Archive for the ‘Skin Stem Cells’ Category

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

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

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

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

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

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

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

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

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

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

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

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Stress and Gray Hair - ThirdAge

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

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

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

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

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

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

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

About the ROCKstar (KD025-213) Trial

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

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

About KD025

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

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About cGVHD

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

About Kadmon

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

Forward Looking Statements

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

Contact Information

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

SOURCE: Kadmon Holdings, Inc.

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

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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Stress could be a major cause of grey hair - BOL News

The first time Bill Cronin Googled his own cancer diagnosis in 2016, his heart sank. He had Szary syndrome, a rare and aggressive form of cutaneous T-cell lymphoma and staring back at him were countless articles predicting a negative prognosis.

However, after receiving a stem-cell transplant at Dana-Farber/Brigham and Womens Cancer Center, Cronin is returning to the life he enjoyed before cancer.

Im at a place I never thought Id get to, Cronin says.

In 2015, Cronin, then 60, started feeling incredibly itchy and developed an accompanying rash. He went to his dermatologist, who diagnosed him with eczema and told him to return in five months. The rash continued to grow, however, and at the five month mark, Cronins dermatologist encouraged him to undergo further testing at Dana-Farber.

A blood test revealed that Cronins T-cells a type ofwhite blood cells that make up part of the immune system had becomecancerous. In the case of Szary syndrome, lymphoma cells will circulatethrough the blood stream and deposit in different areas of the skin. This willgenerally lead to a full-body rash and intense itchiness.

Cronin would need a stem cell transplant to combat the disease, but before he could receive one, his care team had to get him into remission. Patients who do not achieve remission prior to transplant have a high chance of relapsing.

When they first told me everything, I was really scared, says Cronin. But I knew I was in one of the best places in the world to figure out and treat this rare disease.

Cronins pre-transplant care was spearheaded by oncologists David Fisher, MD, and Nicole LeBoeuf, MD, MPH, clinical director of Cutaneous Oncology at Dana-Farber, with his transplant conducted by Corey Cutler, MD, MPH, medical director of the Adult Stem Cell Transplantation Program at Dana-Farber. Initially, Cronins disease was incredibly resistant; for nearly three years, mainstay drugs including steroids, monoclonal antibodies, and enzyme blockers all failed to put his disease into remission.

Ultimately, it would take a new drug, mogamulizumab (a type of immunotherapy that directly kills T-cells involved with Sezary Syndrome) to get Cronins disease into remission.

In May 2019, Cronin was cleared to undergo an allogeneic transplant, a type of transplant that uses a donors stem cells, in this case, Cronins brother. Since his transplant Cronin has remained in remission.

We had to use all of our big guns to get him totransplant, but Im pleased with where we are now, says Cutler.

I know the situation can always change, but it was great tobe able to share some good news with my family and friends, adds Cronin.

Patients like Cronin serve as a reminder of how stem cell transplants have improved and continue to impact patient outcomes, Dana-Farber experts note. Initially offered to only an incredibly small patient population when first performed at Dana-Farber in the 1970s, research advancements have, and continue to, broaden who is eligible for a transplant. In 2019, Dana-Farber/Brigham and Womens Cancer Center (DF/BWCC) surpassed 10,000 total adult transplants.

This milestone indicates our success as a program and our volume has allowed us to do the research to help move the field forward rather impressively, says Joseph Antin, MD, chief emeritus of Adult Stem Cell Transplantation at DF/BWCC.

In 1996, Dana-Farber Cancer Institute and Brigham and Womens Hospital merged their then separate transplant centers. By pooling together physical and intellectual resources, the new combined program was able to more than double the number of transplants each hospital could perform individually.

We always felt collaboration was better than competition, explains Robert Soiffer, MD, vice chair of Medical Oncology for Hematological Malignancies and chief of the Division of Hematologic Malignancies, who oversaw the merger with Antin. Each side could learn from the other, and that helped to catapult us into the leadership position we have today.

The Stem Cell Transplantation Program is also bolstered by the Connell and OReilly Families Cell Manipulation Core Facility (CMCF), which was established in 1996. The state-of-the-art center, led by Jerome Ritz, MD, not only processes the stem cells for transplant; it also assists researchers in developing new cell-based therapies for patients.

Another key component to the programs success has been the creation of the Ted and Eileen Pasquarello Tissue Bank. The Pasquarello Tissue Bank receives, processes, banks, and distributes research samplesof blood, bone marrow, and other tissues. Through a database overseen by Vincent Ho, MD, the Institute is able to log, assess, and later review every patients disease, including all complications and mutations. This technology allows researchers to explore the genetic makeup of past donors and better understand why a transplant was or was not successful.

Were still learning from biological specimens we collected 20 years ago, and it will continue to impact care 20 years from now, Soiffer says.

Today, there is a continuous push to develop new and more precise therapies to complement and improve stem cell transplants. The hope is to bring new treatment options to patients like Cronin who are facing rare and difficult diseases.

Before his diagnosis, Bill, and Barbara Finney, his partner ofnearly 30 years, were avid English Country dancers. English Country dancingevolved from the court dances of Europe in the early 17th century, and Croninand Barbara have friends from all over the country who share their passion forit.

While Cronin isnt dancing just yet, as hes stillrecovering from his transplant, he says he couldnt have gotten through thiswithout his partner on the dance floor and in life.

Barbara has been amazing and has helped take care ofeverything I couldnt do, he adds. Ive been fortunate and privileged to notonly have her, but to have been able to come to Dana-Farber.

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Transplant for Szary Syndrome is Patient's First Step in Returning to the Dance Floor - Dana-Farber Cancer Institute

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

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

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Visualizing the Conversion of Adult Cells to Stem Cells - Technology Networks

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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

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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Anatomy of a grant: Ashley Kramer's yearlong journey to finding her doctoral thesis - The South End

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Of late, there has been an increasing awareness regarding the therapeutic potential of stem cells for management of diseases which is boosting the growth of the stem cell therapy market. The development of advanced genome based cell analysis techniques, identification of new stem cell lines, increasing investments in research and development as well as infrastructure development for the processing and banking of stem cell are encouraging the growth of the global stem cell therapy market.

