Archive for February, 2020

In 2004, Dr. Michael Ackerman got an unexpected phone call.

On the other end of the line was a medical examiner in Kentucky who had recently performed a befuddling autopsy on a 12-year-old Amish girl.

He was perplexed why this seemingly healthy Amish child died suddenly during play, said Ackerman, a genetic cardiologist at Mayo Clinic who studies why some young people die unexpectedly. And he says, I have DNA for you.

Ackerman, who also leads Mayos Windland Smith Rice Sudden Death Genomics Laboratory, pioneered a postmortem test to detect genetic causes behind sudden death. The medical examiner in Kentucky had heard about his work.

That phone call would ignite more than a decade of genetic sleuthing across multiple states to understand why a healthy Amish child had died without an obvious explanation. The mystery of her death and later, the deaths of more than a dozen other Amish children would vex researchers and clinicians for years, until Ackerman and his colleagues finally made a breakthrough in their Mayo lab.

Those findings were recently published in the JAMA Cardiology medical journal. Now, those same researchers are working to find a treatment.

Not long after the medical examiners call in 2004, Ackerman and his team were just beginning their research into the girls DNA when tragedy struck again. Four months after losing their daughter, the family lost her 10-year-old sister under similar circumstances suddenly, while she was outside playing.

Ackerman said his research team had a hunch the siblings deaths involved a gene called RYR2. When there's a single error on the gene, it causes an irregular heart rhythm that often reveals itself in the form of fainting spells while exercising. It can be fatal.

But that was more than 15 years ago, and medical research tools hadnt quite caught up to the teams needs.

Back then, it was painfully slow. It sort of was one gene at a time, Ackerman said.

After extensive testing of the girls' DNA, the Mayo researchers still had no answers.

We basically had a project that was stalled and would stay stalled until we would have evolution of technology, Ackerman said.

Over the next decade, 16 more Amish children died while exercising, without warning. The same family that lost their daughters in 2004 lost two more children under similar circumstances. Amish children in other states died, too.

While Mayos research languished, more than a thousand miles away, doctors at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., encountered a similarly tragic story.

In 2005, a young, apparently healthy Amish child was playing and died suddenly. The autopsy revealed no obvious cause. Several years later, the girls sister experienced cardiac arrest but survived and she is still living, 15 years later.

This started a trend, essentially, in their family, said Kristi Fitzgerald, a genetic counselor at Nemours and an author of the JAMA paper. Its not just a fluke chance, a terrible, tragic event. Now with two girls in one family, the presumption was that this probably was a genetic cause, something to do with a genetic arrhythmia.

But just as in Ackermans lab in Rochester, Minn., genetic testing at Nemours turned up nothing.

Over the years, Nemours staff collaborated with Mayo staff, and in the process learned that the sisters who had died in Kentucky were from the same extended family as the child who had died in Delaware.

Researchers also identified additional relatives in Iowa who have the same genetic defect. To date, no members of Amish communities in Minnesota appear to have the condition.

Clinicians at Mayo and elsewhere are fiercely protective of the families affected, and declined to identify them to maintain their privacy.

In Rochester, Ackerman and his staff continued to collect DNA samples from the children who died in this perplexing way, hoping someday to figure out the cause of their death.

They just needed the technology to catch up. In 2016, it started to.

Ackerman said new testing techniques revealed that the sudden deaths weren't caused by just one error on the RYR2 gene they were caused by 300,000 of them.

What's more, the risk of sudden death came only when the children inherited that faulty gene from both parents.

"We basically did genomic triangulation and figured that all of these sudden deaths and all of these different Amish communities were happening for the exact same reason: a double whammy, a double hit of this exact same duplication, Ackerman said.

Nemours pediatrician Matthew Demczko has made a career working with Amish children who live with an array of genetic abnormalities.

He said the genetic heart defect detected by the Mayo team is likely unique to the Amish community. Thats because researchers think people with the defect are all connected to a small number of people who established a particular Amish community from which the children affected were all descended. Those people are what Demczko calls "founder individuals."

Their genetic information has now become sort of the genetic thumbprint of the entire community, he said.

Demczko said Amish communities tend to be small and insular, and members of the community typically marry and have children with people who are also Amish.

That factor on top of the idea that from a cultural perspective, very few individuals come into the Amish community, there's really no introduction of new genetic material, he said.

Beating heart cells engineered from blood donated by two people living with a condition that has caused the sudden deaths of Amish children are shown on a microscope screen inside of the Mayo Clinic's Windland Smith Rice Sudden Death Genomics Laboratory.

Evan Frost | MPR News

Fitzgerald, Demczkos colleague, is on the front lines of screening members of Amish communities in their region for the defect. She said that Nemours positive reputation in nearby Amish communities helps in her work.

Word of mouth is important, she said. I think that's a great source of referral, to have a patient to say, We had a good experience. This went well.

Fitzgerald said her Amish patients ask the same questions about genetic testing as other families do: What will the test tell them? Why is the test important? What will they do with the information if they test positive?

And she said it's a misconception that Amish people shun medicine.

The families shes worked with, she said, have been open to testing and treatment.

"Parents want what's best for their child. It's about building a relationship, you know, with the family, she said. Most are not at all skeptical."

Fitzgerald said that some parents whose children have tested positive for the condition have opted to get an implantable defibrillator, which is the only available treatment.

But many Amish families dont carry health insurance, so that solution is not only invasive, but can be prohibitively expensive.

Back at Mayo, researcher Dave Tester is trying to better understand the genetic defect he helped discover. Now that theyve pinpointed the cause of the childrens sudden death, theyre trying to find a more affordable and accessible treatment.

"This is sort of phase 2 in this study, said Tester, who also authored the JAMA article.

To do that, the researchers turned to another novel approach: They engineered beating heart cells from blood samples donated by two people living with the condition.

He points to a cluster of heart cells undulating rhythmically under a microscope.

"These cells have the same exact genetic background that our patient does, he said. Here we can understand, at least from this patient's perspective what is the cell doing?"

Beating heart cells from blood samples donated by two people living with a condition that has caused the sudden death of Amish children.

