PCR reagents basically multiply the viral RNA creating billions of copies, which are more easily detected.

After 30 minutes, transfer the contents of the collection tube to a second tube containing dried CRISPR components and leave it at room temperature for 10 to 15 minutes.

Only if CRISPR/Cas finds the specific coronavirus RNA will it become active and chop up the synthetic reporter molecules that are engineered and added to this second tube. This part happens in just six minutes.

We then drop a paper strip into the second tube. Within 30 seconds one or two purple bands reveal the results.

The health care provider can then direct the individual to either quarantine, isolate, and/or recommend further testing such as antibody-based tests. In our study, currently under peer review, we demonstrated that the ENHANCE technology itself is versatile and can also be adopted for detecting a range of targets including HIV, HCV, and prostate cancer.

While there are several labs and companies rushing to develop similar CRISPR-based coronavirus detection kits for saliva testing, we believe our approach offers the fastest detection. We hope to bring the cost of the kit down to between $1 and $2 so that developing countries can also afford a rapid and reliable coronavirus testing kit.

Piyush K. Jain is an assistant professor of chemical engineering at Herbert Wertheim College of Engineering, part of the UF Health Cancer Center at the University of Florida. This article is republished from The Conversation.

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Why CRISPR could be the key to faster at-home coronavirus tests - Fast Company

Recommendation and review posted by Bethany Smith

SAN DIEGO, May 26, 2020 /PRNewswire/ --ViaCyte, Inc., a privately held regenerative medicine company, today announced the close of an approximately $27 million private financing, part of the Series D preferred stock financing entered into in late 2018. Investors included, Bain Capital Life Sciences, TPG Capital, RA Capital Management, Sanderling Ventures, and several individual supporters of the Company. Proceeds from the financing will be used to further advance the Company's multi-product candidate approach to develop medicines that have the potential to transform the way insulin-requiring diabetes is managed, potentially providing a functional cure for patients with type 1 diabetes.

Coinciding with the financing, the Company also appointed Ian F. Smithas Executive Chairperson. Mr. Smith was appointed to the Company's Board of Directors in July 2019 and succeeds Fred Middleton, who remains on the board.

Commenting on the financing, Paul Laikind, Ph.D., Chief Executive Officer and President of ViaCyte, said, "During these difficult times we are grateful for the continued support of our investors as well as our clinical trial participants, whose safety and health remains our focus and commitment. We are steadfast in our mission to deliver potentially life sustaining therapies for patients with insulin-requiring diabetes and to continue the significant progress we have made in the past year. ViaCyte is the first company to demonstrate production of C-peptide, a biomarker for insulin, in patients with type 1 diabetes receiving a stem cell-derived islet replacement. Moving forward, we are optimizing the effectiveness of both PEC-Direct and PEC-Encap, the latter of which incorporates novel device material technology created in collaboration with W.L. Gore & Associates. We are also making important progress on our PEC-QT program with our partner, CRISPR Therapeutics, and are now moving into pre-IND activities. This program is designed to eliminate the need for immuno-suppression and could have a transformative impact on a broader population of insulin-dependent patients."

Dr. Laikind continued, "In conjunction with the closure of the financing, we are also pleased to announce the appointment of Ian F. Smith as our Executive Chairperson, succeeding Fred Middleton. Since joining the board last July, Ian and I have worked closely to accelerate ViaCyte's growth and prepare for the future. We are extremely grateful to Fred for his many years of service as Chairperson of ViaCyte's Board of Directors. Throughout his time leading the Board, Fred provided expert guidance as ViaCyte has consistently broken new ground in the field of regenerative medicine and cell replacement therapies."

Mr. Middleton said, "I am proud to have chaired the Board as ViaCyte developed into a leading company in the regenerative medicine field.I am confident that Ian's unique expertise and executive leadership, specifically with innovative growth-oriented companies, and specifically in corporate strategy and operations, as well as capital markets will help ViaCyte progress its important work and firmly establish itself as a leader in the cell therapy sector."

About ViaCyte's Pipeline

The PEC-Direct product candidate, currently being evaluated in the clinic, delivers ViaCyte's PEC-01 cells (pancreatic islet progenitor cells) in a non-immunoprotective device and is being developed for type 1 diabetes patients who have hypoglycemia unawareness, extreme glycemic lability, and/or recurrent severe hypoglycemic episodes. The PEC-Encap (also known as VC-01) product candidate, also undergoing clinical evaluation, delivers the same pancreatic islet progenitor cells but in an immunoprotective device. PEC-Encap is being developed for all patients with type 1 diabetes. In collaboration with CRISPR Therapeutics, ViaCyte is developing immune-evasive stem cell lines from its proprietary CyT49 cell line. These immune-evasive stem cell lines, which are being used in the PEC-QT program, have the potential to further broaden the availability of cell therapy for all patients with insulin-requiring diabetes, type 1 and type 2. In addition, a pluripotent, immune evasive cell line has the potential to be used to produce any cell in the body, thus enabling many other potential indications.

About ViaCyte

ViaCyte is a privately held regenerative medicine company developing novel cell replacement therapies as potential long-term diabetes treatments to achieve glucose control targets and reduce the risk of hypoglycemia and diabetes-related complications. ViaCyte's product candidates are based on directed differentiation of pluripotent stem cells into PEC-01 pancreatic islet progenitor cells, which are then implanted in durable and retrievable cell delivery devices. Over a decade ago, ViaCyte scientists were the first to report on the production of pancreatic cells from a stem cell starting point and the first to demonstrate in an animal model of diabetes that, once implanted and matured, these cells secrete insulin and other pancreatic hormones in response to blood glucose levels and can be curative. More recently, ViaCyte demonstrated that when effectively engrafted, PEC-01 cells can mature into glucose-responsive insulin producing cells in patients with type 1 diabetes. To accelerate and expand its efforts, ViaCyte has established collaborative partnerships with leading companies including CRISPR Therapeutics and W.L. Gore & Associates. ViaCyte is headquartered in San Diego, California. The Company also has a robust intellectual property portfolio, which includes hundreds of issued patents and pending applications worldwide. ViaCyte is funded in part by the California Institute for Regenerative Medicine (CIRM) and JDRF. For more information on ViaCyte, please visit http://www.viacyte.comand connect with ViaCyte on Twitter, Facebook, and LinkedIn.