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One of the key factors boosting the growth of this market is the limitations of traditional organ transplantation such as the risk of infection, rejection, and immunosuppression risk. Another drawback of conventional organ transplantation is that doctors have to depend on organ donors completely. All these issues can be eliminated, by the application of stem cell therapy. Another factor which is helping the growth in this market is the growing pipeline and development of drugs for emerging applications. Increased research studies aiming to widen the scope of stem cell will also fuel the growth of the market. Scientists are constantly engaged in trying to find out novel methods for creating human stem cells in response to the growing demand for stem cell production to be used for disease management.

It is estimated that the dermatology application will contribute significantly the growth of the global stem cell therapy market. This is because stem cell therapy can help decrease the after effects of general treatments for burns such as infections, scars, and adhesion. The increasing number of patients suffering from diabetes and growing cases of trauma surgery will fuel the adoption of stem cell therapy in the dermatology segment.

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

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Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

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Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Competitive Analysis and Forecast 2017-2025 - News Parents

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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Microbubbles/Ultrasound Contrast Agents Market by Therapeutic Area (Cardiovascular Diseases, Renal and Associated Diseases, and others), by Application (Molecular Imaging, Gene Therapy, Drug Delivery, and Stem Cells Delivery) Global Forecasts to 2024

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Collagen and Gelatin Market for Regenerative Medicine is expected to reach USD 709.9 million by 2022 - PharmiWeb.com

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Dubai: It's an industry on the rise. And it's accelerating the speed by which Dubai is fast becoming the "new Beverly Hills of the Middle East."

Already, cosmetic surgery has topped the list in medical tourism in Dubai. According to a Dubai Health Authority (DHA) report, the emirate has the highest number of cosmetic surgeons per capita in the region about 50 specialists for a million people.

Globally, the cosmetic surgery market size is projected to reach $21.97 billion with 7.8% annual growth rate by 2023, according to a Medgadget report.

These are the top surgery options:

To put this in perspective, we talked to several people.

Myra J., a belly dancer working at a Dubai hotel. She was unhappy. Saddle bags on her thighs were making her performance less graceful. She honestly feared she would be jobless soon.

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.

'Ageing gracefully'

Nina M., (52), always loved how beautiful her eyes were and how youthful her cheeks looked.

Last year, nowever, 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.

- Anna M, a physical trainer

This was affecting her work. 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.

Addiction to surgery?

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.

It 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:

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.

MULTIMILLION BUSINESS

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.

In Dubai, at least 50 per cent of its 30 hospital offer cosmetic and plastic surgery options.

30 number of hospitals in Dubai, of which 70 per cent are internationally accredited

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.

400 Number of aesthetic clinics in Dubai

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.

40% percentage of tourists who come to Dubai come only for medical tourism. Medical tourism sales topped Dh12 billion in 2018, a 5.5% jump in the number of medical tourists

Based on official data, about 46 per cent of the current medical tourists in Dubai come from Asian countries. About a quarter (25 per cent), come 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.

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."

Most popular cosmetic surgery

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.

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

Most popular cosmetic surgery

"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?

"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 rules:

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.

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Dubai is the 'new Beverly Hills of the Middle East': Here's why - Gulf News

]]> 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

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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

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.

Originally posted here:
Building a 'doomsday vault' to save the kangaroo and koala from extinction - CNET

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

Global Stem Cell Banking Market Report 2020comprises of data that can be quite essential when it comes to dominate the market or making a mark in the market as a new emergent. The statistics are represented in graphical format in this business research report for a clear understanding on facts and figures. The report provides market insights which help to have a more precise understanding of the market landscape, issues that may impinge on the Stem Cell Banking industry in the future, and how to position specific brands in the best way. Analysis and discussion of important industry trends, market size, and market share estimates are mentioned in the Tissue-Engineered Products Market analysis report.

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The Increased Market Growth can be identified by the increasing procedures of hematopoietic stem cell transplantation (hsct), emerging technologies for stem cell processing, storage and preservation. Increasing birth rates, awareness of stem cell therapies and higher treatment done viva stem cell technology. Data Bridge Market Research has recently announced publishing of a report, titled Global Stem Cell Banking Market Industry Trends and Forecast to 2026 As per the report, Global stem cell banking market is set to witness a substantial CAGR of 11.03% in the forecast period of 2019- 2026. The Stem Cell Banking Market report provides the details related to fundamental overview, development status, latest advancements, market dominance and market dynamics. The report also presents the evaluation of the competitive landscape of the market.

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Market Definition: Global Stem Cell Banking Market

Stem cells are cells which have self-renewing abilities and segregation into numerous cell lineages. Stem cells are found in all human beings from an early stage to the end stage. The stem cell banking process includes the storage of stem cells from different sources and they are being used for research and clinical purposes. The goal of stem cell banking is that if any persons tissue is badly damaged the stem cell therapy is the cure for that. Skin transplants, brain cell transplantations are some of the treatments which are cured by stem cell technique.

Explore Key Industry Insights In 60 Tables And 220 Figures From The 350 Pages Of Report, Global Stem Cell Banking MarketBy Source (Placental Stem Cells (PSCs), Human Embryo-Derived Stem Cells (hESCs), Bone Marrow-Derived Stem Cells (BMSCs), o Dental Pulp-Derived Stem Cells (DPSCS), Adipose Tissue-Derived Stem Cells (ADSCs) and Other Stem Cell Sources), By Application (Personalized Storage, Clinical, Research), Service Type (Sample Collection and Transportation, Sample Processing, Sample Analysis, Sample Preservation and Storage), Geography (North America, Europe, Asia Pacific, Latin America and The Middle East and Africa) Industry Trends and Forecast to 2026.