Evan Frost | MPR News

In the coming months, Tester and his staff will perform a battery of tests on these cells, looking for clues that point them toward a better treatment.

But in the meantime, Mayo and Nemours continue to collaborate to understand just how common the condition is and how widespread. Their network has also extended to Iowa, where a genetic counselor is working with nearby Amish communities.

To ease that process, Mayo has made the test free for Amish families who may be affected.

Fitzgerald, the genetic counselor, is hopeful additional screening in Delaware and in other Amish communities will reveal more information about the condition.

And while she may not be able to offer her families a perfect solution today, at least they're starting to get some answers.

We don't want to give false hope, but I think it is important to tell families how far we come, she said. We tell people Hold on, stay tuned.

More:
Amish kids were dying mysteriously. Mayo scientists solved it. But can they treat it? - Minnesota Public Radio News

Senator Thomas J. Umberg (D-Santa Ana) announced today his introduction of legislation that would assure consumers that Direct-to-Consumer (DTC) genetic testing companies will use their genetic data solely for the purposes they consented to.

The fact that the Pentagon just warned all of the countrys military personnel to avoid home DNA tests should raise bright red flags for all consumers, said Senator Umberg. Direct-to-Consumer genetic testing companies have, to date, gone largely unregulated by either state or national governments. This has led to the disclosure of consumers private biological information to third parties.

Although the California Consumer Privacy Act (CCPA) regulates DTC genetic companies by allowing consumers to request information on how their data is being used and to opt out if they so wish, it does not solve the fact that current authorization forms are confusing, and consumers often lack clarity about what they are consenting to. Several media outlets have published stories in recent months of genetic data being improperly used to conduct drug research, discriminate against possible consumers in regard to insurance products, or being stored on hackable private servers.

In December 2019, the Pentagon issued a memo asking service members to not use DTC genetic services due to, the increased concern in the scientific community that outside parties are exploiting the use of genetic materials for questionable purposes, including mass surveillance and the ability to track individuals without their authorization or awareness.

Umbergs measure, Senate Bill 980, creates strict guidelines for authorization forms in a manner that allows consumers to have control over how their DNA will be used. In addition, the measure creates civil penalties for companies that fail to comply with the provisions within it. By passing this act, California would be joining four other states that have made it clear that consumers should control their genetic data without fear of third parties exploiting it. Forcing these companies to clarify their consent forms and requiring them to obtain written authorization for any genetic data disclosure, including de-identified data, will reassure California consumers that their most personal information is safe, noted Senator Umberg.

In support of SB 980, Emily Rusch, Executive Director of the California Public Interest Research Group (CALPIRG) noted that, Consumers deserve to have complete control over the sharing of our genetic data, the most personal, private information about our bodies. We strongly support this proposal to require consumers opt-in consent before genetic data is shared with third parties.

Senate Bill 980 (language attached) will be assigned to, and heard, by Senate policy committees in mid-late March.

Courtesy photo

Originally posted here:
Umberg wants consumers to control of their genetic data - EVENT NEWS

Ive had three miscarriages and one ectopic pregnancy, and every single time I blamed my body, says Danielle Campoamor, 33, a mother of two in New York. My self-hatred became so severe I couldnt look at myself in the mirror. I starved my body as if I was paying a penance. I spent so much of the mourning process asking what was wrong with me. What was wrong with my body.

The shame associated with miscarriage can be overwhelming. As a psychologist specializing in womens reproductive and maternal mental health, I find that counseling patients like Campoamor who blame themselves for their pregnancy losses is as common as loss itself. The women in my office are often riddled with guilt, revisiting every minute detail of their lives in search of the reason behind their miscarriage. In the haze of grief, they point the finger at themselves: Was it something they ate? Did they workout too often? Had they done something catastrophic in the weeks before they even knew they were pregnant?

Having access to concrete answers could change a lot.

At least half of all miscarriages are the result of an abnormal number chromosomes in the embryo, according to the American College of Obstetricians and Gynecologists. Its the most common cause of pregnancy loss. But getting access to the genetic testing of fetal tissue is complicated and costlygenetic testing is rarely offered to anyone whos experienced less than three miscarriages, and it can cost thousands of dollars. A new rapid genetic test, developed by Zev Williams, M.D., Ph.D., director of the Columbia University Fertility Center at New York Presbyterian Hospital, and his team, hopes to change that. The new test would take just hours to complete and could cost less than $200. Williams expects the test to be available within a year, but it will need to be approved by medical regulatory agencies.

Campoamor says that kind of info would have made all the difference when she was mourning her losses. What I wouldnt have given to have access to a test that wouldve let me know that my body didnt let me down, that there was a problem with the pregnancies from the beginning, she says.

A 2015 national survey published in the Journal of Obstetrics & Gynecology found that 47% of people whove had a miscarriage feel guilty, and 41% felt they had done something wrong to cause the pregnancy loss: 76% of Americans believe pregnancy loss is caused by a stressful event, 64% believe its caused by the pregnant person lifting a heavy object, 28% believe previously using an intrauterine device causes miscarriages, and 22% blame the use of oral contraceptives, according to the survey. I blamed my IUD. I blamed my decision to use birth control at the age of 15. I blamed my job, my work load, a harmless argument with my partner, running at the gym. I looked for any reasonanythingto blame for my losses, Campoamor says. Theres no evidence that any of these things contribute to miscarriage, but the stigma persists. Years later, I still have to work to not blame myself, what I ate, how much water I did or didnt drink. The self-blame just lingers.

After each loss I felt like I was in the dark. Information about why it happened, why my body didnt hold onto those pregnancies, wouldve felt like a lantern.

The same survey found that 78% of the participants reported wanting to know the cause of their miscarriage, even if no intervention could have prevented it from occurring. Thats precisely why this test is poised to be such a game changer. Getting women answers could help dissolve the feelings of shame and failure that so often shroud a miscarriage. A 2019 study found that one in six women experience long-term post-traumatic stress following a miscarriage, and 1 in 10 women meet the criteria for major depression directly following a loss. Bypassing the mystery can potentially lead to a smoother, less complicated emotional journey.

