Stress may play a key role in just how quickly hair goes from colored to ashen.

Scientists have long understood some link is possible between stress and grey hair.

But this new research more deeply probes the exact mechanisms at play.

The researchers initial tests looked closely at cortisol, the stress hormone that surges in the body when a person experiences a fight or flight response.

Its an important bodily function, but the long-term presence of heightened cortisol links to a host of negative health outcomes.

But the culprit ended up being a different part of the bodys fight or flight response the sympathetic nervous system.

These nerves are all over the body, including making inroads to each hair follicle, the researchers reported.

Chemicals released during the stress response causes pigment producing stem cells to activate prematurely, depleting the hairs reserves of color.

The detrimental impact of stress that we discovered was beyond what I imagined, a lead study author said.

After just a few days, all of the pigment-regenerating stem cells were lost.

Once theyre gone, you cant regenerate pigments anymore. The damage is permanent.

But stress isnt the only reason that most people get grey hair.

In most cases, its simple genetics.

Gray hair caused by loss of melanocytes (pigment cells) in the hair follicle.

This happens as we age and, unfortunately, there is no treatment that can restore these cells and the pigment they produce, melanin, a dermatologist told.

Genetic factors determine when you go grey.

There is nothing that can be done medically to prevent this from happening when it is genetically predetermined to happen.

That doesnt mean environmental factors such as stress dont play a role.

Smoking, for instance, is a known risk factor for premature graying.

So kick the habit if you want to keep that color a little longer.

Other contributing factors to premature graying include deficiencies in protein, vitamin B-12, copper, and iron as well as aging due in part to an accumulation of oxidative stress.

That stress prompted by an imbalance between free radicals and antioxidants in your body that can damage tissue, proteins, and DNA.

And some degree of oxidative stress is a natural part of life.

Changes you can pursue to delay premature grays include eating a diet high in omega-3 fatty acids such as walnuts and fatty fish.

It doesnt spend too much time in the skin-damaging and hair-damaging ultraviolet light of the sun, and taking vitamin B-12 and vitamin B-6 supplements.

That said, if you are going gray prematurely, it wouldnt hurt to go have a checkup just in case natural genetic factors arent the sole culprit.

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Researchers from the group of Vlad Cojocaru together with colleagues the Max Planck Institute in Mnster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.A cells identity is driven by which DNA is read or not read at any point in time. Signaling in the cell to start or stop reading DNA happens through proteins called transcription factors. Identity changes happen naturally during development as cells transition from an undesignated cell to a specific cell type. As it turns out, these transitions can also be reversed. In 2012, Japanese researchers were awarded the Nobel prize for being the first to push a regular skin cell backwards to a stem cell.A fuller understanding of molecular processes towards stem cell therapiesUntil now, it is unknown how the conversion of a skin cell into a stem cell happens exactly, on a molecular scale. Fully understanding the processes with atomic details is essential if we want to produce such cells for individual patients in the future in a reliable and efficient manner, says research leader Vlad Cojocaru of the Hubrecht Institute. It is believed that such engineered cell types may in the future be part of the solution to diseases like Alzheimers and Parkinsons, but the production process would have to become more efficient and predictable.Pioneer transcription factorOne of the main proteins involved in the stem cell generation is a transcription factor called Oct4. It induces gene expression, or activity, of the proteins that reset the adult cell into a stem cell. Those genes induced are inactive in the adult cells and reside in tightly packed, closed states of chromatin, the structure that stores the DNA in the cell nucleus. Oct4 contributes to the opening of chromatin to allow for the expression of the genes. For this, Oct4 is known as a pioneer transcription factor.

The data from Cojocaru and his PhD candidate and first author of the publication Jan Huertas show how Oct4 binds to DNA on the so-called nucleosomes, the repetitive nuclear structures in chromatin. Cojocaru: We modelled Oct4 in different configurations. The molecule consists of two domains, only one of which is able to bind to a specific DNA sequence on the nucleosome in this phase of the process. With our simulations, we discovered which of those configurations are stable and how the dynamics of nucleosomes influence Oct4 binding. The models were validated by experiments performed by our colleagues Caitlin MacCarthy and Hans Schler in Mnster.One step closer to engineered factorsThis is the first time computer simulations show how a pioneer transcription factor binds to nucleosomes to open chromatin and regulate gene expression. Our computational approach for obtaining the Oct4 models can also be used to screen other transcription factors and to find out how they bind to nucleosomes, Cojocaru says.

Moreover, Cojocaru wants to refine the current Oct4 models to propose a final structure for the Oct4-nucleosome complex. For already almost 15 years now, we know that Oct4 together with three other pioneer factors transforms adult cells into stem cells. However, we still do not know how they go about. Experimental structure determination for such a system is very costly and time consuming. We aim to obtain one final model for the binding of Oct4 to the nucleosome by combining computer simulations with different lab experiments. Hopefully, our final model will give us the opportunity to engineer pioneer transcription factors for efficient and reliable production of stem cells and other cells needed in regenerative medicine.ReferenceHuertas et al. (2020) Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding. Biophysical Journal. DOI: https://doi.org/10.1016/j.bpj.2019.12.038

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He asked her for a list of dream projects she would love to investigate. What followed was a year of challenges, stresses and the ultimate reward guided intellectual freedom toward scientific discovery.

Ashley Kramer, a student at the Wayne State University School of Medicine, is enrolled in the schools M.D.-Ph.D. program, an eight-year commitment broken down into three parts the first two years of medical school, four years of graduate school, then the final two years of medical school. Like all M.D./Ph.D. students at the medical school, Kramer had to complete research rotations with faculty she thought would make good dissertation advisors.

Because I have always loved stem cell biology and had experience working with zebrafish in the past, I decided to do an eight-week rotation in Dr. Thummels lab between my medical year one and medical year two, and made the decision that this was absolutely the perfect lab for me, she said.

Ryan Thummel, Ph.D., is an associate professor of Ophthalmology, Visual and Anatomical Sciences. His lab focuses on retinal development and regeneration in zebrafish, an attractive model to study neurodegenerative diseases because of its ability to regenerate neuronal tissues. Zebrafish fully regenerate their retinas in just a matter of weeks, an ability mammals lack.

Zebrafish and mammals both have a cell called Mller glia that supports retinal neurons. In zebrafish, however, these cells convert to stem cells and are responsible for retinal regeneration.

At the end of the rotation, Dr. Thummel floated the crazy idea of starting to work on this grant, a 70-plus page monster undertaking, during my M2 year, and I immediately jumped at the opportunity. I was excited at the idea of having a four-year research project completely planned out by the time I started my Ph.D. after M2 so I could hit the ground running after the dreaded STEP 1, Kramer said.

I came to him two days later with a nine-page document of project ideas. We sat down for three hours discussing projects and came up with a top-two list of cohesive projects for me to move forward with as a grant and thesis, she said. From there, it was a nearly yearlong process of writing, meeting, revising and repeating for each of the many sections of the grant.

The effort was worth it. Kramer secured a five-year, $294,102 grant from the National Eye Institute of the National Institutes of Health last year to study the molecular mechanisms of retinal regeneration in zebrafish, an organism that exhibits a remarkable capacity for regeneration.

"Ashley is a dedicated young scientist and worked very hard on this grant application," Dr. Thummel said.

The grant is one of the NIHs Ruth L. Kirschstein National Research Service awards, also known as an F30. The project, Elucidating the role of DNA methyltransferases in epigenetic regulation of retinal regeneration in the zebrafish, started last month. She is the principal investigator.

This was an incredibly challenging experience that allowed me to grow immensely as a scientist. Grant writing, planning effective and novel longitudinal scientific investigations, and time management will all be critical skills for me moving forward in my career as a physician scientist, she said. I cannot thank Dr. Thummel and my past advisors enough for all of their mentoring and support in the last ten years who have gotten me to where I am today, and I am looking forward to the rest of my training here at Wayne State and beyond.

Kramer earned her bachelors degree in Genetics, Cell Biology and Development from the University of Minnesota in 2014. Her love of research and stem cell biology started when she was an undergraduate research assistant there.

Nearly a decade later, she is studying how epigenetic marks are added to, and removed from, genes in zebrafish retinal stem cells during the process of retinal regeneration. The role of epigenetics in the body is akin to traffic signs on the road.

If roads had no traffic lights, stop signs or barricades, it would be complete chaos. The same is true for your cells. If you used every single gene encoded in your DNA 100% of the time, your cells would be chaos. Epigenetics is what is responsible for telling your skin cell to be a skin cell and your liver cell to be a liver cell, while they both have the exact same underlying DNA sequence, Kramer said. There are various different epigenetic marks that decorate the DNA without actually changing the sequence. These marks come in many forms and can act to either start, stop or change the amount that a particular gene is used, similar to how a green light, road block or stop sign direct traffic rules.

The process is critical for normal embryonic development and everyday cell processes.

If we can gain a deeper understanding of how species like the zebrafish are able to regenerate tissues when mammals cannot, despite having the same cell types, we may be able to start working to translate those mechanisms to mammals, she said. It is possible that certain regeneration pathways have been epigenetically silenced through evolution and we may be able to use modern advances in gene therapy techniques to unlock regenerative capacity in mammals.

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Dubai: Myra, J, a belly dancer working at a Dubai hotel, was unhappy that saddle bags on her thighs were making her performance less graceful and she feared she would be replaced in her job. So on a weekend, she checked into a leading aesthetic clinic and the surgeon trimmed the pockets of fat around her thighs, sculpting her body back into perfect shape. It took her a week to recover and get back to work, but she is delighted with her shapely thighs and feels happier than ever before.

Nina M., (52), always loved how beautiful her eyes were and how youthful her cheeks looked. However last year, as she got busy with her sons marriage preparations, she started to experience bouts of anxiety at the sight of slowly encroaching bags under her eyes and a slight droop in her cheeks. I wanted to look and feel my best and thought a filler and a round of botox were harmless indulgences. It took me just an hour at the clinic and the results were amazing. I am glad I was able to stop the onslaught of aging in time. Its beautiful to age gracefully, but we all do use creams and gels to delay the process. I think of these minor injectibles as tools in our make-up bag. I have used fillers and Botox twice since last year, combined with my beauty regimen. I feel it has given me not just confidence but also psychological boost. I would recommend it to everyone.

Anna M was a physical trainer but vexed with her body shape as she had a masculine build. This was affecting her work as most women were intimidated by her personality and she was losing self-confidence. Four years ago, she went in for breast implants and her life changed. People talk about getting addicted to cosmetic surgery. But that is not so. Most people approach a cosmetic surgeon only when they cannot deal with a physical issue themselves and just like one needs medicine when one is ill, cosmetic surgery acts as a solution to boost confidence and self-esteem. Look at how people have reclaimed their health with gastric bypass!

- Dr Sanjay Parashar, chairman, Scientific of the Emirates Plastic Surgery Society

Changing the world one person at a time and providing them with an incredible burst of confidence, aesthetic and cosmetic surgeons in the UAE have built a practice of reliability that can take as little as one hour to a day to transform your personality. Welcome to the multi-million dirham cosmetic surgery industry in the UAE that is the toast of medical tourism in the region, With a high footfall of Gulf and Asian medical tourists as well as resident expatriates, the industry has accelerated at a speed that is making Dubai be hailed as the new Beverly Hills of the Middle East.

Cosmetic or Plastic Surgery?

These are two different concepts. Cosmetic surgery refers to aesthetic surgery and revolves around enhancement of physical features of an individual and is elective. This includes procedures such as rhinoplasty, face and cheek enhancement, brow lifts, neck and eyelid lift, face peels, laser resurfacing, botox fillers, peels, laser hair removal, breast augmentation, tummy tucks, liposuction, hair implants and dental veneers.

Plastic surgery, on the other hand, is a surgical speciality dealing with life-saving procedures of re-construction of the face and body owing to congenital defects, disfigurement due to accident, trauma, burns, tumour removal due to diseases such as cancer. In most cases, plastic surgery is not elective.

Dh12b Medical tourism sales in 2018

Since the time pop stars began to inundate Instagram with images of their perfect bodies, dazzling smiles, flawless skin and enviable hair volume, elective procedures have become commonplace with teenagers as young as 13 who are going in for instant fixes. While some procedures require a couple of days of hospital stay and being out of circulation for a while, many quick fixes are carried out during lunch breaks in one-hour durations.

Highest Per Capita cosmetic surgeons in UAE

Dr Sanjay Parashar, chairman, Scientific of the Emirates Plastic Surgery Society, told Gulf News: Cosmetic surgery tops the list in medical tourism in Dubai and according to a 2015 report of Dubai Health Authority (DHA), Dubai has the highest number of cosmetic surgeons per capita in the region - about 50 specialists for a million people.

- Dr Zuhair Al Fardan, President of the Emirates Plastic Surgery

Dr Parashar added: The field has grown beyond expectations and much of the credit goes to the development of a world-class infrastructure in this field and the corresponding health regulations. Today, in Dubai, most Day Care Surgery centres where most of the plastic surgery procedures are carried out have the best international accreditations.

Dr Zuhair Al Fardan, President of the Emirates Plastic Surgery, said,Much of the advancement in plastic and cosmetic surgery is work in progress as surgeons are constantly upgrading themselves with techniques, technologies. The UAE is keeping abreast of the best that is taking place in the world. In the last five years or so, there have been tremendous advancements in cosmetic and plastic surgery in the UAE. We have the top plastic surgeons of the world come here to do surgeries and the UAE hosts two major international plastic surgery conferences each year.