The global Stem Cell Banking market report covers scope and product overview to define key terms and offers detailed information about market dynamics to the readers. This is followed by a regional outlook and segmental analysis. The report also consists of the facts and key values of the global Stem Cell Banking market, in terms of sales and volume, revenue and its growth rate.

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Segmentation: Global Stem Cell Banking Market

By Source

By Application

Research

By Service Type

Competitive Analysis: Global Stem Cell Banking Market

The global Stem Cell Banking market is highly fragmented and the major players have used various strategies such as product (software) launches, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of Stem Cell Banking market for global, Europe, North America, Asia Pacific and South America.

Research Methodology: Global Stem Cell Banking Market

Data collection and base year analysis is done using data collection modules with large sample sizes. The market data is analysed and forecasted using market statistical and coherent models. Also market share analysis and key trend analysis are the major success factors in the market report. To know more please request an analyst call or can drop down your enquiry.

The key research methodology used by DBMR research team is data triangulation which involves data mining, analysis of the impact of data variables on the market, and primary (industry expert) validation. Apart from this, other data models include Vendor Positioning Grid, Market Time Line Analysis, Market Overview and Guide, Company Positioning Grid, Company Market Share Analysis, Standards of Measurement, Top to Bottom Analysis and Vendor Share Analysis. To know more about the research methodology, drop in an inquiry to speak to our industry experts.

Primary Respondents

Demand Side: Doctors, Surgeons, Medical Consultants, Nurses, Hospital Buyers, Group Purchasing Organizations, Associations, Insurers, Medical Payers, Healthcare Authorities, Universities, Technological Writers, Scientists, Promoters, and Investors among others.

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Research Methodology: Global Stem Cell Banking Market

Data collection and base year analysis is done using data collection modules with large sample sizes. The market data is analysed and forecasted using market statistical and coherent models. Also market share analysis and key trend analysis are the major success factors in the market report. To know more please request an analyst call or can drop down your enquiry.

The key research methodology used by DBMR research team is data triangulation which involves data mining, analysis of the impact of data variables on the market, and primary (industry expert) validation. Apart from this, other data models include Vendor Positioning Grid, Market Time Line Analysis, Market Overview and Guide, Company Positioning Grid, Company Market Share Analysis, Standards of Measurement, Top to Bottom Analysis and Vendor Share Analysis. To know more about the research methodology, drop in an inquiry to speak to our industry experts.

Customization of the Report

All segmentation provided above in this report is represented at country level.

All products covered in the market, product volume and average selling prices will be included as customizable options which may incur no or minimal additional cost (depends on customization)

Table of Content: Global Stem Cell Banking Market

Continued..

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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

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

More:
Cadets Research Bioprinting to Improve Soldier Care - MilitarySpot

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.

See the rest here:
The Best Serums to Brighten and Refresh Dull, Tired Skin - gearpatrol.com

TOKYO and BOTHELL, Wash., Feb. 19, 2020 /PRNewswire/ --Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle Genetics, Inc. (Nasdaq:SGEN) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for PADCEV (enfortumab vedotin-ejfv) in combination with Merck's (known as MSD outside the United States and Canada) anti-PD-1 therapy KEYTRUDA (pembrolizumab) 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.

The FDA's Breakthrough Therapy process is designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. 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.

"The FDA's Breakthrough Therapydesignation reflects the encouraging preliminary evidence for the combination of PADCEV 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 PADCEV in combination with pembrolizumab as a 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 3 trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients."

The Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the phase 1b/2 trial,EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelialcancer who are unable to receive cisplatin-based chemotherapytreated in the first-line setting with PADCEV in combination with pembrolizumab. 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 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.

About Bladder and Urothelial CancerIt 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 percent 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 withadvanced urothelial cancer is a 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

About PADCEV PADCEV (enfortumab vedotin-ejfv) was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and 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. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.5

PADCEV is 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.5,6 Nonclinical data suggest the anticancer activity of PADCEV 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).5PADCEV is co-developed by Astellas and Seattle Genetics.

Important Safety Information

Warnings and Precautions

Adverse ReactionsSerious adverse reactions occurred in 46% of patients treated with PADCEV. 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%).

Adverse 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%).

Lab AbnormalitiesIn one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased, hemoglobin decreased, phosphate decreased, lipase increased, sodium decreased, glucose increased, urate increased, neutrophils decreased.

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, please visit our website at https://www.astellas.com/en.

About Seattle Genetics Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in people's lives. The company is headquartered in Bothell, Washington, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit http://www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

About the Astellas and Seattle Genetics CollaborationSeattle Genetics and Astellas are co-developing PADCEV (enfortumab vedotin-ejfv) under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide.

About the Astellas, Seattle Genetics and Merck CollaborationSeattle Genetics and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seattle Genetics' and Astellas' PADCEV (enfortumab vedotin-ejfv) and Merck's KEYTRUDA (pembrolizumab), in patients with previously untreated metastatic urothelial cancer. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Astellas Cautionary NotesIn this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seattle Genetics Forward Looking StatementsCertain statements made in this press release are forward looking, such as those, among others, relating to the development of PADCEV in combination with pembrolizumab as a first-line therapyfor patients with advanced urothelial cancerwho are unable to receive cisplatin-based chemotherapy, and the therapeutic potential of PADCEVincluding its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibility that ongoing and subsequent clinical trials may fail to establish sufficient efficacy, that adverse events or safety signals may occur and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2019 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1American Cancer Society. Cancer Facts & Figures 2020.https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.Accessed 01-23-2020.2American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed 05-09-2019.3International Agency for Research on Cancer. Cancer Tomorrow: Bladder.http://gco.iarc.fr/tomorrow 4National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.5PADCEV [package insert]. Northbrook, IL: Astellas, Inc.6Challita-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.

