New Delhi: The usage of stem cells to cure or treat a disease or repair the injured tissue is defined as stem cell therapy. The best example of the stem cell treatment is seen in patients suffering from restoring the vision of the damaged eyes, grafting of the skin in severe burnt conditions.

Stem cell treatments for brain or neural diseases like Parkinsons and Alzheimers disease, multiple sclerosis, preventing heart strokes, curing diabetes, kidney disorders, autism, and spinal cord injuries are progressively making their way.

Undifferentiated cells that are able to differentiate and transform into any type of cells of the body when and where needed. They have an enormous potential to repair, heal and regenerate. Stem cells come from blood, bone marrow, umbilical cord blood and adipose tissue.

Autologous stem cell therapy: Patient receives stem cells from his/her own body

Allogeneic stem cell therapy: Patient receives the stem cells donated by another individual

Autologous stem cell therapy is better than allogeneic stem cell therapy as chances of mismatching are not there and they pose the minimum risk of immune rejection. Also, no side effects or adverse effects are seen as a persons own blood cells are used. They start the healing process immediately in a natural way.

The usage of stem cells to cure or treat a disease or repair the injured tissue is defined as stem cell therapy. Stem cells can be obtained from the bone marrow, adipose tissues etc. Due to their tremendous potential to prevent and to treat various health conditions and to repair the injured tissues global research investigation is continuously being done as to explore the maximum advantage of these cell lines.

The best example of the stem cell treatment is seen in patients suffering from restoring the vision of the damaged eyes, grafting of the skin in severe burnt conditions. Stem cell treatments for brain or neural diseases like Parkinsons and Alzheimers disease, multiple sclerosis, preventing heart strokes, curing diabetes, kidney disorders, autism, and spinal cord injuries are progressively making their way.

Depending upon the disease, different stem cell source can be used in a specific condition. The procedure may involve the extraction of stem cells from adipose tissue-derived stem cells with the combination of PRP (Platelet-rich plasma) or can be obtained from bone marrow that can differentiate into progenitor cells that differentiate into various other tissues which can help in the therapy.

The stem cells are isolated from the bone marrow or adipose tissues followed by their processing and enrichment under sterile conditions. These activated stem cells are placed back into the patients body at the target site for repairing the damaged tissue. It is necessary that the stem cells are injected in the specific area of injury as only then the desired results will be achieved.

Adipose stem cells are preferred over bone marrow stem cells as they are easy to isolate and contain a higher number of stem cells.

The stem cells injections are gaining much interest because it is devoid of the painful procedure, takes less time in comparison to surgery, there are no host and recipient rejections as stem cells are harvested from the patients body itself and a targeted delivery system is available.

The stem cells obtained are processed in a sophisticated stem cell lab and after activation is inserted back into the host with the help of intravenous, intramuscular, intraarterial, intradermal and intrathecal injections as per the requirement of the treatment process.

What is the use of anaesthetics and why? Usually, local anaesthetics are used during a stem cell procedure to numb the area but sometimes general anaesthesia is also given while extracting the stem cells from bone marrow. But it is necessary to find out what anaesthetic your doctor uses during orthopaedic stem cell treatments.

A number of anaesthetics have been found to kill the stem cells thus; the treatments end result will greatly depend on the use of anaesthetics. Some anaesthetics very well sync with the stem cell and hence, aid in the treatment.

Stem cells are to be extracted and processed in a clean room, under aseptic conditions maintaining a controlled environment. The doctor should explain the entire process and the number of viable stem cells infused into the patient during the process. Also, the precision of the injections to provide good quality of stem cells at the site of injury will help in better and faster recovery of the patients damaged area.

Cost of the treatment and its duration varies from one patient to another. The disease which needs to be cured, the severity, age factor, health condition, etc, define the duration of the therapy. One may respond during the treatment phase itself while the other may show results after a few sessions or weeks. Depending upon the disease diagnosed, the stem cells extracted, duration of the therapy, other adjuvants used in the process, the cost of the stem cell therapy can vary.

It is essential that after the stem cell therapy the patient should visit the stem cell doctor for recuperation therapies. The primary goals of such therapy is the prevention of secondary complications, analysis of the recovery of motor, sensory and all the bodily functioning, psychological support/counselling for depression, mood swings or anxiety etc. and reintegration into the community.

There can be different sets of precautions which need to be followed at various steps for the recovery of the damaged tissues. The treatment and post-treatment conditions may vary from person to person depending upon the disease and the severity.

Stem cell therapy has shown results in treating serious ailments like leukaemia, grafting tissues, autism, orthopaedic conditions and skin problems etc. Stem Cell Therapy has been successfully used in the treatment of around 80 serious disorders.

Survival rates among patients who received stem cell treatment are significantly high, whether cell donors are related or unrelated to them. With the ongoing research around the world, scientists are exploring new possibilities in which a number of life-threatening diseases can be prevented and cured hence, the stem cells have proved to be promising in the near future as many aspects are yet to be revealed.

Read: Egg stem cells do not exist, says researchers

-IANS

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10 things to know about stem cell therapy - Newsd.in

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I consider my nighttime skincare routine as me time. I always double cleanse; first with Bioderma Sensibio H20 Micellar Water, 10.80, and then I use Rodial Pink Diamond Cleansing Balm, 55, and massage it into my skin. Its a really light and gentle balm that has enough slip for me to be able to easily move it around my face, and it helps dissolve any left over SPF and make-up while also getting rid of the days dirt and grime.

After a good 10-15 minute cleanse, I sweep Pestle and Mortar NMF Lactic Acid Toner, 28, around my face. Lactic acid works underneath the skin, helping to get rid of dead skin cells without dehydrating my skin. Then I press SkinCeuticals HA Intensifer, 90, into my skin to help increase hydration levels.

I use my final product once Im in bed; Decleors Bigarade Neroli Night Balm, 45, which I do a deep pressure massage with and then I finish off using a gua sha to help drain any fluids and relax the muscles.

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3 skin experts share their morning and evening skincare routines - Stylist Magazine

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4-Mar-2020

Ingredients | Skin Care

inspira: cosmetics produces and markets high-quality, contemporary cosmetic products for individual skin care worldwide

The German company is based in Aachen and was founded in 2000. The development of outstanding and highly effective products with excellent compatibility is a matter of course for inspira: cosmetics.

The products visibly improve the appearance of the skin and let the user look in the best possible way for his/her respective age.

Now Volker Kloubert, Managing Partner of inspira: cosmetics proudly announced: "We are more than happy and feel very honoured that 3 of our entries are finalists in the Pure Beauty Global Awards and we are looking forward to the award ceremony in May in Amsterdam. Lets keep fingers crossed!

The finalist products from inspira: cosmetics reflect the broad scope of cosmetics the brand is covering.

The male scent 4MEN ONLY is nominated in the category Best Male Fragrance. A masculine composition of oriental notes, combined with woods and musk. Adventurous and very sexy! For men only. The sophisticated fragrance was created by master perfumers in Grasse/France.

Finalist in the category Best Lip Product is the Volumizing Lip Remedy, a lip care stick in stylish silver metal packaging with high quality active ingredients like hyaluronic acid, shea butter, coconut oil, spearmint oil for a fresh taste and the Peptide Complex VOLULIP than can increase the lip volume by up to 82% in 4 weeks as it stimulates the production of hyaluronic acid in the lips.

Very important: NO burning sensation, the product is smooth as silk.

Age Reboot Serum is the new holistic anti aging serum in the inspira: med range using state of the art active ingredients to protect and rejuvenate the skin.

Phyto stem cells help the skin to adapt to changing environmental conditions like heat or cold and protect the cells whereas three different hyaluronic acids smooth the skin, even out wrinkles and EGF (Epidermal Growth Factor) stimulates cell renewal.

In clinical studies the skin was rejuvenated by up to 10 years in four weeks of regular use.

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Three of inspira: cosmetics entries are finalists in the Pure Beauty Global Awards 2020 - Cosmetics Business

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FORMS of blood cancer, such as leukaemia or lymphoma, are the fifth most common cancer, and the third biggest cause of cancer deaths.

Yet warning signs can be so unlike those of other cancers, that its often diagnosed at a very late stage.

Research by UK blood cancer charity Bloodwise (bloodwise.org.uk) found more than a third of sufferers had to visit their GP three or more times with symptoms before being a hospital referral. This makes it the worst performing cancer in terms of early diagnosis.

Why is it so difficult to spot? Blood cancers, which stop blood stem cells from working normally and can make you weak and prone to infections, have three main types with many different variations. These variations have numerous diverse symptoms, which can often be mistaken for other less serious conditions.

Not all signs of blood cancer are easily identifiable, or are associated with typical symptoms of cancer, such as a lump or abnormal mole, says haematologist Dr Manos Nikolousis, a medical consultant with UK blood cancer charity DKMS.

Blood cancer often presents in ways which are most commonly associated with unrelated and less serious illnesses, like a cold or flu. In other circumstances, patients notice a change in their body which they cant quite put their finger on.

One of the treatments for blood cancer is a stem cell transplant that restores blood-forming stem cells in patients whove had theirs destroyed by very high doses of chemotherapy and/or radiotherapy. But Nikolousis points out that only one in three blood cancer patients who need a transplant find a matching blood stem cell donor in their family. The remaining two-thirds have to rely on an unrelated donor, which significantly reduces their chance of finding a crucial match.

Here, Nikolousis outlines some blood cancer symptoms and warning signs...

Musculoskeletal pain in muscles, joints, tendons, bones or structures that support the limbs, neck or back.

One of the most common symptoms associated with blood cancer. The frequency and lasting impact of bruising can be a key warning sign, so its important to book an appointment with your GP if this develops.

Unexplained and persistent tiredness is one of the biggest tell-tale signs of blood cancer. People who have cancer-related fatigue find it incredibly challenging to complete simple tasks that we tend to take for granted.

The lymph nodes are small lumps of tissue that contain white blood cells. When inflamed, they can be felt as lumps under the skin; most commonly in the neck, armpit or groin area.

There may be new headaches that feel different. Theyre likely to occur frequently and be severe and long-lasting.

Persistent abdominal discomfort, presenting as a sharp pain or a sense of feeling full.

This can be described as a feeling of pins and needles/numbness that moves up to the legs, or from fingers to the arms.

This can feel like a fluttering, a sudden thump or a fast pounding sensation in the chest. It can also be felt in the neck or ear when lying down.

People may describe this as feeling mentally drained or dizzy.

Blood cancer patients may have continuous trouble falling asleep or staying asleep.

Persistent and irritable, this may be experienced all over the body, or in isolated spots.

These symptoms are common and dont automatically mean you have cancer. But if you notice any unusual or ongoing changes, its always best to see your doctor and get checked.

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Eleven symptoms of blood cancer that everybody needs to know about... - Echo Live

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Pennsylvania state trooper Matt Uram was talking with his wife at a July Fourth party in 2009 when a misjudged spray of gasoline burst through a nearby bonfire and set him alight. Flames covered the entire right side of his body, and after he fell to the ground to smother them, his wife beat his head with her bare hands to put out his burning hair. It was only on the way to the ER, as the shock and adrenaline began to wear off, that the pain set in. "It was intense," he says. "If you can imagine what pins and needles feel like, then replace those needles with matches."

From the hospital, Uram was transferred to the Mercy Burn Center in Pittsburgh, where doctors removed all of the burned skin and dressed his wounds. It was on the border between a second- and third-degree burn, and he was told to prepare for months of pain and permanent disfigurement. Not long after this assessment, however, a doctor asked Uram if he would be willing to take part in an experimental trial of a new device.

The treatment, developed by German researcher Dr. Jrg Gerlach, was the world's first to use a patient's stem cells to directly heal the skin. If successful, the device would mend Uram's wounds using his body's ability to regenerate fully functioning skin. Uram agreed to the procedure without hesitation.

Five days after the accident, surgeons removed a small section of undamaged skin from Uram's right thighabout the size of a postage stampand used it to create a liquid suspension of his stem cells that was sprayed in a fine mist onto the damaged skin. Three days later, when it was time to remove the bandages and re-dress the wounds, his doctor was amazed by what he saw. The burns were almost completely healed, and any risk of infection or scarring was gone.

A study subsequently published in the scientific journal Burns described how the spray was able to regrow the skin across the burn by spreading thousands of tiny regenerative islands, rather than forcing the wound to heal from its edge to the inside. The technique meant "reducing the healing time" and "minimizing complications," with "aesthetically and functionally satisfying outcomes," the paper stated.

Dozens more burn victims in Germany and the U.S. were successfully treated with the spray following Uram's procedure, and in 2014 Gerlach sold the technology to RenovaCare. The medical technology startup has now transformed the proof-of-concept device from a complicated prototype into a user-friendly product called a SkinGun, which it hopes clinicians will be able to use outside of an experimental setting. For that to happen, RenovaCare is preparing clinical studies for later this year, with the aim of Food and Drug Administration approval for the SkinGun.

Once these obstacles are overcome, RenovaCare CEO Thomas Bold believes, the SkinGun can compete with, or even replace, today's standard of care.

Current treatment of severe burns involves transplanting healthy skin from one area of the body and stitching it to another in a process called skin grafting or mesh skin grafting. It is a painful procedure that creates an additional wound at the donor site and can cause restricted joint movement because the transplanted skin is unable to grow with the patient. It is able to cover an area only two to three times as large as the harvested patch. "The current standard of care is just horrible," says Bold. "We are part of regenerative medicineit is the medicine of the future and will be life-changing for patients."

Beyond regulatory matters, there are also limitations to the technology that make it unsuitable for competing with treatments of third-degree burns, which involve damage to muscle and other tissue below the skin. Still, stem cell researcher Sarthak Sinha believes that while the SkinGun may not be that advanced yet, it shows the vast potential of this form of regenerative medicine. "What I see as the future of burn treatment is not skin repair but rather functional regeneration of skin and its appendagessuch as hair follicles, glands and fat," says Sinha. "This could be achieved by engaging deeper layers of skin and its resident stem cells to partake in tissue regeneration."

Research is already underway at RenovaCare to enable treatment of third-degree burns, which Bold describes as "definitely within the range of possibility." Bold claims the adaptations to the SkinGun would allow it to treat other damaged organs using a patient's stem cells, but for now the company is focusing solely on burns and wounds to skinthe largest organ of the human body.

Uram's burns are now completely unnoticeable. There is no scar tissue or even pigment discoloration, and the regenerated skin even tans. "If I show someone where I was burnt, I bet $100,000 they couldn't tell," he says. "There's no scars, no residual pain; it's like the burn never happened. It's a miracle."

Uram is frustrated that the treatment is not available to other burn victims, particularly children. "I want to see the FDA get off their butts and approve this," he says. "A grown man like me to be scarred is OK, but think about the kids that have to live the rest of their lives with pain and scarring. That's not OK."

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Spray-On Skin: 'Miracle' Stem Cell Treatment Heals Burns ...

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Made from the leaves of a shrub called Camellia sinensis, black tea is known for its high content of antioxidants and compounds that have several health and beauty benefits. Most of them can be reaped by drinking a cup or two per day. You could, alternatively also apply it topically on your hair and skin.

Heres how it helps and how you can make it a daily part of your diet:

Black tea is mainly rich in antioxidants known as polyphenols that help combat free radicals.

Free radicals are unstable molecules in the body that result from both natural and environmental factors, and over time, their build-up can damage or change cells in the body.

A cup of Darjeeling black tea has many bioactive compounds that reduce the risk of some cancers, heart diseases, lowers cholesterol and reduces blood sugar.

Most of our illnesses today stem from unregulated stress, courtesy of our fast-paced lifestyle. A cup of lavender bloom tea in the evening, will ensure that your stress levels are in check.

The handpicked tea leaves infused with lavender flowers, and rose petals work as a de-stressor and help you sleep better. The tea also builds immunity and improves digestion.

The massive antioxidants and caffeine content in black tea is beneficial in preventing hair fall, stimulating hair growth and adding shine and lustre to your mane.

For the most part, drinking a cup regularly is all you need to do to see the difference in your hair health.

However, you can also apply black tea extract (room temperature) to your scalp and hair as a conditioner after shampooing every once a week to reap its benefits.

The polyphenols and tannins in black tea are responsible for preventing skin infections, premature ageing, and reducing sunburns or blemishes.

Black tea is also known to reduce inflammation and flush out toxins; hence it also works to reduce under-eye puffiness and accelerate skin regeneration.

Just place a cotton ball soaked in cold black tea on the desired area of your face or body for a few minutes for a healthy glow, and drink a cup or two for overall skin health.

Along with a few lifestyle changes, consuming a cup of black tea regularly is known to aid in weight loss.

A prolonged period of inflammation in the body can induce obesity. Black tea helps prevent visceral fat and lowers the triglyceride levels by decreasing inflammation-inducing genes.