Soaring revenues

With greater acceptance and broadening of scope for the discipline, it is evident that plastic surgery is a major revenue earner and places UAE as one of the leading medical tourism destinations in the region. From a price range of Dh150-250 for a filler to Dh40,000 for a detailed body sculpting procedure, these procedures are money-spinners.

Together, the plastic and cosmetic surgery is a multimillion dirham business in the UAE. While there are no exact figures available, safe estimates can be made, say surgeons. Lets take the emirate of Dubai. There are 30 hospitals in Dubai, of which 70 per cent are internationally accredited. The emirate aims to build 22 hospitals by 2020 - 18 private and 4 public hospitals. At least 50 per cent of these offer cosmetic and plastic surgery options. Besides that there are about 150 Day Care Surgery centres and 400 aesthetic clinics in Dubai. All of them offer a bouquet of cosmetic surgery procedures and their average annual revenue is between Dh4-6 million a year. If one were to compute that with the numbers of facilities including hospitals, the annual revenue from cosmetic surgery would run into many millions of dirhams annually.

High on medical tourism

Currently, Dubai aims to attract 500,000 medical tourists a year by end 2020. In a short priod of time, Dubai has managed to be ranked 17 among the top 25 global destinations for medical tourism and cosmetic surgery, along with fertility, orthopaedic, dental and wellness disciplines in the list of most-billed medical procedures.

As per statistics, about 46 per cent of the current medical tourists in Dubai come from Asian countries, 25 per cent from GCC and Arab countries and 13 per cent from African countries, and the remaining 16 per cent from other countries, mainly the UK and Commonwealth of Independent States (CIS) countries. In fact, 40 per cent of tourists who come to Dubai come only for medical tourism.

- Dr Francis Conroy, consultant plastic, cosmetic and reconstructive surgeon at the American Hospital, Dubai

Medical tourism sales topped Dh12 billion in 2018, with a 5.5 per cent overall increase in medical tourists. Dubai attracted a total of 640,542 international and domestic medical tourists in 2018 (51 per cent were international patients). European tourists consisting mostly of UK, French and Italian citizens, share 16 per cent of health and wellness tourists. A substantial medical tourism revenue, it is evident, is earned through plastic and cosmetic surgery.

Dr Francis Conroy, consultant plastic, cosmetic and reconstructive surgeon at the American Hospital, Dubai, remarked: American Hospital Dubai, is one of the few facilities offering both comprehensive reconstructive and cosmetic surgery services. Our plastic surgeons are fully trained in both reconstructive and cosmetic surgery so we see a wide-ranging case mix, from severe trauma cases to cancer cases and of course, those opting for cosmetic surgery.

The most popular cosmetic surgery is body contouring namely abdominoplasty and liposuction, sometimes combined with a breast lift the mommy make-over. Typically, these patients would be female, who done with having children and raising them, now wish to address the changes in their body. I also see a large number of male patients who want to correct problems associated with their chest with the help of liposuction, said Dr Conroy.

Non-surgical treatments (neuro-modulators, fillers, etc) are still very popular and I have seen a trend in that patients are starting with such treatments at an earlier age.

Given the prestigious reputation of the hospital and the Dubai governments plan to promote medical tourism, I have noticed a huge influx of patients from Africa, Nigeria and Ghana in particular. These patients come mainly for cosmetic surgery, knowing that they are in the hands of a highly qualified surgeon, in a safe, luxurious facility, with standards second to none, said Dr Conroy.

Top six cosmetic surgery procedures in town

The procedures can be divided into categories:

Does health insurance cover plastic surgery?

Dr Parashar said: Lumps, bumps, nerve and tendon transfer, skin transplant, etc, are all covered. Few people know that plastic surgery has a regenerative and reconstructive role to play in case of congenital and disease deformities. Reconstructive surgery such as correction of birth deformities such as a tuberous breast, cleft lip, hand deformities, skin transplant following burns, road trauma and breast augmentation and reconstruction following a mastectomy and rebuilding after a tumour resection is all covered under all leading health insurances. There is also new kinds of stem cell therapy being used to regenerate tissues and nerves especially in diabetic patients.

Know the regulations:

The DHA has made it mandatory for all Day Care Surgery Centres, most of who carry out aesthetic procedures, to have one leading international accreditation from Canada, US, UK or Australia. These accreditations were earlier mandatory for hospitals only, but from 2020, all Day Care Surgery centres compulsorily must have an international accreditation. This ensures that an independent, international medical body enforces global health standards to grant them certification and in case of a sentinel event, conducts its independent inquiry and downgrades these places in case of a serious lapse. DHA on its own has issued a 25-page manual on quality and regulations that is to be followed at all centres.

A close examination of the Day Care Surgery centres indicates several layers of quality control.

Pre surgery quality: This involves free consultation, especially in case of a second opinion or a first time patient seeking to enquire about a procedure based on his/her requirement. When a patient uploads a request on the website of a centre from anywhere in the world, the centre has to provide a detailed consultation free of charge.

Services available to a patient: Once the patient is convinced and comes in person to consult the doctor, quality is upheld in the pre-diagnostic tests that the patient has to undergo.

Infrastructure quality: DHA has graded Day Care Centres into A, B and C categories based on the level of medical facilities that can be accessed by a patient. Anaesthesia methods such as oral, epidural and general also help classify centres. For instance, hair transplant procedures can only be carried out in B and above grade clinics. Day Care Centres that conduct surgeries under general anaesthesia much be equipped with the Advance Cardiac Life Support (ACLS) with their surgeons and registered nurses being certified as trained in administering ACLS to a patient.

Patient safety protocol: There are very specific guidelines for patient safety and the doctor/surgeon must explain the procedure in detail to the patient and his/her family and obtain a written consent to go ahead after ascertaining that all risks and side-effects have been clearly explained to the patient.

Post-operative regulation: There are specific protocols for discharge of patients undergoing cosmetic surgery. Although ambulatory care means the patient has to be discharged within the same day, there is a specification about asking the patient to desist from long-distance travel, specific rehabilitative work to be carried out from the next day for which the patient has to be within Dubai and also specific instructions when an overseas patient is declared fit to fly out of the country. When a patient flies out, he or she is provided with a proper review and notes, with instructions for overseas rehabilitation protocol with reference notes for the rehabilitation instructor and instructions for medication and periodic reviews.

Accountability

The law is clear, said Dr Al Fardan, The DHA regulations constitutes an accountability committee and holds an enquiry to fix the liability. If the centre is found guilty, its licence can be suspended or cancelled depending on the extent of guilt. If the surgeon, anaesthesiologists, nurse and technicians are found guilty, their license to practice is suspended or cancelled. If the crime is lighter, then both the centre and the team are let off with serious warnings. In case of disability following a surgery, the team examines the extent of disability and calculates the financial compensation to the patient. In case of fatality following a surgery, the is provision to pay blood money.

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The global Collagen and gelatin market for regenerative medicine will grow at a CAGR of 8.5% from 2017 to 2022 to reach USD 709.9 million by 2022, according to the latest publication from Meticulous Research. The global collagen and gelatin market for regenerative medicine is driven by rising prevalence of chronic diseases, rapid growth in aging population, and increasing funding for R&D of regenerative medicines. However, growing use of alternate biomaterials inhibits the growth of this market to some extent.

The global collagen and gelatin market for regenerative medicine is mainly segmented by type (collagen and gelatin), by source (porcine, bovine, marine, and other), by application (orthopedics, cardiovascular, wound care, and other), and geography. Based on source, bovine collagen and gelatin held the largest share of the market in 2016, owing to their abundant availability and wide range of applications in the tendon reinforcement, hernia repair, skin & wound healing, and plastic & reconstructive surgery. Further, on the basis of application, orthopedics accounted for the major share of the global collagen and gelatin market for regenerative medicines in 2016, owing to the high prevalence of osteoporosis across the globe due to aging population, growing obesity, and a poor level of physical activity.

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Geographically, this market is segmented into North America (U.S. and Canada), Europe (Germany, France, U.K., Italy, Spain, and RoE), Asia Pacific (China, India, Japan, and RoAPAC), Latin America, and Middle East & Africa. North America commanded the largest share in the global collagen and gelatin market for regenerative medicines in 2016, followed by Europe and Asia-Pacific. The large share of this region is mainly attributed to the increasing prevalence of osteoporosis, chronic wounds, heart diseases; growing meat processing; availability of funding; and presence of many key players in this market. However, Asia Pacific region is expected to witness significant growth during the forecast period due to increasing burden of chronic diseases such as osteoporosis, diabetes, and heart diseases; and growing meat processing.

The key players operating in the global collagen and gelatin market for regenerative medicines are Collagen Solutions Plc (U.S.), Royal DSM (Netherlands), Symatese (France), NuCollagen LLC (U.S.), GELITA AG (Germany), Nitta Gelatin Inc. (Japan), Tessenderlo Group (Belgium), Vornia Biomaterials (Ireland), Advanced BioMatrix (U.S.), Jellagen Pty Ltd (U.K.), EnColl Corporation (U.S.), and XIAMEN HYFINE GELATIN CO., LTD. These vendors have employed various strategies to expand their product and application offerings, global footprint, and augment their market share.

TOP 10 COMPANIES IN COLLAGEN AND GELATIN MARKET FOR REGENERATIVE MEDICINE MARKET

Key questions answered in the report-

Which are the high growth market segments in terms of type, source, application, and regions/countries?

What is the historical market for collagen and gelatin for regenerative medicine across the globe?

What are the market forecasts and estimates from the period 2015-2022?

What are the major drivers, restraints, and opportunities in the global collagen and gelatin market for regenerative medicine?

Who are the major players in the global collagen and gelatin market for regenerative medicineand what share of the market do they hold?

Who are the major players in various countries and what share of the market do they hold?

What are the competitive landscapes and who are the market leaders by sub-region in the global collagen and gelatin market for regenerative medicine?

What are the recent developments in the global collagen and gelatin market for regenerative medicine?

What are the different strategies adopted by the major players in the global collagen and gelatin market for regenerative medicine?

What are the geographical trends and high growth regions/ countries?

Who are the local emerging players in the global collagen and gelatin market for regenerative medicine and how do they compete with the global players?

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R01DK081113, U01DK103152, P50CA127003; Cell Stem Cell

A case of reverse development: Dana-Farber scientists solve long-debated puzzle of how the intestine heals itself

Newswise BOSTON Deep within the lining of the human intestine lies the source of the organs ability to renew itself and recover from damage: intestinal stem cells (ISCs), lodged in pockets of tissue called crypts, generate the cells that continuously repopulate the intestinal lining. Even the stem cells themselves have a safety net: when theyre damaged, healthy replacements appear in less than a week.

For years, scientists have debated how the ISCs re-emergence occurs. Some have held that the intestine keeps a pool of ISCs on reserve a kind of backup-backup supply to replenish the cache of front-line ISCs that have been lost. Others have maintained that something more involuted is as work: The ISCs, like queen bees, give rise to more specialized, or differentiated, progeny in this case, daughter cells that form the inner lining of the intestine. When the ISCs are damaged, this school of thought held, the daughter cells reverse course and de-differentiate reverting into the ISCs from which they arose.

A new study by Dana-Farber Cancer Institute scientists comes down solidly on the latter option.

Published online today by the journalCell Stem Cell, the researchers found that ISCs and their daughter cells have a strikingly reciprocal relationship: under normal conditions, ISCs differentiate into daughter cells, and, if the ISCs are lost, the daughter cells simply reverse course and become ISCs. Our findings suggest that the restoration of intestinal stem cells occurs entirely by the process of de-differentiation, says the studys senior author, Ramesh Shivdasani, MD, PhD, of Dana-Farber, Brigham and Womens Hospital (BWH), and the Harvard Stem Cell Institute. We showed theres no need for a reserve set of ISCs.

Bolstering their findings, the researchers were also able to capture the de-differentiation process in real time. When cells begin to de-differentiate, they switch on a gene that that allows them to be isolated and collected with laboratory techniques, Shivdasani explains. Through this process, researchers were able to capture the cells along a continuum of de-differentiation. Shivdasani likens it to a baseball play in which a runner is tagged out between first and second base.

Heavy turnover

The intestine is one of just three tissues in the body, along with the skin and blood, in which cells are constantly turning over dying and being replaced by freshly made cells. They share this quality because they are the tissues most intimately in contact with material from the environment, and therefore with potentially harmful substances. The constant turnover, its thought, is a way to prevent toxic substances from having lasting effects on cells and their offspring.

The crypts that hold ISCs are, in a sense, misnamed. Far from being enclosures where dead cells are entombed, they are the sites where ISCs daily generate the billions of daughter cells that take the place of defunct intestinal cells.

One of the chief characteristics of ISCs is that they are extremely radiosensitive, or vulnerable to radiation. People exposed to high levels of radioactivity, in the form of nuclear fallout, for example, can suffer severe intestinal damage because the loss of ISCs halts production of cells to regenerate the damaged tissue. But if ISCs succumb easily to radiation, they also make a rapid return. Patients with radiation-induced intestinal damage who can be kept alive for a week often recover as their ISC levels bounce back.