SOURCE Astellas Pharma Inc.

http://www.seattlegenetics.com

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Astellas and Seattle Genetics Receive FDA Breakthrough Therapy Designation for PADCEV (enfortumab vedotin-ejfv) in Combination with Pembrolizumab in...

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

I have this really annoying habit which I know I need to work on. Despite the fact that I'm naturally a very early riser (I'm talking, *wakes up at 6:30 a.m. 365 days a yeareven on the weekends* kind of early riser), I pretty much refuse to adjust my bedtime a few hours earlierto counteract the impact of my early bird identity. I love to stay up late after a long day and binge-watch my favorite shows on Hulu, I love to read 100-page chunks of a novel, and without fail, I also love to fool around on my phone doing who even knows what. You know that feeling when you look at the clock and it's a perfectly respectable 10 p.m. and then the next time you blink it's verging on 1 a.m.?! Well, it happens to me all the time, and while I know I'd be the better for shutting down my phone, burning a candle, switching on my diffuser, and being the well-behaved beauty and wellness editor I know I should be, I really struggle to do that. And, yes, it definitely shows up on my face the next day.

I have notoriously shady under-eyes just naturally, (check out our A-list celebrity guide to dark circles, here), but my lack of sleep and consequential coffee dependence the following morning has exacerbated the situation. Luckily, my job allows me access to the newest and coolest eye creams and treatments which tout all sorts of under-eye miraclesfrom the banishment of dark circles to the erasing of puff, fine lines, and wrinkles. Spoiler: most fall flat. As in, that literally did nothing, kind of flat. However, during my 3 years as a beauty editor, I've collecteda glorified possession of creams and gels and balms that truly do work wonders on my dark circles. Regardless of whether your dark circles are sheerly caused by genetics, allergies, or not-so-stellar sleep habits (me), these shadow-targetingeye creams can lend a helping hand. Keep scrolling! I'm sharing the 15 best eye creams for dark circles I've tried since becoming a beauty editor.

Hot off of L'Occitane's French presses (it literally launched two days ago, but I received ahead of time to test-drive!), this serum has stolen my heart. It's the kid sister to the brand's best-sellingOvernight Reset Oil-in-Serum ($59) (one unit is purchased every minute!) and it uses the formula's same coveted moisture magic to do battle against telltale symptoms of fatigue like dark circles, puffiness, and expression lines. Plus, I have to say I love that you can literally see the 1,600 golden bubbles of precious Immortelle Essential Oil sitting in the stunning bottle. So stunning, right?!

Peter Thomas Roth Vital-E Microbiome Age Defense Eye Cream ($55)

Y'all, brands have really been upping the anty and cadence of eye cream launches because this is another formula for dark circles that JUST hit my vanity. (And stores everywhere.) Say goodbye to fine lines and wrinkles, dullness, uneven texture, and dark circles thanks to this protective solution designed to improve the delicate skin barrier around the eyes and support the skin's natural microbiome as well.

iS Clinical Youth Eye Complex ($105)

iS Clinical is one of the top brands chosen by the top estheticians in the industry, and this anti-aging eye cream is one of their choice formulas. Not only is it insanely creamy and hydrating (but not at all sticky or slimy like some eye creams can be!) it's a huge help in the dark circle departmentI'll apply it before bed and then again in the morning to finish off my morning skin routine. My circles are still there (obviously), but they're a lot less glaring. The key is in the mix of hyaluronic acid, peptides, and antioxidants.

111Skin Space Defence Bright Eye Lift Gel NAC Y2 ($190)

Once I found out that makeup artists use this formula from 111Skin to prep celebs' skin pre-red carpet, I was 88.5% on board. And, after a few applications when I started to notice that my under-eyes looked less shadowy and significantly firmer, tighter, and all-around less fatigued, I lept to a full 120%. Categorically, it's an eye cream, but it's formulated as a soothing, lightweight gel anyone who's against heavy, cloying creams will absolutely adore. Plus, there's the whole eye lifting effect which is pretty dang wonderful in and of itself.

EIGHTH DAY Eye Renewal Cream ($225)

If you're down to feel a little tingle (it's worth it, I promise!) this eye cream has some bite. I mean that literally because one of the reasons it quickly tightens, firms, and de-puffs is thanks to the MVP ingredient: snake venom. This has been one of my favorite formulas for a couple of years now, and it's what I reach for when my under-eyes are in a state of emergency.

RVive Skincare Intensit Complete Anti-Aging Eye Serum ($285)

Not only does the featherlight serum texture feel great underneath your eyes, but this favorite eye cream also features strategic brightening agents to help diffuse any purple circles that like to lurk. (You'll get what I mean once you see the gorgeous pearly finish.) It also looks AMAZING under makeup and concealer. It's a 10/10 if you can stomach the splurge.

By Terry Hydra-clat Eye Contour ($75)

If you have a weakness for anything lovely, French, and downright effective when it comes to your beauty product investments, you should definitely consider eye contour-improving cream from By Terry. Not only does application feel cooling and luxe thanks to the silver applicator, but it also hosts delicate ingredients like Black Rose, plant stem cells, and vitamin E to not ONLY reduce dark circles but to de-puff and soften the look of any fine lines and wrinkles. This is another one that thanks to its lightweight texture is superb under your foundation and/or concealer.

Sunday Riley Auto Correct Brightening and Depuffing Eye Contour Cream ($65)

One of my favorite eye creams of all time, this is probably the one I recommend to friends most often since it's a bit more affordable and so instantaneously affect. One swipe across your under-eyes and the mica-, caffeine-, and antioxidant-rich potion practically blurs away the look of lingering darkness. I honestly think this is Sunday Riley's absolute best product. But, that's just me.