SOURCE ViaCyte, Inc.

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ViaCyte Announces $27 Million Financing to Advance Next Generation Cell Therapies for Diabetes - PRNewswire

Recommendation and review posted by Bethany Smith

Heart problems associated with spinal muscular atrophy(SMA) may be caused partially by calcium dysregulation in heart muscle cells in the absence of the survival motor neuron(SMN) protein, a study suggests.

These findings shed light not only on the underlying mechanisms of heart problems in SMA which may open new therapeutic avenues but also support the monitoring of heart function in this patient population.

The study, SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs, was published in the journal Skeletal Muscle.

SMA is caused by the loss of SMN, a protein produced in several cell types throughout the body and involved inmultiple and fundamental cellular processes. While SMN deficiency in motor nerve cells is considered the diseases root cause, increasing evidence suggests that other cells and organs in the body also are particularly affected, including the heart.

Cardiovascular problems have been reported in patients with the most severe severeforms of SMA and in mouse models of the disease. Moreover, a previous study supported by theSMA Foundation showed that SMA patients have higher-than-normal levels of several heart failure markers, suggesting that sufficient levels of SMN are essential for normal heart function.

However, the mechanisms behind these SMA-associated heart problems remain largely unknown and no study has established that SMN deficiency directly affects heart function.

Researchers have now evaluated whether SMN deficiency compromised the contractile function of heart cells isolated from a mouse model of a severe form of SMA and also those generated from SMA patients-derived induced pluripotent stem cells (iPSCs).

iPSCs are fully matured cells that researchers can reprogram in a lab dish to revert them back to a stem cell state that has the capacity to differentiate into almost any type of cell.

Results showed that the levels of three heart failure markers atrial natriuretic peptide, brain natriuretic peptide, and skeletal alpa-actin were significantly increased in heart tissue from SMA mice prior to considerable neuromuscular degeneration, compared with that from healthy mice.

This suggested that mechanical function of the heart may be altered early in the disease progression of this severe SMA mouse model, the researchers wrote.

In agreement, heart cells from SMA mice showed impaired contractile function, compared with cells from healthy mice. The team noted that contraction problems in the heart often are associated with calcium dysregulation and lower levels of SERCA2, an enzyme that controls calcium levels inside cells.

Further analysis showed that SMN-deficient heart cells, from both SMA mice and SMA patients, had a significant drop in SERCA2 levels and impaired calcium dynamics, compared with healthy cells.

Notably, these deficits were at least partially corrected when patient-derived cells were modified to increase their production of SMN protein. Conversely, heart cells derived from healthy individuals and forced to lower their SMN production mimicked the deficits seen in SMN-deficient heart cells.

These results demonstrate that SMN regulates SERCA2 [levels] and intracellular [calcium dynamics] in [heart cells] that may impair cardiac function and lead to elevation of heart failure markers, as observed in mice and patients with SMA, the researchers wrote.

The data also suggest that heart cell dysfunction occurs early in the disease course and therefore is likely to be a direct result of SMN loss and not secondary to neurodegeneration, the team noted.

Since deficits in calcium dynamics also were previously reported to occur in SMN-deficient motor nerve cells, the researchers hypothesized that calcium dysregulation may be a common disease mechanism in SMA.

Finally, while neuromuscular degeneration remains the hallmark feature of the disease, impaired heart function may be a contributing factor in disease progression that will require monitoring in light of new therapies that are improving motor function and extending survival, the researchers wrote.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 85

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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Study: Heart Problems in SMA May Be Tied to Calcium Dysregulation - SMA News Today

Recommendation and review posted by Bethany Smith

Latest Patent Further Strengthens Intellectual Property Portfolio Covering Novel Platform for Precisely Controlling Core Cell Migration Mechanisms

Decelerator Technology Has Key Potential Applications in Treatment of Cancer and Fibrosis and Serves as Key Complement to Companys Cell Motility Accelerator Platform for Enhanced Tissue Repair

NEW YORK, May 20, 2020 (GLOBE NEWSWIRE) -- MicroCures, a biopharmaceutical company developing novel therapeutics that harness the bodys innate regenerative mechanisms to accelerate tissue repair, today announced the issuance of a new European patent providing broad protection for the companys first-of-its-kind cell movement decelerator technology, which has potential therapeutic applications in combating cancer metastases and fibrosis. The companys decelerator technology is being developed alongside MicroCures accelerator technology, which is designed to enhance repair of tissue, nerves, and organs following trauma. With the newly issued patent in the European Union (#3052117), the companys global patent estate now includes eight issued and 12 pending patents covering its underlying technology, as well as the therapeutic programs that have emerged from the platform.

Our proprietary platform technology represents a fundamentally new way of thinking about how to harness the bodys natural cell movement processes to drive therapeutic outcomes in response to a range of medical challenges. Whether it is removing the brakes from cells to accelerate their migration and drive tissue, nerve and organ repair, or putting the brakes on cell movement to combat tumor metastases and fibrosis, we are pioneering an entirely new treatment paradigm, said Derek Proudian, co-founder and chief executive officer of MicroCures. While we clearly recognize the importance of the development work we are undertaking in support of this platform, it is equally important to build a strong, wide-reaching intellectual property portfolio to protect it. This latest patent issuance provides us yet another key piece of intellectual property, bringing our total number of issued and pending patents to 20.