To determine whether this rebound is due to a reserve stockpile of ISCs or to de-differentiation of daughter cells, Shivdasani and his collaborators performed a kind of time-lapse experiment. They treated a collection of ISC cells with the drug tamoxifen, which caused the cells and their offspring to become fluorescent. They waited 48 hours for the label to take hold, then killed the ISC cells. If the daughter cells were indeed de-differentiating, any ISC cells produced after that point would be fluorescent.Thats exactly what researchers found.

While scientists have been able to convert many kinds of differentiated cells into stem cells using laboratory techniques, Shivdasani and his colleagues discovery demonstrates that de-differentiation ismore than a curious act of nature; it is the principal means to restore damaged stem cell in the intestine. Its not known whether cells in other organs and tissues have this capability, but it remains an open avenue of investigation.

It also isnt clear how the crypt knows that stem cells have died and need to be replaced, Shivdasani remarks, or how the daughter cells receive the signal to de-differentiate. This is a subject were currently exploring.

The lead author of the new paper is Kazutaka Murata, PhD of Dana-Farber and BWH. Co-authors are Unmesh Jadhav, PhD, and Alessia Cavazza, PhD, of Dana-Farber and BWH; Shariq Madha, Justin Dean, Kai Wucherpfennig, MD, PhD, and Franziska Michor, PhD, of Dana-Farber; and Johan van Es, PhD, and Hans Clevers, MD, PhD, of Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre, Utrecht, the Netherlands. The research was supported by the National Institutes of Health (grants R01DK081113, U01DK103152, and P50CA127003) and gifts from the Lind family.

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Dana-Farber Cancer Institute is one of the worlds leading centers of cancer research and treatment. It is the only center ranked in the top 5 of U.S. News and World Reports Best Hospitals for both adult and pediatric cancer care.

Dana-Farbers mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. We provide the latest in cancer for adults through Dana-Farber/Brigham and Women's Cancer Care and for children through Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

Dana-Farber is dedicated to a unique and equal balance between cancer research and care, translating the results of discovery into new treatments for patients locally and around the world.

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A case of reverse development: Dana-Farber scientists solve long-debated puzzle of how the intestine heals itself - Newswise

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(BPT) - For many people with cancer and other life-threatening diseases, stem cell transplants provide hope and can impact the course of the disease, but they also come with risks. One of those risks is graftversushost disease (GVHD).

What is GVHD?

GVHD is a potentially life-threatening condition that can occur after an allogeneic stem cell transplant from a donor, in which the donated cells initiate an immune response and attack the recipient's organs and tissues. There are two major forms of GVHD, acute and chronic, that can affect multiple organ systems including the skin, gastrointestinal (digestive) tract and liver.

Although the exact incidence of GVHD is unknown, it is estimated that up to 70% of stem cell transplant recipients will develop either acute or chronic GVHD, resulting in significant morbidity and mortality. Due to these concerning statistics, health care experts and the entire GVHD community are calling for additional research and support.

People with GVHD and their caregivers face a multitude of challenges, often including limited support, minimal information and few treatment options. Its time to change the future for those living with GVHD.

New award inspires the GVHD community

The Incyte Ingenuity Award aims to encourage innovation in GVHD care and other serious diseases. As part of the award, one unique proposal that addresses a critical unmet need in the GVHD community will be awarded up to $100,000 for the proposed initiative to be developed and executed. Specific initiatives may include patient and/or professional educational programs, policy-focused activities as well as awareness and support campaigns.

Incyte wanted to create a community driven program dedicated to improving the lives of patients with serious diseases, such as GVHD, which can be difficult to treat and have a devastating impact on the lives of patients, says Barry Flannelly, Pharm.D., Executive Vice President and General Manager, U.S., Incyte. Through this award, we hope to spark creativity and innovation, resulting in impactful and actionable initiatives for the GVHD community.

Get involved to make a difference

Submissions are accepted from nonprofit 501(c)(3), patient, policy and caregiver organizations, as well as health care providers and midlevel or junior faculty who submit under their health care organizations. To apply, visit http://www.IncyteIngenuityAward.com and submit an online application featuring a summary of the proposed initiative. The application window is now open and will close April 30, 2020.

All applications will be reviewed and evaluated by an independent judging panel that will select the top three entries, who will then be asked to submit a more detailed proposal of their initiative. The final award recipient will be announced in August of 2020. Apply now!

MAT-INC-00717 02/20

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Health insights: What is GVHD and why is innovation so critical? - Eagle & Times

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The road into Batlow is littered with the dead.

In the smoky, gray haze of the morning, it's hard to make out exactly what Matt Roberts' camera is capturing. Roberts, a photojournalist with the Australian Broadcasting Corporation, keeps his lens focused on the road as he rolls into the fire-ravaged town 55 miles west of Canberra, Australia's capital. At the asphalt's edge, blackened livestock carcasses lie motionless.

The grim scene, widely shared on social media, is emblematic of the impact the 2019-20 bushfire season has had on Australia's animal life. Some estimates suggest "many, many billions" of animals have been killed, populations of endemic insects could be crippled and, as ash washes into riverways, marine life will be severely impacted. The scale of the bushfires is so massive, scientists are unlikely to know the impact on wildlife for many years.

But even before bushfires roared across the country, Australia's unique native animals were in a dire fight for survival. Habitat destruction, invasive species, hunting and climate change have conspired against them. Populations of native fauna are plummeting or disappearing altogether, leaving Australia with an unenviable record: It has the highest rate of mammal extinctions in the world.

A large share of Australia's extinctions have involved marsupials -- the class of mammals that includes the nation's iconic kangaroos, wallabies, koalas and wombats. A century ago, the Tasmanian tiger still padded quietly through Australia's forests. The desert rat-kangaroo hopped across the clay pans of the outback, sheltering from the sun in dug-out nests.

Now they're gone.

Australia's 2019-20 bushfire season has been devastating for wildlife.

In a search for answers to the extinction crisis, researchers are turning to one lesser-known species, small enough to fit in the palm of your hand: the fat-tailed dunnart. The carnivorous mouse-like marsupial, no bigger than a golf ball and about as heavy as a toothbrush, has a tiny snout, dark, bulbous eyes and, unsurprisingly, a fat tail. It's Baby Yoda levels of adorable -- and it may be just as influential.

Mapping the dunnart's genome could help this little animal become the marsupial equivalent of the lab mouse -- a model organism scientists use to better understand biological processes, manipulate genes and test new approaches to treating disease. The ambitious project, driven by marsupial geneticist Andrew Pask and his team at the University of Melbourne over the last two years, will see scientists take advantage of incredible feats of genetic engineering, reprogramming cells at will.

It could even aid the creation of a frozen Noah's Ark of samples: a doomsday vault of marsupial cells, suspended in time, to preserve genetic diversity and help prevent further decline, bringing species back from the brink of extinction.

If that sounds far-fetched, it isn't. In fact, it's already happening.

Creating a reliable marsupial model organism is a long-held dream for Australian geneticists, stretching back to research pioneered by famed statistician Ronald Fisher in the mid-20th century. To understand why the model is so important, we need to look at the lab mouse, a staple of science laboratories for centuries.

"A lot of what we know about how genes work, and how genes work with each other, comes from the mouse," says Jenny Graves, a geneticist at La Trobe University in Victoria, Australia, who has worked with marsupials for five decades.

The mouse is an indispensable model organism that shares many genetic similarities with humans. It has been key in understanding basic human biology, testing new medicines and unraveling the mysteries of how our brains work. Mice form such a critical part of the scientific endeavor because they breed quickly, have large litters, and are cheap to house, feed and maintain.

The lab mouse has been indispensable in understanding physiology, biology and genetics.

In the 1970s, scientists developed a method to insert new genes into mice. After a decade of refinement, these genetically modified mice (known as "transgenic mice") provided novel ways to study how genes function. You could add a gene, turning its expression up to 11, or delete a gene entirely, shutting it off. Scientists had a powerful tool to discover which genes performed the critical work in reproduction, development and maturation.

The same capability does not exist for marsupials. "At the moment, we don't have any way of manipulating genes in a devil or a kangaroo or a possum," says Graves. Without this capability, it's difficult to answer more pointed questions about marsupial genes and how they compare with mammal genes, like those of mice and humans.

So far, two marsupial species -- the Tammar wallaby and the American opossum -- have been front and center of research efforts to create a reliable model organism, but they both pose problems. The wallaby breeds slowly, with only one baby every 18 months, and it requires vast swaths of land to maintain.

The short-tailed opossum might prove an even more complicated case. Pask, the marsupial geneticist, says the small South American marsupial is prone to eating its young, and breeding requires researchers to sift through hours of video footage, looking for who impregnated whom. Pask also makes a patriotic jab ("they're American so we don't like them") and says their differences from Australian marsupials make them less useful for the problems Australian species face.

But the dunnart boasts all the features that make the mouse such an attractive organism for study: It is small and easy to house, breeds well in captivity and has large litters.

"Our little guys are just like having a mouse basically, except they have a pouch," Pask says.

Pask (front) and Frankenberg inspect some of their dunnarts at the University of Melbourne.

A stern warning precedes my first meeting with Pask's colony of fat-tailed dunnarts.

"It smells like shit," he says. "They shit everywhere."

I quickly discover he's right. Upon entering the colony's dwellings on the third floor of the University of Melbourne's utilitarian BioSciences building, you're punched in the face by a musty, fecal smell.

Pask, a laid-back researcher whose face is almost permanently fixed with a smile, and one of his colleagues, researcher Stephen Frankenberg, appear unfazed by the odor. They've adapted to it. Inside the small room that houses the colony, storage-box-cages are stacked three shelves high. They're filled with upturned egg cartons and empty buckets, which work as makeshift nests for the critters to hide in.

Andrew Pask

Frankenberg reaches in without hesitation and plucks one from a cage -- nameless but numbered "29" -- and it hides in his enclosed fist before peeking out of the gap between his thumb and forefinger, snout pulsing. As I watch Frankenberg cradle it, the dunnart seems curious, and Pask warns me it's more than agile enough to manufacture a great escape.

In the wild, fat-tailed dunnarts are just as inquisitive and fleet-footed. Their range extends across most of southern and central Australia, and the most recent assessment of their population numbers shows they aren't suffering population declines in the same way many of Australia's bigger marsupial species are.

Move over, Baby Yoda.

As I watch 29 scamper up Frankenberg's arm, the physical similarities between it and a mouse are obvious. Pask explains that the dunnart's DNA is much more closely related to the Tasmanian devil, an endangered cat-sized carnivore native to Australia, than the mouse. But from a research perspective, Pask notes the similarities between mouse and dunnart run deep -- and that's why it's such an important critter.

"The dunnart is going to be our marsupial workhorse like the mouse is for placental mammals," Pask says.

For that to happen, Pask's team has to perfect an incredible feat of genetic engineering: They have to learn how to reprogram its cells.

To do so, they collect skin cells from the dunnart's ear or footpad and drop them in a flask where scientists can introduce new genes into the skin cell. The introduced genes are able to trick the adult cell, convincing it to become a "younger," specialized cell with almost unlimited potential.

The reprogrammed cells are known as "induced pluripotent stem cells," or iPS cells, and since Japanese scientists unraveled how to perform this incredible feat in 2006, they have proven to be indispensable for researchers because they can become any cell in the body.

"You can grow them in culture and put different sorts of differentiation factors on them and see if they can turn into nerve cells, muscle cells, brain cells, blood vessels," Pask explains. That means these special cells could even be programmed to become a sperm or an egg, in turn allowing embryos to be made.

Implanting the embryo in a surrogate mother could create a whole animal.

It took about 15 minutes to get this dunnart to sit still.

Although such a technological leap has been made in mice, it's still a long way from fruition for marsupials. At present, only the Tasmanian devil has had iPS cells created from skin, and no sperm or egg cells were produced.

Pask's team has been able to dupe the dunnart's cells into reverting to stem cells -- and they've even made some slight genetic tweaks in the lab. But that's just the first step.

He believes there are likely to be small differences between species, but if the methodology remains consistent and reproducible in other marsupials, scientists could begin to create iPS cells from Australia's array of unique fauna. They could even sample skin cells from wild marsupials and reprogram those.

Doing so would be indispensable in the creation of a biobank, where the cells would be frozen down to -196 degrees Celsius (-273F) and stored until they're needed. It would act as a safeguard -- a backup copy of genetic material that could, in some distant future, be used to bring species back from the edge of oblivion, helping repopulate them and restoring their genetic diversity.

Underneath San Diego Zoo's Beckman Center for Conservation Research lies the Frozen Zoo, a repository of test tubes containing the genetic material of over 10,000 species. Stacked in towers and chilled inside giant metal vats, the tubes contain the DNA of threatened species from around the world, suspended in time.

It's the largest wildlife biobank in the world.

"Our goal is to opportunistically collect cells ... on multiple individuals of as many species as we can, to provide a vast genetic resource for research and conservation efforts," explains Marlys Houck, curator at the Frozen Zoo.

The Zoo's efforts to save the northern white rhino from extinction have been well publicized. Other research groups have been able to create a northern white rhino embryo in the lab, combining eggs of the last two remaining females with frozen sperm from departed males. Scientists propose implanting those embryos in a surrogate mother of a closely related species, the southern white rhino, to help drag the species back from the edge of oblivion.

For the better part of a decade, conservationists have been focused on this goal, and now their work is paying off: In the "coming months," the lab-created northern white rhino embryo will be implanted in a surrogate.

Sudan, the last male northern white rhinoceros, was euthanized in 2018.