While other beverages such as coffee and green tea are great too if consumed in the right manner, this beverage takes it a notch higher with its incredible health benefits.

Also Read: Dark Chocolate Is Healthy! 5 Reasons to Make It a Part of Your Daily Diet

(Edited by Gayatri Mishra)

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5 Reasons Science Says Your Health, Skin and Hair Needs Black Tea - The Better India

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At several labs across the US, researchers use fetal tissue from humans to investigate everything from viral infections to the developing brain. Such studies have been ongoing for decades, as have politically fraught debates about this research, because it primarily relies on tissue donated after terminated pregnancies.

Last summer, President Donald Trumps administration announced that it would be placing restrictions on experiments involving fetal tissue obtained from elective abortions, which included banning government scientists from using this material for research and applying increased scrutiny for National Institutes of Health (NIH) grant proposals from nongovernmental scientists.

Researchers say that the new restrictions on fetal tissue research have required them to change their plans for future work or to search for alternative sources of funding. Its impacted almost all of the facets of the lab, says Carolyn Coyne, a microbiologist at the University of Pittsburgh who uses fetal tissue to study how viruses penetrate the placenta.

Its affected pretty much every grant application that that weve written.

Mana Parast, University of California, San Deigo

One of the main concerns, according to several researchers who spoke to The Scientist,is the lack of clarity regarding what the NIH will require in grant applications for this work. The Department of Health and Human Services (HHS), which oversees the NIH, has stated that it would put together a new ethics advisory board to review such proposals. Last week (February 20), HHS posted a notice indicating its intent to convene the NIHs fetal tissue ethics advisory board in 2020. In a written statement to The Scientist,the NIH states that it is in the process of setting up the Ethics Advisory Board for the purpose of evaluating research proposing the use of human fetal tissue from elective abortion.

Scientists are waiting to find out who will be appointed to the board and how it will evaluate proposals once it convenes. [Well] see whether the administration is going to act in good faith and appoint a decent ethics review committee, or if theyre going to ignore the value of the scientific and medical research that needs to be done in this area and let ideology weigh out over logic, says Lawrence Goldstein, a stem cell scientist at the University of California, San Diego, whose lab has worked with fetal cells in the past. The fetal tissue that were talking aboutif we dont use it for research, it will be discarded. Thats the choice. Discard the fetal tissue in the in the trash, or use it for valuable research.

This is not the first time such a ban has been put in place. In 1988, former US President Ronald Reagan placed similar restrictions on federal funding for fetal tissue studies, which stayed in place until President Bill Clinton overturned them during the first year of his term in 1993.

Fetal tissue used for research is primarily obtained from elective abortions, which women can consent to donate after deciding to terminate a pregnancy. This is because there are some major limitations to tissue obtained through other means, such as miscarriages, according to Anita Bhattacharyya, a stem cell scientist at the University of Wisconsin-Madisons Waisman Center. Supply is limited and the underlying factors that lead to pregnancy loss can complicate experiments. On top of that, such events often happen unexpectedly, meaning that the collected tissue is not always intact. We would worry about using poor quality tissue as a foundation for the work we do, says Bhattacharyya, who uses donated fetal brain tissue to study brain development and disorders such as Down syndrome and fragile X syndrome.

Bhattacharyya says that although her lab currently has the tissue it needs to complete experiments from a prior grant, shes not comfortable submitting proposals for studies that require obtaining new fetal tissue. Its because I dont know whats going to happen. If I spend hours writing a grant that I think is really good science, and I send it to NIH . . . its going to get stuck there, Bhattacharyya explains. Were so busy as scientists that to just write a grant that isnt going to go anywhere is a waste of our time.

As such, her projects may suffer. According to Bhattacharyya, not only is brain development difficult to study in model organisms such as rodents, but fragile X and Down syndrome in particular are difficult, if not impossible, to model in animals. Induced pluripotent stem cells (iPSCs), which can be generated by reprogramming cells from skin or blood in adults, have offered an alternative means of studying the development and disorders of the brain, yet researchers still need to validate the results they obtain, Bhattacharyya says. Really, the only way to do that is using fetal tissue.

In addition to cells and tissue from the fetus itself, the restrictions on NIH funding were also applied to other biological materials obtained in the process of abortions, such as umbilical cord, placenta, and amniotic fluid. While some of these can be useful to scientists when collected after birth, placental tissue obtained in this way has limitations. Full term placentas are actually aged tissues, explains Coyne. If were studying a full-term placenta post-delivery, the gnawing question is: Has that placenta changed from the placenta that exists in the first or second trimester?

Mana Parast, a stem cell and placental biologist at the University of California, San Diego, who studies placental development and disorders, tells The Scientist that while the policy change has left ongoing projects unscathed, its affected pretty much every grant application that that weve written since then. While Parasts team has used fetal tissue in the past, they are now focusing on using iPSC-based models. However, like Bhattacharyya, she notes that this isnt the perfect solutionas these models are fairly new and not yet broadly accepted, it is still necessary to validate them with cells from human placentas.

Coyne says that in addition to limiting access to grants for her research, the restrictions have also made it more difficult to procure tissue. A lot of major medical schools have federally funded tissue banks, Coyne explains. Our institutional tissue bank has been affected by this such that we cant obtain tissue from elective terminations anymore.

For researchers who have been able to obtain funding from alternative sources, such as philanthropists or private foundations, the effects of the restrictions have been minimal. Thomas Reh, a biologist at the University of Washington whose team uses fetal tissue to study the developing retina, says that his groups work is currently supported by a grant from the Open Philanthropy Project, a nonprofit organization. When the political climate gets more restrictive, private donors will often step in, Reh says. I wont say that works for everybody, or that it works all the time. At least in my own case, this is whats allowed me to sort of fill these gaps when [restrictions on fetal tissue] happen.

Its the next generation of trainees that are going to be most impacted, not just because they cant get funding, but if I were one of them, I would think to myself, is this really an area that I want to specialize in?

Carolyn Coyne, University of Pittsburgh

Andrew McMahon, a stem cell scientist at the University of Southern California, still has about a year left before he needs to apply for more funding, and hes started looking into potential alternatives to NIH. My understanding is that its not entirely clear at the moment what that process is going to be, McMahon says. Ive been using the time to obtain non-NIH funding to support aspects of the research that I would have tried to get NIH funding [for] in the future.

Private funds are not available to everyone, and can be more difficult for researchers in some fields to obtain than others. For some of the disorders that I work on, the major private funding foundation does not allow fetal tissue research, Bhattacharyya says. And sometimes the foundation funding can be quite a bit less than NIH funding.

For researchers in some states, nonprofits are not the only option. In California, the states stem cell agency, the California Institute for Regenerative Medicine (CIRM) has provided funding for stem cell studies using fetal tissue since it was founded in 2004. That fund is about to run out, but a bill that would provide $5.5 billion in funding to CIRM will come before voters in November.

That will hopefully provide funding for areas of fetal tissue research that involves stem cells, Goldstein says. But . . . its ridiculous to rely on one or two states to self-fund, because we dont have all of the best and brightest [scientists], and it means lots of students and postdocs will train in areas where federal training support will be unavailable to them.

Goldstein isnt the only one concerned that the most profound effect of the governments restrictions will be on early-career investigators and trainees. While established researchers may be able to circumvent the effects of the restrictions in the short term, the ramifications for trainees in this field will likely be much longer-lasting, Coyne says. Its the next generation of trainees that are going to be most impacted, not just because they cant get funding, but if I were one of them, I would think to myself, is this really an area that I want to specialize in and get into?

One scientist, who asked to remain anonymous for fear of being harassed by anti-abortion activists, tells The Scientist that the restrictions have been a source of huge stress and anxiety for his lab, which he only established a few years ago. He adds that while his team has pivoted to using animal models and organoids generated from iPSCs, these are imperfect models of the developing human brain, which is the focus of his work.

It makes no sense to limit this research, given that the tissue from abortions will get discarded now that donation is not an option, Parast says. Were not talking about encouraging this procedurewere trying to use the material from patients who have already decided to undergo this procedure in order to be able to help other women.

Diana Kwon is a Berlin-based freelance journalist. Follow her on Twitter@DianaMKwon.

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Scientists Grapple with US Restrictions on Fetal Tissue Research - The Scientist

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INTRODUCTION

Severe combined immunodeficiency (SCID) is a heterogeneous group of genetic diseases characterized by severe T cell lymphopenia, causing increased susceptibility to viral, bacterial, and fungal infections since early in life (1). Most forms of SCID are due to genetic defects that are intrinsic to hematopoietic cells and can be successfully treated by allogeneic hematopoietic stem cell transplantation (HSCT). However, SCID may also be caused by genetic abnormalities that are intrinsic to thymic epithelium development and function; in such cases, thymus transplantation, but not hematopoietic cell transplantation, is required to cure the disease. Only a few genetic abnormalities, including complete DiGeorge syndrome, and pathogenic variants affecting FOXN1 or CHD7, are known to cause SCID as a result of abnormal thymic development in humans (1).

PAX1 is a member of the paired box (PAX) family of transcription factors and plays a critical role in pattern formation during embryogenesis. It is expressed in the pharyngeal pouches that give rise to the thymus, tonsils, parathyroid glands, thyroid, and middle ear development during human embryogenesis (2). Pax1 deficiency in mice is characterized by anomalies of the vertebral column and variable degrees of thymic hypoplasia and thymocyte number and maturation (35). In humans, a homozygous pathogenic PAX1 p.Gly166Val variant (6) and a homozygous frameshift insertion (c.1173_1174insGCCCG) (7) have been identified in patients with otofaciocervical syndrome type 2 (OTFCS2), a rare disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. Recently, another homozygous pathogenic PAX1 variant (p.Cys368*) has been reported in two affected children from a consanguineous family of North African descent, who presented with OTFCS2 associated with T B+ SCID (8). However, limited information was provided on the immunological phenotype of these patients, and the functional consequences of the PAX1 variant were not investigated. Here, we provide an in-depth clinical, biochemical, and immunological description of multiple patients with OTFCS2 associated with SCID who carried biallelic deleterious PAX1 variants. By performing transfection experiments, molecular modeling, molecular dynamics (MD) simulation, and in vitro differentiation of control- and patient-derived induced pluripotent stem cells (iPSCs) to thymic epithelial progenitor (TEP) cells, we sought to assess the effects of human PAX1 deficiency on thymus development and function.

Patient 1 (P1) is a male infant born to parents whose families were from the same rural region in Germany (Fig. 1A). Bilateral microtia, malar prominence, narrow alae nasi, cupid bow lip, and retrognathia were noticed at birth (fig. S1, A and B). Imaging studies demonstrated severely stenotic external auditory canal on the right side and narrow left auditory canal (fig. S1C), congenital kyphosis at C3-C4 and L3 levels, moderate spinal canal narrowing (fig. S1, D to F), and traction on the cauda equina (fig. S1G). Diffuse erythematous rash (fig. S1H), lymphadenopathy, elevated serum immunoglobulin E (IgE), and eosinophilia were present, consistent with Omenn syndrome. On chest x-ray, the thymus shadow was not visible, and split cervical vertebral bodies, hooked distal clavicles, and a shallow dysplastic glenoid fossa were seen (fig. S1I). This infection history during infancy included Staphylococcus aureus bacteremia, pneumonia, cellulitis, and diarrhea due to Clostridium difficile.

(A) Pedigrees and results of Sanger sequencing in patients with PAX1 variants and in healthy controls. For both family A and family B, results of Sanger sequencing in the heterozygous parents are also shown. (B) Schematic representation of the PAX1 protein and location of the variants identified in affected individuals.

P2 and P3 have been previously described (8) as patients V:1 and V:18, respectively, and are part of a large consanguineous family of Moroccan origin (Fig. 1A). At birth, P2 was noticed to have frontal and parietal bossing, hypertelorism, small nose with hypoplastic nasal root, low-set ears with agenesis of the left pinna and hypoplasia of the right pinna, scapular winging, and bilateral cryptorchidism. Imaging studies showed impaired development of internal auditory canals bilaterally and lack of a thymic shadow. P3 manifested similar facial dysmorphisms as P2, along with left facial nerve palsy, severe dorsal and lumbar scoliosis, and deafness. Imaging studies documented lack of thymic shadow, abnormal appearance of vertebrae, clavicles and shoulder blades, narrowing of both external auditory canals (fig. S1J), abnormalities of the middle ear, and presence of tubular structures with features of a dental element behind the mandibular condyle (fig. S1, K and L). Subject V:3 from the same family died early in life with a history of severe infections, but no formal medical records are available.

P4 and P7 are siblings born to consanguineous parents from Saudi Arabia. P7 was noticed to have severe bilateral microtia, postauricular sinuses, and micrognathia. He suffered from chronic diarrhea, recurrent respiratory infections, exfoliative dermatitis, regional dissemination of Bacille Calmette-Guerin (BCG-itis), and lymphadenopathy and died at 1 year of age.

P4 is a female with a history of chronic diarrhea, recurrent respiratory infections, and poor weight gain since the age of 1 month. Physical examination showed small malformed ears, a skin tag on the right ear, facial asymmetry, small nose with depressed nasal bridge, and small almond-shaped eyes. A skeletal survey showed wedge-shaped vertebral body at T11 and deficient posterior element of the sacrum at S4 and S5.

P5 and P6 were siblings born to consanguineous parents and belonged to the same extended family as P4 and P7. P5 had small, low-set malformed ears, triangular mouth, down-slanting palpebral fissures, a small nose with a depressed nasal bridge, and right facial palsy. She developed recurrent respiratory infections, chronic diarrhea, severe exfoliative dermatitis, and BCG-itis and was diagnosed with Omenn syndrome. She died at 8 months of age with progressive severe pneumonitis.

P6 was screened for immunodeficiency at birth because of the positive family history. She had malformed and low-set small ears, small chin, protruding forehead, and generalized eczema. A skeletal survey showed central depression of the vertebral bodies in the thoracic and lumbar spine. Her immunological workup was consistent with T B+ NK+ (natural killerpositive) SCID. She suffered from recurrent respiratory infections and chronic diarrhea and died at 9 months of age with respiratory syncytial virus (RSV) pneumonia.

The main immunological findings at presentation in P1 to P6 are shown in Table 1. In particular, P1 had significant T cell lymphopenia. His CD4+ lymphocytes were largely (98%) CD45R0+, no CD4+ CD45RA+ CD31+ cells were detected, and T cell proliferation to phytohemagglutinin (PHA) was impaired (fig. S2A). T cell receptor (TCR) excision circles (TRECs) were below the limit of detection, indicating lack of thymopoiesis. TCR V spectratyping revealed T cell oligoclonality (fig. S2B). Elevated serum IgE and eosinophilia were present, consistent with an Omenn syndrome presentation.

AEoC, absolute eosinophil count; ALC, absolute lymphocyte count; ANC, absolute neutrophil count; n.d.: not done; cpm, counts per minute.

Laboratory investigations in P2 at 2 weeks of age revealed profound T cell lymphopenia, markedly reduced proliferative response to mitogens, and increased serum IgE. An inguinal lymph node biopsy showed severe lymphoid depletion, with primary follicles without germinal centers, associated with nearly complete absence of CD3+ T cells, but presence of B and NK cells and sparse plasma cells, and increased number of CD68+ histiocytes and eosinophils (fig. S3). A diagnosis of T B+ NK+ SCID was established.

Severe T cell lymphopenia was observed in P3, P4, and P6, associated with virtually absent in vitro T cell proliferation to PHA in P4 and P6, consistent with a diagnosis of T B+ NK+ SCID (Table 1). Last, P5 was diagnosed as having Omenn syndrome based on generalized erythroderma, lymphocytosis, eosinophilia, hypogammaglobulinemia, increased IgE, and severely reduced in vitro T cell proliferation to PHA.

Because of severe immunological abnormalities, HSCT was attempted in P1 to P4 before the gene defect was known. Details of transplant, chimerism, and immune reconstitution are shown in Table 2. In all cases, a conditioning regimen was used. Two patients (P1 and P4) attained full donor chimerism. P2 failed to engraft, developed interstitial pneumonitis, and died 5.5 months after HSCT. In P3, initial engraftment was followed by secondary graft failure, and a second HSCT was performed, resulting in mixed chimerism. Although three of the patients attained either full or mixed donor chimerism, none of them achieved reconstitution of the T cell compartment. In P1, who exhibits full donor chimerism, all T cells have a CD45R0+ phenotype and therefore likely represent donor-derived T cells contained in the graft that have undergone peripheral expansion. P3 attained mixed chimerism but remained with persistent severe T cell lymphopenia. She developed Pneumocystis jiroveci pneumonia, recurrent gastrointestinal infections, and liver failure and died of septic shock at the age of 4 years and 7 months. P4, who attained full chimerism but failed to reconstitute T cells, developed severe autoimmune hemolytic anemia, requiring multiple courses of rituximab and immunosuppressive therapy. Together, these data indicate that HSCT was unable to correct the profound T cell immunodeficiency of this disease.