MicroCures technology is based on foundational scientific research at Albert Einstein College of Medicine regarding the fundamental role that cell movement plays as a driver of the bodys innate capacity to repair tissue, nerves, and organs. The company has shown that complex and dynamic networks of microtubules within cells crucially control cell migration, and that this cell movement can be reliably modulated to achieve a range of therapeutic benefits. Based on these findings, the company has established a first-of-its-kind proprietary platform to create siRNA-based therapeutics capable of precisely controlling the speed and direction of cell movement by selectively silencing microtubule regulatory proteins.

The company has developed a broad pipeline of therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. Unlike regenerative medicine approaches that rely upon engineered materials or systemic growth factor/stem cell therapeutics, MicroCures technology directs and enhances the bodys inherent healing processes through local, temporary modulation of cell motility. Additionally, the company is developing a decelerator technology based on the same foundational science. Instead of accelerating cell movement for therapeutic repair and regeneration, this technology is designed to slow or halt the movement of cells, potentially offering a unique, natural approach to preventing cancer metastases and fibrosis.

About MicroCures

MicroCures develops biopharmaceuticals that harness innate cellular mechanisms within the body to accelerate and improve recovery after traumatic injury. MicroCures has developed a first-of-its-kind therapeutic platform that precisely controls the rate and direction of cell migration, offering the potential to deliver powerful therapeutic benefits for a variety of large and underserved medical applications.

MicroCures has developed a broad pipeline of novel therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. The companys lead therapeutic candidate, siFi2, targets excisional wound healing, a multi-billion dollar market inadequately served by current treatments. Additional applications for the companys cell migration accelerator technology include dermal burn repair, corneal burn repair, cavernous nerve repair/regeneration, spinal cord repair/regeneration, and cardiac tissue repair. Cell migration decelerator applications include combatting cancer metastases and fibrosis. The company protects its unique platform and proprietary therapeutic programs with a robust intellectual property portfolio including eight issued patents, as well as 12 pending patent applications.

For more information please visit: http://www.microcures.com

Contact:

MicroCuresinfo@microcures.com

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MicroCures Announces Issuance of New European Patent Providing Broad Protection for First-of-its-Kind Cell Movement Decelerator Technology -...

Recommendation and review posted by Bethany Smith

By Matthew Tontonoz Tuesday, May 26, 2020

Starving skin cancer tumors of serine increases cancer stem cell differentiation in mice. In this image, skin stem cells undergoing differentiation are magenta and those remaining as stem cells are green.

Summary

A team of scientists at the Sloan Kettering Institute and The Rockefeller University has discovered that cancer stem cells rely on a steady external supply of the amino acid serine. This dependency makes them vulnerable to restrictions on this supply, a discovery that could potentially be exploited therapeutically.

In recent years, cancer biologists have come to understand that metabolism the way that cells acquire and use nutrients can directly affect their tendency to become cancerous.

SKI cell biologist Lydia Finley and colleagues in the Elaine Fuchs lab at The Rockefeller University have now deepened knowledge of this relationship in the context of squamous cell carcinoma, a cancer that arises from stem cells in the skin. Using mouse models and cells growing in tissue culture, they found that the amount of the amino acid serine present in a stem cells environment influences its decision to keep dividing or to grow up (differentiate). Differentiated cells generally do not form cancer.

The stem cells that give rise to squamous cell carcinoma seem to be highly dependent on extracellular serine for their growth, Dr. Finley says. Trying to starve these cells of this source of serine could be a strategy to try to curb their growth by forcing them to differentiate.

A normal stem cell will respond to a shortage of extracellular serine by synthesizing more. Atthe same time, they will begin differentiating: The biochemical pathways involved with serine synthesis interact with proteins called histones that wrap DNA like a spool of thread and allow specific genes to be turned on. Stem cells with cancer-predisposing mutations, on the other hand, seem intent onavoiding new serine synthesis.

Cancer stem cells heightened reliance on extracellular serine reflects what Dr. Finley calls metabolic rewiring: By relying on extracellular serine, the cancer stem cells can avoid serine synthesis, with the happy side effect (for the cancer cell) that the path toward differentiation is blocked.

Our findings link the nutrients that a skin stem cell consumes to their identity and their ability to initiate a tumor, says Sanjeethan Baksh, a Tri-Institutional MD/PhD student in the Fuchs lab and the papers first author. Not only do nutrients allow stem cells and cancer cells to grow, but our study also shows that metabolism directly regulates gene expression programs important for cancer stem cell identity.

Although restricting serine in the diet is not feasible in humans, the team is currently looking for ways that they might be able to interfere with cancer stem cells ability to take up serine in the hope of curbing cancer growth.

The findings were reported on May 25 in the journal Nature Cell Biology.

This study received financial support from the Howard Hughes Medical Institute, the National Institutes of Health (grants R01-AR31737, F31CA236465, F30CA236239-01, and 1F32AR073105), the Human Frontiers Science Program, the European Molecular Biology Organization, NYSTEM (CO29559), The Starr Foundation, the Damon Runyon Cancer Research Foundation, the Concern Foundation, the Anna Fuller Fund, The Edward Mallinckrodt, Jr. Foundation, and the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748. The study authors declare no competing interests.

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Cancer Stem Cells Reliance on a Key Amino Acid Could Be an Exploitable Weakness - On Cancer - Memorial Sloan Kettering

Recommendation and review posted by Bethany Smith

The Faculty of Health and Medical Sciences at the University of Copenhagen recently discovered how a particular protein, Phosphoprotein phosphatase 2A (PP2A), inhibits tumor development in mice.

Proteins are complex molecules in cells that are necessary for the function, structure, and regulation of the body's organs and tissues. Proteins have five primary functions: antibodies, enzymes, messengers, structural components, and transport or storage of atoms or small molecules.

Professor Jakob Nilsson, from the Novo Nordisk Foundation Center for Protein Research, explained that PP2A is called a household protein as it can be commonly found in most places. Everything that lives with simple cells or complex cells contain PP2A.

The PP2A Protein is also being studied by pharmaceutical companies as it is known to show unique patterns of kinase opposition, or simply, it is a tumor suppressor. Protein kinases are enzymes that induce change, switching active proteins into an inactive form.