Marisa Korody, a conservation geneticist at the Frozen Zoo, stresses that this type of intervention was really the last hope for the rhino, a species whose population had already diminished to just eight individuals a decade ago.

"We only turn to these methods when more traditional conservation methods have failed," she says.

In Australia, researchers are telling whoever will listen that traditional conservation methods are failing.

"We've been saying for decades and decades, many of our species are on a slippery slope," says John Rodger, a marsupial conservationist at the University of Newcastle, Australia, and CEO of the Fauna Research Alliance, which has long advocated for the banking of genetic material of species in Australia and New Zealand.

In October, 240 of Australia's top scientists delivered a letter to the government detailing the country's woeful record on protecting species, citing the 1,800 plants and animals in danger of extinction, and the "weak" environmental laws which have been ineffective at keeping Australian fauna alive.

Institutions around Australia, such as Taronga Zoo and Monash University, have been biobanking samples since the '90s, reliant on philanthropic donations to stay online, but researchers say this is not enough. For at least a decade, they've been calling for the establishment of a national biobank to support Australia's threatened species.

John Rodger

"Our real problem in Australia ... is underinvestment," Rodger says. "You've got to accept this is not a short-term investment."

The current government installed a threatened-species commissioner in 2017 and committed $255 million ($171 million in US dollars) in funding to improve the prospects of 20 mammal species by 2020. In the most recent progress report, released in 2019, only eight of those 20 were identified as having an "improved trajectory," meaning populations were either increasing faster or declining slower compared to 2015.

A spokesperson for the commissioner outlined the $50 million investment to support immediate work to protect wildlife following the bushfires, speaking to monitoring programs, establishment of "insurance populations" and feral cat traps. No future strategies regarding biobanking were referenced.

Researchers believe we need to act now to preserve iconic Australian species like the koala.

In the wake of the catastrophic bushfire season and the challenges posed by climate change, Australia's extinction crisis is again in the spotlight. Koalas are plastered over social media with charred noses and bandaged skin. On the front page of newspapers, kangaroos bound in front of towering walls of flame.

Houck notes that San Diego's Frozen Zoo currently stores cell lines "from nearly 30 marsupial species, including koala, Tasmanian devil and kangaroo," but that's only one-tenth of the known marsupial species living in Australia today.

"Nobody in the world is seriously working on marsupials but us," Rodger says. "We've got a huge interest in maintaining these guys for tourism, national icons... you name it."

There's a creeping sense of dread in the researchers I talk to that perhaps we've passed a tipping point, not just in Australia, but across the world. "We are losing species at an alarming rate," says Korody from the Frozen Zoo. "Some species are going extinct before we even know they are there."

With such high stakes, Pask and his dunnarts are in a race against time. Perfecting the techniques to genetically engineer the tiny marsupial's cells will help enable the preservation of all marsupial species for generations to come, future-proofing them against natural disasters, disease, land-clearing and threats we may not even be able to predict right now.

Pask reasons "we owe it" to marsupials to develop these tools and, at the very least, biobank their cells if we can't prevent extinction. "We really should be investing in this stuff now," he says. He's optimistic.

In some distant future, years from now, a bundle of frozen stem cells might just bring the koala or the kangaroo back from the brink of extinction.

And for that, we'll have the dunnart to thank.

Originally published Feb. 18, 5 a.m. PT.

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Building a 'doomsday vault' to save the kangaroo and koala from extinction - CNET

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Understanding the genetic causes of rare diseases supports drug development. Credit: Shutterstock.

Developing drugs to treat rare diseases is fraught with challenges; these range from trying to recruit from tiny patient populations to fill much-need clinical trials to the complex reimbursement landscape for these innovative, and often bespoke, therapies. However, as scientists improve their understanding of the genetic causes of many rare conditions and regulators explore new reimbursement options, pharma companies and smaller biotech firms are increasingly being empowered to address more of these tricky indications.

In this context, could 2020 be a breakthrough year for patients with rare diseases? Here are three case studies of companies on the verge of having treatments for rare diseases approved Rocket and Fanconi anaemia, PTC Therapeutics and aromatic l-amino acid decarboxylase (AADC) deficiency and, finally, Amryt and epidermolysis bullosa.

Fanconi anaemia (FA) is a rare paediatric inherited diseasecharacterised by bone marrow failure and predisposition to cancer, in the words of Rocket Pharmas CEO Gaurav Shah. Caused by a mutation in the FANC genes, patients with Fanconi experience bone marrow failure as they are unable to create new blood cells.

The current standard of care for Fanconi is a stem cell transplant, but Shah explains the risks involved with these pioneering procedures.

While these transplants do prolong patients lives, the procedure is incredibly difficult and is associated with a high potential for graft-versus-host disease, he says. Stem cell transplants can also lead to an even higher risk of head and neck cancer risk for Fanconi patients; almost everyone with FA who undergoes this procedure dies in their 30s.

Rocket wants to change this situation with its lentiviral vector gene therapy, RP-L102. It is specifically for Fanconi-A, which Shah explains is the most common form of the disease. He adds that the therapy contains patient-derived haematopoietic stem cells that have been generally modified to contain a functional copy of FANCA gene, a mutation which causes Fanconi-A.

RP-L102 is currently in a global registrational Phase IIA study, which has been efficacious and safe in patients so far. The data demonstrate that a single dose of RP-L102 leads to both genetic and functional correction as measured by a progressive increase in corrected peripheral blood and bone marrow cells, says Shah. Most importantly, this treatment can be administered without a conditioning regimen [of chemotherapy and radiation]. [This] means we may be able to treat patients as a preventative measure before bone marrow failure occurs, like a vaccine, with a single dose administration early in life.

Based on these promising signals, RP-L102 has received all accelerated regulatory tools from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The company is hoping to complete its biologics license applications and marketing authorisation applications (MAA) to the two regulators within the next few years.

To overcome challenges facing Rocket in the development of RP-L102, Shah explains the company worked to improve upon its own expertise in rare diseases by working with world-class research and development partners, as well immersing itself within patient communities to learn more about their treatment needs.

Slightly further along the drug approval journey is PTC Therapeutics AADC deficiency drug, PTC-AADC, for which the company recently submitted an MAA to the EMA. The company expects full EMA approval towards the end of 2020 and to treat the first patients either in the first or second quarter of 2021.

PTC acquired PTC-AADC, alongside other gene therapy assets, when it bought rare central nervous system-focused Agilis Biotherapeutics in July 2018, PTCs EMEA and Asia Pacific senior vice-president and general manager Adrian Haigh explains.

AADC deficiency is a rare condition caused by a mutation in the DDC gene, which leads to issues with the AADC enzyme and subsequent reductions in the production of dopamine. Children suffering with AADC deficiency fail to reach neurological and development milestones and have a high risk of death early in life. The only current approach to treating the condition is through dopamine agonists, which Haigh notes are largely ineffective.

The particular approach developed by Agilis, [which is] unlike other forms of gene therapy, involves delivering a very small dose of gene therapy directly into the affected, post-mitotic cells, Haigh says. The rationale is that once youve delivered the drug to post-mitotic cells, which are not dividing, it is going to stay there for a long time.

Other advantages include a reduced chance of significant immune reaction and since the dose is smaller, the treatment could overcome some of the manufacturing issues facing other gene therapies. PTC has decided to bring PTC-AADCs manufacturing in house so they are not reliant on third parties schedules and capacities.

PTCs MAA for its AADC deficiency gene therapy is based on two clinical trials of 26 patients in total. Haigh explains the company has mapped motor milestones, and he noted that in advisory boards with payers theyve been incredibly impressed by our videos showing children progressing from lying flat on their backs to walking around.

He notes that in this case, it is certainly not ethical to drill a hole in a patients head and inject a virus containing a placebo and instead PTC has successfully completed a single-arm trial by comparing with patients natural history. Regulators need to be open to novel clinical trial design, particularly in rare diseases where you have ethical problems, Haigh argues.

The company had to abandon a previous drug in development because they could not agree an economic and deliverable clinical trial design with the FDA.

One of the main challenges that faced PTC in the development of PTC-AADC was diagnosis. Haigh explains they found a lot of patients have been misdiagnosed with either cerebral palsy or epilepsy so the company launched a free genetic testing programme. This also allowed them to find patients to recruit into the trial and estimate the number of patients with AADC deficiency who might be able to benefit from this gene therapy.

Epidermolysis bullosa (EB) is a group of rare skin conditions caused by genetic mutations in the genes that encode for the proteins of the skin, particularly in collagen VII.

There are currently no approved treatments for this condition, EB charity DEBRAs UK branch director of research Caroline Collins notes the condition is managed by regular changing of dressings and the lancing of blisters.

EB is characterised by blisters and wounds on the skin; these wounds are extremely painful and can cover huge areas of the patients body, such as their whole back or entire legs. However, Collins explains these are not like the kinds of wounds you get with ulcers or burns, and they move continuously.

As well as making it incredibly challenging for patients to deal with these never-healing wounds, it also makes it difficult for drug developers to find and establish accepted clinical trial endpoints centred on wound healing. DEBRA is therefore advocating for natural history to be considered in clinical trial designs, Collins explains.

Despite these challenges, UK drug company Amryt is hoping to submit authorisation applications to the FDA and EMA by the end of 2021 for its EB drug, AP101. The company has repurposed the topical gel created for burns wounds to treat EB. It is made from a combination of an extract from the bark of the birch tree and pure sunflower oil, the companys chief medical officer Dr Mark Sumeray explains.

AP101 is currently being studied in a Phase III study Amryt claim this is the biggest global EB trial ever undertaken and has been granted rare paediatric disease designation from the FDA.

Although the current results are blinded, Sumeray explains a recent analysis by an independent data monitoring board found that the firm only needed to increase the number of patients slightly, suggesting that at this point in time, the data would have looked encouraging. Too small a patient population makes it hard for efficacy to be statistically significant.

Since Amryts AP101 may be the first drug approved for EB, Collins emphasises it is important that the company has productive conversations with regulators about the specific challenges of EB. This will help to set the ground for others to follow and further transform the lives of EB patients.

It is clear that Amryt is committed to EB because the company in-licensed a second EB candidate, a topical gene therapy called AP103 in 2018.

Sumeray explains: We have invested a lot of time and effort in the development, not only of the lead product, but also of relationships with physicians and scientists working in EB. If we can figure out how to successfully bring products to the market and have them reimbursed, then all of that knowledge can applied again.

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Rare disease outlook 2020: three therapies set to make waves this year - pharmaceutical-technology.com

Skin Stem Cells Comments Off on Rare disease outlook 2020: three therapies set to make waves this year – pharmaceutical-technology.com | February 20th, 2020

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to enfortumab vedotin-ejfv (Padcev; Astellas Pharma and Seattle Genetics) in combination with Mercks (known as MSD outside the United States and Canada) anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.

It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020. [1] Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. [2] Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide. [3]

The recommended first-line treatment for patients with advanced urothelial cancer is cisplatin-based chemotherapy. For patients who are unable to receive cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens. [4]

Conditionally approvedEnfortumab vedotin-ejfv, a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, was conditionally approved by the FDA in December 2019 based on the Accelerated Approval Program. [5][6]

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

With seven approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.

Continued approval for enfortumab vedotin-ejfv in combination with pembrolizumab for the treatment of patients with advanced or metastatic urothelial cancer may be contingent upon verification and description of clinical benefit in confirmatory trials. [5]

The drug is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.

Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). [5]

Breakthrough therapyThe Breakthrough Therapy process is designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. The designation is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. In the case of enfortumab vedotin, the designation was based on the initial results from Phase Ib/II EV-103 Clinical Trial.

The FDAs Breakthrough Therapy designation reflects the encouraging preliminary evidence for the combination of enfortumab vedotin and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options, said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.

We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.

This is an important step in our investigation of enfortumab vedotin in combination with pembrolizumab as first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy, said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.

Based on encouraging early clinical activity, we recently initiated a phase III trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.

Clinical trialThe Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the Phase Ib/II trial, EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy-treated in the first-line setting with enfortumab vedotin-ejfv in combination with pembrolizumab.

The initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019 Congress, and updated findings at the 2020 Genitourinary Cancers Symposium.

EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of PADCEV alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive, locally advanced and first- and second-line metastatic urothelial cancer.

Adverse eventsSerious adverse reactions occurred in 46% of patients treated with enfortumab vedotin-ejfv. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Discontinuing treatmentAdverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Specific recommendations

HyperglycemiaHyperglycemia occurred in patients treated with enfortumab vedotin-ejfv, including death and diabetic ketoacidosis (DKA), in patients with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C 8% were excluded.

Physicians are recommended to closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia and, if blood glucose is elevated (>250 mg/dL), withhold the drug.

Peripheral neuropathyPeripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Two percent (2%) of patients experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with enfortumab vedotin-ejf with or without preexisting peripheral neuropathy.

The median time to onset of Grade 2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement.

Physicians should:

Occular disordersOcular disorders occurred in 46% of the 310 patients treated with enfortumab vedotin-ejf. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with enfortumab vedotin-ejf.

The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2).

Physicians should monitor patients for ocular disorders and consider:

Skin reactionsSkin reactions occurred in 54% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Twenty-six percent (26%) of patients had a maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3).

Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement.

Physicians should monitor patients for skin reactions, and consider:

Infusion site extravasationSkin and soft tissue reactions secondary to extravasation have been observed after the administration of enfortumab vedotin-ejf. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed.

Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation.