ATG, anti-thymocyte globulin; PBSC, peripheral blood stem cells; URD, unrelated donor.

Before HSCT, karyotype analysis revealed no cytogenetic abnormalities in P1, P2, and P3. No evidence for copy number variation (CNV) was found by chromosomal microarray analysis in P1, and search for 22q11 deletion in P2 by in situ fluorescence hybridization was negative. No pathogenic variants in any of the known SCID-causing genes were identified in P4 by a targeted next-generation sequencing primary immunodeficiency gene panel. In an attempt to define the molecular mechanisms of the disease, whole-exome sequencing (WES) was performed in P1, P2, and P4 independently (fig. S4 and table S1). In P1, a total of 153,376 variants were identified. Assuming autosomal recessive inheritance, and upon filtering for homozygous, rare, nonsynonymous changes in coding regions and splice sites, 38 variants were considered. Among these, functional annotation identified the PAX1 NM_006192.3 c.463_465del variant, predicted to cause an in-frame deletion of asparagine at position 155 (p.Asn155del) of the PAX1 protein, as the most likely cause of the disease. In P2, 87,423 variants were detected. Assuming an autosomal recessive inheritance, and upon filtering for homozygous, nonsynonymous, and rare (minor allele frequency < 0.01) variants falling in coding regions or splice sites, 18 such variants were considered. Functional filtering of these revealed the PAX1 c.1104C>A variant, predicted to cause a premature termination at codon 368 (p.Cys368*), as the most likely cause of the disease. In P4, 60,772 variants were detected. Upon filtering for homozygous, nonsynonymous, rare (in-house Saudi variant database <0.005) variants, which were restricted to exonic or splice sites, contained in an autozygome region identified on chromosome 20 by high-density genotyping, and shared with P5 and P6, only two variants were identified, including the PAX1 c.439G>C variant, predicted to cause a p.Val147Leu amino acid change.

Sanger sequencing confirmed homozygosity for the suspected pathogenic PAX1 variants in P1 to P6 (Fig. 1A). The Val147 and the Asn155 amino acid residues are in the DNA-binding paired box domain, and the Cys368 residue is in the transactivation domain of the PAX1 protein (Fig. 1B). All these positions are evolutionarily conserved (fig. S5). The scaled CADD (combined annotation dependent depletion) score (CADD-Phred) for the p.Val147Leu, p.Asn155del, and p.Cys368* variants is 28.1, 21.2, and 38, respectively, significantly higher than the mutation significance cutoff (MSC) score (9), which for the PAX1 gene is 12.06. Together, these data strongly support a pathogenic role of the PAX1 variants identified. Of note, while molecular and cellular studies to confirm the pathogenic role of the PAX1 variants were under way, another group independently attempted WES in P3 and in other family members (but not in P2) and reported the occurrence of the p.Cys368* variant in P3 (8).

To examine the effects of the PAX1 variants at the protein level, we transfected 293T cells with plasmids encoding for either wild-type (WT) or mutant PAX1 complementary DNA (cDNA) and analyzed protein expression by Western blot. In this assay, we also included the PAX1 p.Gly166Val variant, which had been previously reported in a patient with OTFCS2 (6). As shown in Fig. 2A, all mutant proteins were expressed at similar levels as WT PAX1, with the p.Cys368* mutant migrating as a lower molecular weight product, as predicted. To check whether the identified variants altered the subcellular localization of the PAX1 protein, 293T cells were transfected with PAX1 constructs with an N-terminal HA tag, and immunofluorescence was performed with tetramethyl rhodamine isothiocyanate (TRITC)conjugated anti-HA antibody. As shown in Fig. 2B, both WT and mutant PAX proteins were detected in the nucleus, indicating that these variants do not affect subcellular localization.

(A) Western blot showing expression of WT and mutant human PAX1 proteins upon transient transfection in 293T cells. (B) Left: Intracellular protein localization upon transfection of HA-tagged WT and mutant PAX1 constructs into 293T cells, followed by staining with TRITC anti-HA. Right: Counterstaining with DAPI, demonstrating that the mutant PAX1 protein retains nuclear translocation capacity. Scale bar, 10 m. (C) Results of a luciferase reporter assay demonstrating reduced transcriptional activity of mutant PAX1 proteins, corresponding to the PAX1 variants detected in patients. The promoter region of Nkx3-2 was used to drive luciferase expression. Results of six independent experiments (each run in triplicate) are shown (means SEM). P value was calculated with one-way ANOVA and adjusted by Dunnetts multiple comparisons test. **P < 0.01; ***P < 0.0001.

Next, we tested the transcriptional activity of the PAX1 mutant proteins. Little is known on transcriptional targets of human PAX1; however, the Nkx3-2 promoter has been identified as a PAX1 target in mice (10). Therefore, we generated a reporter system in which luciferase expression is driven by the mouse Nkx3-2 promoter. In parallel, we generated both WT (Pax1WT) and mutant (Pax1Val138Leu, Pax1Asn146del, Pax1Cys359*, and Pax1Gly157Val) N-terminal HA-tagged mouse Pax1 constructs, which encode for mouse mutant PAX1 proteins corresponding to the human p.Val147Leu, p.Asn155del, p.Cys368*, and p.Gly166Val variants, respectively. Western blot analysis confirmed that the mutant mouse PAX1 proteins were expressed at similar levels as WT PAX1 (fig. S6). Upon cotransfection of the Nkx3.2-luciferase reporter plasmid and of either WT or mutant PAX1 expression plasmids into 293T cells, analysis of luciferase activity showed that the p.Val138Leu, p.Asn146del, and p.Cys359* PAX1 mutant proteins had significantly reduced reporter expression when compared with WT PAX1 (Fig. 2C and data file S1). A similar defect was also observed for the p.Gly157Val mutant, confirming previous findings (6). These data suggest that the human p.Val147Leu, p.Asn155del, and p.Cys368* variants do not affect protein stability or subcellular localization but alter PAX1 transcriptional activity.

The structure of the human PAX1 protein has not been solved experimentally. However, a crystal structure is available for the paired box domain of the highly homologous PAX6 protein (11). Sequence alignment between the paired box domain of PAX6 and PAX1 proteins reveals a high level of conservation with a similarity of 71%, with a 100% coverage of the region to be modeled as calculated with the BLOSUM80 matrix from PSI-BLAST (E = 1.3691 1020). As reported by Kelm et al. (12), this degree of homology often yields a model for the target (PAX1) with an accuracy of less than 1 root mean square deviation (RMSD) of atomic mobility to the experimentally solved structure of the template (PAX6). Because the p.Val147Leu and p.Asn155del mutants fall within the paired box domain of the protein, we assessed whether the reduced functional activity of the mouse p.Val138Leu and p.Asn146del (and by inference, the human p.Val147Leu and p.Asn155del) variants results from an altered structure and/or abnormal DNA binding. To do this, we first developed a structural model of the paired box domain of WT and mutant PAX1 bound to DNA, based on its homology to the published crystal structure of PAX6 [Protein Data Bank (PDB): 6PAX] (11) by the satisfaction of spatial restraints method using Modeler (13). Structural alignment revealed that the paired box domains of the PAX1 and PAX6 proteins are almost identical with a template modeling (TM) score of 0.99963 and RMSD of 0.08 as measured by the TM align algorithm (14). In addition, the high quality of the model is reflected by the fact that 99% of the residues are in the allowed regions of the (phi) versus (psi) angles of the Ramachandran plot, as shown in fig. S7 (15). Therefore, we used this model to derive a corresponding model for the p.Val147Leu and p.Asn155del variants and for the previously described p.Gly166Val PAX1 variant (6), using in silico site-directed mutagenesis and energy minimization refinement as previously described (16). As shown in Fig. 3A, the paired box domain of all three mutant PAX1 proteins retains a structure composed of two globular domains separated by a linker. These structural models were then used in MD simulations for both their free and DNA-bound forms to define how they differ in both structure and time-dependent dynamic behavior from the canonical WT PAX1 protein.

(A) Molecular modeling of the paired box domain of WT and mutant PAX1 proteins, showing the presence of two globular domain separated by a linker. Note that the asparagine residue at position 155 is adjacent to linker domain, and its deletion results in shortening of the last turn of the third helix in the first globular domain of the paired box domain. (B) Molecular superimposition of WT (in light blue) and mutant PAX1 variants after MD simulation, showing that both the Val147Leu and Asn155del variants predominantly affect the conformation of the C-terminal globular domain, whereas both globular domains are affected by the Gly166Val variant. (C) RMSF values of WT PAX1 and of the Val147Leu, Asn155del, and Gly166Val variants during MD simulations. RMSF values are used here as a measure of the flexibility of different regions of the protein during the MD simulations. The Y axes indicate the magnitude of the fluctuation, whereas the X axes indicate the specific location of each amino acid within the paired box domain.

Because the p.Val147Leu variant is located in the first globular domain, the p.Asn155del is also located in this domain and adjacent to the highly flexible linker, and the p.Gly166Val variant is within the linker, we initially performed 200-ps MD simulations of PAX1 in the absence of DNA to capture potential alterations of the rapid movement of this region of the protein in relationship to the N- and C-terminal helix-loop-helix domains. To gain additional insights into the behavior of the protein, we extended these simulations to 10 ns, in the absence or presence of DNA. When a harmonic restraint is applied to reduce the conformational changes in both globular domains during the 200-ps simulation, the linker is observed to move freely. In this situation, the molecular movement of WT PAX1 paired box domain resembles a barbell-shaped harmonic oscillator, where the globular domains move relative to each other without forming bonds that lock them together in space.

At the end of the 200 ps, in the absence of DNA, the linker of PAX1 shortens and the protein populates a conformational landscape where the globular domains come in close proximity to each other, with the linker located between the N-terminal helix 3 (H3) and the C-terminal helix 1 (H1), respectively (fig. S8). In the most extended conformation of the linker, the interglobular domain distance measured from the Gly158 -C to the Pro175 -C shortens from an original 38.946 to 21.414 (SD = 2.421, P = 0.0001). This shortening contributes to the differences in the RMSD curve, where in the first part of the simulation we observed significant changes due to this shortening, whereas the difference in conformational sampling decreases toward the end of the run. Identical results were obtained in 10-ns simulations. Thus, this H3-Linker-H1 state is likely the one that the PAX1 binding domain adopts when in conformational equilibrium before binding to DNA. In this manner, the linker would be free to contact the minor groove of the DNA and extend in a manner that allows the positioning of both globular domains for full binding. These results led us to set up simulations that would enable gathering information on potential differences in DNA binding among the WT and mutant PAX1 variants.

To investigate whether alterations in the structure or the dynamics of the PAX1 variants have the potential to affect the protein function as a transcription factors, we modeled these proteins in complex with DNA. For this purpose, we again used the bound form of PAX6 as a template. Figure S9 shows the energy-minimized structure of these models before MD simulations. Because the variants identified in the patients either change the sequence of the linker (p.Gly166Val) or the N-terminal globular domain (p.Val147Leu and p.Asn155del), we compared the structures of these variants with WT PAX1 after MD simulation. Because the structure of the DNA interacting with WT or mutant PAX1 proteins was the same in all models shown in fig. S9, we removed it to facilitate the observation of changes that occur in the PAX1 polypeptide chain. When compared with WT PAX1, the p.Val147Leu and the p.Asn155del variants associated with OTFCS2 + SCID differ in particular at the C-terminal second globular domain, as shown by molecular superimposition (Fig. 3B). This result is consistent with the measured root mean square fluctuation (RMSF) values, which shows that the second globular domain is highly flexible in the p.Val147Leu and p.Asn155del mutant proteins (Fig. 3C). By contrast, RMSF values in the first globular domain were lower in all mutant proteins (and especially so in the p.Asn155del and p.Gly166Val mutants) as compared with WT PAX1. Considering these changes, we evaluated potential alterations in the ability of these proteins to recognize and bind to DNA in silico. For this purpose, we analyzed the PAX1-DNA interface. As shown in Fig. 4, as compared with WT PAX1, a lower number of amino acid residues contacting DNA were present within the paired box domain of the p.Val147Leu and p.Asn155del PAX1 mutants. These alterations are more pronounced for the C-terminal region of the domain, which contacts the 3 half of the oligonucleotide and is necessary to maintain appropriate binding to DNA. This altered pattern of interaction with DNA observed in silico may contribute to the altered transcriptional activity of the PAX1 mutant proteins.

Nucleotide residues, in which the paired box domain of either WT or PAX1 mutant proteins establishes interaction, are shown in black. The amino acids contacting nucleotides of target DNA are indicated on the Y axis for each PAX1 protein. The red and green colors indicate loss and gain of DNA binding, respectively.

To gain insights into how pathogenic PAX1 variants may perturb the developmental program of thymic epithelial cells (TECs), we reprogrammed fibroblasts from a healthy control, P1, and P4 to iPSCs and subsequently differentiated these to TEP cells using a previously published protocol (17) with some modifications (see Materials and Methods). Quantitative real-time polymerase chain reaction (qRT-PCR) showed a comparable stemness profile in both control and patient iPSCs (fig. S10), and cytogenetic analysis confirmed their karyotypic integrity. iPSCs were then exposed in vitro to a cocktail of growth factors and molecules that provide essential cues to allow differentiation into definitive endoderm (DE) and eventually into TEP cells (fig. S11A).

To assess changes in the gene expression profile of cells during differentiation, we performed RNA sequencing (RNA-seq) in control cells collected in triplicate at iPS [day 0 (d0)], DE (d5), and TEP (d14) stages of cell differentiation. For each condition, between 15 and 20 million reads were obtained per well. As shown in fig. S11B, during differentiation of control iPSCs to DE and TEPs, we observed progressive changes of gene expression profile, with increased expression of stemness (OCT4, MYC, SOX2, TERT, DNMT3B, and NANOG), endoderm (EOMES, CXCR4, and SOX17), and epithelial (KRT8, CLDN1, EPCAM, LAMA1, and KRT19) genes at iPS, DE, and TEP stages, respectively. In addition, expression of ASXL1, HES1, SHH, GATA3, HOXA3, PSEN1, ZBTB1, HAND2, and MAFB genes, which are all part of the gene set Thymus development, was up-regulated at TEP stage (fig. S11B). Gene set enrichment analysis (GSEA) confirmed differential expression of genes involved in somatic cell maintenance and endoderm development, as well as in other pathways related to differentiation of tissues derived from the third and fourth pharyngeal pouches (fig. S11C).

To assess the reproducibility of the differentiation protocol, we differentiated the same control iPS line twice to TEP cells (named C1 and C2, respectively) in parallel to differentiation of P1 and P4 iPSCs to TEP cells in two distinct differentiation experiments. As shown in Fig. 5A, a similar pattern of changes in the gene expression profile was observed when differentiating control (C1) and P1 iPSCs or control (C2) and P4 iPSCs to TEP cells. In both experiments, control and patient cells showed increased expression of stemness genes at the iPS stage, whereas enhanced expression of epithelial marker genes and of other genes included in the Thymus development gene set was detected at TEP stage. Furthermore, immunohistochemistry analysis confirmed that both control and P1 TEP cells expressed cytokeratin 8 (KRT8), a marker of TECs (fig. S12) (18).

(A) Heatmap of differentially expressed genes between iPS and TEP stage as determined by RNA-seq. Each heatmap shows the top 3000 genes, which were differentially expressed between iPS and TEP cells, with a significance (q < 0.01) by the two-group comparison (t test). Genes whose expression was found to be up-regulated at the TEP stage included epithelial cell markers (EPCAM, KRT8, and KRT19) as well as several genes (PSEN1, HES1, ASXL1, HOXA3, HAND2, EPHB3, and GATA3), which appeared at the leading edge of GSEA of thymus development in (B). (B and C) GSEA on thymus development gene set by preranked genes according to signed log10 adjusted P value. The adjusted P value was acquired by DEseq2 analysis using normalized read count of RNA seq data. FDR, false discovery rate. (D) qRT-PCR analysis of FOXN1 and DLL4 expression at TEP stage of differentiation. Results are from five independent experiments for control and P1, and four independent experiments for control and P4, with triplicates in each case (mean SEM). The P value was calculated with two-tailed paired t test. P < 0.05 was considered to be significant. (E) Thymus development genes with evidence of differential expression between patient and control cells (adjusted P < 0.1 and concordant pattern of expression in both RNA-seq experiments). For this comparison, we considered genes that were part of the Thymus development gene set in MSigDB v7.0, and in the top 30 FOXN1 target genes reported in (19). The values displayed are the signed log10 adjusted P value for differential expression.