While there is still insufficient research on which specific types of proteins PP2A regulates to prevent cancer, results from the new data do gain more insight.

Other tumor suppressor proteins include the retinoblastoma protein (pRb) and the p53 gene. Both regulate the cycling behavior of cells in a process called cell proliferation and growth are known as cell cycle progression.

Rb has a vital part in regulation G1/S transition, which is the 'start' checkpoint which controls the production of starter kinase proteins. What follows is Rb's 'role in the functioning of normal andcancer stem cells,' as well as its effect on the 'energy metabolism of cancer cells.'

According to a study called Nanostructures for Cancer Therapy, P53 is a protein that can 'respond to hypoxia, DNA damage, and loss of normal cell contacts when activated,' as it mediates the growth and death of cells.

The same study notes, 'targeting p53-MDM2 interaction would be attractive in cancer therapy.'

Read Also: Metformin, a Drug for Diabetes, is Investigated for Cancer-Causing Contaminant

Associate Professor Marie Kveiborg from the Biotech Research and Innovation Centre notes that what is new about their study is that they can show how the specific PP2AB56 'selects the phosphate groups that shall be removed from other proteins,' while it turns off the enzyme ADAM17. ADAM17 being switched off resulted in 'inhibition of tumor growth in mice.'

A disintegrin and metalloprotease domain 17 (ADAM17) is a protein-coding gene associated with diseases including inflammatory skin (psoriasis), inflammatory bowel disease (Crohn's disease), and breast cancer. The test mice were all injected with three variations of ADAM17 cells.

On the day of injection, '4T1 A17wt, I762A, and LEE cells,' all ADAM17 variants, were given and the scientists monitored tumor growth through time.

When they began observing how PP2A-B56 interacted with ADAM17, 'none of the mice injected with ADAM17 LEE cells reached tumor endpoint criteria, as opposed to ADAM17 wt or I762A injected mice, which exhibited only 50% survival by the end of the experiment.'

The newly discovered data on cancer research will hopefully develop into studies with human tumors, expressed by the researchers. The scientists concluded, 'the B56 inhibitor displays excellent specificity toward the PP2AB56 holoenzyme family.' As a result, scientists also want to make additional research to determine if PP2A also can regulate other proteins with its tumor suppressor function.

Read Also:Will COVID-19 End Scientific Breakthroughs?

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BREAKTHROUGH! Scientists Discover Particular Protein That Could Block Cancer Growth - Science Times

Recommendation and review posted by Bethany Smith

For those yet to be acquainted with iS Clinical, it is fast becoming a cult-favourite skincare brand with celebrities like Rosie Huntington-Whiteley, Chrissy Teigen, January Jones and Zoey Deutch (to name a few) and beauty experts like Melanie Grant and Shani Darden all lining their bathroom cabinets with the recognisable iS' blue bottles.

Known for their skin-changing serums and gentle cleanser, the brand recently launched in Australia and is now stocked at Sydney-based salon, The Parlour Room Clovelly. And you don't just have to be a local to get your hands on it, you can purchase it online from TPR's online store.

Their formulas, revered for combining highly active ingredients and plant-derived extracts with modern science, are fragrance and paraben-free and directly tackle all major skin concerns dry, dull skin, anti-aging, pigmentation, uneven skin tone and texture. Their range revolves around four key steps: cleanse, treat, hydrate and protect, and with each product conceptualised and produced in-house, a 'dupe' would be hard to find.

When it comes to ingredients, think high-grade, dermatologist recommended ingredients like plant-derived acids, vitamins A to E, stem cells and ceramides, all combined to deliver real results in real time. Users of the brand's star serum and cleanser have reported visible improvements in a matter of days.

Given that Winter is looming, I decided to swap out my regular moisturiser in favour of their Reparative Moisture Emulsion to see what all the hype was about, and it's good, real good. The texture is rich and creamy, the kind you'd expect from a moisturiser that lines the walls of a celebrity dermatologist. Two pumps evenly coat my face and dcolletage and leave my skin feeling thoroughly hydrated and slightly tacky, though not in a bad way. In a way that tells me my skin now has a glassy barrier protecting it from environmental factors and sealing in much needed hydration.

After a week or so of wear my skin is noticeably brighter, softer, bouncier and less dry than before. I've also been using their famous Pro-Heal Serum on alternate days underneath the moisturiser, which is what I suspect is to thank for my brighter complexion. This little baby is potent, the good kind of potent, hence why I'm only using it on alternating days. The formula is a fierce combination of active vitamin A and C, meaning it does wonders for dull, uneven skin tone, minimising acne scars and pigmentation and restoring life to tired skin (Hi, me). It is safe enough to use daily for most skin types, but given that my skin is about as sensitive as a Cancer during Gemini season, I tend to play it safe with high-active serums.

While I've only sampled two products from the highly sought after range (and seen pretty incredible results thus far), I'm keen to stock up on some more of their cult-favourites read: the cleanser and SPF to see if I can reach Rosie HW level skin.

Scroll to shop our edit of iS Clinical Skincare.

Original post:
Celebrities Swear by This Cult Skincare Brand, and It Just Got An Aussie Stockist - POPSUGAR Australia

Recommendation and review posted by Bethany Smith

The health focus today is squarely on the bodys natural defense system. Until there is a vaccination, preventative measures are all we can turn to. Ayurveda can help, experts believe, especially a technique thats been gaining popularity. It's called Photo Bio Modulation (PBM). Availableat Indus Valley AyurvedicCentre (IVAC) in Mysore, itsan emerging medical practicein which exposure to low-level laser light or light-emitting diodes stimulates cellular function. This results in beneficial clinical outcomes for various conditions and diseases, primarily low immunity, in addition to lung disorders, respiratory disorders, joint problems, skin issues, and stress.