Physicians should ensure adequate venous access prior to starting enfortumab vedotin-ejf and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicityEnfortumab vedotin-ejf can cause fetal harm when administered to a pregnant woman.

Physicians should advise patients of the potential risk to the fetus and advise female patients of reproductive potential to use effective contraception during enfortumab vedotin-ejf treatment and for 2 months after the last dose. At the same time, they should advise male patients with female partners of reproductive potential to use effective contraception during treatment with enfortumab vedotin-ejf and for 4 months after the last dose.

Clinical trialA Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) NCT03288545

References[1] American Cancer Society. Cancer Facts & Figures 2020. Online. Last accessed on January 23, 2020.[2] American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. Last accessed on January 23, 2020.[3] International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed on January 23, 2020.[4] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. Online. Last accessed on January 23, 2020.[5] Enfortumab vedotin-ejfv (Padcev; Astellas Pharma [package insert]. Northbrook, IL)[6] Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

A version of this article was first published in ADC Review | Journal of Antibody-drug Conjugates.

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Combination Enfortumab Vedotin + Pembrolizumab Granted Breakthrough Therapy in Bladder Cancer - OncoZine

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On August 23, 2019, the FamilieSCN2A Foundation held their biennial SCN2A Professional and Family meeting, in Seattle, Washington. The gathering brought together 37 families of individuals with mutations in the SCN2A gene, 60 investigators, eight clinicians and five industry groups that conduct research and/or clinical work on conditions related to this genetic change. A number of SFARI scientists and staff also attended the event.

The SCN2A family meeting was one of many events that family organizations of rare, neurodevelopmental disorders organized last summer. These meetings help families connect with others similarly affected as well as professionals working to better understand these conditions and develop new therapeutics. SFARI often attends and facilitates research opportunities carried on at these events.

SCN2A is a high-confidence autism risk gene, which encodes a subunit of a sodium channel in the brain called Nav1.2. When the channel malfunctions, conditions like epilepsy and autism follow. As part of its mission to understand the genetics and neurobiological underpinnings of autism, SFARI has awarded about $3 million for research on SCN2A, and some of this research was presented at the meeting. SFARI also supports a genetics first initiative called Simons Searchlight (formerly known as Simons VIP), which enrolls people with a genetic diagnosis showing rare genetic changes associated with autism and related neurodevelopmental conditions, such as SCN2A.

Many stories that may reflect the different ways SCN2A can be disabled were told at the meeting. One child had his first seizure when he was days old, and now spends many of his days irritable and immobilized by dystonia. Another developed normally until his first seizure as a toddler, which seemed to wipe out all of his skills; his milestones are now hard won in the face of continuing seizures and an autism diagnosis. Another had a sudden regression at 1 year of age, and after a misdiagnosis and seizure medication, she goes to a school for children with autism. Still another suffered from relentless seizures, which robbed her of speech; she died last year at the age of 12.

So far, about 300 different variants of the SCN2A gene have beendocumented, and the functional consequences of many are unclear. Some researchers have developed high-throughput experiments to systematically test each of thesevariants, and to screen compounds that could normalize their function2. Another approach may use genetherapy to boostexpression of the remaining good copy of SCN2A. Either way, finding appropriate in vitro testing grounds for these SCN2A variants is essential and may help personalize treatment approaches or identify more homogeneous patient groups for drug trials.

The meeting also underscored the power of family gatherings to push the science ahead. Investigators could see multiple examples of a rare genetic condition and engage new participants in research studies such as The Investigation of Genetic Exome Research (TIGER), a project of the University of Washington that compares phenotypes of single-gene conditions. In turn, families had the opportunity to express their concerns to scientists and infuse the research proceedings with urgency.

My biggest takeaway from this years conference was the mutual inspiration between the scientists and the families, says Leah Schust, meeting organizer and executive director of the FamilieSCN2A Foundation. Her son has a mutation in SCN2A.

Meeting the researchers working on a cure for our kids motivates us to fight on, Schust says. Then the scientists all say that meeting the families inspires them to go back to their labs and work even harder.

Family focus. The family meeting helped researchers reconsider what would be meaningful clinical endpoints for potential treatments. Schust says that most researchers and industry groups had thought seizure control was the most important issue. After listening to us, they realized that quality of life, movement disorders and autonomic dysfunction are higher on our list of where we would like to see improvement, she says.

When SCN2A mutations were first linked to autism, the gene stood out because it encodes a relatively well-understood protein, unlike many of the other identified genes. Nav1.2 is a voltage-gated channel found exclusively on excitatory neurons in the brain, where it controls the flow of sodium ions into the neuron, and thus its propensity for firing action potential. Experiments have revealed detailed pictures of Nav1.2s structure3, and known drugs alter its function4.

SCN2A also stands out because of its high recurrence rate in autism: unlike other autism genes, SCN2A is mutated with somewhat regular frequency5 (Figure 1).

Just as understanding why a car wont start is critical to fixing it, researchers need to understand how these SCN2A mutations alter the Nav1.2 channel. A current model1 posits that some mutations are gain-of-function, rendering the channel too active and the brain hyperexcitable, leading to infantile epilepsy; conversely, loss-of-function mutations reduce excitability and seem associated with autism and/or intellectual disability, as well as childhood-onset (as opposed to neonatal) seizures.

Yet the functional consequences of most SCN2A mutations remain unknown, and some may not fall neatly into a loss-of-function or gain-of-function category. A way of making sense of these mutations may come from looking at the working parts of Nav1.2, said Arthur Campbell of the Broad Institute of MIT and Harvard. For example, missense SCN2A variants linked to epilepsy seem to hit the channel randomly. But when marking their location on a crystal structure model of the channel, the missense variants cluster in several places: on the voltage sensor, on the linker helix responsible for conveying voltage sensor movement to the channel pore, on an area thought to interact with the beta-subunits involved in chaperoning the channel to the right place, and on the inactivation gate, which closes the pore off from sodium ion flow. He suggested that this knowledge, combined with the structural similarities between all sodium channels, may help drug development for SCN2A-related conditions.

High-throughput systems that can assay hundreds of cells at a time are helping researchers systematically explore SCN2A mutation, explained SFARI Investigator Al George of Northwestern University. While conventional electrophysiology would require weeks of work to characterize a single SCN2A variant, Georges group uses an automated patch-clamp system that can characterize multiple variants transfected into non-neuronal cell lines in a day. Using this system, two variants associated with neonatal seizures both exhibited an exceptional willingness to activate and a slowness to inactivate, which are properties consistent with a gain-of-function interpretation.

The high-throughput set up also promises to expedite the hunt for drugs to normalize SCN2A function: George described a 384-well plate design that allows measurement of the effects of two different drugs, at four different concentrations, on the SCN2A variant and control channels simultaneously. A known drug (carbamazepine) and an experimental drug (PRX-330) shifted channel inactivation to more hyperpolarized voltages, which could help quiet channels with gain-of-function mutations.

To narrow in on potentially therapeutic compounds, Jeff Cottrell and colleagues at the Broad Institute of MIT and Harvard have come up with a two-stage screen to find small molecule activators or inhibitors of Nav1.2 channels. First, compounds are initially tested on non-neural cells transfected with Nav1.2 sodium channels and potassium channels, which enables them to spike. The cells in 384-well plates are stimulated in parallel, and voltage-sensitive dyes give a readout of spiking activity; remarkably, Cottrells system allows data collection from up to 96 wells simultaneously. Any compounds that modulate spiking would then be subjected to the second stage, in a high-throughput electrophysiology assay similar to that described by George. Compounds with helpful mechanisms would then be tested for selectivity for Nav1.2 versus other sodium channels. A selective compound would then be tested in neurons, first in vitro then in vivo. This step-wise process has identified an activating compound that makes Nav1.2 more likely to open at rest and has potent effects on action potentials in brain slices and on electroencephalogram (EEG) traces from mice engineered to carry a disabled copy of SCN2A; however, Cottrell said this particular compound is not a therapeutic candidate in part because it broadens the action potential in a way that could promote seizures. A full screen is underway, and so far has identified 378 modulators from a library of 77,000 compounds.

Beyond academia, J.P. Johnson Jr. of Xenon in Burnaby, British Columbia, discussed the companys work to create sodium channel inhibitors for treating epilepsy. To obtain selective compounds, the group targets the voltage-sensing domain because its structure is the most diverse region of sodium channels. Xenon uses a trial-and-error method to optimize sodium channel inhibitor potency and selectivity. The methodical process has yielded some interesting compounds, including both selective Nav1.6 inhibitors and dual Nav1.6 and Nav1.2 inhibitors. Both quashed spiking in mouse excitatory pyramidal neurons, which contain only Nav1.2 and Nav1.6, but they did not alter spiking in Nav1.1-containing inhibitory neurons. A Nav1.6 selective inhibitor, XEN901, is currently undergoing safety trials in humans.

Kathrin Meyer of Nationwide Childrens Hospital in Columbus, Ohio, addressed the possibility of using gene therapy to normalize malfunctioning Nav1.2 channels. Meyer has been involved in several gene-therapy trials for neuromuscular disorders, including a successful one for infant-onset spinal muscular atrophy type6. Gene therapy for brain diseases was spurred by the discovery of adeno-associated virus 9 (AAV9), which can cross the bloodbrain barrier to deliver genetic material to the central nervous system. AAV9 is small, cannot replicate, does not integrate into host DNA and seems not to cause disease in humans. In considering gene therapy for SCN2A-related conditions, Meyer emphasized an approach that adds back a working copy of the gene, thus sidestepping the need for gene editing to make mutation-specific corrections. Such a treatment would only apply to those with loss-of-function mutations.

The large size of the SCN2A gene precludes its delivery by AAV9, however. As a workaround, Meyer suggested that SCN2As mRNA transcript could be targeted in an attempt to replace only the affected area of the mRNA. So far, such strategies have not been very efficient, but there are new ideas that might address some of the difficulties. Because access to tissue samples of patients with neurological disorders is limited, the development and testing of new therapies is complicated. Meyer suggested developing gene therapies in vitro using neurons reprogrammed from skin cells of patients. This might help identify which patients would react best to a certain treatment. There is likely not a one-fit-for-all situation, she said.

SFARI deputy scientific director John Spiro underscored the need for in vitro systems, citing the organizations initiative to bank blood cells to systematically generate induced pluripotent stem cells from individuals with autism. Simons Searchlight is also a resource of many different biospecimens for researchers. So far, 186 families with SCN2A-related changes have registered, and 83 of these have completed consent, lab reports and medical histories with a large number of blood samples as well. (On the sidelines of the meeting, 18 parents, 11 of their children with SCN2A mutations, and three unaffected siblings donated blood toward this initiative.) Spiro also stressed a need to come up with more quantitative methods of phenotyping, such as wearable electronics that can monitor sleep and circadian rhythms. Data that can be collected longitudinally and at home might provide sensitive outcome measures for clinical trials.

A new role for Nav1.2 has been revealed in recent work described by SFARI Investigator Kevin Bender of the University of California, San Francisco: the channels mediate back-propagating action potentials, which travel into the dendritic trees of neurons. Mice engineered to lack one copy of SCN2A a situation that mimics people with truncating SCN2A mutations that render the resulting Nav1.2 channels useless had cortical neurons with slower action potentials, reduced dendritic excitability and immature synapses based on their shape and function7. This role for Nav1.2 was particularly important later in development: when conditional knockout mice lost an SCN2A copy later in life, their cortical neurons exhibited immature synapses, though their density remained normal. Preliminary experiments suggest that adding back a working copy of SCN2A later in life through transgenic methods or by upregulating transcription of the remaining good copy of SCN2A via CRISPR techniques can restore action potential velocity and synaptic maturity.

Bender stressed how interacting with the SCN2A family group helped focus his research on important aspects of their childrens conditions. For example, parents have noted sensory hypersensitivity in their children, leading Bender to collaborate with colleague Evan Feinberg to use an eye-tracking assay in mice to measure their visual responses. He noted that SCN2A haploinsufficient mice were more sensitive to certain visual stimuli than control mice; if the assay is robust, it could help bridge the gap between SCN2A-related phenotypes in humans and behaviors measured in mice.

As meeting attendees sorted through the new findings, therapeutic questions lingered. An important issue for any therapy, whether drug or gene, will be how early in development one will have to intervene to help someone with an SCN2A mutation. Bender noted that synaptic properties could be rescued in his mice when they were 30 days old equivalent to a 10-year-old human but these and other experiments will have to probe the time periods during which therapies will be maximally effective. To find good measures of efficacy also means understanding the full complement of conditions that beset people with SCN2A mutations. For example, though seizures afflict many, Keith Coffman of Childrens Mercy Hospital in Kansas City, Missouri, suggested that, in some cases, these represent a movement disorder rather than epilepsy. Basic descriptive knowledge like this is imperative for guiding future treatment approaches.

Another smaller SCN2A meeting is planned for this year from July 30 to August 2, in Columbus, Ohio. This will be more family focused, says Schust, and there will be opportunities to participate in research.

There is clearly a lot more work to do before all the terrific basic research that was discussed at this meeting produces meaningful results for families, but it is extremely gratifying to see how much progress has been made on so many fronts and how many new good ideas are emerging, Spiro says. And its terrific to witness firsthand the positive cycle of how families drive researchers and vice versa.

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Seeing through a forest of SCN2A gene variation - SFARI News

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FEBRUARY 19, 2020 When Lt. Col. Jason Barnhill traveled to Africa last summer, he took with him not only the normal gear of an Army officer, but also a 3D printer.