The test wont answer every question about a miscarriage. For starters, it requires tissue from the pregnancy to test, and doctors may not always have the opportunity to gather it. If a test reveals that there were no genetic abnormalities, it could trigger even more questionsand self-blameabout the cause. But even that can be helpful. In the minority of cases where the cause of the loss was not genetics, it allows us to look for the cause soonerbefore waiting for the women to have multiple more losses, says Williams. If a cause is discovered, it can be corrected so the couple can have the best chance for success in the next pregnancy.

As humans, we like to know why. Ive sat across from hundreds of women and heard the desperation in their voices as they search for a reason why they didnt carry a pregnancy to term. This test could help mitigate some of the psychological fallout of pregnancy loss by separating fact from fiction, science from a pervasive cultural misunderstanding that fuels self-blame and self-hatred.

After each loss I felt like I was in the dark, Campoamor says. Like I was just feeling my way through grief, trying to hold onto something, anything, before I floated away. Information about why it happened, why my body didnt hold onto those pregnancies, wouldve felt like a lantern. It wouldnt have assuaged my pain, but it would have lit a path through it.

Jessica Zucker is a Los Angeles-based psychologist specializing in womens reproductive health and the author of the forthcoming book I Had a Miscarriage: A Memoir, a Movement (Feminist Press, 2021).

More:
Women Blame Themselves for Miscarriages. This Test Could Change That - Glamour

Feb. 19, 2020 11:00 UTC

HUNTINGTON BEACH, Calif.--(BUSINESS WIRE)-- Cicero Diagnostics Inc., a womens healthcare diagnostic company, is pleased to announce the awarding of a $1 million Phase II SBIR Fast Track grant from the National Institutes of Health (NIH). The grant, titled "SIRT1 and BCL6: Dual Biomarkers of Endometriosis and Endometrial Receptivity follows completion of Phase I, successfully demonstrating concordance of the protein markers BCL6 and SIRT1 to endometriosis, a leading cause of unexplained infertility. According to the American Society of Reproductive Medicine, endometriosis is associated with 30-50% of all cases of unexplained infertility (over 500,000 cases a year). Cicero Diagnostics on-going commercialization of protein markers to assess uterine receptivity impacted by endometriosis inflammation has proven to be a significant breakthrough in helping women successfully achieve pregnancy.

Cicero Diagnostics currently offers BCL6 as part of their ReceptivaDx test for unexplained infertility, failed implantation and recurrent pregnancy loss. Over 300 fertility centers representing more than 1,000 reproductive endocrinologists across the US and globally are successfully using the test for assessing uterine lining dysfunction typically caused by endometriosis without the cost and invasiveness of surgical laparoscopy. Once identified and treated, outcomes data from both published studies and fertility centers using the test commercially have demonstrated significantly higher success rates in women with IVF failure histories.

Chris Jackson, CEO of Cicero Diagnostics, states, Were proud that ReceptivaDx has helped so many women challenged with infertility. While IVF success rates are now approaching 50-60%, we remain focused on finding answers for the 40-50% of patients where IVF and genetic testing of embryos still doesnt result in pregnancy. This doesnt even begin to address the financial and emotional toll experienced by these women, their partners and their families as a result of those failures. By detecting uterine lining conditions without requiring expensive invasive surgery, we have created a tremendous value proposition for women that have experienced IVF failure and want answers before repeating the IVF process. Phase II of the NIH grant will also let us focus on developing testing for the 85% of women in the US that dont have fertility coverage or the means for seeking advanced fertility help. Expanding the offering to the OB market has been a goal of Cicero Diagnostics from day one and remains a primary goal looking forward.

The Phase II portion of the NIH grant includes a broad range of prestigious universities with significant experience in fertility studies. Patients will be drawn from three main centers and include Wake Forest Health Sciences, University of North Carolina and Stanford University. The NIH grant will continue studies building on published data already in the public domain showing the accuracy of these markers in uncovering and treating women with unexplained infertility. The study is designed to end in late 2021.

Specifically, the new studies will:

Cicero Diagnostics is a medical diagnostic company located in Huntington Beach, California. ReceptivaDx is the companys signature test panel in the area of unexplained infertility. Cicero Diagnostics is the exclusive licensed provider of BCL6 and SIRT1 for the detection of endometriosis. Working with IVF centers across the U.S. and in 15 other countries, Cicero Diagnostics continues to expand their offering globally and is investing in continuing research in the field.

For more information, go to http://www.CiceroDx.com or http://www.ReceptivaDx.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200219005339/en/

Read the original post:
Cicero Diagnostics Awarded $1 Million NIH Grant to Further Research on Markers for Unexplained Infertility, Failed Implantation and Recurrent...

Obit Larry Tesler self-described "primary inventor of modeless editing and cut, copy, paste" has died at the age of 74.

Tesler had a hand in many of the computing concepts taken for granted today. On his website he wrote: "I have been mistakenly identified as 'the father of the graphical user interface for the Macintosh'. I was not. However, a paternity test might expose me as one of its many grandparents."

After a stint at Stanford culminating in AI research in 1973, Tesler became a member of the research staff at Xerox's famed Palo Alto Research Center (PARC).

There, thanks to his intense dislike of operation modes of the era, he conceived and implemented many graphical user interface (GUI) features taken for granted today.

Tesler was very keen on "modeless" software, where a user would not have to, for example, use a keyboard to switch to a command mode before switching back to edit text. Tesler's vision was that a user's action should have a consistent effect there should be no "modes."

It is therefore unsurprising that while at Xerox PARC he laid claim to coming up with the ability to point and click to insert or overwrite text without needing to enter a mode. Entering a mode was also not required for the cut, copy and paste operations.

Apple snapped him up in 1980 and during his time at the firm he rose to vice president and chief scientist. He worked on user interface design and software engineering for the Lisa application API and led development of the first commercial object-orientated frameworks. He was also a voice of support of the spinout of Arm from Acorn (see below) and would go on to serve on Arm's board for 13 years.