How does it work?Also known as Low-Level Laser Therapy (LLLT), it increases the production of Adenosine Triphosphate (ATP) in the mitochondria of the cells, which scavenges the free radicals. By doing so, it stimulates stem cell proliferation, lymph nodes associated with respiratory tract, the immune system and stimulates local tissues to support lung function leading to protection from asthma, bronchitis, pneumonia and Chronic Obstructive Pulmonary Disease, says Dr Talavane Krishna, Founder,President, IVAC.

Nasal ApplicationWhile PBM is gaining prominence now, processes such as nasal application, part of Panchakarma (five actions) treatment, have been a standard Ayurvedic antidote to viruses for aeons. One has to apply different herbal powders, liquid extracts, medicated ghee or oil inside the nostrils. Medications like Anu Taila, sesame or coconut oil, Brahmi ghrutha etc are antimicrobial and act as a protective filter inside the nose and throatthe primary entry point for the viruses. This simple procedure could be a daily practice for both adults and children.

Oil pulling Likewise, oil pulling with sesame or coconut oil as a daily oral health practice is useful. It involves swishing a teaspoon of oil in the mouth for three-five minutes and then spitting the oil, followed by washing/brushing the mouth. This kills bacteria that may lead to tooth decay, bad breath, and gum disease.

Rasayana This is one of the eight major branches of Ayurveda. Popularly known as a form of rejuvenation therapy, not only does it focus on anti-aging, but also immunity. This is accomplished by taking certain Ayurvedic preparations, food based on body constitution, and following an Ayurvedic way of life. This increases Ojas, the very essence of the bodys immunity. Medicines include single herbs like Ashwagandha, Shatavari, Amrita, and formulations like Chyavanaprash, Triphala, Makaradhwaja, notto mention regular body-mind detoxifications like Panchakarma and Rejuvenation.

Balance is keyKeeping the body alignedwith its natural rhythms is a prerequisite to the success of your health. For this, Ayurvedic principles namely Dhincharya (daily regime) and Rithucharya (seasonal regime) are crucial. Dhinacharya looks at aspects such as oral hygiene, yoga, pranayama, meditation, diet, bowel movements and more. Ritucharya describes the various changes in our body during the different seasonsand its effect on health. Italso teaches us how to keepa good balance.

The importance of dietcannot be negated, therefore ensure you add ginger, garlic, pepper, turmeric, clove, cumin, fenugreek and cinnamon in your food as all these ingredients build the immunesystem and bring aboutperfect balance, says Gita Ramesh, Joint MD, Kairali Ayurvedic Group.Dont forget to take warm showers and apply sesame oil on the entire body before the morning bath. Allow nostrils to be lubricated by application of cow ghee or oil, and do warm turmeric water gargles regularly, says Dr Aruna Bhide, Senior Ayurveda Doctor and Consultant, Mercure Goa Devaaya Retreat. Breathing exerciseslike Anulom vilom pranayama (alternate breathing), Kapal bhati (forceful exhalation) and Nadi shuddhi pranayama are beneficial too. Keep in mind to exercise until you sweat as this is the best way to excrete toxins.

Potions for healing(Do consult an Ayurvedic doctor)

Indukantha Kashyam Prevents the recurrence of debilitating diseases and keeps the body healthyVilwadi GulikaA tablet used as a treatment for insect bites, rodent bites, gastroenteritis etc.

Chyawanprash High in Vitamin C, it aids in the production of haemoglobinand white blood cells

Kushmandarasayana Comes in a herbal jam form and is used in respiratory conditions

TriphalaGhritam Support bowel health and aids digestion. As an antioxidant, its also thought to detoxify the body and support immunity.

AshwagandhaIt has demonstrated excellent immune-boosting effects, and has also shown to encourage anti-inflammatory and disease-fighting immune cells, thatkeep illnesses at bay

Amrita Used as a blood purifierMakaradhwaja A mineral-based preparation used for its aphrodisiac characteristics, it enhances the effectiveness of several medicines

See original here:
COVID-19: The Prevention Prescription - The New Indian Express

Recommendation and review posted by Bethany Smith

Cosmetic Skin CareMarketBusiness Insights and Updates:

The latest Marketreport by a Data Bridge Market Researchwith the title[Global Cosmetic Skin CareMarket Industry Trends and Forecast to 2026].The new report on the worldwide Cosmetic Skin CareMarketis committed to fulfilling the necessities of the clients by giving them thorough insights into the Market. The various providers involved in the value chain of the product include manufacturers, suppliers, distributors, intermediaries, and customers.The reports provide Insightful information to the clients enhancing their basic leadership capacity identified.Exclusive information offered in this report is collected by analysis and trade consultants.

Global cosmetic skin care market is set to witness a substantial CAGR of 5.5% in the forecast period of 2019- 2026.

Cosmetic skin care is a variety of products which are used to improve the skins appearance and alleviate skin conditions. It consists different products such as anti- aging cosmetic products, sensitive skin care products, anti- scar solution products, warts removal products, infant skin care products and other. They contain various ingredients which are beneficial for the skin such as phytochemicals, vitamins, essential oils, and other. Their main function is to make the skin healthy and repair the skin damages.Get PDF Samplecopy(including TOC, Tables, and Figures) @https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-cosmetic-skin-care-market

Thestudy considers the Cosmetic Skin CareMarketvalue and volume generated from the sales of the following segments:Major Marketmanufacturerscovered in the Cosmetic Skin CareMarketare:LOral, Unilever, New Avon Company, Este Lauder Companies, Espa, Kao Corporation, Johnson & Johnson Services, Inc., Procter & Gamble, Beiersdorf, THE BODY SHOP INTERNATIONAL LIMITED, Shiseido Co.,Ltd., Coty Inc., Bo International, A One Cosmetics Products, Lancme, Clinique Laboratories, llc., Galderma Laboratories, L.P., AVON Beauty Products India Pvt Ltd, Nutriglow Cosmetics Pvt. Ltd, Shree Cosmetics Ltd