Barnhill, who is the life science program director at the U.S. Military Academy, traveled to Africa to study how 3D printers could be used for field medical care. Barnhills printer was not set up to print objects made out of plastics as the printers are frequently known for. Instead, his printer makes bioprinted items that could one day be used to save Soldiers injured in combat.

The 3D bioprinting research has not reached the point where a printed organ or meniscus can be implanted into the body, but Barnhill and a team of cadets are working to advance the research in the field.

Twenty-six firsties are doing bioprinting research across seven different projects as their capstone this year. Two teams are working on biobandages for burn and field care. Two teams are working on how to bioengineer blood vessels to enable other bioprinted items that require a blood source, such as organs, to be viable. One team is working on printing a viable meniscus and the final team is working on printing a liver.

The basic process of printing biomaterial is the same as what is used to print a plastic figurine. A model of what will be printed is created on the computer, it is digitally sliced into layers and then the printer builds it layer by layer. The difference is the ink that is used.

Instead of heating plastic, 3D bioprinting uses a bioink that includes collagen, a major part of human tissue, and cells, typically stem cells.

A lot of this has to do with the bioink that we want to use, exactly what material were using as our printer ink, if you will, Class of 2020 Cadet Allen Gong, a life science major working on the meniscus project, said. Once we have that 3D model where we want it, then its just a matter of being able to stack the ink on top of each other properly.

Cadets are researching how to use that ink to create a meniscus to be implanted into a Soldiers injured knee or print a liver that could be used to test medicine and maybe one day eliminate the shortage of transplantable organs.

The research at West Point is funded by the Uniformed Services University of Health Science and is focused on increasing Soldier survivability in the field and treating wounded warriors.

Right now, cadets on each of the teams are in the beginning stages of their research before starting the actual printing process. The first stage includes reading the research already available in their area of focus and learning how to use the printers. After spring break, they will have their first chance to start printing with cells.

For the biobandage, meniscus and liver teams, the goal is to print a tangible product by the end of the semester, though neither the meniscus or liver will be something that could be implanted and used.

There are definitely some leaps before we can get to that point, Class of 2020 Cadet Thatcher Shepard, a life science major working on the meniscus project, said of actually implanting what they print. (We have to) make sure the body doesnt reject the new bioprinted meniscus and also the emplacement. There can be difficulties with that. Right now, were trying to just make a viable meniscus. Then, well look into further research to be able to work on methods of actually placing it into the body.

The blood vessel teams are further away from printing something concrete because the field has so many unanswered questions. Their initial step will be looking at what has already been done in the field and what questions still need to be answered. They will then decide on the scope and direction of their projects. Their research will be key to allowing other areas of the field to move forward, though. Organs such as livers and pancreases have been printed, so far, they can only be produced at the micro level because they have no blood flow.

Its kind of like putting the cart before the horse, Class of 2020 Cadet Michael Deegan, a life science major working on one of the blood vessel projects, said. Youve printed it, great, but whats the point of printing it if its not going to survive inside your body? Being able to work on that fundamental step thats actually going to make these organs viable is what drew me and my teammates to be able to do this.

While the blood vessel, liver and meniscus projects have the potential to impact long-term care, the work being done by the biobandage teams will potentially have direct uses in the field during combat. The goal is to be able to take cells from an injured Soldier, specifically one who suffers burns, and print a bandage with built in biomaterial on it to jumpstart the healing process.

Medics would potentially be deployed with a 3D printer in their Humvee to enable bandages to be printed on site to meet the needs of the specific Soldier and his or her exact wound. The projects are building on existing research on printing sterile bandages and then adding a bioengineering element. The bandages would be printed with specialized skin and stem cells necessary to the healing process, jumpstarting healing faster.

Were researching how the body actually heals from burns, Class of 2020 Cadet Channah Mills, a life science major working on one of the biobandage projects, said. So, what are some things we can do to speed along that process? Introducing a bandage could kickstart that healing process. The faster you start healing, the less scarring and the more likely youre going to recover.

The meniscus team is starting with MRI images of knees and working to build a 3D model of a meniscus, which they will eventually be able to print. Unlike a liver, the meniscus doesnt need a blood flow. It does still have a complex cellular structure, though, and a large part of the teams research will be figuring out how and when to implant those cells into what theyre printing.

Of the 26 cadets working on bioprinting projects, 17 will be attending medical school following graduation from West Point. The research they are doing gives them hands-on experience in a cutting-edge area of the medical field. It also enabled them to play a role in improving the care for Soldiers in the future, which will be their jobs as Army doctors.

Being on the forefront of it and just seeing the potential in bioengineering, its pretty astounding, Gong said. But it has also been sobering just to see how much more complicated it is to 3D print biomaterials than plastic.

The bioprinting projects will be presented during the academys annual Projects Day April 30.

By Brandon OConnor

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Cadets Research Bioprinting to Improve Soldier Care - MilitarySpot

Skin Stem Cells Comments Off on Cadets Research Bioprinting to Improve Soldier Care – MilitarySpot | February 20th, 2020

(MENAFN - GetNews) Age Stop Switzerland luxury line of ground-breaking anti-aging solutions provides women the opportunity to regain their youthful appearance again.

Age Stop Switzerland is a premier skincare solutions company, globally reputed for their exceptional anti-aging products that are backed by scientific results. The Swiss-based beauty products developer and manufacturer have incorporated a powerful combination of innovative ingredients known to stimulate and prolong the skin's youthful appearance.

'At Age Stop Switzerland, our core philosophy is to provide our customers exceptionally advanced skincare formulations that can repair and reverse the visible signs of aging on their facial skin, says the spokesperson for Age Stop Switzerland. 'We are proud to offer you our bouquet of luxury anti-aging treatments that can make skin appear visibly renewed, softer and younger. We strive to take age-defying skin care to a new level with our exceptionally effective formulations.

The Age Stop Switzerland product line contains a high concentration of anti-aging elements in well-researched and tested combinations. Some of the innovative ingredients used in these products include bio-mimetic peptides, Swiss Snow Algae, Alpine Flower Stem Cells, hyaluronic acid, oxygen fusion, vitamins, and bio-available precious stone extracts.

The refreshingly unique and exceptionally effective snow algae powder is sourced from algae found on the snowfields of high mountains. The valuable molecules found in the algae helps protect and maintain the skin's youthful appearance.

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About Age Stop Switzerland:

Age Stop Switzerland is a premium Swiss skin care brand committed to advancing the science of staying young. The company offers a wide range of luxury anti-aging skincare products that redefines skin protection. The products from Age Stop Switzerland are created to deliver the latest in globally proven, award-winning anti-aging science based on the revolutionary discovery of ingredients such as Swiss Snow Algae Powder and the pioneering Plant Stem Cell research.

Media Contact Company Name: Age Stop Switzerland Contact Person: Customer Support Email: Send Email Phone: +447432691133 City: Kettering State: Northamptonshire Country: United Kingdom Website: http://age-stop.eu

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Age Stop Switzerland Creates an Exceptional Range of Skincare Products That Can Repair and Rejuvenate Aging Skin - MENAFN.COM

Skin Stem Cells Comments Off on Age Stop Switzerland Creates an Exceptional Range of Skincare Products That Can Repair and Rejuvenate Aging Skin – MENAFN.COM | February 18th, 2020

New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptor-interacting serine-threonine protein kinases (RIPKs), nuclear factor B (NF-B)inducing kinase, and mitogen-activated protein kinases (MAPKs). Furthermore, there is an increasing interest in specifically targeting the substrates of IAP-mediated ubiquitylation, especially RIPK1, RIPK2, and RIPK3, as druggable nodes in inflammation control. Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis. Expanding research on innate immune signaling through pattern recognition receptors that stimulate proinflammatory NF-B and MAPK signaling may further contribute to uncovering the complex molecular roles used by IAPs and downstream RIPKs in inflammatory signaling. This may benefit and guide the development of SMs or selective RIPK inhibitors as anti-inflammatory therapeutics for various chronic inflammatory conditions.

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SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases - Science

Skin Stem Cells Comments Off on SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases – Science | February 18th, 2020

Going gray is a natural part of getting older. It typically starts with a small streak of white in the hair or beard, a sign that a man has reached a certain level of maturity and is now on that steady, inevitable decline to the grave. Hell, it is even conceivable (and highly likely) that some of you might even pluck one of those pale bastards out of your pube patch one night while trying to determine if the source of a vicious case of crotch itch is the crabs or just dry skin. Listen, all were saying is dont be surprised if, within the next few years, you find yourself staring down at your junk, thinking about how that lustrous man bush of yours is starting to resemble Colonel Sanders with a skinless chicken leg dangling out of his mouth. It happens to the best of us.

But hey, getting old isnt always indicative of a silver coiffure. I knew a guy back in high school who had more gray hair on his head than my 73-year-old father does now. So, it seems that age alone isnt always the culprit. In fact, it has been long since believed that stress also plays a critical role in making some men look distinguished beyond their years. Well, come to find out, the concept of stressful events turning us into gray beasts before we are officially deemed DILFs is probably real. Only science says it really comes down to how our fight or flight response is triggered throughout the years that determine when our manes will be deprived of color.

Researchers at Harvards Stem Cell Institute believe they have found a direct correlation between stress and going gray. They recently published a study in the journal Nature, which shows that three kinds of extreme stress mild, short-term pain, psychological stress, and restricted movement has a way of bringing around the gray quicker than what would happen under natural circumstances. At least that is the conclusion reached by lead researcher Dr. Ya-Chieh Hsu and team after putting a legion of mice through the wringer and watching for their response.

The graying process happens as pigment cells called melanocytes start to fade from our hair follicles. Its just that over time, these cells become less prevalent and we begin brandishing that salt and pepper look popularized by legendary screen stars like Brad Pitt and George Clooney.

Eventually, however, all of those cells fade into extinction and our hair just goes completely white, we start receiving AARP benefits and eating apple sauce with every meal. Yet, researchers say that stress can cause these cells to fade out quicker than theyre supposed to long before we start collecting social security and yelling at the neighborhood kids to get off our lawn.

Without getting overly scientific about it, researchers found that high stress seems to produce elevated levels of a chemical in the brain known as noradrenaline. Its one of the kick-ass substances manufactured by the adrenal gland when a persons fight or flight response starts firing on all cylinders. Thats the real culprit to early aging, researchers concluded. They say that once mice were injected with this chemical, they began losing melanocytes and going gray. And the transformation didnt take long either. It turns out that stress can zap our hair color in a matter of days.

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 said in a statement. 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.

While it might be challenging to manage stress in a way that keeps us looking young forever, there is a silver-lining here, boys. Women, presumably the root of all of that premature grayness in the first place, are especially hot for this look. Seriously, a recent survey from Match.com finds that 72 percent of the women on the dating scene find men with gray hair more attractive than those with darker dos. Other studies on the subject have turned out similar results. The only caveat is that women are really only turned on by the gray as long as it doesnt make the man look old. This has something to do with them wanting to feel like a guy can provide some safety and security without having to worry about changing his diapers down the road.

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Getting Gray Hair Early Actually Can Mean You Are Stressed The F*ck Out - BroBible

Skin Stem Cells Comments Off on Getting Gray Hair Early Actually Can Mean You Are Stressed The F*ck Out – BroBible | February 18th, 2020

The following are the top rated Healthcare stocks according to Validea's Small-Cap Growth Investor model based on the published strategy of Motley Fool. This strategy looks for small cap growth stocks with solid fundamentals and strong price performance.