Not mentioned on his CV was his involvement in Apple's personal digital assistant (PDA) Newton project, which Tesler took over in 1990 and set in motion events that would see the Arm dominance of today. The low power consumption of the silicon while idle appealed, as did its ability not to hammer the battery of the doomed handheld while running. The Newton, or MessagePad as it was eventually branded, launched in 1993, resplendent in a case designed by a young Jony Ive.

While innovative, the PDA did not set the market on fire and, despite updates, was eventually killed off in 1998, shortly after the return of Steve Jobs to Apple.

By then Tesler had moved on, putting four years into an educational software startup called Stagecast then to Amazon in 2001 and creating the usability group as well as managing data mining and market research to give Bezos' brigade a more effective insight in customers.

Between 2005 and 2008 he was VP of user experience and design at Yahoo! before a year-long stint as a product fellow at genetic testing outfit 23andMe. He rounded out his career as a technology consultant specialising in user experience management, research and design.

While Tesler's name may not have the fame (or infamy) of Jobs (or even Ive) his impact, his work from the earliest free-wheeling days of computing through to projects like the MessagePad continue to be felt today.

Sponsored: Detecting cyber attacks as a small to medium business

Read the rest here:
Larry Tesler cut and pasted from this mortal coil: That thing you just did? He probably invented it - The Register

This transcript has been edited for clarity.

I'm Dr Richard Isaacson, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian.

Hormone replacement therapy (HRT) for Alzheimer's prevention is a loaded topic, around which there are a lot of differing opinions out there. Over the past 5 years, I can tell you that my own comfort level with discussing this topic has definitely evolved exponentially.

Five years ago, I wouldn't have even wanted to talk about a topic like this because the data were all over the place. At that time, I may have been able to state one thing: HRT during the perimenopause transition may have some protective effect on the brain. I couldn't say whether it's protective against dementia, Alzheimer's, or cognitive declinejust that taking HRT for 5-7 years during the menopause transition was okay. But I'd add, "I don't know. I'm just a brain doctor. You should probably go see an ob/gyn."

Today, things are a little bit different. Now when I see a woman with a family history of Alzheimer's disease at our program who wants to try to do anything to reduce her risk for dementia, I spend at least 10-15 minutes in the first hour-and-a-half visit just talking about HRT.

We talk about what her symptoms are. Is she having hot flashes? If so, I explain that hot flashes are not necessarily just an endocrine-related thing; it's really a neurologic manifestation of a hormonal shift in the brain.

I take a pretty comprehensive history of the perimenopausal changes. When was the very first time she started having any symptom whatsoever? Is it night sweats? Is it mood changes? Is it something else?

I also don't ask just about brain symptoms but about other symptoms that maybe neurologists don't focus on too much: Is there vaginal dryness? Is there pain during intercourse? These are really important things to understand, because it helps me fine-tune my understanding of the underlying issues. I can hone in on whether there is a local problem of too little estrogen in the reproductive organs or whether it is just neurologic complaints.

When it comes to HRT, I don't think we know exactly what the right treatment is. However, my general feeling, based on the evidence, being cautious, and wanting to do no harm, is that less is more. For example, is it really necessary to take a pill of estrogen when a very small dose of a cream or even a patch may give a smoother, more continuous delivery over time, which may in fact replicate the body's natural process anyway? Based on my own gut instinct and reviewing the best available evidence on my own and in conversation with many ob/gyns and reproductive endocrinologists, a patch may be sufficient.

Does a person just need estrogen or perhaps progesterone as well? This requires taking a clinical history. Even though we're an Alzheimer's prevention clinic, we now look at hormones, estradiol, progesterone, and all sorts of different things. We obtain these baseline results and follow them over time, just as we track other objective measures. In addition to body composition (eg, fat levels or muscle mass), cognitive function, cholesterol levels, and metabolism, hormones are now one of the important puzzle pieces we consider.

Another aspect of this that we're really just starting to look at is brain function. For example, what if a woman in the perimenopause transition has glucose hypometabolism, meaning reduced glucose activity in specific brain regions that are worrisome for the earliest phases of Alzheimer's disease, even before they exhibit symptoms? Is that someone who I may want to pay more attention to from a hormone replacement perspective? If someone has normal brain metabolism versus impaired brain glucose metabolism, maybe that can give us a clue as to whether they need HRT, and if so, which specific type of treatment.

Although the jury is still out about some of these seminal questions, there has been a big difference in my response to hormone replacement as a potential protective intervention for Alzheimer's prevention.

Now, I understand these idiosyncrasies. I understand that, in the future, whether it's 2 or 10 years away, patients will get an examination, blood test, and perhaps a brain scan, followed by a conversation with their physician to really understand the specific aspects of hormone deficiency that may need to be replaced or balanced in an effort to protect brain function over time.

Also in a few years, when someone goes on HRT, aside from just getting a bone scan and perhaps responding to a questionnaire, they may also get a brain scan. By better understanding this, perhaps we can tell whether whatever variation or specific regimen of HRT the person was put on needs to be changed because cognitive function actually declined.

I truly believe that the perimenopause transition is an exceptional window of opportunity in our fight against Alzheimer's disease. Two out of every three brains affected by Alzheimer's disease is a woman's brain. Five to 10 years ago, I had no idea why. It's not just because women live longer; it's because hormone transition affects brain pathology, brain metabolism, and the person's risk for Alzheimer's disease.

Another key consideration is weighing the risks versus the benefits of HRT so we can get everyone on the same page. For example, if someone has a familial risk for breast cancer, or if the woman has actually had a stroke, a blood clot, or currently smokes, these are all things that increase the potential risks of using HRT. Also, what if a person is using progesterone and she has her uterus? Maybe she will be increasing her risk for uterine cancer. These are really important aspects to consider.

But overall, I would say the gestalt about HRT and its specific impact on women's Alzheimer's risk is that it's an individual decision. One must balance the risks versus benefits, take into account the evolving evidence, and really consider the type, dose, method of delivery, and duration of the HRT. For example, in our practice, 5-7 years of HRT sounds reasonable, but does 10, 12, 15 years, or more? I'm not sure that we really know enough to have a one-size-fits-all approach to this.