Segmentation:Global Cosmetic Skin Care Market

By Product

By Application

By Gender

By Distribution Channel

Get Table of Contents with Charts, Figures & Tables @https://www.databridgemarketresearch.com/toc/?dbmr=global-cosmetic-skin-care-market

Based on regions, the Cosmetic Skin CareMarketis classified into North America, Europe, Asia- Pacific, Middle East & Africa, and Latin AmericaMiddle East and Africa (GCC Countries and Egypt)North America (United States, Mexico, and Canada)South America(Brazil, Argentina etc.)Europe(Turkey, Germany, Russia UK, Italy, France, etc.)Asia-Pacific(Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia)

Market Drivers:

Market Restraints:

Key Developments in the Market:

Key Benefits for Cosmetic Skin CareMarket:

Enquire Here For Discount Or Cosmetic Skin CareMarket Report Customization@https://www.databridgemarketresearch.com/inquire-before-buying/?dbmr=global-cosmetic-skin-care-market

About Us:Data Bridge Marketresearch endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process Data Bridge set forth itself as an unconventional and neoteric Marketresearch and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best Marketopportunities and foster efficient information for your business to thrive in the Market.We ponder into the heterogeneous Markets in accord with our clients needs and scoop out the best possible solutions and detailed information about the Markettrends. Data Bridge delves into the Markets across Asia, North America, South America, Africa to name few.

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Original post:
Cosmetic Skin Care Market is Thriving with Rising Latest Trends by 2026 | Top Players- L'Oreal, Unilever, New Avon, Estee Lauder Companies, Espa, Kao,...

Recommendation and review posted by Bethany Smith

Goldstar Insurance and Prudential Uganda have partnered to offer a new insurance cover to offer life insurance cover to Goldstars Workmans Compensation and Group Personal Accident Policyholders.

The new insurance product called COVID19 Group Life Extension Insurance Cover covers groups of individuals of companies and organizations against devastating COViD19 pandemic. It is underwritten by Prudential.

In the new partnership, Prudential shall offer cover against Natural Death to all Goldstar Workmans Compensation and Group Personal Accident Policyholders against death due to natural causes.

Goldstar Insurance said this cover is an extension of your existing Workmans Compensation & Group Personal Accident policy with Goldstar to bridge the gap left out by this class of insurance.

The death benefit enshrined under the traditional workers compensation and group personal accident is only payable if death is due to accidental causes and does not include death due to natural causes including Covid19,

Because of the above shortcoming, Goldstar Insurance has partnered with Prudential Life to offer cover against natural death to all Goldstar and GPA Policy Holders and death due to Covod19 is hereby covered, Goldstar has said.

Meanwhile, Very early on in the COVID 19 crisis, Prudential took the decision to ensure that all their clients, staff, agents and indeed as many Ugandans that might, unfortunately, get diagnosed with Covid-19, are given a cash payout to help their families manage expenses.

This according to Arjun Mallik the Managing Director Prudential East Africa, was to cushion the families with financial assistance as their loved ones get healed from COVID- 19.

BY EABW REPORTER

Related

Read the rest here:
Goldstar Insurance and Prudential partner to offer COVID -19 cover - Uganda

Recommendation and review posted by Bethany Smith

Energy companies have been slashing exploration and production budgets since the Covid-19 pandemic took hold and sent oil prices tumbling, but, with few profitable investment alternatives, operators are now likely to increase spending in decommissioning work. Rystad Energy estimates the total value of the global pool of decommissioning projects that will accumulate through 2024 could reach $42 billion. With an average asset age of 25 years, the Northwest European decommissioning market could grow 20% in annual commitments through 2022 if the current low oil prices dont show signs of substantial recovery soon. In addition to a rapidly maturing asset base and low oil prices that erode commercial viability and potential life extensions, the North Sea decommissioning market will also be helped by favorable service contract prices.

Only about 15% of North Sea assets have been decommissioned to date, but in the coming five years we expect an average of 23 assets to cease production annually. The UK is poised to lead the way with nearly 80% of total estimated expenditure on Northwest European decommissioning in the next five years, followed by Norway with 14% and Denmark with 4%. The pool of removal projects in the region for that period is estimated at about $17 billion. By comparison, decommissioning costs in the US for the same period are estimated at $5.7 billion.

A protracted low price environment can potentially motivate operators to leverage low contract prices and commit to their asset retirement obligations, thus spurring decommissioning activity in the Northwest Europe region. This will also provide welcome opportunities for contractors in an otherwise gloomy oilfield services market, says Sumit Yadev, energy service analyst at Rystad Energy.

(Click to enlarge)

The high market share of the UK can be largely attributed to its rapidly maturing production levels, as almost 80% of the countrys oil and gas assets have produced more than 75% of their available resources. Additionally, lackluster exploration results, growing regulatory stringency and a prolonged low oil price environment may lead operators to fulfill their asset retirement obligations in the absence of any lucrative competing investments.

Related: Europe Set To Unveil Its $500 Billion 'Green Deal'

Some of the leading assets that will drive the decommissioning market in the region include the Brent, Ninian and Thistle fields in the UK and Gyda in Norway. Shells Brent project would emerge as the single largest asset ever decommissioned globally, representing an outlay of nearly $3 billion alone over the coming decade. Ninian and Gyda would collectively present contracting opportunities worth nearly $2 billion.

The increased spending on decommissioning may limit the room for operators to invest in other segments such as exploration, development and enhanced oil recovery projects. Leading players such as Shell, Total, Repsol and Premier Oil are expected to assign 10% or more of their North Sea spending in the next five years to decommissioning activities.

Plugging and abandonment (P&A) of wells is expected to make up about 45% of decommissioning costs for the period, followed by platform removals, which account for nearly 20% of the total costs. Platform wells are set to be the dominant segment for well P&A activity, making up about 65% of the total wells to be abandoned, while the rest are subsea wells. However, in terms of costs, subsea wells will take the lead as they cost on average $11 million each to abandon, compared with $5 million for an average platform well.