La Prairie Skin Caviar Eye Lift Serum ($485)

Now, I wouldn't include a nearly $500 eye cream if it didn't work true sorcery against dark circles now would I? The sticker shock might be a bit gut-wrenching but this is probably THE most luxurious option for dark circles on the market. Plus, if you're consistent with use, the combination of La Prairie's iconic encapsulated caviar beads and an innovative gel-cream emulsion is probably just as effective as a pricey in-office treatment. The effect is a visual lift to the eye and brow area, less puffiness, lines, shadows, you get the idea.

Ole Henriksen Banana Bright Eye Crme ($39)

If you have dark circles, the yellow tint to this brightening elixir can definitely help with that. It's rich in vitamin C, it's anti-aging, and it even makes your concealer and foundation apply smoother. Wins all-around!

GlamGlow BRIGHTEYES Illuminating Anti-Fatigue Eye Cream ($39)

For glowing skin and under-eyes that mirror a full ten hours of sleep, try GlamGlow's new formula. It features illuminating spheres to brighten up dullness and darkness, caffeine to tighten and lift, hyaluronic acid to plump and moisturize, and last but not least peptides to diminish the appearance of fine lines and wrinkles.

Tula Skincare Glow & Get It Cooling & Brightening Eye Balm ($28)

Technically, this circle-eraser is a balm and not a cream, but please bear with meit works! Like, so, so good. You know those mornings when for whatever reason you wake up feeling like you've been hit by a freight train? Sweeping this cooling, aloe-, and caffeine-infused stick all around your eye area feels almost as good as a deep tissue marathon post-Barry's Bootcamp. (Oh, and there's also a radiance-enhancingRose Glow version FYI!)

SkinMedica Instant Bright Eye Cream ($88)

Did you know Hailey Bieber (and a slew of other celebs) is a huge fan of this brand? I don't know if miss HB has tried this brightening eye cream from SkinMedica, but if not, I personally recommend she get on that. It's brimming with tons of great ingredients like phenylethyl resorcinol (which helps to support melanin balance and correct hyperpigmentation), a hyaluronic acid blend for hydration, marine extracts to supporta healthy skin barrier, plus all the other good stuff for blue and purple under-eyes like caffeine, Persian silk tree extract, and St. Pauls Wort which aidvascular and lymphatic function for a firmer, more radiant result.

Versed Zero-G Smoothing Eye Cream ($18)

My 73-year-old mom and I agreethis affordably priced eye cream from clean skincare brand Versed, is seriously spectacular. I immediately noticed how it diminished the severity of my dark circles post-flight when I visited home recently, and my mom agreed that it reduced her puff, wrinkles, so on and so forth.

Belif Moisturizing Eye Bomb ($48)

This eye cream isn't actually touted as an eye cream for dark circles. That said, it's one of the most deeply hydrating formulas I've ever tested and due that insane moisture, I notice that my under-eys look less dried and skeletal and brighter, dewier, and plumper instead. It's a lightweight, very soothing formula that boasts a whopping 26-hour span of hydration endurance. It's one to throw in your basket the next time you find yourself wandering the aisles of Sephora.

Up next,How to Get Rid of Dark Circles Like an A-List Esthetician

This article originally appeared on Who What Wear

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I Average 5 Hours of Sleep, But No One Knows Thanks to These 15 Eye Creams - Yahoo Lifestyle

Meticulous Research a leading global market research company published a research report titled In-Vitro Toxicology/Toxicity Testing Market by Product& Service, Technology (Cell Culture, OMICS), Method (Cell-based Assays, In-Silico), End-point (ADME, Genotoxicity, Organ Toxicity, Dermal Toxicity), End-user, and Geography Global Forecast to 2025.

According to this latest publication from Meticulous Research, the globalin-vitro toxicology testing marketis expected to grow at a CAGR of 9% from 2019 to reach $14.4 billion by 2025.

Download Free Sample Copy Of The Report:: https://www.meticulousresearch.com/download-sample-report/cp_id=5047

Key questions answered in the report-

Which are the high growth market segments in terms of product & service, technology, method, end-point, end-user, and region/countries?

What was the historical market size for in vitro toxicology testing across the globe?

What are the market forecasts and estimates for the period 2019-2025?

What are the major drivers, restraints, opportunities, and challenges in the global in vitro toxicology testing market?

Who are the major players in the global in vitro toxicology testing market?

How is the competitive landscape and who are the market leaders in the global in vitro toxicology testing market?

What are the recent developments in the global in vitro toxicology testing market?

What are the different strategies adopted by the major players in the global in vitro toxicology testing market?

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

Who are the local emerging players in the global in vitro toxicology testing market and how do they compete with the global players?

Have Any Query? Ask Our Expert https://www.meticulousresearch.com/speak-to-analyst/cp_id=5047

The growth of this market is driven by factors, such as ethical issues and pressure from animal activists groups concerning the use of animals for testing, ban on animal testing on cosmetic products, support from regulatory bodies regarding the approval of in-vitro tests, low costs associated with in-vitro toxicology testing, and advancements in in-vitro methodologies. Moreover, synergetic relationships between various stakeholders in the industry and increasing toxicology databases to facilitate the use of in-vitro test methods are expected to offer significant growth opportunities for the players operating in this market.

The global in-vitro toxicology testing market study presents historical market data in terms of value (2018), estimated current data (2019), and forecasts for 2025-by product & service (equipment, assay kits, consumables, software, services), technology (cell culture technologies, high-throughput screening technologies, OMICS technologies), method (cell-based assays, biochemical assays, in-silico, ex-vivo), end-point (ADME; skin irritation, corrosion, sensitization; genotoxicity; cytotoxicity; ocular toxicity; organ toxicity; phototoxicity; and dermal toxicity), end-user (pharmaceutical & biotechnology industries, cosmetics industry, food industry, and chemical industry). The study also evaluates industry competitors and analyzes the market at a regional and country level.