In the next several years, I expect much new data to come from our research and from others'. I think, following that, we will have the recipe, algorithm, or at least a general set of recommendations for HRT to reduce Alzheimer's risk.

Thanks so much for listening.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

Originally posted here:
Why a Brain Doctor Asks About Hormone Replacement Therapy - Medscape

TPG Specialty (TSLX) came out with quarterly earnings of $0.51 per share, beating the Zacks Consensus Estimate of $0.47 per share. This compares to earnings of $0.67 per share a year ago. These figures are adjusted for non-recurring items.

This quarterly report represents an earnings surprise of 8.51%. A quarter ago, it was expected that this business development company would post earnings of $0.48 per share when it actually produced earnings of $0.55, delivering a surprise of 14.58%.

Over the last four quarters, the company has surpassed consensus EPS estimates three times.

TPG, which belongs to the Zacks Financial - Mortgage & Related Services industry, posted revenues of $66.50 million for the quarter ended December 2019, surpassing the Zacks Consensus Estimate by 3.62%. This compares to year-ago revenues of $74.74 million. The company has topped consensus revenue estimates three times over the last four quarters.

The sustainability of the stock's immediate price movement based on the recently-released numbers and future earnings expectations will mostly depend on management's commentary on the earnings call.

TPG shares have added about 5.7% since the beginning of the year versus the S&P 500's gain of 4.3%.

What's Next for TPG?

While TPG has outperformed the market so far this year, the question that comes to investors' minds is: what's next for the stock?

There are no easy answers to this key question, but one reliable measure that can help investors address this is the company's earnings outlook. Not only does this include current consensus earnings expectations for the coming quarter(s), but also how these expectations have changed lately.

Empirical research shows a strong correlation between near-term stock movements and trends in earnings estimate revisions. Investors can track such revisions by themselves or rely on a tried-and-tested rating tool like the Zacks Rank, which has an impressive track record of harnessing the power of earnings estimate revisions.

Ahead of this earnings release, the estimate revisions trend for TPG was favorable. While the magnitude and direction of estimate revisions could change following the company's just-released earnings report, the current status translates into a Zacks Rank #2 (Buy) for the stock. So, the shares are expected to outperform the market in the near future. You can see the complete list of today's Zacks #1 Rank (Strong Buy) stocks here.

It will be interesting to see how estimates for the coming quarters and current fiscal year change in the days ahead. The current consensus EPS estimate is $0.49 on $64.50 million in revenues for the coming quarter and $1.96 on $267.42 million in revenues for the current fiscal year.

Investors should be mindful of the fact that the outlook for the industry can have a material impact on the performance of the stock as well. In terms of the Zacks Industry Rank, Financial - Mortgage & Related Services is currently in the top 8% of the 250 plus Zacks industries. Our research shows that the top 50% of the Zacks-ranked industries outperform the bottom 50% by a factor of more than 2 to 1.

To read this article on Zacks.com click here.

Zacks Investment Research

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

Read more here:
TPG Specialty (TSLX) Q4 Earnings and Revenues Top Estimates - Nasdaq

America's Car-Mart (CRMT) came out with quarterly earnings of $1.83 per share, beating the Zacks Consensus Estimate of $1.78 per share. This compares to earnings of $1.55 per share a year ago. These figures are adjusted for non-recurring items.

This quarterly report represents an earnings surprise of 2.81%. A quarter ago, it was expected that this auto retailer would post earnings of $1.85 per share when it actually produced earnings of $2, delivering a surprise of 8.11%.

Over the last four quarters, the company has surpassed consensus EPS estimates four times.

America's Car-Mart, which belongs to the Zacks Automotive - Retail and Whole Sales industry, posted revenues of $186.73 million for the quarter ended January 2020, surpassing the Zacks Consensus Estimate by 5.51%. This compares to year-ago revenues of $161.05 million. The company has topped consensus revenue estimates two times over the last four quarters.

The sustainability of the stock's immediate price movement based on the recently-released numbers and future earnings expectations will mostly depend on management's commentary on the earnings call.

America's Car-Mart shares have added about 10.9% since the beginning of the year versus the S&P 500's gain of 4.3%.

What's Next for America's Car-Mart?

While America's Car-Mart has outperformed the market so far this year, the question that comes to investors' minds is: what's next for the stock?

There are no easy answers to this key question, but one reliable measure that can help investors address this is the company's earnings outlook. Not only does this include current consensus earnings expectations for the coming quarter(s), but also how these expectations have changed lately.

Empirical research shows a strong correlation between near-term stock movements and trends in earnings estimate revisions. Investors can track such revisions by themselves or rely on a tried-and-tested rating tool like the Zacks Rank, which has an impressive track record of harnessing the power of earnings estimate revisions.

Ahead of this earnings release, the estimate revisions trend for America's Car-Mart was favorable. While the magnitude and direction of estimate revisions could change following the company's just-released earnings report, the current status translates into a Zacks Rank #2 (Buy) for the stock. So, the shares are expected to outperform the market in the near future. You can see the complete list of today's Zacks #1 Rank (Strong Buy) stocks here.

It will be interesting to see how estimates for the coming quarters and current fiscal year change in the days ahead. The current consensus EPS estimate is $2.13 on $189.46 million in revenues for the coming quarter and $8.12 on $728.64 million in revenues for the current fiscal year.

Investors should be mindful of the fact that the outlook for the industry can have a material impact on the performance of the stock as well. In terms of the Zacks Industry Rank, Automotive - Retail and Whole Sales is currently in the top 21% of the 250 plus Zacks industries. Our research shows that the top 50% of the Zacks-ranked industries outperform the bottom 50% by a factor of more than 2 to 1.

To read this article on Zacks.com click here.

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

Read this article:
America's Car-Mart (CRMT) Beats Q3 Earnings and Revenue Estimates - Nasdaq

Human development research focused on often overlooked communities

In California, Hispanics have surpassed whites as the largest ethnic group in the state. Although it is often thought that this increase is due to immigration, it is actually caused by individuals already living in the state and building families.