The low oil prices could play a pivotal role in boosting decommissioning spending in the UK if they persist beyond the end of this year. Nearly 10% of all UK offshore assets have lifting costs above $25 per barrel, which will hamper their life extension prospects and make decommissioning a better financial option if low prices persist.

Operators implemented strong cost optimization measures after the oil price crash of 2014 and therefore have little room for further cost and efficiency gains now, which may also expedite decommissioning spending.

Overall, more than 2,500 oil and gas wells are expected to be decommissioned across the North Sea in the coming decade, of which 1,500 are in the UK. The UKCS will also witness the removal of nearly 300,000 tonnes of topsides in the next five years, with nearly 50 topsides set to be decommissioned, representing an average topside removal cost of $5,300 per tonne. Additionally, almost 100,000 tonnes of substructures are expected to be removed in UK waters. In line with the broader North Sea trends, platform wells are expected to account for the bulk of the well P&A activity with nearly 70%.

While decommissioning is becoming a pressing concern for North Sea operators, the prevailing low-price environment presents an opportunity for driving down costs. For instance, after the oil price slump of 2014, rig and vessel rates declined by 30% to 40%. We expect rig and vessel rates to exhibit a downward trend this time as well, with declines likely lasting until 2022, Yadev concludes.

By Rystad Energy

More Top Reads From Oilprice.com:

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Oil & Gas Decommissioning To Total $42 Billion Through 2024 - OilPrice.com

Recommendation and review posted by Bethany Smith

Transhumanists believe humans can and should use technology to artificially augment their capabilities.Natasha Vita-More is Executive Director of Humanity+, formerly the World Transhumanist Association, and is one of the co-authors of the 1998 Transhumanist Declaration.

Speaking toExpress.co.ukshe said: We certainly do need to upgrade our biology and Ive been speaking about this for 30-something years.

The fact that our biology is vulnerable. We exist on a daily basis with an incredible vulnerable vehicle, our bodies, that anything could go wrong at any time.

As far as genetic engineering goes weve seen great work done with certain diseases like Tay-Sachs and sickle-cell anemia, certain cancers, certain diseases that handicap us.

Other gene therapies are in the works and there still needs to be far more work in this area and I think most of us will be undergoing gene therapy as soon as it comes online as needed.

Say 50 years from now I think well be looking at alternative bodies and we can see that really growing in the field of prosthetics.

Transhumanists think human lifespans can be radically extended, with many believing ageing can be reversed and death from disease abolished.

Ms Vita-More argued future humans will look to backup the content of their brains as an insurance policy against death or injury.

She asserted: It is essential our memories be stored some place.

Currently our memories are stored in our brain but thats vulnerable. We have hackers all the time in our brains and those are called viruses and disease.

Disease is constantly hacking our neurons so in order to protect that we need to have copies of it, we need to back it up and you see certain industry leaders like Google looking at how to back up the brain.

I see uploading as a necessary technology for not only backing up the brain but as a means for us to go into different environments.

Were currently in this physical/material world, this biosphere, there are other worlds yet to be explored just as were looking at space exploration.

READ MORE:Oxford academic claims future humans could live for thousands of years

Another area is virtual reality, augmented reality, all these other systems even in games to go into games and participate as yourself taking on an avatar or maybe something else.

Asked about those who might object, on religious or moral grounds, to radical life extension Ms Vita-More expressed confidence their arguments would be overcome.

She commented: I think its largely religious but I think it is also innate.

I think the narrative is engrained in culturalization, it seems to be endemic across cultures.

Given that plus the largest percentage of people on our planet are religious that puts a damper on it too. However it doesnt prevent it.

It could be interesting if we see religious doctrines changing a little bit to include life extension and changing as weve seen with divorce.

If you believe an afterlife it doesnt have to happen at exactly a certain time. Maybe instead of 90 as a lifespan maybe 300 if you want to go that route.

So well see a realisation that religions have to keep up with the state of society and their members within that.

Ms Vita-More is also an advisor to the Singularity University and co-editor and contributing author to The Transhumanist Reader: Classical and Contemporary Essays on the Science, Technology, and Philosophy of the Human Future.

Asked what most excites her about the future she replied: I would like to totally reengineer my body, its not available yet but Id like to have a whole new body thats smoothly integrated not only with narrow artificial intelligence (AI) but with artificial general intelligence and Id like to have a metabrain where Id have AI working with me like a best friend or cohort.

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Humans will be able to replace their bodies within 50 years claims transhumanist writer - Express.co.uk

Recommendation and review posted by Bethany Smith

The study on Global Cryonics Technology Market , offers deep insights about the Cryonics Technology market covering all the crucial aspects of the market. Moreover, the report provides historical information with future forecast over the forecast period. Some of the important aspects analyzed in the report includes market share, production, key regions, revenue rate as well as key players. This Cryonics Technology report also provides the readers with detailed figures at which the Cryonics Technology market was valued in the historical year and its expected growth in upcoming years. Besides, analysis also forecasts the CAGR at which the Cryonics Technology is expected to mount and major factors driving markets growth. This Cryonics Technology market was accounted for USD xxx million in the historical year and is estimated to reach at USD xxx million by the end of the year 2025..

This study covers following key players:PraxairCellulisCryologicsCryothermKrioRusVWRThermo Fisher ScientificCustom Biogenic SystemsOregon CryonicsAlcor Life Extension FoundationOsiris CryonicsSigma-AldrichSouthern Cryonics

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To analyze the global Cryonics Technology market the analysis methods used are SWOT analysis and PESTEL analysis. To identify what makes the business stand out and to take the chance to gain advantage from these findings, SWOT analysis is used by marketers. Whereas PESTEL analysis is the study concerning Economic, Technological, legal political, social, environmental matters. For the analysis of market on the terms of research strategies, these techniques are helpful.It consists of the detailed study of current market trends along with the past statistics. The past years are considered as reference to get the predicted data for the forecasted period. Various important factors such as market trends, revenue growth patterns market shares and demand and supply are included in almost all the market research report for every industry. It is very important for the vendors to provide customers with new and improved product/ services in order to gain their loyalty. The up-to-date, complete product knowledge, end users, industry growth will drive the profitability and revenue. Cryonics Technology report studies the current state of the market to analyze the future opportunities and risks.