You Can Directly Buy This Report From Here:: https://www.meticulousresearch.com/buy_now.php?pformat=348&vformat=1030

(Get key industry insights spread across 189 pages with 120 market data tables & 30 figures & charts from the report)

On the basis of product, the consumables segment is estimated to dominate the overall in-vitro toxicology testing market in 2019, mainly due to increasing number of in-vitro tests being performed across the globe leading to recurrent purchase of reagents and other labware. However, the software segment is projected to grow at the highest CAGR during the forecast period. The high growth of this segment can be attributed to increasing computer models and algorithms being developed to predict toxicity of test substances.

On the basis of technology, the cell culture technologies segment is estimated to account for the largest share of the in-vitro toxicology testing market in 2019, owing to growing adoption of 3D cell culture and stem cell models for toxicity testing.

On the basis of method, the in-vitro toxicology testing market is sub-segmented into cell-based assays, biochemical assays, in silico testing, and ex vivo testing. Cell-based assays segment is estimated to command the largest share of the in-vitro toxicology testing market in 2019. Advancements in cell-based technologies such as high-content screening and label-free detection are the key factors attributed to the large share of this segment in the overall market.

On the basis of end point, the ADME segment is estimated to account for the largest share of the overall in-vitro toxicology testing market in 2019. This is primarily attributed to the increasing number of early stage in-vitro ADME screening tests to prevent failure at later stage.

On the basis of end user, the in vitro toxicology testing market is segmented into pharmaceutical and biotechnology companies, cosmetics, food industry, and chemical industry. The pharmaceutical and biotechnology companies segment is estimated to account for the largest share of the overall in-vitro toxicology testing market in 2019. This is primarily attributed to increasing drug attrition rates and growing adoption of early in-vitro preclinical safety testing to filter out molecules with a higher potential for toxicity. However, the cosmetics industry segment is expected to grow at a higher rate owing to the ban on use of animals for testing toxicity of cosmetics and its ingredients.

Here are the top Market companies in the world:: https://meticulousblog.org/top-10-companies-in-in-vitro-toxicology-toxicity-testing-market/

Key Players::

In-vitro toxicology testing market is a highly consolidated in nature, wherein 3 major players Thermo Fisher Scientific (US), Merck (Germany), and GE Healthcare (US) accounted for major share of the global in-vitro toxicity testing market. Other key players operating in this market are Bio-Rad Laboratories (US), SGS SA (Switzerland), Laboratory Corporation of America Holdings (U.S.), Qiagen N.V. (Netherlands), and Eurofins Scientific (Luxembourg), among others.

Geographical Analysis::

This research report analyzes major geographies and provides comprehensive analysis of Europe (Germany, U.K., France, Italy, Spain, and RoE), North America (U.S., Canada), Asia-Pacific (China, Japan, India,and RoAPAC), Latin America, and Middle East & Africa. Europe commanded the largest share of the global in-vitro toxicology testing market, followed by North America and Asia Pacific (APAC). The large share of this region is mainly attributed to the factors such as ban on animal testing for cosmetics and its ingredients, and government initiatives to promote the reduction of use of animals for toxicity testing. Asia-Pacific region is expected to grow at the highest CAGR during the forecast period of 2019 to 2025, owing to increasing biotech investments in this region and growing collaborations between local and foreign companies.

Download Free Sample Copy Of The Report:: https://www.meticulousresearch.com/download-sample-report/cp_id=5047

Related Reports::

1Veterinary Immunodiagnostics Market Size by Product (Analysers, Consumables), by technology (ELISA, Radioimmunoassay, Rapid tests, and others), by animal type [Livestock (Cattle, Pigs, Poultry) and Companion (Feline, Canine, Equine)], by application (Infectious diseases, autoimmune disorder, endocrinology & oncology, and bone & mineral diseases), and by End-user Global Forecasts to 2022

2 Cancer Immunotherapy Market By Type (Monoclonal Antibodies, Checkpoint Inhibitors, Immunomodulators, Vaccines, Cell Therapy), Application (Lung, Breast, Multiple Myeloma, Colorectal, Melanoma, Prostate), and End User- Global Forecast to 2024

3 Competent Cells Market by Type (Cloned Competent Cells, Agrobacterium Tumefaciens Competent Cells, and Expression Competent Cells), Treatment (Chemically Competent Cells and Electrocompetent Cells), Application (Cloning, Protein Expression, others), and by End User (Pharmaceutical and Biotechnology Industry, Academic and Research Institutes, and Contract Research Organizations) Global Forecasts to 2023

About Meticulous Research

The name of our company defines our services, strengths, and values. Since the inception, we have only thrived to research, analyze and present the critical market data with great attention to details. Meticulous Research was founded in 2010 and incorporated as Meticulous Market Research Pvt. Ltd. in 2013 as a private limited company under the Companies Act, 1956. Since its incorporation, with the help of its unique research methodologies, the company has become the leading provider of premium market intelligence in North America, Europe, Asia-Pacific, Latin America, and Middle East & Africa regions.

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In-Vitro Toxicology/Toxicity Testing Market is Expected to Grow at a CAGR of 9% From 2019 to Reach $ - PharmiWeb.com

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

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

Santiago Riviello-Goya, MD1; Aldo A. Acosta-Medina, MD2; Sergio I. Inclan-Alarcon, MD3; Sofa Garcia-Miranda, MD2; and Christianne Bourlon, MD, MHSc2

1Department of Medicine, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico; 2Department of Hematology, Instituto Nacional de Ciencias Mdicas y Nutricin Salvador Zubirn, Mexico City, Mexico; 3Cancer Center, Centro Mdico ABC, Mexico City, Mexico

A 43-year-old male with a history of B-cell acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic stem cell transplantation (HSCT) 5 months prior, presented to the emergency department with a 5-day history of progressive bilateral lower extremity weakness. On physical examination, there were no additional neurologic findings; sensory function and urethral and anal sphincter tone were preserved.