GSEA confirmed that upon differentiation of control iPSCs to TEP cells, genes involved in thymus development were more abundantly expressed at the TEP stage both in control and in PAX1 mutant cells (Fig. 5B). Despite similar changes in gene expression profile during differentiation of control- and patient-derived iPSCs to TEP cells, GSEA demonstrated that genes involved in thymus development were more abundantly expressed in control than in patient TEP cells (Fig. 5C). To gain additional mechanistic insights into the severe T cell immunodeficiency of P1 and P4, we performed multiple rounds of differentiation of control and patient iPSCs to TEP cells (five times for control and P1 and four times for control and P4 cells, respectively) and used qRT-PCR to analyze the expression of FOXN1, a master regulator of TEC development (19, 20), and to its target DLL4, a Notch ligand that plays a critical role in T cell commitment (21). FOXN1 expression was significantly reduced in P1 and P4 TEPs as compared with control cells, and a similar trend was observed for DLL4, although the latter significance was reached only when comparing P1 with control TEPs (Fig. 5D and data file S1). Analysis of RNA-seq data revealed several other genes that showed concordantly reduced expression in P1 and P4 TEPs versus control TEPs, reaching statistical significance in at least one of the patients TEP lines (Fig. 5E and table S2). These included STC2, CD83, ZAR1, and ANKMY1, which are known FOXN1 target genes (19); TP63, a regulator of TEC proliferation and aging (22, 23); BMP4, which has been implied in thymus development (24, 25) and in maintenance of TEPs (26, 27); and EYA1 and PAX9, which are involved in patterning of pharyngeal endoderm (28, 29). Together, these data indicate that multiple mechanisms contribute to the thymic defects associated with PAX1 deficiency. Consistent with this, and with the syndromic features manifested by the patients, we observed that several genes included in the Neural crest cell differentiation, Ear development, Cartilage development, Pharyngeal system development, and Skeletal system development gene sets also manifested differential expression in P1 and P4 versus control TEPs (fig. S13).

We have studied six patients from three unrelated families in whom biallelic, loss-of-function PAX1 variants underlie a clinical phenotype characterized by OTFCS2 and severe T cell immunodeficiency. The first example of a biallelic, rare PAX1 variant (p.Gly166Val) in a patient with autosomal recessive OTFCS2 was provided by Pohl et al. (6), who also showed reduced transcriptional activity of the mutant PAX1 protein. However, no data on the patients immunological phenotype were provided. More recently, Patil et al. (7) have described two siblings with a homozygous frameshift PAX1 variant causing OTFCS2; one of them lacked a thymic shadow on chest x-ray. Last, the clinical features of OTFCS2 and SCID have been recently reported by Paganini et al. (8) in two of the patients studied here (P2 and P3), but no immunological or mechanistic characterization was provided.

Several mouse models of PAX1 deficiency, due to distinct variants in the Pax1 gene, have been described, including the undulated (un), undulated extensive (unex), undulated short-tail (unS), and undulated intermediate (un-i) models (30). All of these mutant strains display thymic abnormalities, which are more severe in the unS model (30); however, none of them results in complete athymia. A more profound phenotype, with lack of thymus and parathyroids, associated with craniofacial and skeletal abnormalities, has been observed in Pax9/ mice (31). No cases have been reported of humans with biallelic PAX9 pathogenic variants, and heterozygous PAX9 variants in humans are associated with hypodontia but not with thymic defects (32). Together, these data suggest that the impact of PAX1 and PAX9 on thymus development may be different in humans and mice.

To gain insights into the molecular mechanisms by which PAX1 deficiency may cause syndromic SCID in humans, we have first investigated the expression, subcellular localization, and transactivation activity of PAX1 mutant proteins using transient transfection and luciferase reporter studies. Although transient transfection may result in protein overexpression and therefore cannot be directly compared with protein expression in vivo, the PAX1 p.Val147Leu, p.Asn155del, and p.Cys368* mutant proteins retained the capacity to translocate to the nucleus, and the equivalent murine mutant proteins showed decreased transcription factor activity in vitro. Similar results were obtained for the PAX1 p.Gly166Val (and the mouse equivalent p.Gly157Val) variants, confirming previous observations (6). To further investigate the mechanisms underlying the impaired transcriptional activity of the mutant PAX1 proteins, we have performed structural modeling, using the crystal structure of the PAX6 paired box domain as a template. The results suggest that the structural behavior of the paired box domain (consisting of two globular domains interconnected by a linker) was retained in the p.Val147Leu, p.Asn155del, and p.Gly166Val mutants. MD simulation studies have demonstrated that these variants alter the flexibility of the paired box domain and are predicted to alter binding of PAX1 to its target DNA. Our in silico studies suggest that the mutants differ in their ability to gain or lose binding to distinct nucleotides, with possible impact on the severity of clinical and immunological phenotype. Fine characterization of the molecular mechanisms underlying such heterogeneity will require resolution of the crystal structure of the PAX1 paired box domain and precise identification of its human DNA target sequence(s).

By exposing control- and patient-derived iPSCs to defined differentiation cues, we have successfully differentiated iPSCs to TEPs. Comparison of gene expression profile in control- and patient-derived cells at the TEP stage of in vitro differentiation demonstrated altered expression of genes involved in thymus development in patient cells. In particular, qRT-PCR analysis revealed reduced expression of FOXN1, a master gene of thymus development, and of several FOXN1 target genes, including DLL4. Biallelic FOXN1 pathogenic variants in humans are responsible for a syndromic form of SCID that is the equivalent to what is observed in the nude mouse (33, 34). We have recently reported that FOXN1 haploinsufficiency in humans causes severe T cell lymphopenia at birth (35). The reduced levels of FOXN1 expression observed in patient TEPs (and, by inference, in the patients thymus) may therefore play a direct role in the severe T cell lymphopenia observed in these patients. However, analysis of gene expression profile in patient and control TEPs suggests that other mechanisms, besides reduced FOXN1 expression, may also contribute to impaired thymic development associated with PAX1 deficiency. In particular, reduced TP63 expression may cause impaired TEC proliferation and hence thymic hypoplasia. Moreover, we observed that both P1 and P4 TEPs displayed significantly reduced expression of BMP4 as compared with control TEPs. Conditional deletion of Bmp4 from the pharyngeal endoderm before Foxn1 expression disrupts thymus morphogenesis in mice (24). Furthermore, recent studies have indicated that BMP4 plays a critical role in maintenance of TEC progenitors (27), and reduced BMP4 expression might alter replenishment of the TEC compartment. Future studies based on precise enumeration of TEPs generated in vitro from patient- and control-derived iPSCs may help test this hypothesis. In any case, these data suggest that PAX1 deficiency causes early and more global effects on the development of tissues derived from the third and fourth pharyngeal pouches, including the thymus. Consistent with this hypothesis, patient TEPs were concordant in the abnormal expression of a number of genes involved in skeletal, cartilage, pharyngeal, neural crest, and ear development. Abnormalities in these pathways during differentiation of tissues derived from the third and fourth pharyngeal pouches are likely to contribute to the broad range of malformations observed in the patients reported here.

Last, we have reported that HSCT, which was attempted in four of the six patients, failed to correct the T cell immunodeficiency, despite engraftment in three of them. PAX1 deficiency should be added to the list of severe T cell immunodeficiencies characterized by a primary thymic defect, which also includes complete DiGeorge syndrome, CHARGE syndrome, and FOXN1 deficiency (1). Thymus transplantation represents the treatment of choice to correct the immunodeficiency in these disorders (3638). By contrast, use of unmanipulated HSCT may allow engraftment of donor-derived postthymic T cells that may expand in the recipient, as also observed in P1 in this study, but does not permit de novo generation of a polyclonal repertoire of nave T cells (39). In summary, we have provided mechanistic insights into the pathophysiology of OTFCS2 associated with severe T cell immunodeficiency, an autosomal recessive condition caused by PAX1 variants, and have demonstrated the thymic-intrinsic nature of the immunodeficiency of this condition.

The scope of the study was to identify the molecular basis of a syndromic form of SCID and to perform genomic, molecular, biochemical, structural modeling, and in vitro disease modeling studies to analyze deleterious effects of the PAX1 variants identified. All patients provided written informed consent, according to protocols approved by the local Institutional Review Boards (IRBs). Research studies were performed under National Institutes of Health (NIH) IRB-approved protocol 16-I-N139. For P4, public disclosure of secondary genomic findings was not permitted by the protocol and consent form approved by the local IRB.

WES was performed on P1 and his healthy parents and on P2 and P4 without parental samples. Detailed methods for capture, library preparation, and bioinformatic analysis are described in the Supplementary Materials. Candidate variants were confirmed by Sanger sequencing and described according to Human Genome Variation Society (HGVS) guidelines. For P1 and P2, WES data have been deposited to the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) Submission Portal, with the following ID: PRJNA601119.

Flow cytometry studies were performed on either a 10-color Gallios (Beckman Coulter, Brea, CA) or an 8-color Canto II (BD Biosciences, San Jose, CA) cytometer, and results were analyzed using Kaluza software v1.5 (Beckman Coulter, Brea, CA). T cell proliferation studies were performed using Edu-based (Thermo Fisher Scientific, Waltham, MA) flow cytometry method in P1, and tritiated thymidine (3HTdR) incorporation in P2, P4, P5, and P6. TCR V repertoire spectratyping was carried out using a fragment length method on a capillary electrophoresis system (ABI 3730xl DNA Sequencer, Applied Biosystems Inc., Thermo Fisher, Waltham, MA), and data were analyzed using the GeneMarker (v.2.4.0) software (SoftGenetics, State College, PA). All reference values for interpretation were established in the laboratory using healthy pediatric donors recruited via an IRB-approved protocol.

293T cells were plated as 4 105 cells per well in a 12-well plate. After 24 hours, cells were transfected with 1.2 g of pCMV-HA-N vector containing either WT or mutant PAX1 cDNAs, with the Lipofectamine 3000 transfection kit (Thermo Fisher Scientific) following the manufacturers instructions. After 24 hours, cells were collected, lysed, and transferred onto a nitrocellulose membrane. Immunoblotting was performed with rat anti-PAX1/Pax1 monoclonal antibody (mAb) (clone 5A2) (40), followed by staining with horseradish peroxidase (HRP)conjugated goat anti-rat IgG (ab97057; Abcam, Cambridge, MA). After stripping, the membrane was reblotted with rabbit anti-actin mAb (clone 13E5; Cell Signaling Technology, Danvers, MA), followed by Amersham enhanced chemiluminescence anti-rabbit IgG, HRP-linked whole antibody (NA934; GE Healthcare, Helsinki, Finland).

To analyze PAX1 subcellular localization, 293T cells were cultured in polylysine-coated -Slide 8 well (ibidi, Fitchburg, WI) and transfected with 100 ng of pCMV-HA-N vector containing either WT or mutant PAX1 cDNA, with the Lipofectamine 3000 transfection kit (Thermo Fisher Scientific) following the manufacturers instructions. After 24 hours, cells were fixed in 4% paraformaldehyde with phosphate-buffered saline (PBS) for 30 min at room temperature, washed twice in PBS, and then blocked for 1 hour with 10% donkey serum and 0.1% Triton X-100 with PBS at room temperature. Cells were incubated with mouse anti-HA-TRITC mAb (clone H9037; MilliporeSigma, St. Louis) diluted 1:200 in PBS and with 4,6-diamidino-2-phenylindole (DAPI) at room temperature for 1 hour in the dark. Images were obtained with a Leica SP8 (690/730) confocal microscope.

For immunofluorescence analysis of KRT8 expression by TEPs, cells were fixed in 4% paraformaldehyde with PBS for 30 min at room temperature, washed twice in PBS, blocked for 1 hour in 10% donkey serum and 0.1% Triton X-100 with PBS at room temperature, and incubated overnight at 4C with mouse anti-KRT8 antibody (ab2530, C-43) (Abcam, Cambridge, MA) diluted 1:200 in PBS, then for 1 hour at room temperature in the dark with donkey anti-mouse IgG (H+L) Alexa Fluor 488 (ab150105; Abcam) at 1:500 dilution in PBS, and with DAPI (Thermo Fisher Scientific) at 1:1000 dilution in PBS. Images were taken with a Leica SP8 (690/730) confocal microscope.

The promoter region of the mouse Nkx3-2 gene was amplified and cloned into the firefly reporter plasmid pGL4.10 luc2 vector (Promega, Madison, WI), as described (6, 10). To generate expression plasmids containing the mouse Pax1WT, Pax1V138L, Pax1N146del, Pax1G157V, and Pax1C359* coding sequences, the coding sequence of mouse Pax1 (NM_008780.2) was amplified by RT-PCR from isolated adult mouse thymus RNA and cloned into a pCMV-HA-N vector (Addgene, Cambridge, MA) with the In-Fusion HD EcoDry Cloning Kit (Clontech, Mountain View, CA). Pax1 mutant variants were generated by site-directed mutagenesis, and the PCR products were ligated with the Quick Ligation Kit (NEB, Ipswich, MA) and cloned by Turbo competent cells (NEB, Ipswich, MA). The correct sequence of the constructs was confirmed by Sanger sequencing.

The transcriptional activity of WT and mutant PAX1 mouse proteins was assessed in a luciferase reporter assay. 293T cells were cultured in Dulbeccos modified Eagles medium (DMEM) containing 10% fetal bovine serum with antibiotics and plated in 24-well plates 24 hours before transfection. Transient transfections were performed in triplicate with TransIT-293 Transfection Reagent (Mirus, Madison, WI) according to the manufacturers instructions. Cells were cotransfected with 30 ng of either WT or mutant Pax1 expression plasmids, 15 ng of firefly reporter plasmid Nkx3-2-pGL4.10 luc2, and 3 ng of pRL-TK vector (Promega, Madison, WI) for normalization. After 48 hours, cell extracts were collected and frozen in lysis buffer overnight at 20C. After thawing, firefly and renilla luciferase activities were measured using a Dual-Luciferase Reporter Assay Kit (Promega, Madison, WI) and Paradigm Detection platform (Beckman Coulter, Indianapolis, IN). To correct for variations in transfection efficiency, firefly luciferase activity was normalized to renilla luciferase activity. The luciferase activity of pCMV-HA-N vector, which had no Pax1 cDNA, was assumed to have 0% activity, whereas the Pax1WT vector was assumed to have 100% activity.

The three-dimensional complex structures of WT and mutant PAX1 models bound to DNA were generated by homology-based methods (16) using the previously solved structure of the highly homologous protein, PAX6 (PDB: 6PAX) (11). Intermolecular interactions of the PAX1 paired box domain of WT/mutant PAX1 to DNA complex were calculated in the Receptor-Ligand function of Discovery Studio Client 4.0 using the default parameters (BIOVIA, San Diego, CA). The MD simulations were performed as described (16).

Primary skin fibroblasts from P1, P4, and a healthy control (BJ fibroblast line, American Type Culture Collection) were reprogrammed to iPSCs by infection with the nonintegrating CytoTune Sendai viral vector kit (Thermo Fisher Scientific) as described (41).

For differentiation, iPSCs were transferred to plates coated with Corning Matrigel human embryonic stem cell (hESC)qualified Matrix. After four to five passages, the cells were plated on Matrigel-coated 24-well plates at a density of 2.5 105 cells/cm2. For differentiation to DE and TEPs, iPSCs were exposed to various factors and differentiation cues, according to the protocol by Parent et al. (17), with some modifications. In particular, between d1 and d5, iPSC differentiation was carried out in RPMI 1640 medium (Thermo Fisher Scientific, Waltham, MA) supplemented with 1% penicillin/streptomycin, 1% l-glutamine, and increasing concentrations of KSR (0% on d1, 0.2% on d2 and d3, and 2% on d4 and d5). In the period d6 to d14, cells were differentiated in DMEM/F12 with 1% penicillin/streptomycin, 1% l-glutamine, and 0.5% (v/v) B-27 supplement (Thermo Fisher Scientific, Waltham, MA). During this period of time, the following factors were added to the culture: activin A, 100 ng/ml (d1 to d5); Wnt3a, 25 ng/ml (d1) or 50 ng/ml (d8 to d14); all-trans retinoic acid (RA), 0.25 M (d6 to d8) or 0.1 M (d9 to d14); BMP4, 50 ng/ml (d6 to d14); LY364947, 5 mM (d6 to d9); FGF8b, 50 ng/ml (d8 to d14); and KAAD-cyclopamine, 0.5 mM (d8 to d14). Supplements and factors were from Thermo Fisher Scientific, Waltham, MA (B27, KSR); R&D Systems, Minneapolis, MN (activin A, Wnt3a, BMP4, and FGF8b); and MilliporeSigma, St. Louis, MO (RA, KAAD-cyclopamine, LY364947).