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Market segment by Type, the product can be split into Slow freezingVitrificationUltra-rapid

Market segment by Application, split into Animal husbandryFishery scienceMedical sciencePreservation of microbiology cultureConserving plant biodiversity

For the study of the Cryonics Technology market it is very important the past statistics. The report uses past data in the prediction of future data. The keyword market has its impact all over the globe. On global level Cryonics Technology industry is segmented on the basis of product type, applications, and regions. It also focusses on market dynamics, Cryonics Technology growth drivers, developing market segments and the market growth curve is offered based on past, present and future market data. The industry plans, news, and policies are presented at a global and regional level.

Some Major TOC Points:1 Report Overview2 Global Growth Trends3 Market Share by Key Players4 Breakdown Data by Type and ApplicationContinued

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About Us : With unfailing market gauging skills, has been excelling in curating tailored business intelligence data across industry verticals. Constantly thriving to expand our skill development, our strength lies in dedicated intellectuals with dynamic problem solving intent, ever willing to mold boundaries to scale heights in market interpretation.

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Global Cryonics Technology Market Projected to Reach USD XX.XX billion by 2025- Praxair, Cellulis, Cryologics, Cryotherm, KrioRus, VWR, etc. - News...

Recommendation and review posted by Bethany Smith

Global Cell and Gene Therapy Market

The Global Cell and Gene Therapy Market report consists of the latest discoveries and technological advancements recorded in the industry, along with an analysis of the factors and their effect on the markets future development. The report focuses on the current businesses and the present-day headways, and the future growth prospects for the Cell and Gene Therapy market.

This report covers the current COVID-19 effects on the economy. This outbreak has brought along drastic changes in world economic situations. The current scenario of the ever-evolving business sector and present and future appraisal of the effects are covered in the report as well.

The Global Cell and Gene Therapy market size will reach XX Million USD by 2027, from XX Million USD in 2019, at a CAGR of XX% during the forecast period.

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The global Cell and Gene Therapy marketreport gives a 360 approach for a holistic understanding of the market scenario. It relies on authentically-sourced information and an industry-wide analysis to predict the future growth of the sector. The study gives a comprehensive assessment of the global Cell and Gene Therapy industry, along with market segmentation, product types, applications, and value chain.

The study also delivers accurate insights into the market in the forecast duration and other key facts and figures pertaining to the global Cell and Gene Therapy market.

Leading Cell and Gene Therapy manufacturers/companies operating at both regional and global levels:

Amgen Inc., bluebird bio, Inc. Dendreon Pharmaceuticals LLC., Fibrocell Science, Inc., Human Stem Cell Institute, Kite Pharma, Inc., Kolon TissueGene, Inc., Novartis AG, Orchard Therapeutics plc., Organogenesis Holdings Inc., Pfizer, Inc., Spark Therapeutics, Inc., Vericel Corporation, and ViroMed Co., Ltd., among others.

The report also inspects the financial standing of the leading companies, which includes gross profit, revenue generation, sales volume, sales revenue, manufacturing cost, individual growth rate, and other financial ratios.

Research Objective:

Our panel of trade analysts has taken immense efforts in doing this group action in order to produce relevant and reliable primary & secondary data regarding the global Cell and Gene Therapy market. Also, the report delivers inputs from the trade consultants that will help the key players in saving their time from the internal analysis. Readers of this report are going to be profited with the inferences delivered in the report. The report gives an in-depth and extensive analysis of the Cell and Gene Therapy market.

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Cell and Gene Therapy Market has maintained a steady growth rate in the past decade and is predicted to grow at a higher growth rate during the forecast period. The analysis offers an industry-wide evaluation of the market by looking at vital aspects like growth trends, drivers, constraints, opinions of industry experts, facts and figures, historical information, and statistically-backed and trade valid market information to predict the future market growth.

The Global Cell and Gene Therapy Market is segmented:

In market segmentation by types of Cell and Gene Therapy, the report covers-

ell and gene therapy manufacturing landscape:

upstream manufacturing, and downstream manufacturing.

product landscape:

therapeutic market and pipeline analysis.

In market segmentation by applications of the Cell and Gene Therapy, the report covers the following uses-

oncology, hematology, cardiovascular, ophthalmology, neurology

This Cell and Gene Therapy report umbrellas vital elements such as market trends, share, size, and aspects that facilitate the growth of the companies operating in the market to help readers implement profitable strategies to boost the growth of their business. This report also analyses the expansion, market size, key segments, market share, application, key drivers, and restraints.

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Cell and Gene Therapy Market Regional Analysis:

Geographically, the Cell and Gene Therapy market is segmented across the following regions: North America, Europe, Latin America, Asia Pacific, and Middle East & Africa.

Key Coverage of Report:

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In conclusion, the Global Cell and Gene Therapy Market report provides a detailed study of the market by taking into account leading companies, present market status, and historical data to for accurate market estimations, which will serve as an industry-wide database for both the established players and the new entrants in the market.

About Us:Planning to invest in market intelligence products or offerings on the web? Then marketexpertz has just the thing for you reports from over 500 prominent publishers and updates on our collection daily to empower companies and individuals catch-up with the vital insights on industries operating across different geography, trends, share, size and growth rate. Theres more to what we offer to our customers. With marketexpertz you have the choice to tap into the specialized services without any additional charges.

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Cell and Gene Therapy Market Segmentation By Qualitative And Quantitative Research Incorporating Impact Of Economic And Non-Economic Aspects By 2027 |...

Recommendation and review posted by Bethany Smith