Initial clinical laboratory testing showed peripheral blood cell counts, a peripheral blood smear, and a comprehensive metabolic panel within normal limits. Neuroimaging by computed tomography (CT) and magnetic resonance showed no evidence of acute intracranial processes or lesions suggestive of leukemic relapse. A lumbar puncture for cerebrospinal fluid (CSF) analysis was performed and documented the presence of lymphoid-appearing blasts (Figure 1). Flow cytometry (FC) confirmed central nervous system (CNS) infiltration by B-lineage lymphoid blasts (CD34+, CD45+, CD22+, CD19+, and CD10+) (Figure 2). Bone marrow aspirate and biopsy, including FC evaluation, were negative for systemic relapse. Bone marrow chimerism was 98%.

With a diagnosis of isolated extramedullary leukemic relapse (iEMR), the patient was initiated on weekly intrathecal chemotherapy and was weaned off graft-versus-host disease (GVHD) prophylaxis, achieving CSF clearance after 4 weeks of therapy. Against Hematology service recommendations, the patient declined systemic therapy and received only whole brain radiation therapy (24 Gy in 12 fractions).

The patient experienced remission of neurologic symptoms; however, after 5 months, he developed bilateral testicular tenderness and enlargement. An ultrasound was performed and was suggestive of leukemic infiltration (Figure 3). Chemotherapy with methotrexate and L-asparaginase in addition to radiotherapy to the testes (24 Gy in 12 fractions) was given without complications.

One year after initial CNS iEMR, the patient developed overt bone marrow relapse (BMR), as evidenced by development of bone pain throughout the lumbosacral region, and the appearance of multiple blastic and lytic lesions throughout the appendicular and axial skeleton. A positron emission tomography-CT scan documented abdominal lymphadenopathy (Figure 4). With this rapidly progressive picture, the patient was transitioned to supportive care and died 2 months later.

Is the risk of iEMR following HSCT modified by the choice of conditioning regimen? If so, which of the following approaches would have been the best choice to prevent iEMR in this patient?

A. There is no role of conditioning therapy in preventing iEMRB. Reduced intensity of regimen to favor graft-versus-leukemia (GVL) effectC. Nonmieloablative regimens including fludarabineD. Mieloablative regimens including total body irradiation (TBI)

CORRECT ANSWER: D. Mieloablative regimens including total body irradiation (TBI).

Allogeneic HSCT is an effective treatment for ALL, which can achieve long-term remission and even a potential cure.1 Antineoplastic activity is dependent on both high-dose chemotherapy and graft alloreactivity, with the latter manifested in the GVL effect, and undesirably yet inherently, in GVHD.2 Despite recent advances in allogeneic HSCT strategies, disease relapse is common and remains the most important cause of death in this population. Relapse is reported in 30% to 40% of patients but can increase to 60% in patients who are in a second complete remission (CR) at time of HSCT.2,3

Risk factors for relapse in patients with ALL who have undergone HSCT include disease- and transplant-related features. Reported high-risk disease characteristics include: hyperleukocytosis at diagnosis (white blood cell count >30 x109/L for B-lineage ALL and >100 x109/L for T-lineage ALL); cytogenetics associated with poor outcomes, including chromosome 11 translocations and t(9;22); a short remission timespan; more than a first CR; and a failed or delayed remission after induction therapy.4 In the HSCT population, transplant-related factors should be considered, including alternative donors other than those who are matched related and matched unrelated, the type of conditioning regimen, and the development of GVHD.2

ALL relapse following HSCT most commonly involves the medullary compartment, with a cumulative incidence of 41% at 5 years. Conversely, extramedullary relapse (EMR) is uncommon, with a 5-year cumulative incidence of 11.0% and 5.8% for EMR and iEMR, respectively.5 Due to the rarity of EMR, its prognostic impact remains controversial and the ideal management strategies are a subject of active study.

EMR is associated with poor clinical outcomes; however, the subgroup of patients with iEMR (as presented in this patient case) is gaining attention due to its increasing frequency, its role heralding a systemic relapse, and its clinical behavior showing better survival outcomes compared with BMR and EMR.6-8

Isolated EMR is defined as the presence of clonal blasts in any tissue other than the medullary compartment; bone marrow evaluation must show less than 5% of clonal blasts and a full donor chimerism. Most commonly affected sites include the skin, soft tissues, lymph nodes, and immune sanctuaries including the CNS and testes.1,5,9 Because prevention rather than treatment of relapse is related to improved survival outcomes, it is important to define subgroups of patients who may benefit fromearly intervention with a personalized transplant strategy.

Higher rates of iEMR have been linked to patients of younger age. This is thought to be secondary to: (1) a higher incidence of ALL compared with acute myeloid leukemia (AML) in this age subgroup, the former of which is most associated with EMR; (2) the relative overrepresentation of myelomonocytic/monocytic phenotypes in AML presenting in young individuals; and (3) the higher likelihood of a history of EMR in children compared with adults.1,10

A history of extramedullary (EM) disease, which has consistently been found to impact the development of iEMR, is preexistent in up to half of patients. In 2 out of 3 cases of EMR, disease affects the site of original EM involvement, possibly due to low efficacy of both high-dose chemotherapy and the GVL effect.1,5 An exception to this is CNS involvement, despite being a risk factor for subsequent CNS iEMR, which is commonly reported de novo, reflecting the protective effect of regularly administered prophylaxis to patients at high risk of CNS infiltration.11

The effect of GVHD on risk of iEMR is highly nuanced. Despite its well-known role as a protective factor for BMR, the same effect does not appear to hold true for iEMR.12 Initial reports in this population showed no differences in relapse-free survival regardless of acute or chronic GVHD (cGVHD) or a positive association between extensive cGVHD and iEMR development.10,13 This has led to investigators to postulate that the underlying physiopathology differs among different types of relapse, with decreased expression of human leukocyte antigen (HLA) minor histocompatibility antigens and adhesion molecules and decreased penetration of both immune cells and high-dose chemotherapy to EM sites.14 These mechanisms lead to decreased effectivness of T-cell dependent cytotoxicity of donor lymphocytes as compared with the medullary compartment, with subsequent clone selection and escape, enabling the development of iEMR.6