Hispanics increasingly choose to raise families in the U.S., yet little research has gone into understanding their family dynamics and childhood development. Instead, research in human development has historically been focused on white Americans of European descent, resulting in a lack of representative knowledge. Leah Hibel, an associate professor of human development and family studies, is striving to bridge this racial gap in scientific research and learn more about the lives of Hispanics in the U.S.

The California Babies Project began in 2017 with the intention of learning how stress factors impact childhood development in Mexican families in the Yolo County area. The project selected families that had already been studied through the California Families Project, a childhood development study that started at UC Davis in 2006.

The children that are part of the ongoing California Babies Project are the descendants of those who participated in the 2006 California Families Project as children. Hibels study hopes to better understand the daily lives of the families through understanding the main stressors they are facing and the resilience mechanisms they rely on to combat challenges.

The main goals of the project are to understand daily life as its lived, how parents are supporting their infants development and their infants ability to regulate their physiology, emotions and sleep said Andrea C. Bhler-Wassman, a doctoral candidate in human development.

To collect data on the families and children, the study started with children at six months old and plans to follow them until they reach the age of four. A key part of data collection relies on the diaries that the families use to document the many fluctuations in daily life during two-week periods.

What is unique about this project is that we have the families filling out questionnaires each day, so we can see how life is lived each day and how each day is impactful, Hibel said.

Beyond the daily diaries, a quantifiable aspect of the study is the recording of the stress hormone cortisol. To measure cortisol, saliva is collected from both the parents and the children. This physiological measure serves as an objective view of the parents stress levels and as an indicator for the way in which the parents stress is impacting their children. Additionally, sleep patterns are recorded to understand how differing amounts of sleep impact the health of the family members.

Although the study is still primarily in the data collection phase, early analysis has already identified stress factors and resilience methods among the families. Correlations can be found between partner hostility and the amount of sleep mothers receive each night. For mothers sleeping the recommended seven to eight hours a night, less partner conflicts are observed. These are experiences to which many families in the U.S. can relate; however, a specific stressor for the families in this study is the fear of deportation.

The study has seen a significant difference in the depression symptoms for mothers who are worried about deportation compared to mothers with less concerns about deportation. Bhler-Wassman pointed out that it is not just undocumented mothers who are negatively impacted by the fear of deportation. Regardless of citizenship status, these mothers still have fears surrounding deportation from concerns about other family members to racist assumptions that they might be undocumented which may result in symptoms of depression.

In the face of these stress factors, the families have shown strong resilience through familial support. The importance of family and the support members receive from one another helps them fight the challenges they face in the U.S.

We are currently studying how social support affects the families mental health, because when families are living in these stressful environments, the main thing that buffers that stress is familial support, Bhler-Wassman said.

The researchers hope that more evidence-based research on Mexican families in the U.S. will ultimately lead to positive changes and more enjoyable lives for the families they study.

I really want to make this research be reflective of the needs of the community and I hope that this research will be able to help them and give back to them, Bhler-Wassman said.

To help the families, policy and social services need to be catered to their specific needs. It is important for the societal support to be inclusive of all family types. This research will help policy-makers come up with specific solutions that will be most beneficial to the families they hope to serve.

Its important to meet families where they are at and be able to provide families with prevention and intervention, Hibel said. We need to make sure those interventions are culturally appropriate and need them to be able to fit into their day to day lives.

Although there has been widespread objection to policies that are negatively impacting immigrants and their families, Jonathan Mulligan Seplveda, a staff attorney for the UC Davis Immigration Law Clinic, emphasized that such policies have been this way for years.

There does seem to be significant push back that is saying this is extremely inhumane policy, yet it seems like policy has been this way for a long time, Mulligan Seplveda said.

Hibel stressed that it is ultimately a societal limitation to not support all the diverse aspects and people of the U.S.

What is important to recognize is that our country is diverse and our communities are diverse, and that diversity is an asset, Hibel said. If we are not supporting and acknowledging aspects of our society, it holds our society back.

Written by: Alma Meckler-Pacheco science@theaggie.org

See the original post:
California Babies Project works to better understand lives of Mexican families in Yolo County - The Aggie

Prosecutors in the trial of Jerry Lynn Burns rested their case Wednesday. Burns is suspected of killing high schooler Michelle Martinko in Cedar Rapids in 1979 and he faces a first degree murder charge.

Eighteen-year-old Martinko was found stabbed to death in her familys Buick parked in the Westdale Mall parking lot early on the morning of December 20, 1979. Her killing upended the lives of her family members and shocked Cedar Rapids residents. The case has stuck in the memories of many for decades.

Thirty-nine years after Martinko was killed, investigators arrested 66-year-old Burns of Manchester, Iowa, after covertly collecting his DNA and testing it. Genetic material retrieved from a straw that Burns used is consistent with DNA found on the dress Martinko was wearing when she died, according to court testimony by forensic genetics experts.

On Wednesday prosecutors argued the scientific evidence in the case is irrefutable and that it links Burns to the scene of the crime.

They also argued the suspect acted with malice aforethought, willfully, deliberately, with premeditation and a specific intent to kill, as is articulated in Iowa Criminal Code.

Investigators and forensic analysts have previously testified that Martinko died after being stabbed repeatedly, and that she suffered defensive wounds, signs that she put up a fight.

There is also evidence that Martinkos assailant wore gloves during the attack, leaving behind prints of the glove material at the crime scene but obscuring their own fingerprints. An investigator testified that based on their analysis, the gloves appeared to be common kitchen gloves, the kind that are often used for dishwashing and are sold at grocery stores.

Prosecutors have argued the use of these gloves is evidence of premeditation.

Prosecutors have not been able to establish that Martinko and Burns knew each other or had any kind of relationship, and have described the killing as a random act of violence committed by a stranger."

Jurors heard more testimony Wednesday from investigator Matt Denlinger of the Cedar Rapids Police Department, one of the many officers who have worked on the case over the years.