Microgram quantities of total RNA were isolated using the RNeasy Kit (QIAGEN, Hilden, Germany) from triplicate samples of control-, P1-, and P4-derived iPSCs, as well as from the corresponding iPSC-derived cells at DE and TEP stages. RNA integrity was tested by microfluidic electrophoresis on a TapeStation system (Agilent, Santa Clara, CA). RNA purity and concentration were assessed using the NanoDrop One UV-Vis Spectrophotometer (Thermo Fischer Scientific, Waltham, MA). Directional, mRNA-seq libraries for experiment 1 were produced using TruSeq Stranded mRNA Library Prep Kit for NeoPrep (catalog no. NP-202-1001) from Illumina (San Diego, CA). Directional, mRNA-seq libraries for experiment 2 were produced using New England Biolabs product NEBNext Poly(A) mRNA Magnetic Isolation Module (catalog no. E7490L), New England Biolabs product NEBNext Ultra II Directional RNA Library Prep Kit for Illumina (catalog no. E7760L), and NEBNext Multiplex Oligos for Illumina (Dual Index Primers Set 1) (catalog no. E7600S) (New England Biolabs, Ipswich MA), with an input of 100 ng of total RNA per sample.

Sequencing was performed on an Illumina NextSeq 500 system, running Illumina NextSeq Control Software System Suite version 2.1.2 and RTA version 2.4.11. The final library pool was sequenced via 1 75base pair (bp) run configuration using the product NextSeq 500/550 High Output v2 sequencing kit, 75 cycles (catalog no. FC-404-2005). Between 15 106 and 20 106 reads were obtained from each sample. RNA-seq FASTQ files were aligned to the reference human genome assembly (GRCh38) with STAR v2.6.0 (42). The transcript annotation (GTF) file was obtained from GENCODE (release 28) (43). The binary alignment files (.bam) were then used to generate a matrix of read counts with the featureCounts program of the package Subread v.1.6.2 (44). Exonic fragments were grouped at the level of genes, based on the GENCODE 28 annotation file. Normalization and differential expression analysis for RNA-seq data were performed with the DESeq2 (45) package in R (46).

Independent pairwise analyses were performed on triplicate samples of cells at each stage of differentiation (iPSC, DE, and TEP). To handle the lower power associated with small numbers of samples, DESeq2 uses an empirical Bayesian procedure to stabilize the log fold change estimates. The Wald test was then applied to the log fold change in each gene, followed by multiple-testing adjustment with the method of Benjamini and Hochberg (47).

For the heatmap of gene expression, t test and hierarchical clustering were computed by Qlucore Omics Explorer 3.3 (Qlucore, Lund, Sweden) for iPSC and TEP stage comparison (Fig. 5A), with cutoff q values of less than 0.01. Analysis of variance (ANOVA) and hierarchical clustering were used for the three-stage (iPSC, DE, and TEP) comparison (fig. S11B). Normalization and differential expression analysis of the RNA-seq data used for GSEA were performed with DESeq2 package in R v.3.5.1. RNA-seq data have been uploaded to the NCBI Gene Expression Omnibus (GEO), under accession no. GSE138784.

GSEA was performed with the GSEA software (48) (http://www.broadinstitute.org/gsea) using a preranked dataset of gene expression differences, 1000 permutations, and the softwares classic enrichment statistic option. Genes were ranked based on the DESeq2 output by taking the signed log10 adjusted P value for differential expression. Gene sets for enrichment analysis correspond to Gene Ontology (GO) Biological Processes and were obtained from the Molecular Signatures Database version 7.0 (GMT file: c5.bp.v7.0.symbols.gmt).

RNA was isolated from control, P1, and P4 cells at iPSC and TEP stages of differentiation, using RNeasy kit (QIAGEN, Hilden, Germany). cDNA was synthesized by a qScript cDNA Synthesis kit (Quantabio, Beverly, MA) according to the manufacturers protocol. qRT-PCR was performed on a 7500 RT-PCR system (Applied Biosystems, Waltham, MA) using PerfeCTa SYBR Green FastMix, Low ROX (Quantabio, Beverly, MA). Gene expression was quantified by normalization to the housekeeping gene TBP for each sample. Primers used for individual genes are reported in the Supplementary Materials.

Statistical analysis was undertaken in GraphPad Prism (v8.0). For luciferase reporter assay, P values were calculated with one-way ANOVA and adjusted by Dunnetts multiple comparisons test. The data are means SEM of six independent experiments (WT, n = 6; Val138Leu, n = 3; Asn146del, n = 5; Cys359*, n = 5; Gly157Val, n = 5; empty, n = 6). For qRT-PCR data, Students t test (paired, two-tailed) was performed. The data are means SEM in Fig. 5D, and means SD in fig. S10. P < 0.05 was considered to be significant. Statistical analysis of RNA-seq data is described above.

Acknowledgments: We thank E. Thorland for interpretive assistance with the CNV analysis and B. Bigio for uploading WES data. WES data have been deposited to the NCBI SRA Submission Portal, with the following ID: PRJNA601119. RNA-seq data have been uploaded to the NCBI GEO, under accession no. GSE138784. Funding: This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH and by the Angelo Nocivelli Foundation. Y.Y. was supported by JSPS Research Fellowship for Japanese Biomedical and Behavioral Research at the NIH and had travel support from The ITO Foundation for the Promotion of Medical Science. R.U. was supported by NIH/NIDDK R01 DK52913, Advancing a Healthier Wisconsin (AHW) Endowment and the Linda T. and Johm A. Mellowes Endowed Innovation and Discovery Fund. L.M.F. is funded by the Division of Intramural Research of the National Institute of Arthritis, Musculoskeletal and Skin Diseases, at the National Institutes of Health. A.A. is supported by King Abdulaziz City for Science and Technology. Author contributions: Y.Y. performed experiments and wrote the manuscript. R.U. performed structural modeling and MD simulation studies. L.M.F. supervised analysis of RNA-seq and GSEA data. F.O.-C., T.G.M., and S. Ganesan assisted with RNA-seq studies. S. Giliani and S.M. performed Sanger sequencing and Western blot analysis and analyzed WES data. K.Z., A.M.A., H.A., F.Z., C.A.V., and B.B. performed and analyzed WES. A.K.D. generated iPSCs. A.J., R.W.M., A.H.F., C.A., B.K.A.-S., and H.A.-M. provided clinical care and description of the patients. F.F. performed lymph node pathology. M.P.B., M.L.H., and C.M. performed and interpreted imaging studies. J.L.C. and R.S.A. contributed to supervision of the project and to writing of the manuscript. L.D.N. was responsible for the entire research project and wrote the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: Fibroblast and iPSC lines from P1 and P4 are available upon request but are contingent upon approval of material transfer agreement by the NIAID, NIH. WES data have been uploaded to the NCBI SRA Submission Portal, with the following ID: PRJNA601119. The RNA-seq dataset for this study has been uploaded to the NCBI GEO, under accession no. GSE138784. The GEO accession includes links to the NCBI SRA database, from which the raw data will be accessible in FASTQ format, under accession no. SRP225226.

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PAX1 is essential for development and function of the human thymus - Science

Skin Stem Cells Comments Off on PAX1 is essential for development and function of the human thymus – Science | February 29th, 2020

When an animal, such as a dog or cat, is sick or unwell, its first natural instinct is to refuse food. Their body automatically cuts down appetite till they recover. They may drink water, but nothing else. This is bodys intelligence taking over to heal and recover.Intuitive eatingHumans arent any different. At least, intuitively. All of us are products of nature and we have been designed the same. When we call in sick, the first thing that happens is that our appetites shut down too. Our taste of mouth changes and our sensitivity to smell and taste is numbed. This is our bodys intelligence and subtle biofeedback trying to tell us that its time we give our body some rest.

This is fasting in a way and has been practised since the longest time across all religions. Fasting is inbuilt in us and is considered medicinal if you actually go back and read its history. It is our bodys uncomplicated way of cleaning and healing. Unfortunately, we have moved too far from nature and our natural instincts. We are constantly eating and munching even when sick, thereby compromising our own immunity and masking the inbuilt mechanism to heal.Take a break

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Dont feed sickness - Times of India

Skin Stem Cells Comments Off on Dont feed sickness – Times of India | February 29th, 2020

Augustinus Bader The Rich Cream ($265)

In the nearly two years since its launch, Augustinus Baderssignature moisturizer, aptly named The Rich Cream, has seen moresuccess than perhaps any beauty product before it. Alexa Chung, Margot Robbie,and Ashley Graham are all fans, and Victoria Beckham loves the brand so muchthat she even collaborated with Bader to create a serum for her eponymousbeauty line. The Rich Cream, developed by Dr. Bader, a German stem cell andbiomedical scientist, is said to promises to reduce signs of aging and skindamage, leaving skin restored, regenerated, and glowing with health. The keyto the moisturizers magic is TFC-8, Dr. Baders proprietary Trigger Factor Complexthat is essentially a blend of more than 40 amino acids, vitamins, andsynthesized molecules. The complex helps activate the skins stem cells,pushing them into healing mode to promote everyday turnover and furthermoresoften the appearance of fine lines and wrinkles, even tone and texture, andhydrate the skin. Starting at $265 for a 50ml bottle, The Rich Cream is farfrom cheap, but its benefits are well worth the large price tag.

For a more affordable alternative, try the Josie Maran Whipped Argan Oil Face Butter($42). Among thelightweight moisturizers selling points is its use of argan oil, areplenishing ingredient also found in Augustinus Baders Rich Cream that helpsprotect skin from free radicals.

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Moisturizers Worth the Money - NewBeauty Magazine

Skin Stem Cells Comments Off on Moisturizers Worth the Money – NewBeauty Magazine | February 29th, 2020

If youve ever felt overwhelmed by the thousands of beauty products on the market, we hear you. Thats why we spent hundreds of hours doing the leg work and finding the best ones for you! We read through scientific studies to understand how ingredients work, did market research to find the best and newest products on the market, and asked our most-trusted experts what products they live and swear by. We take beauty seriously, because we understand the importance a product can play in our lives.

Because sometimes a $5 cheap thrill is as good (or *gasp* better) than its pricey counterpart, we decided to throw in a drugstore and luxe pick for almost every item, and we interviewed experts to get their picks, too. Each product deserves a place on this list for its unique features, and we cant wait to share them with you. Youll also find standout stars that were so great that we had to feature themeven though they didnt fit into any one product category.

The HelloGiggles team poured our hearts, souls, and most importantly, brainpower into this project and we found the best of the best. We stand behind each and every one of these products so that you can find the ones that speak to you. Consider the Beauty Crush Awards your shopping list for the yearmade by your best friends for the people they love.

Put your best face forward with these top-of-the class moisturizers, serums, face masks, and more. We tested hundreds of skincare products to find the crme de la crme. And, because we know skin can mean a hell of a lot of things to a lot of different people, we made sure that every winner blessed the face of women and men with different skin concerns, textures, and tones.

Best Drugstore Cleanser: Honest Beauty Gel-to-Milk Cleanser, $12.99 (orig. $14.99), amazon.com

This cleanser is a godsend for those with sensitive skin because of both the affordable price and the rosewater-infused formula. (Studies show that rose extract has anti-inflammatory benefits, which tackles irritation, making it perfect for those with skin prone to irritation.) The product starts as a gel-like formula and, upon contact with water, turns into a milky liquid that gently and effectively cleanses skin.

Best Luxury Cleanser: SkinCeuticals Glycolic Renewal Cleanser Gel, $38, dermstore.com

If your skin is looking dull or is congested, consider using an exfoliating cleanser two to three times a week to decongest and reveal bright, glowy skin. This cleanser uses glycolic acid, a chemical exfoliant that helps turn over dead skin cells to treat concerns such as uneven skin tone, rough skin, and fine lines.

Best Expert-Recommended Cleanser: Differin Daily Refreshing Cleanser, $8.49, amazon.com

I am a big fan of Differin Gel .1% adapalene, [and] I love this new addition to the line, says Dendy Engelman, M.D., a board-certified dermatologist. When cleansing, you dont want to strip the skin of natural oils. This can cause your skin to go into oil production overdrive. This cleanser uses vitamin B and glycerin to gently cleanse; vitamin B to calm the skin and provide relief to inflammation and redness, and glycerin to prevent water loss so the skins natural oils can nourish and repair.

Best Drugstore Makeup Remover: Almay Micellar Biodegradable Makeup Wipes, $4.99 (orig. $5.99), amazon.com

By now we all know and love micellar water for how effectively it removes makeup and cleanses skin in just one step. For those who need a refresh, micelles work like tiny magnets to attract impurities off the skin. We love these makeup wipes because they allow us to easily remove our makeup (even the stubborn waterproof kind) at the end of the day without irritating even the most sensitive of skin. This product won five extra points during our testing period for its biodegradable material, which is made up of plant fibers and wood pulp, and it will completely compost in just three months.

Best Luxury Makeup Remover: First Aid Beauty Conditioning Eye Makeup Remover, $18, ulta.com

Eye makeup can be a fickle foe when it comes to taking it off at the end of the night. Too often leftover mascara clings to our lashes, eyeshadow lingers in the creases of our lids, and eyeliner finds its way to our inner eye areano thank you. This oil-free formula works to remove even waterproof makeup without leaving a trace or any greasy residue. To use, apply some liquid onto a cotton ball, place over the eye area for five seconds, then gently pull down and away. Bonus pointit uses soothing chamomile and is fragrance-free, so its suitable for sensitive skin, too.

Best Expert-Recommended Makeup Remover: Simple Water Boost Micellar Make-up Remover Eye Pads, $8.49, cvs.com

This budget-friendly product uses micellar technologies to remove even the most longwear makeup without irritating skin. Anyone who knows me can attest to the fact that I go all out with both eyeshadow and mascara every day, so when it comes to taking it off, I need something thats going to really workand requires the least amount of elbow grease on my part, says Lisa DeSantis, Deputy Beauty Director of Real Simple and Health magazines. These rounds are saturated with just enough of the hardworking micellar formula to remove even the most stubborn eye makeup.

Best Drugstore Toner: Burts Bees Micellar Toning Water With Rose Water, $8.99, target.com

If youre looking for a wallet-friendly toner that wont sting your skin (no skincare product ever should) or dry you out, this product is for you. This alcohol-free formula uses calming rose petal extract, hydrating glycerin, and tone-balancing lactic acid.

Best Luxury Toner: belif Aqua BombHydrating Toner, $28, sephora.com

Imagine a facial toner that feels like a cup of water for your skinthats this one. It combines hydrating ingredients like glycerin with soothing ones like oat extract and calendula for a pleasant experience thats both effective in removing makeup and debris and gentle on the skin.

Best Expert-Recommended Toner: Peter Thomas Roth Water Drench Hyaluronic Cloud Hydrating Toner Mist, $28, dermstore.com

This product uses hyaluronic acid to hydrate and instantly reduce the appearance of fine lines and wrinkles, says Deanne Robinson, M.D., a dermatologist based in Connecticut.

Best Drugstore Serum: Honest Beauty Vitamin C Radiance Serum, $27.99, amazon.com

Vitamin C is a powerful antioxidant that neutralizes free radicals, which come from the sun, pollution, stress, and smokingfactors that can ultimately damage the cells DNAand gives your skin a radiant boost. Regularly using a vitamin C skincare product can boost collagen production and reverse cell damage, which in turn helps skin look firmer and looking younger, and even helps fade and prevent brown spots or pigmentation.

Best Luxury Serum: La Mer Regenerating Serum, $365, sephora.com

Environmental factors such as pollution, free radicals, and harmful UV rays can take a real toll on your skin, making it show signs of aging sooner. This super-charged serum uses antioxidants, seaweed extract, and a new proprietary blend that helps boost the skins natural collagen to reduce the appearance of fine lines, pores, and redness. One HG tester says that after using it for a few weeks, shed never seen her skin look healthier: I feel like I can see a whole new layer of skin on my face.

Best Expert-Recommended Serum: La Roche-Posay Hyalu B5 Serum, $29.99, dermstore.com

Kavita Mariwalla, M.D., a board-certified dermatologist based in West Islip, NY, adores this budget-friendly pick: I love this product for a few reasons: 1) Price point. For the quality of ingredients in it, it is priced really well. 2) B5 is a great ingredient for all skin types and madecassoside is a hero ingredient that acts as an antioxidant but also skin soother. Combine that with its hyaluronic acid and youve got a serum that has great workhouse ingredients in it.

Best Drugstore Moisturizer: Olay Regenerist Whip Face Moisturizer SPF 40, $38.99, ulta.com

To protect your skin from the sun, opt for a face moisturizer with SPF to streamline your routine. Testers loved that this Olay pick looked smooth on skin and acted as the perfect primer for makeup.

Best Luxury Moisturizer: Drunk Elephant Lala RetroWhipped Cream Moisturizer, $60, sephora.com

Testers liked that this cream instantly melted into their skin and made it feel healthy, hydrated, and glowy. It uses a mix of oils, ceramides, and antioxidants, which together provide moisture and help skin retain that moisture. Its also formulated at an ideal pH level of 5.2, so it wont throw your skin off. Oh, and did we mention it has a fun pump? The pump dispenses the perfect-sized amount of moisturizer onto your skin without any of the mess.