CORCEPT THERAPEUTICS INCORPORATED (CORT) is a small-cap growth stock in the Biotechnology & Drugs industry. The rating according to our strategy based on Motley Fool is 83% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Corcept Therapeutics Incorporated is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic, psychiatric and oncologic disorders. The Company is developing mifepristone, a compound that modulates the effects of cortisol by acting as a competitive antagonist at the glucocorticoid receptor (GR). As of December 31, 2016, it had discovered three structurally distinct series of selective cortisol modulators, all of which share mifepristone's affinity for GR but, unlike mifepristone, do not bind to the progesterone receptor. It is conducting two clinical trials of its selective cortisol modulator, CORT125134. One trial is investigating CORT125134 as a treatment for patients with Cushing syndrome. The second trial is investigating the combination of CORT125134 and nab-paclitaxel (Celgene Corporation's Abraxane) to treat patients with solid-tumor cancers.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

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ZYNEX INC. (ZYXI) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 83% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Zynex, Inc. operates through the Electrotherapy and Pain Management Products segment. The Company conducts its business through its subsidiaries and the operating subsidiary is Zynex Medical, Inc. (ZMI). Its other subsidiaries include Zynex Monitoring Solutions, Inc. (ZMS) and Zynex Europe, ApS (ZEU). ZMI designs, manufactures and markets medical devices that treat chronic and acute pain, as well as activate and exercise muscles for rehabilitative purposes with electrical stimulation. ZMS is in the process of developing its blood volume monitoring product for non-invasive cardiac monitoring. ZEU intends to focus on sales and marketing its products within the international marketplace, upon receipt of necessary regulatory approvals. It markets and sells Zynex-manufactured products and distributes private labeled products. Its products include NexWave, NeuroMove, InWave, Electrodes and Batteries. ZMI devices are intended for pain management to reduce reliance on drugs and medications.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

INMODE LTD (INMD) is a small-cap growth stock in the Medical Equipment & Supplies industry. The rating according to our strategy based on Motley Fool is 79% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Inmode Ltd is an Israel-based company. It designs, develops, manufactures and commercializes energy-based, minimally-invasive surgical aesthetic and medical treatment solutions. The Company's proprietary technologies are used by physicians to remodel subdermal adipose, or fatty, tissue in a variety of procedures including fat reduction with simultaneous skin tightening, face and body contouring and ablative skin rejuvenation treatments. Its products target a wide array of procedures including simultaneous fat killing and skin tightening, permanent hair reduction, skin appearance and texture, among others. The Company's products may be used on a variety of body parts, including the face, neck, abdomen, upper arms, thighs and intimate feminine regions. It owns six product platforms: BodyTite, Optimas, Votiva, Contoura, Triton and EmbraceRF. All are market and sell traditionally to plastic and facial surgeons, aesthetic surgeons and dermatologists, among others.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

MEDPACE HOLDINGS INC (MEDP) is a mid-cap growth stock in the Biotechnology & Drugs industry. The rating according to our strategy based on Motley Fool is 76% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: Medpace Holdings, Inc. is a clinical contract research organization. The Company provides clinical research-based drug and medical device development services. The Company partners with pharmaceutical, biotechnology, and medical device companies in the development and execution of clinical trials. The Company's drug development services focus on full service Phase I-IV clinical development services and include development plan design, coordinated central laboratory, project management, regulatory affairs, clinical monitoring, data management and analysis, pharmacovigilance new drug application submissions, and post-marketing clinical support. The Company also provides bio-analytical laboratory services, clinical human pharmacology, imaging services, and electrocardiography reading support for clinical trials. The Company's operations are principally based in North America, Europe, and Asia.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

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CRISPR THERAPEUTICS AG (CRSP) is a mid-cap growth stock in the Biotechnology & Drugs industry. The rating according to our strategy based on Motley Fool is 72% based on the firms underlying fundamentals and the stocks valuation. A score of 80% or above typically indicates that the strategy has some interest in the stock and a score above 90% typically indicates strong interest.

Company Description: CRISPR Therapeutics AG is a Switzerland-based gene-editing company. It focuses on the development of transformative gene-based medicines for serious diseases. The Company develops its products using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene-editing platform, which allows for precise directed changes to genomic deoxyribonucleic acid (DNA). The Company has a portfolio of therapeutic programs in a range of disease areas, including hemoglobinopathies, oncology, regenerative medicine and rare diseases. Its lead product candidate is CTX001, an ex vivo CRISPR gene-edited therapy for treating patients suffering from transfusion-dependent beta thalassemia or severe sickle cell disease in which a patient's hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin in red blood cells. The Company has business operations in London and the United Kingdom, as well as research and development operations in the United States.

The following table summarizes whether the stock meets each of this strategy's tests. Not all criteria in the below table receive equal weighting or are independent, but the table provides a brief overview of the strong and weak points of the security in the context of the strategy's criteria.

For a full detailed analysis using NASDAQ's Guru Analysis tool, click here

Since its inception, Validea's strategy based on Motley Fool has returned 625.78% vs. 240.03% for the S&P 500. For more details on this strategy, click here

About Motley Fool: Brothers David and Tom Gardner often wear funny hats in public appearances, but they're hardly fools -- at least not the kind whose advice you should readily dismiss. The Gardners are the founders of the popular Motley Fool web site, which offers frank and often irreverent commentary on investing, the stock market, and personal finance. The Gardners' "Fool" really is a multi-media endeavor, offering not only its web content but also several books written by the brothers, a weekly syndicated newspaper column, and subscription newsletter services.

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The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.

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Validea's Top Five Healthcare Stocks Based On Motley Fool - 2/16/2020 - Nasdaq

Skin Stem Cells Comments Off on Validea’s Top Five Healthcare Stocks Based On Motley Fool – 2/16/2020 – Nasdaq | February 17th, 2020

Heres the truth about serum: Its the biggest secret to having younger-looking, radiant skin.

You know all the other steps to staying healthyand showing it: wearing SPF, and applying retinol. You stay hydrated and eat healthy foods. You get lots of exercise and plenty of sleep. But, are you applying serums? They can give your skin some of the most immediate and impactful benefits.

Serum seeps into all three layers of your skin to work its magic at deeper levels than moisturizer ever could. Those moisturizing creams merely sit atop your skin. Theyre equally important, and shield skin from toxins, but they do little to reverse dark spots and smooth wrinkles. Serums, on the other hand, can correct hyperpigmentation and puffy eyes.

Serum brightens your skin complexion, and can preserve moisture levels in ways that moisturizers never could (funny, given its name). No two serums are alike in terms of ingredients and overall benefits, but almost all of them brighten your skin and smooth complexion. Here are seven of our favorite serums; apply them to clean, dried skin before moisturizers, SPFs, retinol or night creams.

If your skin suffers from redness or discoloration, then look for a corrective serum. SkinCeuticals gel serum uses thyme and cucumber extract to soothe irritation, as well as mulberry extract to even skin tone and gently hydrate the skin. If most moisturizers make your skin break out, then this is a gentle and top-notch moisturizing alternative.

Vitamin C is one of the best ingredients you can apply to skin for brighter, more even complexion. Glossiers serum is packed with it, along with magnesium, for an instant pick-me-up for tired or dull skin. Use it daily to preserve a fresh face, and to get ahead of the inevitable hangovers or early mornings.

The skin around your eyes is more sensitive than the rest of your face, and is much thinner, too hence why you quickly show signs of tiredness. (Its fluid buildup from a lack of rest, shining through your skin.) So, target the eyes with a special-blend serum that tightens and brightens at the same time. In OSEAs eye serum, hyaluronic acid preserves firmness and moisture levels, grape-seed-derived resveratrol shields this thin skin from toxins, and algae extract plumps and nourishes tired eyes (and alert eyes, if youre plenty rested already everyone benefits). It also prevents and helps reverse fine lines and other signs of aging.

Some serums are best worn during the day those that focus on hydration and pure brightening. Others, like corrective and exfoliating serums, are often best suited for bedtime so that they can sync with your bodys circadian rhythm to boost cellular turnover (and in turn guarantee that you wake up looking rested and more youthful). However, some serums cover both bases: Brickells night serum is ultra-hydrating so much so that its impact is maximized by wearing it overnight. Its loaded with plant stem cells, hyaluronic acid and vitamin C, and promises to magnify the benefits of a full nights sleep. Your friends and colleagues will notice the difference within days. (Assuming you arent pairing it with a lovely binge-drinking or chain-smoking habit.)

Theres an entire family of serums that focuses on exfoliation, by using ingredients that dissolve dead skin cells and reduce hyperpigmentation (dark spots and discoloration). Herbivores serum does so with alpha- and beta-hydroxy acids, all of which are naturally derived, despite their sciencey-sounding names. Theyre extracted from things like willow bark and sugar maple, and in turn leave skin bright, while minimizing pore size and smoothing skin texture.

Its hard to categorize Caudelies skin-brightening serum, since it uses the brands proprietary blend of ingredients (Viniferine, derived from grape vines) but they seem to deliver on their promise to brighten skin 62 times better than Vitamin C. All around the globe, this is what Caudelies spa customers pay top dollar for, and you can enjoy the same complexion-smoothing effects for less than a buck a day (assuming you just use a couple drops daily).

If your skin texture needs attention just as much as your skin tone, then look for a corrective and smoothing serum. This one from PCA Skin is pumped with peptides, and it waxes poetic on your skin to undo signs of aging (like the appearance of fine lines, wrinkles, dark spots and acne spots). It also helps skin retain moisture thanks to the inclusion of hyaluronic acid, rice bran extract, squalene, ensuring firmness and brightness.

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The Best Serums to Brighten and Refresh Dull, Tired Skin - gearpatrol.com

Skin Stem Cells Comments Off on The Best Serums to Brighten and Refresh Dull, Tired Skin – gearpatrol.com | February 17th, 2020

Stephanie Singleton for BuzzFeed News

Do you miss being a scientist? some people ask.

Sometimes.

When people talk about science, they usually mean people in white lab coats doing things, like solving equations on the board or preparing solutions in beakers. What they mean is science as this crude mechanism of discovery by which humans refine over decades and centuries a small kernel of knowing. What they mean is grant dollars. What they mean is wild hair. What they mean is clean, aseptic, analytical. Brainy little robot people. White.

I try to be honest about my time in science about the feeling of satisfaction I had when I plotted all of my confocal data and there was a beautiful curve depicting the drop-off in signal as one moved further down the tissue of the gonad. I think about the calculations we did on scraps of paper to check the ratios of inheritance of the genes we introduced. I think of the little side room where we took our coffee and bagels. I think of the feeling of friendship and family that comes with being in a big lab, where everyone has a place, a role, an expertise, a skill. I remember the surprise I felt when people started to come to me because I knew something, because I could help. And how rare that was for me.

For the better part of several years, I saw my labmates every day. For hours and hours. Every holiday, every break, we stayed. We worked. We supported each other. We fought. We feuded. We gossiped. We threw parties for each other. We celebrated. We said goodbye at graduations and retirements. There were people who supported me and cherished me and looked after me. People who treated me like I mattered. A lab is a family. In a way.

Science was beautiful and it was wild and it was unknowable. Science was spending days and weeks on a single experiment with no way to know if it would work and no real way to tell if it had worked. Science was like trying to find your way to a dark forest only to realize that you had always been inside of the forest and that the forest is inside of another, greater, darker forest. Science was laughing with my labmates about television the night before, about the song of the summer, about tennis, about the unruly nature of mold growing on our plates, about cheap wings at Buffalo Wild Wings. Science was being taught to think. Taught to speak. Science was a finishing school. Science was a brutal education. Science made me ruthless. Science made me understand the vast beauty of the world.

But science was also working 15 hours a day for weeks or months. Science was working weekends and holidays. Science was being called lazy for taking a break. Science was the beat of doubting silence after I answered a question put to me. Science was being told that racism was not racism. Science was being told that I was fortunate that I had running water while growing up and that I was actually privileged because there are some places that do not. Science was being told that I was mistaken for a waiter at a party because I had worn a black sweater. Science was being told that I had to work harder despite working my hardest. Science was being told that I talked too much. Science was being told that I was too loud. Science was being told that I was behind, always behind. Science was being told that I had failed but had been gifted a pass by virtue of who you are. Science was being told that I had never once been to class despite attending every session and office hour because I was mistaken for someone else.

Science was being the only black person in the program for four years. Science was saying nothing because I was tired of being corrected about the particulars of my own experience. Science was being told that I should consider moving to the other side of town where more black people live. Science was someone suggesting that I find a church in order to find community. Science was having my hair stroked and touched. Science was being told that I was articulate. Science was watching peoples eyes widen slightly in surprise when I told them what program I was in. Science was the constant humiliation of wondering if I had justified my presence or if I had made it harder for the next black person to get admitted. Science was having to worry about that in the first place.

Science was a place I ultimately left, not so much because I wanted to, but because I had to. Science is not being able to say that because I reflexively feel the rebuttal waiting on the other end of that sentence: You could have made it work if you wanted it enough. Science is not knowing whether I wanted it enough.

Does science influence your writing?

Oh, sure. I guess.

Do you write science fiction?

No, I write domestic realism.

After the above exchange, people sometimes look at me like Im joking and at any moment will drop the faade to reveal that I do in fact write and love science fiction, after all.

But no, I do not write science fiction. I think that if people knew more scientists and spent significant time in their company, they would understand that the worst possible preparation for a career as a science fiction writer is an intensive science education. My training as a scientist makes it difficult to absent myself in the way I need to in order to write good fiction. I can never turn off the part of my brain that knows about protein folding or microscopy or tissue preparation or stem cells or physics or chemistry. Writing science fiction would be an extended exercise in pedantry.

People presume that science and writing are quite different. But they are both ways of knowing. They are ways of understanding the greater mystery of the world. They are systems of knowledge and inquiry. I do not understand something until I have written it, or more accurately put, until I have written my way through it.

Science was being the only black person in the program for four years. Science was saying nothing because I was tired of being corrected about the particulars of my own experience.

I think in many ways, the best preparation for a writer is a period of prolonged and rigorous thought about a difficult and complicated question. You learn to assemble your resources. You learn to fight with yourself. You learn to quarrel on the page with your worst ideas and with the ones you hold dearest. You treat your expectations with suspicion. You demand proof. You demand evidence. You think hard about the alternate hypothesis or other explanations, and you devise strategies to root these out. You learn to live with doubt. You try to prove yourself wrong. You look for places where you have been too soft. Too vague. You eliminate language that contains falsehoods. You eliminate language that can mislead your reader. You ask questions. You pursue answers with all the energy you can muster. You try to put language to what it is you observe. You develop a stamina for iteration. You develop a thick skin. You learn to seek criticism. You treat criticism like kindness. You churn the raw material of life into something that can be understood, and when you fail, you marvel at the mystery of things.

Do you miss science?

Yes. No. Yes. No.

Sometimes, when I dont feel well, I consider the question of how to derive an expression for the degradation of a molecular species in a particular tissue under a given set of circumstances. Old calculus. I turn to YouTube lectures from MIT about thermodynamics. I think of my first winter in Madison, Wisconsin.