With the increased use of alternative donors, this has been contested in the haploidentical setting, with a recent report showing significantly increased rates of iEMR in patients who do not develop cGVHD. It is suggested that the role of GVL, coupled with GVHD, in this HLA-mismatched setting could partially explain the added benefit of GVHD in this subgroup. This report also evidenced increased tumor chemosensitivity in patients with EMR compared with BMR, possibly explained by reduced concentrations of conditioning therapy at EM sites.9

Cytogenetics associated with poor outcomes and advanced disease at the time of HSCT were described as risk factors for iEMR in initial cohort studies.1,5,10,15,16 However, recent publications that include alternative-donor HSCT recipients have reported that a haploidentical source could overcome this negative impact.9

The influence of type of conditioning regimen on likelihood of iEMR has been studied only retrospectively, mainly comparing TBI-based versus chemotherapy-based approaches. The landmark paper by Simpson et al showed a significantly elevated rate of iEMR in patients receiving busulfan-based conditioning. This finding has been related to the lack of penetration of drugs into the immune sanctuaries with chemotherapy-only regimens.17

Multiple approaches, including combination and single treatment for iEMR, have been described. Combination therapy including systemic chemotherapy plus local radiotherapy (or in CNS disease, radiation to the craniospinal axis, intrathecal chemotherapy, and systemic chemotherapy) has been associated with higher response rates than single-treatment strategies.9 Nonetheless, the best responses have been observed when combination therapy is followed by a cellular therapy (eg, second allogeneic HSCT, donor leukocyte infusion, and donor stem cell infusion), leading to CR rates of greater than 80%.5,13 Whether this increase in CR rate translates to an increase in survival outcomes remains debatable due to conflicting results in the current literature for iEMR.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Corresponding author:

Christianne Bourlon, MD, MHScVasco de Quiroga No. 15.Belisario Domnguez Seccin XVI

Tlalpan, C.P. 14080, Ciudad de Mxico, Mxico

E-mail: chrisbourlon@hotmail.com

References:

1. Ge L, Ye F, Mao X, et al. Extramedullary relapse of acute leukemia after allogeneic hematopoietic stem cell transplantation: different characteristics between acute myelogenous leukemia and acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2014;20(7):1040-1047. doi: 10.1016/j.bbmt.2014.03.030.

2. Pavletic SZ, Kumar S, Mohty M, et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol Blood Marrow Transplant. 2010;16(7):871-890. doi: 10.1016/j.bbmt.2010.04.004.

3. Devillier R, Crocchiolo R, Etienne A, et al. Outcome of relapse after allogeneic stem cell transplant in patients with acute myeloid leukemia. Leuk Lymphoma. 2013;54(6):1228-1234. doi: 10.3109/10428194.2012.741230.

4. Hoelzer D, Bassan R, Dombret H, Fielding A, Ribera JM, Buske C; ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v69-v82. doi: 10.1093/annonc/mdw025.

5. Shem-Tov N, Saraceni F, Danylesko I, et al. Isolated extramedullary relapse of acute leukemia after allogeneic stem cell transplantation: different kinetics and better prognosis than systemic relapse. Biol Blood Marrow Transplant. 2017;23(7):1087-1094. doi: 10.1016/j.bbmt.2017.03.023.

6. Lee JH, Choi SJ, Lee JH, et al. Anti-leukemic effect of graft-versus-host disease on bone marrow and extramedullary relapses in acute leukemia. Haematologica. 2005;90(10):1380-1388.

7. Xie N, Zhou J, Zhang Y, Yu F, Song Y. Extramedullary relapse of leukemia after allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore). 2019;98(19):e15584. doi: 10.1097/MD.0000000000015584.

8. Shi JM, Meng XJ, Luo Y, et al. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis. Leuk Res. 2013;37(4):372-377. doi: 10.1016/j.leukres.2012.12.002.

9. Mo XD, Kong J, Zhao T, et al. Extramedullary relapse of acute leukemia after haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes. Biol Blood Marrow Transplant. 2014;20(12):2023-2028. doi:10.1016/j.bbmt.2014.08.023.

10. Harris AC, Kitko CL, Couriel DR, et al. Extramedullary relapse of acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcomes. Haematologica. 2013;98(2):179-184. doi: 10.3324/haematol.2012.073189.

11. Hamdi A, Mawad R, Bassett R, et al. Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(11):1767-1771. doi: 10.1016/j.bbmt.2014.07.005.

12. Giralt SA, Champlin RE. Leukemia relapse after allogeneic bone marrow transplantation: a review. Blood. 1994;84(11):3603-3612.

13. Solh M, DeFor TE, Weisdorf DJ, Kaufman DS. Extramedullary relapse of acute myelogenous leukemia after allogeneic hematopoietic stem cell transplantation: better prognosis than systemic relapse. Biol Blood Marrow Transplant. 2012;18(1):106-112. doi: 10.1016/j.bbmt.2011.05.023.

14. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112(12):4371-4383. doi: 10.1182/blood-2008-03-077974.

15. Lee KH, Lee JH, Choi SJ, et al. Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course. Bone Marrow Transplant. 2003;32(8):835-842. doi: 10.1038/sj.bmt.1704223.

16. Clark WB, Strickland SA, Barrett AJ, Savani BN. Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome. Haematologica. 2010;95(6):860-863.

17. Simpson DR, Nevill T, Shepherd JD, et al. High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation. Bone Marrow Transplant. 1998;22(3):259-264. doi: 10.1038/sj.bmt.1701319.

Excerpt from:
Isolated Extramedullary Relapse in Acute Lymphoblastic Leukemia: What Can We Do Before and After Transplant? - Cancer Network