Best Expert-Recommended Moisturizer: Cetaphil Ultra Healing Lotion with Ceramides, $19.97, amazon.com

Although this moisturizing lotion is technically formulated for the body, Tiffany Libby, M.D., a board-certified dermatologist in Rhode Island, recommends it for the face as well. I use this on my body and face when I need to double down on my moisture, especially in the winter months, and I love that it is formulated with ceramides to help enhance my skin barrier and keep my skin smooth and hydrated, she says.

Best Drugstore Face Oil: e.l.f. All The Feels Facial Oil, $11.99, target.com

Squalane, hemp seed oil, and rosehip seed oil make this lightweight facial oil the perfect last step in your skincare routine. Simply apply a few drops onto your skin after your moisturizer, then pat it in to encourage absorption and help lock in your skincare.

Best Luxury Face Oil: Snow Fox Herbal Youth Oil, $40, saksfifthavenue.com

This silky-feeling serum combines hydrating and anti-aging properties into one product. It uses blueberry seed oil, which studies show contains high levels of antioxidant properties that protect skin from free radicals, and an exotic herb called Brazilian Paracressextract, which is a muscle relaxant that helps relieve micro-tension. HG testers raved that it gave their skin a healthy glow, one of them even saying it made her skin look like there was a ring light shining on her face at all times. Natural-looking radiance with no filterwere here for it.

Best Expert-Recommended Face Oil: Mary Kay Naturally Nourishing Oil, $48, marykay.com

[This blend] uses a delicious combination of almond, olive, and sesame oils which leave your skin super hydrated, says Ursula Carranza, Beauty and Fashion Director of People en Espaol. You can even use it on your cuticles and on the ends of your hair!

Best Drugstore Eye Cream: Inkey List Caffeine, $9.99, sephora.com

Consider this concentrate a cup of coffee for your under-eye area. Studies show that when applied topically, caffeine can temporarily plump the skin, so a jolt of java-infused product to your weary eyes will make you look instantly more awake.

Best Luxury Eye Cream: Cl de Peau Enhancing Eye Contour Cream Supreme, $270, nordstrom.com

It takes six years to extract the iris extract in this luxe cream (three to cultivate and three to dry), the key result being plumper, firmer, revived skin. Using the cold steel applicator is kind of like jade rolling, and I visibly notice it de-puffing my eyes, mentioned one HG tester, adding that the difference between eyes after applying on just one side was very drastic.

Best Expert-Recommended Eye Cream: Care Skincare Eye + Lip Nourishing Cream, $30, careskincare.com

Formulated to treat and repair the delicate area around the eyes and around the lips, this dense cream with a light diffusing finish softens the look of fine lines and dark circles, says Dr. Robinson. It absorbs quickly and wont drift into eyes or interfere with makeup.

Best Drugstore Exfoliator: Yes To Grapefruit AHA + BHA Exfoliating Tonic, $14.99, amazon.com

AHAs and beta hydroxy acids (BHAs) are known chemical exfoliants that help remove dead skin cells and excess sebum inside the pores. This product is packed with 10% AHA and BHA, making it a powerful exfoliator that more sensitive skin types should probably avoid. However, if your skin can tolerate it, using it two to three times a week will help you achieve a more even skin texture and a newfound radiance.

Best Luxury Exfoliator: Pestle & Mortar Exfoliate Glycolic Acid Toner, $38, neimanmarcus.com

Brighten, tone, and reveal a more radiant face with the help of this glycolic-based exfoliator that will gently slough away dead skin cells. This non-irritating, vegan, and fragrance-free formula is suitable for all skin types.

Best Expert-Recommended Exfoliator: SkinBetter AlphaRet Peel Pads, $95, skinbetter.com

This new peel is an exfoliation powerhouse. Using lactic, glycolic, and salicylic acids, it exfoliates using AHAs and BHAs, targeting discoloration and age spots, boosting collagen and elastin production, and penetrating deep into the cell to dissolve dead skin buildup, explains Dr. Engelman. It contains a patented retinoid, AlphaRet and it also helps treat acne.

Best Drugstore Face Mask: AveenoOat Face Mask with Pomegranate Seed Extract, $8.38, amazon.com

This brightening face mask is a great option for people with dry skinit uses colloidal oatmeal to maintain the skins natural moisture barrier while treating and calming, dried skin. Studies show that pomegranate, the products key ingredient promotes skin cell turnover, which will help users achieve a more radiant appearance. The texture is rich and velvety, and youll get the best results if used two to three times a week.

Best Luxury Face Mask: Glow Recipe Avocado Melt Retinol Sleeping Mask, $49, sephora.com

Face masks dont have to be rinse-and-go. This Glow Recipe mask can be used overnight for added benefits or can work in as little as 20 minutes as a quick skin-boost if thats your preference. Its a good introduction to retinol, the gold-standard of anti-aging ingredients, since its gentle enough that even sensitive skin types can use it without irritation. One HG tester commented that her skin looked less congested the day after using it, and adding that she didnt notice any dryness sometimes associated with retinol products. Additionally, our testers were impressed by how cooling it felt on skin, how soft it felt after washing off, and how it didnt transfer onto their pillows when using overnight.

Best Expert-Recommended Face Mask: SkinBetter Refresh Detoxifying Scrub Mask, $55, skinbetter.com

The clay minerals [in this mask] absorb unwanted oil and remove toxins, while biodegradable spherical beads to lightly resurface the skin, explains Dr. Robinson of her top pick. It can even be used as a spot treatment on areas of focus!

Best Drugstore Sunscreen: La Roche-Posay Anthelios SPF 50 Mineral Sunscreen, $22.99, amazon.com

This mineral sunscreen is oil-free (so non-comedogenic), non-greasy, and easily blends into all skin shades without leaving a white cast. If youre a minimalist who prefers multi-purpose products, this SPF 50 made for face and body should be your go-to. Its TSA-approved too, so you can throw it into your carry-on next time you travel to the beach.

Best Luxury Sunscreen: Coola Mineral Sun Silk Crme SPF 30, $42, amazon.com

The silky feel this mineral sunscreen leaves on the skin will make you feel like a million bucks. And while yes, it makes you feel like you have a Chinchilla-soft face, what we love most about this sunscreen is its formulabecause science. It has UVA and UVB protection, which means that it will help protect your skin from both the suns harmful rays and also from the blue-light emitted from your smart-phone and laptop.

Best Expert-Recommended Sunscreen: Paulas Choice On-The-Go Shielding Powder SPF 30, $29, dermstore.com

Dermatologists recommend reapplying your sunscreen every two hours, but realistically, not too many of us are down for applying a lotion over our makeup throughout the day. Thats why this powder formula is so greatit comes in what looks like a makeup brush, and all you have to do is swipe it across your face to achieve your recommended SPF dose. Plus, it gets rid of excess shine, as Carranza points out.

Best Drugstore Lip Treatment: Awake BeautyMoisture Balm Daytime Lip Mask, $14, ulta.com

This hydrating lip mask smells a little like a watermelon Jelly Rancher and works like a charm thanks to its concentrated blend of vitamin E, olive, argan, rosehip, and raspberry seed oil. Testers unanimously gave it a high score for seeing noticeably healthier lips the day after using it. For best results, use overnight since it is on the thicker side.

Best Luxury Lip Treatment: Biossance Squalane + Rose Vegan Lip Balm, $18, sephora.com

A recent poll showed that 3 percent of the US population say they are vegan, which may not seem like a lot, but that amounts to nearly 10 million people (or nearly the entire population of the state of Michigan). For those 10 million, it may be important to pick a vegan lip treatment that aligns with their dietand this is the best one. It uses plant-derived squalane, rose oil, ceramides, and algae to nourish and plump skin. Apply at night and wake up to smoother and visibly healthier lips.

Best Expert-Recommended Lip Treatment: Hourglass No 28 Tinted Lip Treatment Oil, $49, sephora.com

Treat your mouth to a luxurious anti-aging treatment that rivals even the best high-shine lip glosses on the market. It uses top-notch ingredients that work to hydrate and plump the lips, comes in four colors, and has Carranzas stamp of approval: Its the perfect lip oilits deeply hydrating without being sticky, gives your lips an amazing shine, and the gold-plated applicator is to die for!

Best Self-Tanning Face Towelettes: Haute Bronze Face Towel, $35, haute-bronze.com

For those hoping to get a sun-kissed glow without having to spend time in the sun, these bronzing face towels are a holy grail, and theyre so easy to use! Just unfold the towel, and using circular motions apply it to dry, clean skinthats it! Plus, since it is a towel, its carry-on approved.

Best Self-Tanning Face Serum: Tan-Luxe Super Glow Hyaluronic Self-Tan Serum, $49, sephora.com

My goal: maintaining a year-round healthy glow without the harmful sun exposure. The answer: this magic fluid, shares DeSantis. Its an anti-aging serum and tanning formula rolled into one, so it helps me cut down on my skincare steps every morning and night, and Im left with a believable bronze that scores me tons of compliments.

Best Face Roller: MDNA Skincare The Beauty Roller, $150 (orig. $200), nordstrom.com

This tool is great for de-puffing and encouraging lymphatic drainage, since the grooves and rolling action stimulates circulation and relieves tension, says Dr. Engelman. It can also help drive your serum deep into the skin which allows your products to work better for younot to mention, it feels great! Regular lymphatic drainage can help reduce puffiness and can temporarily help sculpt the face for a more lifted look.

Best Gua Sha: Wildling Empress Stone, $65, wildling.com

If youre more of a Gua Sha person, clean beauty expert and HelloGiggles columnist Jessica Yarbrough recommends this product, saying its at the top of her list. I have an extensive collection of what I like to call non-skincare skincare products, things that support my skin without technically absorbing into my skin, she explains. With this in hand, [giving myself a] mindful facial massage has become a daily morning ritual, and my skin is healthier and glowier for it.

Best Device: Finishing Touch Flawless Dermaplane Glo, $19.88, amazon.com

Dermaplaning is a treatment primarily found at a dermatologist or estheticians office, wherein a sharp blade sloughs away the peach fuzz and dead skin cells from the uppermost layer of the skin, leaving your face radiant and baby-soft. This at-home device isnt as sharp as a professionals would be, for obvious safety reasons, but its effective in removing fuzz and excessive dead skin cell buildup. It also comes with a built-in light that improves visibility and in turn, helps you get better results.

Best Tweezers: Tweezerman Rose Gold Point Tweezer, $20.32, amazon.com

Designed for precision, this pointed-tip tweezer is the answer to effectively removing stubble, pesky ingrown hairs, and super-fine facial strands.

Skincare products arent, and shouldnt, be reserved for only the face. Advancements in skincare technology have allowed for the creation of body care products that blew our minds this year. From those that protect our skin from environmental aggressors and reverse signs of aging by altering our genetic code to innovative fuss-free packaging and bath products that are vagina-friendly, here are the body products were currently crushing on.

Best Drugstore Body Wash: Dove Body Wash Mousse with Rose Oil, $5.99, target.com

Body wash, but in a mousse. This gentle body wash has a subtle rose scent that you can actually scratch-and-sniff on the bottle to test out before purchasing. A little goes a long way for head-to-toe moisture.

Best Luxury Body Wash: LOccitane Almond Shower Shake, $25, amazon.com

Because we clearly love a fun body wash, its no wonder we loved this shower shake. Studies show that when applied topically, almond oil improves skin tone and prevents UV damage, and its the key ingredient in this product. To use, shake the bottle to mix the ingredients into a milky formula and apply onto wet skin. It will leave your body feeling hydrated and soft.. Now, Alexa, play OutKasts Hey Ya!.

Best Expert-Recommended Body Wash: Olay Moisture Ribbons Plus Shea Butter + Blue Lotus Body Wash, $6.99, walgreens.com

Dr. Mariwalla recommends this moisturizing body wash for its shea butterwhich studies show is anti-inflammatory, rich in antioxidants, and is a rich emollientperfect for sensitive skin types.

Best Drugstore Body Lotion: Curl Dry Skin Therapy Itch Defense, $10.94, amazon.com

Tackle dry, itchy skin with this fast-absorbing body lotion that almost instantly soothes and calms skin. This moisturizer, has approval from the National Psoriasis Foundation and holds a seal from the National Eczema Association, is packed with ceramides, vitamin E, and oatmeal extractand its moisturizing effects last all day.

Best Luxury Body Lotion: Augustinus Bader The Body Cream, $165, neimanmarcus.com

The advanced skincare technology in this cream makes this splurge worth the while. It uses epigenetic technology, which essentially tells the skin cells to be healthy overall and can over time alter your genetic code, and helping treat stretch marks, bumpy skin, and cellulite.

Best Expert-Recommended Body Lotion: CetaphilRestoring Lotion with Antioxidants, $19.97, amazon.com

Cetaphil took their classic lotion and supercharged it, says Dr. Engelman. This product is safe for sensitive skin and the added antioxidants and niacinamides will neutralize free radical damage and repair the skin barrier. Niacinamides have a similar effect to retinol, strengthening the skin barrier. However, unlike retinol, it fortifies from the get-go without sensitivity or irritation.

Best Drugstore Hand Cream: eos Shea Better Coconut Hand Cream, $2.98, amazon.com

Original post:
The best beauty products from the 2020 Beauty Crush Awards - Yahoo Lifestyle

Skin Stem Cells Comments Off on The best beauty products from the 2020 Beauty Crush Awards – Yahoo Lifestyle | February 29th, 2020

Numerous revelations about the world have been made in various forms throughout history. Researchers and scientists have continuously managed to discover new ways we can understand the world around us.

Major scientific breakthroughs have been made that helped improve our way of life and will make it easier for us to achieve even more amazing innovation eventually. The 21st century was especially fruitful for the advancements in technology and science. Many of the essential revelations in history were made during the last 100 years. This article will attempt to name the most important ones.

In 2015, the National Aeronautics and Space Administration managed to find evidence that proves that there is liquid water on Mars. Scientists were aided by the first spectrometer provided by NASA, called the Mars Reconnaissance Orbiter.

With its help, they were able to detect hydrated salts all over the distant planet. The hydrated salts are more prevalent during the warmer seasons, which means that water is a crucial ingredient in their development.

Many scientists believe this to be the most crucial discovery of the 21st century. Since Albert Einsteins theory of relativity was published, the thought of time travel has excited scientific minds all over the world.

The LIGO (Laser Interferometer Gravitational-Wave Observatory) project in the United States is responsible for the detection of gravitational waves, which would imply that with enough research time travel could be possible. Journey to the earliest parts of our universe does not seem as impossible as before since this discovery.

Proof of the existence of Dark Matter was found in 2006 by a team of researchers, led by Maxim Markevitch of the Harvard-Smithsonian Center for Astrophysics in Cambridge. They proved its existence by measuring the location of mass that gets created when galaxies collide. Specific clusters of mass get disconnected, and a large amount of visible matter is what makes up dark matter. While this sounds overly complex, the important thing to remember is that this proves that dark matter makes up for 68% of the universe.

Through stem cell research, we can provide better access to organs for patients, meaning that patients no longer need to wait for donors, making it easier to cure certain conditions. Stem cells make it possible to grow an indefinite number of cells of the same type, but other types of cells also arise from that process. This means that it is possible to regenerate organs using skin cells. In the future, the discovery could make it so that the organs needed for treatment are created in a laboratory.

The process of face transplantation uses tissues of a dead person to replace another persons face. It is a complicated process that was first successfully performed in France in 2005. This transplant was only partial, but the first full-face transplant happened only five years later in Spain.

Since then, people with significant congenital disabilities or facial disfigures caused by diseases or burns have had this procedure performed on them in multiple countries. What seemed like science fiction in the 1990s is a reality now.

HIV is considered to be one of the deadliest viruses in the history of humankind. While we still have not found a cure for AIDS, the disease that is a result of an HIV that has advanced too much, we did manage to improve the treatment of HIV.

With the new methods, some of which were developed in Germany, patients with HIV can live longer, almost being able to lead healthy lives. With these exciting advancements, millions of lives have been saved, and it is only a matter of time before we find a complete cure.

Scientists atthe Massachusetts Institute of Technology (MIT)managed to find a way to create false memories and plant them into the brains of mice. While this enormous scientific breakthrough can help us better understand the concept of mind and help us with dealing with mental health issues, it can still be problematic.

It does seem like a scene out of an old science fiction movie, but with this advancement, it could be possible to manipulate a persons memory, and who knows what consequences that could have.

Scientists at the University of Twente have developed robotic body parts using biomechanics. They managed to create robotic arms that can make life easier for people with severe muscular dystrophy. They also implemented previous research on prosthetics in creating these limbs. These robotic body parts could prove to be extremely helpful for wounded soldiers, people suffering from disabilities or older people.