It was under Denlingers tenure that the male genetic profile developed from crime scene evidence was shared with private genetic analysis firms and was uploaded to a public family genealogy website and used to develop a family tree. Investigators say these steps were instrumental in leading them to Burns, who has no previous criminal history.

In court on Wednesday, prosecutors played a video recording of Denlinger interviewing Burns, in handcuffs, in the back of a squad car on the way to the Cedar Rapids Police Department. There are long periods where the men sit in silence, but Denlinger also repeatedly asks Burns about what happened the night Martinko was killed.

I wish you could talk me through the issues that night, put me in your shoes if it would help me understand what was going through your mind, Denlinger said.

I dont recollect, Burns replied.

Since Burns was arrested in December of 2018, a criminalist at the Iowa Department of Criminal Investigation laboratory has analyzed DNA from a cheek swab taken from Burns, and has testified that Burns genetic profile is consistent with the genetic profile from the crime scene.

Questioned in court by prosecutor Nick Maybanks, Denlinger testified that during the car ride when he asked if its possible Burns forget what happened that night in 1979, Burns told him it is possible for people to block out their memories.

Besides the comment that Mr. Burns made about blocking out memories, did Mr. Burns offer an explanation as to what happened that night? Maybanks asked.

No, Denlinger replied.

And besides saying that he does not recollect or does not know, to questions about what was going on in his life, did he offer more explanation of his life circumstances? Maybanks asked.

No, Denlinger responded.

In further questioning, Denlinger went on to testify that Burns never told him that he had the wrong guy," and that the suspect never denied killing Martinko.

Where in the action, interaction between you and Mr. Burns in the squad car does he deny killing Michelle Martinko? Maybanks asked.

He never denied it, Maybanks said.

Burns has pleaded not guilty to the charge. If convicted, he could face life in prison.

Judge Fae Hoover Grinde has ruled that there is sufficient evidence for the case to go to the jury, overruling a motion for a judgement of acquittal by the defense. Burns defense team will take up the case Thursday.

More here:
Prosecutors Rest Their Case Against Man Accused Of Killing Martinko - Iowa Public Radio

What if I told you that you originated from Asia, although, you reside in East Africa? Yes, thats right- its possible.

You see, the world is changing rapidly- especially technologically. Oh, you really wish to explore the innermost subset of your existence- your DNA? With genetic testing, its possible.

Probably, youve heard or read so much about this topic, yet, you remain skeptical about its effectiveness- how important is it? How sure am I that I would receive accurate results? questions upon questions, challenging its usefulness and accuracy, speed across your mind as the topic is mentioned.

Companies like 23 and Me offer genetic testing services that could be a great benefit to you. Check out how.

According to Mendel, genes are the units of inheritance. DNA is an integral part of genes, and they are a much smaller subset of chromosomes.

That said, DNA code for proteins that dictate specific traits ranging from your eye color to your diet and physique. This probably explains its complex nature.

The whole essence of modern genetics is to simplify the complexity of DNA and demystify its whole importance in the hereditary process. Although it has been quite hard, weve definitely gone a long way from Mendel Peas experiment.

In 2003, we edged closer to achieving this aim when technology capable of interpreting DNA sequence, in its entirety, was developed. With this came an unprecedented speed in understanding an individuals DNA for frugal costs as well as commercial exploitation.

23 and Me (see in-depth review on MyFamilyDNATest) is one, amongst the many companies that explore the DNA of individuals to reveal the hidden script they have inside of them.

Luckily, through genetic testing, you can get to understand where you are from; your ancestry. If you are interested in your family history, you can learn more than what youve known through what your relatives told you or historical documentation.

Presently, there are three major ways you can undergo ancestry testing.

Y- chromosome DNA tests are used to understand the paternal line of ancestry of an individual. Because Y-chromosomes are only passed from father to sons and are absent in women, this kind of test is carried out only in males. Women who are interested in the result this test provides are required to recruit a male relative.

Mitochondrial DNA tests are used to understand the maternal line of ancestry of an individual. This is because a mitochondrion is a semi-autonomous organelle that has its own DNA. Since it is transferred down to a child by the mother, it can be carried out in both sexes.

Single nucleotide polymorphism tests evaluate a large section of variants of an individual genome and compare it to others of known ethnicity.

Whats more in it for you? DNA mutation is the basis for a faulty protein formation, whose end result is a sprout of genetic-related diseases. Genetic testing helps you recognize these potential diseases, so you can channel your lifestyle in a path that reduces the chances of exhibiting these diseases.

Heres where it gets murky. Test providers use different databases to determine the ancestry or ethnicity of individuals. This means that there might be discrepancies when it comes to the determination of your ancestry.

But then, the term accurate could be quite subjective. This is what I mean: if you use the term accurate to infer that these provide correct results based on their individual databases, then, yeah- they are accurate. On the other hand, comparing two or more genetic testing companies would mean neither of their results is accurate due to different databases.

Post Views: 21

Go here to see the original:
How Useful and Accurate is 23 and Me Genetic Testing? - The Union Journal

Genetics testing conducted by Colorado Parks and Wildlife adds to the growing evidence that a wolf pack has formed in Moffat County.

In a press release, CPW officials said four scat samples collected near a scavenged elk carcass in early January came from wolves, according to lab results. The DNA indicated three females and one male, according to CPW, and that the wolves were likely siblings. This is the first official documentation of a pack of wolves in the state since the 1940s.

The DNA doesnt tell us the age, CPW Species Conservation Program Manager Eric Odell said in a release. We dont know where or when they were born. We cant say. But that there are closely related wolves is a pretty significant finding.

Wolves are a federally endangered species and fall under the jurisdiction of the U.S. Fish and Wildlife Service. According to officials with the agency, killing a wolf can result in federal charges, including a $100,000 fine and a year in prison, per offense.

Anyone who sees or hears wolves, or finds evidence of any wolf activity is urged to contact CPW. A Wolf Sighting Form can be found on the CPW website.

Read the rest here:
Genetics tests confirm wolf presence in Colorado - The Grand Junction Daily Sentinel

Feb. 19, 2020

A Michigan State University scientist is determined to increase the number of women and girls going into STEM fields. Kayla Conner is a doctoral candidate in theDepartment of Microbiology and Molecular Geneticswho says she wouldnt be the student she is today if it werent for her high school chemistry teacher, Ms. Hardin.