The first snowfall was in October. It had been a hot, rainy summer, so much so that the weather seemed to turn all at once with very little warning. I was either in the middle or at the start of my second rotation as a biochemistry graduate student, working in a biophysical chemistry lab and spending most of my day in the windowless instrument facility in the basement. My project was to deduce the effect of protein concentration on the ability of a polymer of DNA to wind itself. I spent a lot of time pipetting various liquids into each other in little cuvettes, slotting them into a machine, and then waiting for the reading. It was the kind of work to which I felt ideally suited, and I could have gone on that way forever. I had recently moved to the Midwest from Alabama to pursue a PhD, and it seemed as likely as anything else that I would go on pipetting and measuring the effect of things like DNA polymer length and protein concentration on DNA winding. It was as removed from the circumstances of my previous life as anything else, and so I didnt have a compelling reason to doubt that this would be the shape my life held.

But I remember sitting down at the desk in the lab and looking out the broad window. There was a large tree at the center of the courtyard that had recently turned yellow. Fall was there in name, but not in temperature. The labs were kept quite cold, and so I wore a sweater indoors and shucked it as soon as I got outside. But that day, I looked out of the window and saw snow drifting down. The flakes were thick and fluffy, and they seemed almost fake. It was the first time I had seen snow in years, and I was totally enamored by it. The other people in the lab were on edge because snow in October portended something dark and awful a hard winter, a long, brutal freeze. Where they saw inconvenient travel and slushy roads, I saw something beautiful if frivolous, a minor novelty. Winter came early that year, and it didnt end until the very beginning of the following summer. When I went to the lake on my birthday in early June, there was still ice in the water.

People presume that science and writing are quite different. But they are both ways of knowing.

When people ask me about my time in science, it is this day which presents itself to me in jewel-like clarity. It is the day something about my life altered irrevocably. Or perhaps it is that the snow has accumulated, the way all such moments do in life, the weight of meaning, of prophecy. Inevitability is an artifact of retrospection. It is because the snow represented a stark deviation from the previous course of events in my life, at the precise moment when my life was changing so wildly, that I remember it. It is not that the snow changed me, but it came at a point when I was starting not to resemble myself. I cannot use the snow to explain to people what my life was like in science. It has the whiff of superstition, folklore. It feels too much like a memory and not enough like an answer. I do not tell them about the snow or how it seemed a benediction at the outset of something I needed desperately to work.

It was only later that I realized this was wishful thinking, and that the snow was just snow.

Do you think youd ever go back to science?

That part of my life is over now.

Ive come to understand that what people want in such a situation is to have their own conceptions of the world confirmed. That is, they want me to say that when you leave science because you have written a novel and a book of stories and have decided to attend an MFA program in creative writing, you are doing something that is antithetical to science. People presume that it is akin to picking up and leaving your home in the middle of the night under great duress, never to return. What they want is the spectacle of the forgotten treasured item, the confirmation that something has been lost, perhaps forever.

I think if people knew what it was that I left, then theyd know better than to ask. It would be like asking someone if they were sad to have left their home with no prospect of returning. It would be like asking someone if they were sad to have left their faith behind. It would be like asking someone if they were sad to have given up some fundamental idea about who they are. It would be like asking someone if they were sad to have watched their life burn to the ground. It would be like asking someone if they were sad to have left their family and friends.

They would mind their own business if they knew.

But they do not know, and so they say things like Science, wow, thats so cool, like, do you miss it?

And I smile because that is what I have learned to do. Because explaining is too hard. Too messy. There is no clean or easy or simple way to make it known to others that I left because I had to, because it was necessary to leave that I do miss it, but I also dont because Im still that person but not that person, that every day I remind myself less of the person I was then. Its sad, like losing a memory of myself, and all those years are lost to me now, all the little tricks and habits of home dropping down and away, as I become this other person known for this other thing, and its too much in the moment to say that I miss it both more and less every day, that I become a person more capable of appreciating what is lost in the grand scheme of things but less a person who knows what it is Ive actually lost, and that there is some painful, brutal, awful misalignment in the scale of those two losses.

When people ask if I miss science, the only answer available to me is an incomplete solution to the problem: Yes. No. Sometimes. Its over now.

Brandon Taylor is the senior editor of Electric Literatures Recommended Reading and a staff writer at Literary Hub. His writing has earned him fellowships from Lambda Literary Foundation, Kimbilio Fiction, and the Tin House Summer Writer's Workshop. He holds graduate degrees from the University of Wisconsin-Madison and the University of Iowa, where he was an Iowa Arts Fellow at the Iowa Writers Workshop in fiction. Learn more about his first novel Real Life here.

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Working In Science Was A Brutal Education. Thats Why I Left. - BuzzFeed News

Skin Stem Cells Comments Off on Working In Science Was A Brutal Education. Thats Why I Left. – BuzzFeed News | February 17th, 2020

Marie Antoinette, the last queen of France, is best remembered for her reckless extravagance and her tragic death. French revolutionaries executed her with a guillotine in 1793 for treason. Popular belief is that her hair turned grey the night before her death.

There are other stories and anecdotes like this which suggest that stressful experiences are correlated with the phenomenon of hair greying. Now, for the first time, Harvard University scientists have found the real mechanism behind it.

Published in the journal Nature, the study was initiated with the aim of analysing the effect of stress on various tissues. Hair and skin are the tissues that are visible from outside. So, the researchers started with effects of stress on hair colour.

Their initial hypothesis was that stress initiates an immune attack on pigment-producing cells in the hair follicles. However, when they tested it on mouse, they found those lacking immune cells (nude mouse) also exhibited hair greying. Then, their attention turned to a hormone called cortisol. It is responsible for regulating a wide range of processes through the body, including metabolism and the immune response. In response to stress, extra cortisol is released to help the body to respond appropriately. Surprisingly, when the researchers removed the adrenal gland from the miceto prevent production of cortisol-like hormone aldosteroneand triggered stress, their hair still turned grey.

Finally, the researchers tested the sympathetic nerves that branch out to each hair follicle. The sympathetic nerve system is responsible for the bodys fight-or-flight response. They found that in a stressful condition, the sympathetic nerves release a chemical called norepinephrine, which is taken up by certain stem cells in the hair follicle. Stem cells act as a reservoir for pigment-producing cells. During hair regeneration, some of these stem cells are converted into pigment-producing cells to give colour to new hair strands.

When these stem cells take norepinephrine, they are activated excessively and all of them get converted into pigment-producing cells. This would prematurely deplete the reservoir for pigment-producing cells. Once all of them are consumed, pigment regeneration would stop, resulting in permanent damage. The fight-or-flight response has been traditionally viewed as beneficial. But now it is proved that it has its own detrimental effects, too.

The study established how neurons interact at the cellular and molecular level to link stress with hair greying. The findings are expected to put light on the broader effects of stress on various body parts. The scientists will initiate new studies that seek to modify or block the damaging effects of stress.

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The ghost behind grey - THE WEEK

Skin Stem Cells Comments Off on The ghost behind grey – THE WEEK | February 16th, 2020

People usually start gradually greying in their thirties. Once across the age of 50, one will be hard-pressed to successfully disguise ones white hair without paying monthly visits to a hairdresser.

However, medical reports suggest the process of hair colour loss, which scientists call canities or achromotrichia, can be greatly accelerated by persistent acute stress or severe trauma.

Some historians have speculated that the French Queen Marie Antoinettes hair turned white when she heard she was to be guillotined at the height of the French Revolution in 1793.

For the longest time, its been said that stress makes the hair turn white, but until now, there was no scientific basis for this belief.

Our study proved that the phenomenon does indeed occur and we identified the mechanisms involved.

In addition, we discovered a way of interrupting the process of hair colour loss due to stress, said Thiago Mattar Cunha, a researcher affiliated with the Center for Research on Inflammatory Diseases (CRID) a Research, Innovation and Dissemination Center funded by FAPESP and hosted by the University of So Paulos Ribeiro Preto Medical School in Brazil.

The study was conducted in partnership with a group led by Hsu Ya-Chieh, a professor of regenerative biology at Harvard University in the United States.

According to Cunha, the results, published recently in the journal Nature, were partly serendipitous.

We were conducting a study on pain using black C57 mice, a dark-furred laboratory strain, he said.

In this model, we administered a substance called resiniferatoxin to activate a receptor expressed by sensory nerve fibres and induce intense pain.

Some four weeks after systemic injection of the toxin, a PhD student observed that the animals fur had turned completely white.

The experiment was repeated several times until the CRID researchers concluded that the phenomenon was indeed due to the application of resiniferatoxin, a naturally-occurring chemical found in resin spurge (Euphorbia resinifera), a cactus-like plant native to Morocco.

We set out to check the hypothesis that the loss of fur colour resulted from pain-induced stress, Cunha said.

We designed a very simple experiment to see if the phenomenon was dependent on activation of sympathetic nerve fibres.

He explained that the sympathetic nervous system is directly affected by stress.

This division of the autonomic nervous system consists of nerves that branch from the spine and run throughout the body.

It controls the organisms fight or flight response to imminent danger, triggering the release of adrenaline and cortisol to make the heart beat faster, blood pressure rise, respiration accelerate and the pupils dilate, among other systemic effects.

After injecting resiniferatoxin into the mice, we treated them with guanethidine, an anti-hypertensive capable of inhibiting neurotransmission via sympathetic fibres.

We observed that the process of fur colour loss was blocked by the treatment, Cunha said.

In another experiment, neurotransmission was interrupted by the surgical removal of sympathetic fibres.

In this case too, fur colour was not lost in the weeks following pain induction.

These and other experiments conducted by our group demonstrated the participation of sympathetic innervation in achromotrichia and confirmed that pain is a powerful stressor in this model.

But it remained to detail the mechanisms involved, he explained.

Maturing too quickly

Cunha spent a period at Harvard as a visiting professor in 2018-19 with a scholarship from the joint programme Harvard holds with CAPES, the Brazilian Education Ministrys Office for Faculty Development.

In conversations with colleagues, he heard that a Harvard group had made similar discoveries to those of his group at So Paulo, and that their findings were also partly accidental.

Professor Hsu Ya-Chieh invited me to join a project in which the phenomenon was being investigated in more detail.

Shes a leading researcher on processes that control skin stem cell differentiation, Cunha said.

His group already knew by then that pain-related stress was somehow making the melanocyte stem cells in the hair follicle bulb mature too soon.

These cells are responsible for yielding melanin-producing cells. Melanin is the pigment primarily responsible for skin and hair colour.

In a young individual, the cells are undifferentiated like all stem cells, but with ageing, they gradually differentiate.

Once the process is complete, they stop producing the melanocytes that produce melanin, Cunha explained.

We used various methodologies to show that intense sympathetic activity speeds up differentiation significantly.

In our model therefore, pain accelerated the ageing of melanocyte stem cells.

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, Prof Hsu said.

After just a few days, all of the pigment-regenerating stem cells were lost. Once theyre gone, you cant regenerate pigment anymore. The damage is permanent.

Study lead author and postdoctoral fellow Zhang Bing added: Acute stress, particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animals survival.

But in this case, acute stress causes permanent depletion of stem cells.

Other systems in the organism are probably affected by intense stress in a similar manner to the hair follicle bulb.

We dont know for sure what the implications are, Cunha said.

Im currently working with other researchers on an investigation of the effects of sympathetic activity in other stem cell subpopulations.

Altered gene expression

RNA (ribonucleic acid) sequencing was one of the methodologies used to explore the mechanisms that promote melanocyte stem cell differentiation.

The researchers used this technology to compare the gene expression profiles of mice that received the injection of resiniferatoxin developing pain, stress and fur colour loss with those of mice injected with a placebo.

We looked for genes whose expression was most altered after stress induction, and one caught our attention: the gene that encodes a protein called CDK (cyclin-dependent kinase).

This is an enzyme that participates in cell cycle regulation, Cunha said.

When the researchers repeated the pain induction procedure and treated the mice with a CDK inhibitor, they found that melanocyte stem cell differentiation was prevented, as was fur colour loss.

This finding shows that CDK participates in the process and could, therefore, be a therapeutic target, he said.

Its too soon to know whether it will actually become a target someday in clinical practice, but its worth exploring further.

In another experiment, the researchers demonstrated that when the sympathetic system is robustly activated, the fibres that innervate hair follicle bulbs release noradrenaline very near the melanocyte stem cells.

We showed that melanocyte stem cells express the protein ADRB2 (beta-2 adrenergic receptor), which is activated by noradrenaline, and we discovered that the stem cells differentiate when this receptor is activated by noradrenaline, Cunha said.

To confirm the finding, the researchers repeated the experiment using mice that had been genetically modified so as not to express ADRB2.

As suspected, their fur did not turn white after they were injected with resiniferatoxin.

In another test, we injected noradrenaline directly into the skin of the mouse.

As a result, the fur around the site of the injection turned white, Cunha said.

Finally, the group treated a primary culture of human melanocytes (melanin-producing cells obtained directly from the skin of a volunteer) with noradrenaline, which as noted earlier, is released by the sympathetic nerve fibres in hair follicles.

The result was an increase in expression of CDK similar to that observed in mice.

According to Cunha, the researchers do not yet know if there will be future aesthetic applications for their findings, such as the development of a drug that prevents the hair colour loss associated with ageing.

It would be necessary to see if a CDK inhibitor has side effects, and if so, whether they would be outweighed by the aesthetic benefit, he said. Agncia FAPESP

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What makes your hair turn white faster - The Star Online

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