A photon was teleported into space with the help of a laser beam by Canadian scientists. This process is called quantum teleportation, and it can be used to transport information about something, not its physical state. However, it is a step in the right direction of possibly making teleportation of physical matter possible someday.

The process itself was incredibly hard and required extreme precision. Photons are tiny, meaning that it will be a while until we can successfully teleport larger items.

Although the World Wide Web originated much earlier, it was not until the 21st century that we saw everything the internet is capable of. And it is a fitting way to end this list because it impacted more lives than anything else. Thanks to the internet, we can do things we could only imagine 20 years ago, basically from anywhere in the world. We can access any information, watch every movie in existence, or talk to people halfway around the world. It is the discovery of all the possibilities of the internet that made this century what it is, at least for now.

Where and when was the first face transplant procedure performed?

The first face transplant procedure was performed in France in 2005.

Read more:
10 Of The Biggest World Revelations In The 21st Century - World Atlas

Skin Stem Cells Comments Off on 10 Of The Biggest World Revelations In The 21st Century – World Atlas | February 29th, 2020

There is new hope for patients with a rare autoimmune disorder. In mild cases, scleroderma causes areas of hardened skin. But in severe cases, it can also cause deadly hardening of internal organs like the lungs.

A transplant typically used to treat cancer is having remarkable results for patients who had little hope of surviving.

A year ago, Chuck Beschta couldn't walk more than a few minutes without stopping to rest.

"Just going out and doing normal activities outside raking the lawn, mowing the grass, shoveling the driveway, whatever, snow blowing those became impossible," he said.

After months of testing, he was diagnosed with severe scleroderma, which was hardening his skin. But even worse, it was hardening his lungs, making it hard to breathe.

"He was getting worse despite the best therapy we had to offer," University of Wisconsin rheumatologist Dr. Kevin McKown said.

McKown recommended a stem cell transplant newly approved for scleroderma to reboot Beschta's immune system.

"There's a process by which they try to remove the autoreactive immune cells, the cells that are caught in the immune process, and then they infuse that back in and hope that the body will basically take up and graft that immune system," McKown said.

Beschta saw almost immediate results. His skin was softer and his breathing improved. He hopes his scleroderma has been cured.

"I think we can be optimistic, and so far the people who have been followed out as far as 10 years out don't seem to be getting it back," McKown said.

Without a transplant, less than half the patients who have diffuse scleroderma and severe lung disease live 10 years past diagnosis.

Stem cell transplants are commonly used to treat leukemia and lymphoma, cancers that affect the blood and lymphatic system.

MEDICAL BREAKTHROUGHSRESEARCH SUMMARYTOPIC: NEW THERAPY FOR SCLERODERMAREPORT: MB #4698

BACKGROUND: Scleroderma is an autoimmune rheumatic disease where an overproduction of collagen produced in the body tissues causes the skin and internal organs to harden. The symptoms and effects range by person, but some common symptoms include hardened patches of skin (locations on the body vary,) painful and numb-feeling fingers and toes, and sharp internal pain in the esophagus, intestines, heart, lungs, or kidneys. Women are four times as likely to have scleroderma and the onset is between 30 and 50 years of age. However, anyone from infants to the elderly can have scleroderma. Possible risk factors include having certain gene variations as other family members, ethnic groups, exposure to certain medications or drugs, and already having another autoimmune disease, like rheumatoid arthritis, lupus or Sjogren's syndrome. (Source: https://www.scleroderma.org/site/SPageNavigator/patients_whatis.html;jsessionid=00000000.app30132b?NONCE_TOKEN=9B76519DF6B5819859319F0B63B805C9#.XheCGVVKhaQ , https://www.mayoclinic.org/diseases-conditions/scleroderma/symptoms-causes/syc-20351952 )

DIAGNOSING: A physical exam will be conducted as well as a blood test to check for elevated levels of antibodies the immune system produced. The doctor will also take a sample of skin to be tested in the lab. If there are complaints about internal pain, the doctor may run other tests, including imaging, organ function, and other blood tests. (Source: https://www.mayoclinic.org/diseases-conditions/scleroderma/diagnosis-treatment/drc-20351957 )

NEW TECHNOLOGY: A new stem cell transplant that's commonly known to treat cancer is improving the quality and quantity of life for those with scleroderma. Rheumatologists at University of Wisconsin Health tested the treatment since they have already been conducting bone marrow transplants for decades. Surgeons take out a sample of the patient's bone marrow, isolate the stem cells, and use radiation and chemotherapy to clean out their immune system. The same stem cells are later injected back into the patient's immune system with the hope that new cells will grow and the system is rid of the bad ones. The process is dangerous when the cells are taken out because the patient's immune system is more vulnerable, making infections more likely to occur. However, after four and a half years, 79% of patients that underwent the treatment were alive without serious complications compared to 50% that were treated with the original drugs. (Source: https://madison.com/wsj/news/local/health-med-fit/man-with-severe-autoimmune-disease-gets-stem-cell-transplant-at/article_7e8e17a5-21da-52f8-b728-fe584dab2b77.html)

Read more:
New technique developed to treat hardening of internal organs - WNDU-TV

Skin Stem Cells Comments Off on New technique developed to treat hardening of internal organs – WNDU-TV | February 28th, 2020

A mum has shared the emotional experience of meeting the stranger who saved her son's life.

Alfie Commons, now aged four, was just seven months old when he was diagnosed with leukaemia in 2016.

After three rounds of chemotherapy failed, Alfie received a life-saving bone marrow donation from a school teacher in Germany, who recently made the trip to the UK to meet him.

Alfie's mum, Lorna Commons, 40, of Toton has spoken about the experience in the hope it will encourage more people to sign up to become potential donors.

Looking back to the day of diagnosis, she said Alfie had been to his GP for a third time in February 2016 after suffering a cold since Christmas.

She said: "The GP told us to go to A&E for further tests as he was a little concerned.

"We got to Queen's Medical Centre in the morning and by early evening, we had the diagnosis; Alfie had infant acute lymphoblastic leukaemia (ALL)."

Ms Commons, who works in HR, added: "Even now, four years down the line, I still feel the emotions of that day. Nothing can prepare you."

The plan was to treat Alfie with chemotherapy, but after the first round failed, Ms Commons was told his only chance of survival was to get a bone marrow transplant.

The family was told Alfie was unlikely to leave hospital for the next six months.

She added: "Worse was to follow, his second course also failed and on the same day, we were told that Alfies nine-year-old brother, Billy, wasnt a bloodstemcellmatch for him either.

"The fear of losing Alfie was overwhelming, I felt helpless but I had to carry on for Alfies sake.

The transplant could not go ahead without the cancer being near enough eradicated and even when the good news came that a donor had been located, Alfie still had a mountain to climb.

After a third failed round of chemotherapy, Alfie was put on a trial immunotherapy drug as a '"last ditch attempt". Against all the odds, it worked.

"I think at that point all the doctors and nurses were preparing us for the worst. Your head has to go there," Ms Commons said.

"But then the cancer went, and it was enough to give us the bridge to getting the transplant done."

While the transplant was a success, Alfie suffered for months with Graft versus Host Disease (GvHD) on his skin and in his gut, which is the body's reaction to the new stem cells.

However, doctor's were encouraged the body was gradually accepting the cells and beginning to produce cells of their own.

On February 19, Alfie and his mum were able to meet the woman who saved his life after she made the 600-mile trip.

Christin Bouvier, 34, from Schwerin in Germany, was matched with Alfie after she registered in 2010 with DKMS, a charity dedicated to the fight against blood cancer.

The school teacher had been on the bloodstemcellregister for a number of years before she was contacted and tested as a match for Alfie.

Ms Bouvier said: When they told me that the recipient was a baby I just cried.

"Its a moment that is always with me and whenever I feel a bit down, I think back to it as it always brings me so much happiness!"

Ms Commons said she had been able to contact Ms Bouvier anonymously, as per UK law, but they were permitted to meet two years after the transplant.

Ms Bouvier added: It was always a dream to meet Lorna and Alfie and I never thought it would happen I was so delighted when Lorna invited me. I was very nervous but also very excited to meet them both in person.

"I knew the meeting would be one of those very special moments in my life."

Ms Commons feels the meeting has meant a new chapter has begun in both hers and Alfie's life and she is now focussed on the positives.

She added: "For something so small, there really is no greater gift than being a donor - I get to see my child grow up. To meet Christin, I was able to say 'this is what you've done'.

"We will be in each other's lives forever now - Alfie has her DNA in his blood. But Christin and I also share a special bond, we're just so similar and some people say we even look like sisters.

Alfie is such a special little boy and I truly believe that this story can make a real difference and save more lives.

"There is a match out there for everyone with blood cancer, people just need to come forward and register."

Anyone aged between 17-55 and in general good health can go on standby as a potential lifesaver.

See the original post:
Mum meets the stem cell donor who saved her four-year-old son's life - Nottinghamshire Live

Skin Stem Cells Comments Off on Mum meets the stem cell donor who saved her four-year-old son’s life – Nottinghamshire Live | February 26th, 2020

Scientists believe that humans will soon be able to recover from injuries such as broken spines, as treatment looks to boost the body's ability to heal itself.

A new study in the journal Regenerative Medicine describes how scientists were able to stimulate the self-repair response in rats.

Rats in the study were given two drugs, one of which is usually given to bone marrow transplant patients, and another which is used for bladder control.

This cocktail caused the rats' bone marrow to produce a greater number of mesenchymal stem cells, the cells which can develop into bone tissue.

As a result, enhanced calcium binding was seen at the site of the rats' spinal injuries, speeding up the production of new bone as well as healing wounds.

The study's authors hope that one day, such treatments will work on humans.

"We know that when bones break they will heal, and this requires the activation of stem cells in the bone," study co-author Sara Rankin from the National Heart and Lung Institute at Imperial College London, said in a statement.

"However, when the damage is severe, there are limits to what the body can do of its own accord.

"We hope that by using these existing medications to mobilise stem cells, as we were able to do in rats in our new study, we could potentially call up extra numbers of these stem cells, in order to boost our bodies' own ability to mend itself and accelerate the repair process."

Both drugs tested on rats are already widely used, so researchers are hopeful human trails can begin soon.

If these trials produce the same results as those seen in rats, then it's hoped the treatment could help to not only repair spinal injuries but also speed up the rate at which broken bones heal and mend damaged tissues in other organs.

Dr Tariq Fellous, first author of the research, said: "We first need to see if these medications release the stem cells in healthy volunteers before we can test them in patients with fractures.

"We have the drugs and know they are safe to use in humans we just need the funding for the human trials."

Dr Andia Redpath, who also co-authored the paper, added that repurposing existing medicines - so-called Regenerative Pharmacology - could have major potential as an efficient and cheaper way of treating diseases.

"Rather than devising new stem cell treatments from scratch that involve lengthy and expensive trials, our approach harnesses the power of the body's own stem cells, using existing drugs.

"We already know the treatments in our study are safe, it's now just a matter of exploring further if they help our bodies heal."

Stem cells are providing incredible new medical breakthroughs all the time.

Earlier this month, scientists trialled 3D-printed skin containing stem cells to treat burns victims .

Read more from the original source:
Humans soon able to regrow spines as body given 'new power to heal itself' - Daily Star

Skin Stem Cells Comments Off on Humans soon able to regrow spines as body given ‘new power to heal itself’ – Daily Star | February 26th, 2020

The most emotional issue my patients have is hair loss, says New York dermatologist Cheryl Karcher, MD below a jaw-dropping before-and-after photo shared to her Instagram page. On the left half of the photo shared is a young womans exposed hairlinethe hair is so thin and sparse, the entire scalp is visible wherever your eye is drawn. On the right side of the photo, the same woman, but with an almost unbelievable amount of thicker hair, and, somehow, a sense of renewed confidence.

The secret? A little thing called nanofat.

In the past we only had PRP to offer that had to be done three times or more. Sometimes it would work, sometimes it didnt. Now we have nanofat hair restoration, which needs to be done just once, and is much more effective way to treat hair loss and grow hair, explains Dr. Karcher.

You May Also Like: How Low Level Laser Therapy Actually Works to Thicken Hair

So what is nanofat? According to Dr. Karcher, its derived from our own adipose tissue, whereas the ever popular PRP is derived from our blood. Nanofat includes adipose-derived stromal vascular fraction, which contains stem cells as well as growth factors. PRP contains the growth factors released from platelets in the blood, she adds. The procedure itself involves extracting anywhere from 20 to 40 millilitersof fat, usually from the abdomen, then processing it through mechanical filters, before injecting.

Like PRP, the possibilities of what nanofat can help with doesnt stop at the hairline. After the nanofat is processed to the point where there is no fat left, only stem cells and growth factors, it is injected into the scalp, the face, the neck, the decollete, or to improve sun damage, skin pigmentation, decrease wrinkles, and of course grow hair, says Dr. Karcher.

When nanofat is used for hair restoration, Dr. Karcher says she first injects the nanofat, then injects the patients PRP on top of it to act as a fertilizer for the nanofat. Perhaps the best part? Theres little to no painDr. Karcher says the most pain patients feel is during the PRP injections, so the scalp is numbed topicallyand no downtime. When nanofat is used on the face, chest or other areas, Dr. Karcher warns there may be some downtime of erythema and swelling or bruising. If injected for [skin] rejuvenation via microneedling the downtime is only about 48 hours.

While Dr. Karcher has seen unparalleled results from nanofat hair restoration, it is only ideal for patients who have some hair still present on the scalppatients who are completely bald may not be ideal candidates for the procedure. The only time I ever use PRP for hair restoration now is in a patient that doesnt have enough fat to harvest. The nanofat is just one treatment and the results seem to be superior. However, as La Jolla, CA plastic surgeon Robert Singer, MD notes, there is no safety or efficacy data surrounding nanofat treatment as of press time.

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Link:
Doctors Are Injecting This Naturally-Derived Substance to Restore Hair Thicknessand Its Not PRP - NewBeauty Magazine

Skin Stem Cells Comments Off on Doctors Are Injecting This Naturally-Derived Substance to Restore Hair Thicknessand Its Not PRP – NewBeauty Magazine | February 26th, 2020

- Axol Softwave Therapy is a new treatment for erectile dysfunction (ED) and for men who want enhanced sexual performance

- The in-office treatment is non-invasive, safe, and effective with virtually no side effects

- Axol Therapy uses low-intensity sound waves

- Axol Therapy is an alternative to ED medications, surgical implants, penile pumps, and injections

DENVER, Feb. 24, 2020 /PRNewswire/ -- The men's sexual health specialists at Colorado Urology now offer an exciting new treatment option for men living with erectile dysfunction (ED) called Axol Softwave Therapy. This safe and non-invasive treatment option is helping many men with ED achieve spontaneous and natural erections without the help of medications. The therapy can also be used to enhance a man's sexual performance.

Colorado Urology (PRNewsfoto/Colorado Urology)

About 5 in 10 men experience erectile dysfunction (ED) at some point in their lives. First-line therapies often include oral medication to help men achieve an erection. Now, Axol Therapy is providing a safe and effective alternative.

This non-invasive procedure uses gentle full-spectrum, low-intensity sound waves that stimulate revascularization, a process in which new blood vessels form. Axol Therapy promotes improved blood flow to the penis, reduces inflammation, and stimulates the migration of the body's stem cells for long-term healing. The new treatment is helping men to achieve natural erections without ED medications, pumps, injections, or penile implants.

Learn about Axol Softwave Therapy at Colorado Urology: https://www.coloradouro.com/specialties/axol-softwave-therapy/.

Axol Therapy How it Works

Axol Therapy is a modern approach to healing the body by using four types of energy: Heat, Electrohydraulic, Acoustic, and Light (HEAL). Unfocused acoustic waves are delivered to the shaft of the penis using a treatment wand that features a patented unfocused electrohydraulic acoustic wave.

The pulsed acoustic waves are delivered through the skin into the tissue to open and repair aging blood vessels, stimulate new blood vessel growth, restore blood flow, and improve erectile quality. Axol Therapy typically takes only 20 minutes, once a week, for a total of six sessions in the physician's office.

How Well Does Axol Therapy Work?

For men who are the right candidates, Axol Therapy is a safe and effective option without the side effects often experienced with oral medications. Most patients can get the quality, rigid erections they once had with Axol Therapy's gentle acoustic pulse treatment within just six office visits. Incremental improvement in erectile function may be seen after just a few sessions.

Restoring Vitality and Quality of Life

There are a number of significant benefits to Axol Therapy. For men who are candidates for this treatment option, a future without erectile dysfunction is perhaps the biggest one. The restoration of a man's vitality and spontaneous active sex life are also major benefits of this exciting new treatment.

Learn more about Axol Softwave Therapy, the benefits, and how to schedule a consultation. Visit https://www.coloradouro.com/specialties/axol-softwave-therapy/or call 888-401-7149.

About Colorado Urology

Colorado Urology, an affiliate of United Urology Group, is Eastern Colorado's premier urology practice, which was formed when Advanced Urology, Alpine Urology, and Foothills Urology became one urology group in April 2019. The group provides a broad array of urologic services, and its integrated approach to urologic care provides patients with access to experienced specialists, a comprehensive support team of healthcare professionals, innovative diagnostic tools, and highly advanced treatments and therapies. Colorado Urology operates 12 medical offices throughout the Denver metro and Boulder area, has 18 urologists, 9 advanced practice providers, and more than 130 employees.

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About United Urology Group

United Urology Group is a national management services organization whose member groups of urology practices include: Arizona Urology Specialists with locations across the greater Phoenix area; Chesapeake Urology, with offices located throughout Maryland and Delaware; Tennessee Urology, based in Knoxville, TN; and Colorado Urology, located in the greater Denver, Boulder and Front Range areas. United Urology Group members' collective staff today number more than 1,400 employees, including 150 physicians. United Urology's vision is to support the creation of a national network of urology affiliates, which will enable urologists to better meet the needs of their patients and provide the highest level of urological care.

Media Contact:

Patricia Schnably, Senior Vice President, Marketing & Communications United Urology Group25 Crossroads Drive, Suite 306, Owings Mills, MD 21117443-738-8107 pschnably@uniteduro.com

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Breakthrough, Non-Invasive Treatment Called Axol Therapy For Erectile Dysfunction And Enhanced Sexual Performance Now Available At Colorado Urology -...

Skin Stem Cells Comments Off on Breakthrough, Non-Invasive Treatment Called Axol Therapy For Erectile Dysfunction And Enhanced Sexual Performance Now Available At Colorado Urology -… | February 25th, 2020

Recent developments in the field of stem cell research are paving a path towards a radical shift in the way we diagnose and treat dementia. Stem cells have excited scientists for years and research groups across the globe are using them to advance modern medicine. Using stem cells to aid the fight against dementia is perhaps one of the most critical applications of the technology. Dementia is the leading cause of death in the UK, sixth in US and fifth globally, with an estimated 50 million people currently affected.

The term dementia does not relate to a single disease, but more an array of symptoms that can arise from multiple conditions. The most common is Alzheimers disease (AD) which accounts for up to 80% of all cases. Dementia itself is caused by the death of cells that make up the complex circuitry of our brains and an eventual loss of large portions of the brain. Patients suffering with dementia often exhibit the same general symptoms such as confusion, memory loss and an inability to perform day to day functions. It is a debilitating condition that often strikes the most vulnerable members of society and, consequently, many research groups around the globe work to try to understand dementia-causing diseases to provide better diagnostic and treatment platforms.

In 2007, a research group at Kyoto University in Japan published a study with the potential to change the face of research into dementia along with many other fields. Professor Shinya Yamanaka and his research team developed a method whereby stem cells (cells that can be transformed/differentiated into cells from any tissue) could be generated from a sample of skin. The study, which resulted in a 2012 Nobel Prize for Prof. Yamanaka, demonstrated that skin cells could be isolated from a patient and genetically reprogrammed into induced pluripotent stem cells (iPSCs). In short, this technology made it possible to generate and study brain cells from a patient with dementia without having to remove any of their brain. All they would need to do is provide scientists with a sample of skin.

Since this development, research groups around the globe have started using iPSCs from many patients with dementia in order to understand the biological mechanisms that underlie disease. Dr Eric Hill runs a research group at Aston University in the UK that specializes in iPSCs for dementia research and he had the following to say about the technology:

Its really exciting because it allows us to study cells with genetic mutations that are patient specific. We can get a much better picture of what is actually happening in the brains of these patients. We can now generate all the different cell types found in the human brain and understand how they function together and map the changes that result in disease.

The latter was perhaps most powerfully demonstrated in a study published by a team at the University of North Carolina, led by Professor Hansang Cho. The team was able to generate three key cell subtypes that play important roles in brain function; study the impact of mutations associated with Alzheimers disease; and even replicate some of the core malfunctions found to trigger disease in the brains of patients.

Studies like this are of significance because a large part of the focus in dementia research is on trying to understand how such changes in function arise. When a patient is diagnosed with a disease such as Alzheimers it is often too late for effective treatment. Scientists, instead, seek to elucidate those early changes in brain cell function in order to diagnose patients earlier to give more time for treatment. It is very much a case of prevention being better than a cure. Dr Hill provided an encouraging statement regarding this:

When we generate brain cells from iPSCs the cells we get are developmentally very young. What is interesting is the fact we still see differences between cells from dementia patients versus healthy patients suggesting we could find markers to help us detect and prevent disease some years before it develops.

Despite such promise, however, iPSCs have yet to provide the field of dementia research with that big break. Multiple treatments have progressed into clinical trials since the technology first emerged but no therapies have been approved. Drugs that show promise in the lab fail to deliver on their potential in patient clinical trials, sending researchers back to square one.

We should not be disheartened by this, however, and should instead view it as space into which the technology of using iPSCs to study dementia can grow. A lot of drugs fail in clinical trials because the platforms used to run initial tests dont provide scientists with a wide enough perspective of how those drugs will influence human cells. Additionally, many preclinical studies use animals with dementia-causing disease artificially induced into them. Studies like this often fail to translate into humans because the initial data is not from a human perspective. This is where researchers like Dr. Hill think iPSCs can provide us with an advantage:

iPSCs could provide us with much better platforms for screening drugs to treat and prevent these diseases. They can really add to what we already have, and while we might not be able to grow a full human brain, we can generate the cells that provide the building blocks for one. They give us the chance to screen new therapies more efficiently, better test their effectiveness and reduce the amount of animal use in dementia research.

Dr Hill is not alone in seeing the promise of using iPSCs to find better treatments for preventing the progression of dementia. Multiple research groups around the world have shown the potential of iPSC-derived brain cells for studying the effectiveness of new therapies.

In the last 12 months we have observed a wave of new studies using iPSCs to try to develop better treatments for diseases like Alzheimers, Parkinsons, Huntingtons disease and ALS. From studies in the University of California identifying cholesterol metabolism as a potential target to treating Alzheimers to studies in Luxembourg helping us find better treatments for Parkinsons, it is easy to see why the global effort to get that big break from iPSCs continues to gain interest. We might still be waiting for that next Noble Prize-winning discovery that will improve the lives of millions of patients but the collective effort of iPSC research groups across the world brings us a step closer with every study they publish. Dementia may, one day, be a thing of the past and iPSC research will likely be a significant part in getting us there.

Sam Moxon has a PhD in regenerative medicine and is currently involved in dementia research. He is a freelance writer with an interest in the development of new technologies to diagnose and treat degenerative diseases. Follow him on Twitter @DrSamMoxon

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Searching for the 'big break' that could turn stem cells into a weapon against dementia - Genetic Literacy Project

Skin Stem Cells Comments Off on Searching for the ‘big break’ that could turn stem cells into a weapon against dementia – Genetic Literacy Project | February 25th, 2020

Medical ResearchThe belief that acute stress can turn hair gray is a popular one, but until now it hasnt been scientifically proven.

But findings that appeared in the publication Nature indicate that the belief may be more than a myth. The study, which used mice as models, was funded in part by the National Institutes of Healths National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and other NIH components.

Hair color is determined by cells called melanocytes, which produce the pigment melanin. New melanocytes are made from melanocyte stem cells that live within the hair follicle at the base of the hair strand. As we age, these stem cells gradually disappear. The hair that regrows from hair follicles that have lost melanocyte stem cells has less pigment and appears gray.

A research team, led by Dr. Ya-Chieh Hsu of Harvard University, used mice to examine stress and hair graying. The mice were exposed to three types of stress involving mild, short-term pain, psychological stress, and restricted movement. All caused noticeable loss of melanocyte stem cells and hair graying.

Having established a link between stress and graying, the scientists then explored several potential causes, including the role of the stress hormone corticosterone, but altering its levels didnt affect stress-related graying.

The researchers eventually turned to the neurotransmitter noradrenaline, which, along with corticosterone, was elevated in the stressed mice. They found that noradrenaline, also known as norepinephrine, was key to stress-induced hair graying. By injecting noradrenaline under the skin of unstressed mice, the researchers were able to cause melanocyte stem cell loss and hair graying.

Noradrenaline is produced mostly by the adrenal glands. However, mice without adrenal glands still showed stress-related graying. Noradrenaline is also the main neurotransmitter of the sympathetic nervous system, which is responsible for the fight-or-flight reaction in response to stress.

Ultimately, the team discovered that signaling from the sympathetic nervous system plays a critical role in stress-induced graying. Sympathetic nerves extend into each hair follicle and release noradrenaline in response to stress. Normally, the melanocyte stem cells in the follicle are dormant until a new hair is grown. Noradrenaline causes the stem cells to activate.

Using fluorescent labelling, the researchers observed the stem cells change to melanocytes and migrate away from their reserve in the hair follicle. With no remaining stem cells, no new pigment cells can be made, and any new hair becomes gray, then white.

When we started to study this, I expected that stress was bad for the body but the detrimental impact of stress that we discovered was beyond what I imagined, Hsu says. After just a few days, all of the melanocyte stem cells were lost. Once theyre gone, you cant regenerate pigments anymore. The damage is permanent.

The authors highlight the need to further study the interactions between the nervous system and stem cells in different tissues and organs. A news release from the NIH said that the knowledge gained in this work will be useful in future investigations into the impact of stress on the body and the development of new interventions.

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Stress and Gray Hair - ThirdAge

Skin Stem Cells Comments Off on Stress and Gray Hair – ThirdAge | February 24th, 2020

Patient Analyses and Safety Data Continue to Underscore Positive Impact of KD025 in cGVHD

Pre-NDA Meeting with FDA Planned for March 2020; Topline Results of Primary Analysis to be Announced in Q2 2020

NEW YORK, NY / ACCESSWIRE / February 23, 2020 / Kadmon Holdings, Inc. (NYSE:KDMN) today announced expanded results from the previously reported interim analysis of ROCKstar (KD025-213), its ongoing pivotal trial of KD025 in chronic graft-versus-host disease (cGVHD). The data were presented today in the oral latebreaker session at the 2020 Transplantation & Cellular Therapy (TCT) Meetings.

As announced in November 2019, KD025 met the primary endpoint of Overall Response Rate (ORR) at the study's planned interim analysis, two months after completion of enrollment. KD025 showed statistically significant and clinically meaningful ORRs of 64% with KD025 200 mg once daily (95% Confidence Interval (CI): 51%, 75%; p<0.0001) and 67% with KD025 200 mg twice daily (95% CI: 54%, 78%; p<0.0001). In the expanded KD025-213 dataset presented today, ORRs were consistent with the previously reported interim analysis across key subgroups, including in patients with four or more organs affected by cGVHD (n=69; 64%), patients who had prior treatment with ibrutinib (n=45; 62%) and patients who had prior treatment with ruxolitinib (n=37; 62%). Three patients achieved a Complete Response. Responses were observed in all affected organ systems, including in organs with fibrotic disease. KD025 has been well tolerated: adverse events were consistent overall with those expected to be observed in cGVHD patients receiving corticosteroids, and no apparent increased risk of infection was observed. Additional secondary endpoints, including duration of response, corticosteroid dose reductions, Failure-Free Survival, Overall Survival and Lee Symptom Scale reductions continue to mature and will be available later in 2020.

"KD025 has been well tolerated and has already demonstrated high response rates in patients with severe and complex cGVHD after a median of five months of follow-up," said Corey Cutler, MD, MPH, FRCPC, Associate Professor of Medicine, Harvard Medical School; Medical Director, Adult Stem Cell Transplantation Program, Dana-Farber Cancer Institute and a KD025-213 study investigator and Steering Committee member.

"We are extremely pleased with the interim outcomes of this pivotal trial of KD025 in cGVHD, which track closely our findings from our earlier Phase 2 study. KD025 achieved robust response rates across all subgroups of this difficult-to-treat patient population, who had a median of four prior lines of therapy, and 73% of whom had no response to their last line of treatment," said Harlan W. Waksal, M.D., President and CEO of Kadmon. "We plan to meet with the FDA for a pre-NDA meeting in March 2020 and to announce topline results from the primary analysis of this trial in Q2 2020."

At the TCT Meetings, Kadmon also presented long-term follow-up data from KD025-208, its ongoing Phase 2 study of KD025 in cGVHD (Abstract #15205). These data were recently presented at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in December 2019.

About the ROCKstar (KD025-213) Trial

KD025-213 is an ongoing open-label trial of KD025 in adults and adolescents with cGVHD who have received at least two prior lines of systemic therapy. Patients were randomized to receive KD025 200 mg once daily or KD025 200 mg twice daily, enrolling 66 patients per arm. Statistical significance is achieved if the lower bound of the 95% CI of ORR exceeds 30%.

While the ORR endpoint was met at the interim analysis, which was conducted as scheduled two months after completion of enrollment, topline data from the primary analysis of the KD025-213 study, six months after completion of enrollment, will be reported in Q2 2020. Full data from the primary analysis will be submitted for presentation at an upcoming scientific meeting.

About KD025

KD025 is a selective oral inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a signaling pathway that modulates immune response as well as fibrotic pathways. In addition to cGVHD, KD025 is being studied in an ongoing Phase 2 clinical trial in adults with diffuse cutaneous systemic sclerosis (KD025-209). KD025 was granted Breakthrough Therapy Designation and Orphan Drug Designation by the U.S. Food and Drug Administration for the treatment of patients with cGVHD who have received at least two prior lines of systemic therapy.

About cGVHD

cGVHD is a common and often fatal complication following hematopoietic stem cell transplantation. In cGVHD, transplanted immune cells (graft) attack the patient's cells (host), leading to inflammation and fibrosis in multiple tissues, including skin, mouth, eye, joints, liver, lung, esophagus and gastrointestinal tract. Approximately 14,000 patients in the United States are currently living with cGVHD, and approximately 5,000 new patients are diagnosed with cGVHD per year.

About Kadmon

Kadmon is a clinical-stage biopharmaceutical company that discovers, develops and delivers transformative therapies for unmet medical needs. Our clinical pipeline includes treatments for immune and fibrotic diseases as well as immuno-oncology therapies.

Forward Looking Statements

This press release contains forward-looking statements. Such statements may be preceded by the words "may," "will," "should," "expects," "plans," "anticipates," "could," "intends," "targets," "projects," "contemplates," "believes," "estimates," "predicts," "potential" or "continue" or the negative of these terms or other similar expressions. Forward-looking statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. We believe that these factors include, but are not limited to, (i) the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; (ii) our ability to advance product candidates into, and successfully complete, clinical trials; (iii) our reliance on the success of our product candidates; (iv) the timing or likelihood of regulatory filings and approvals; (v) our ability to expand our sales and marketing capabilities; (vi) the commercialization of our product candidates, if approved; (vii) the pricing and reimbursement of our product candidates, if approved; (viii) the implementation of our business model, strategic plans for our business, product candidates and technology; (ix) the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates and technology; (x) our ability to operate our business without infringing the intellectual property rights and proprietary technology of third parties; (xi) costs associated with defending intellectual property infringement, product liability and other claims; (xii) regulatory developments in the United States, Europe, China, Japan and other jurisdictions; (xiii) estimates of our expenses, future revenues, capital requirements and our needs for additional financing; (xiv) the potential benefits of strategic collaboration agreements and our ability to enter into strategic arrangements; (xv) our ability to maintain and establish collaborations or obtain additional grant funding; (xvi) the rate and degree of market acceptance of our product candidates; (xvii) developments relating to our competitors and our industry, including competing therapies; (xviii) our ability to effectively manage our anticipated growth; (xix) our ability to attract and retain qualified employees and key personnel (xx) the potential benefits from any of our product candidates being granted orphan drug or breakthrough designation; (xxi) the future trading price of the shares of our common stock and impact of securities analysts' reports on these prices; and/or (xxii) other risks and uncertainties. More detailed information about Kadmon and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the U.S. Securities and Exchange Commission (the "SEC"), including the Company's Annual Report on Form 10-K for the fiscal year ended December 31, 2018 and subsequent Quarterly Reports on Form 10-Q. Investors and security holders are urged to read these documents free of charge on the SEC's website at http://www.sec.gov. The Company assumes no obligation to publicly update or revise its forward-looking statements as a result of new information, future events or otherwise.

Contact Information

Ellen Cavaleri, Investor Relations646.490.2989ellen.cavaleri@kadmon.com

SOURCE: Kadmon Holdings, Inc.

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Kadmon Announces Expanded Results of Interim Analysis of Pivotal Trial of KD025 in cGVHD - Benzinga

Skin Stem Cells Comments Off on Kadmon Announces Expanded Results of Interim Analysis of Pivotal Trial of KD025 in cGVHD – Benzinga | February 24th, 2020