Conner is part of MSUsBroadening Experiences in Scientific Training, an experimental program dedicated to empowering graduate student trainees to develop professional skills and experiences. Recently, reporters with WKAR News sat down with some of the BEST students to learn more about their inspiring life stories. Listen to the audio clip to hear Conners story in her own words and those of Hardin.

Conner is currently studying what happens to the placenta when a woman gets an infection during pregnancy and what that could mean for the fetus. Shes researching possible ways to stop some of the negative consequences that happen because of infection.

If a woman gets infected with any sort of ailment during pregnancy, whether it be the cold or the flu, it causes inflammation in the mother, says Conner. And that can lead to downstream effects, whether that is stillbirth, preterm labor, birth defects or even ailments later in life.

Conner was raised in Maynardville, Tennessee, and attended a small high school where she found the atmosphere to be less than encouraging and lacking resources for students who wanted to pursue higher education.

A lot of people have the mentality, Im from here so, therefore, I cant, and its really sad, she says. I really dont want people to have that mentality because even though you are from there you can do wonderful things. I dont think I would have had that drive without Ms. Hardin.

Conner looked up to her chemistry teacher and found encouragement to continue her studies.

She told me how well I was doing even when I felt like I wasnt, says Conner. I thought, Man, you know if she thinks I can do it, then maybe I can.

Hardin says that Conner gives her too much credit.

She has a scientific mind and shes curious, says Hardin. It was obvious to me. She had a natural talent for it. As a teacher, I encourage all my students, especially girls, to not look at science and math as something that boys do. You work at it. You keep plugging away and you can do it too.

For Conner, having women who have helped support her has been extremely important. Ive had women who told me that I can and who have helped me in every way they possibly can, she says. I think its important to give back and be that person for someone else. I go to the Girl Scout troops. I have a little outreach program where I do some hands-on activities and I give a talk. Its a fun time.

Only about 24 percent of the STEM workforce is made up of women. There have been studies that have shown that girls in lower education elementary and middle school show the same interest in STEM courses and enroll in courses at the same rates as their male student counterparts, but once it reaches the level of higher education, women do not seek out STEM courses as frequently as men do.

Conner recognizes the disconnect that is happening and strives to inspire talented women to pursue STEM careers.

Its not a mans game, Conner says. It is absolutely a womans game as well. We can be awesome scientists and be awesome mothers, friends and daughters and be whatever we want to be.

MSU BEST seeks to enhance trainees abilities to develop the confidence and competencies useful in navigating and choosing from diverse career opportunities.Learn more about becoming part of the BEST community.

Photos and video by Alec Gerstenberger.

More here:
Shaping the future: Microbiologist's career inspired by influential teacher - MSUToday

Feb. 19, 2020 13:12 UTC

BOTHELL, Wash. & TOKYO--(BUSINESS WIRE)-- Seattle Genetics, Inc. (Nasdaq:SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., Astellas) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation for PADCEV (enfortumab vedotin-ejfv) in combination with Mercks (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 FDAs 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.

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 FDAs Breakthrough Therapy designation 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.

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 urothelial cancer who are unable to receive cisplatin-based chemotherapy treated 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 Cancer

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 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 with advanced 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 FDAs 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).5 PADCEV is co-developed by Astellas and Seattle Genetics.

Important Safety Information

Warnings and Precautions

Adverse Reactions

Serious 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 Abnormalities

In 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 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 peoples 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 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 the Seattle Genetics and Astellas Collaboration

Seattle 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 Seattle Genetics, Astellas and Merck Collaboration

Seattle Genetics and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seattle Genetics and Astellas PADCEV (enfortumab vedotin-ejfv) and Mercks 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.

Seattle Genetics Forward Looking Statements

Certain 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 therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy, and the therapeutic potential of PADCEV including 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 companys 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.

Astellas Cautionary Notes

In 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 managements 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.

____________________________1 American 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 01-23-2020.2 American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed 05-09-2019.3 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow 4 National 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.5 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.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.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200219005512/en/

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

Ever since Charles Darwin began investigating the early evolution of humans, scientists have worked to understand just how far back our species goes, where man first lived, and how his DNA traveled out of Africa and into the world at large.

Ancient humanoids have been found in large portions of Africa, which led to scientific understandings of how man both on and off that continent evolved. What was less understood until recently is how man evolved in areas of Eurasia, and who ancient species bred with to create what researchers are calling a ghost species.

Modern Eurasian species have been easier for scientists to investigate because cold temperatures preserved DNA samples so much better than those in Africa, where hot temperatures caused DNA to deteriorate. That made learning about how man evolved within Africa a challenge to scientists.

Broken Hill Skull from Kabwe, Zambia of Homo rhodesiensis, renamed as Homo erectus, also sometimes named Homo heidelbergensis or archaic Homo sapiens. Photo by Gerbil CC by 3.0

But a study done in 2017 by more than a dozen scholars and published in Cell, an online scientific journal, shed new light on these matters that had challenged researchers for years. In the study, sample genomes were examined from people who lived in southern Africa 10,000 years ago. This revealed that the history of these populations is far more complicated than researchers once believed.

RESTORATION BY A. FORESTIER OF THE RHODESIAN MAN WHOSE SKULL WAS DISCOVERED IN 1921

The samples were taken from Cameroon, which has the earliest and best preserved archaeological site in Africa. Now, a new study confirms the theories put forth in the 2017 paper, and asserts that, in fact, humanoids from Africa left the continent, bred with Neanderthals, and returned to Africa at some point, thereby creating a whole new ghost species, as the new study refers to it.

Anatomical comparison of skulls of Homo sapiens (left) and Homo neanderthalensis (right)

The study, entitled Identifying and Interpreting Apparent Neanderthal Ancestry In African Individuals, was also published in the journal Cell. In the study, 16 sample genomes were examined from people who lived in South Africa during the past 10,000 years. This examination revealed that the history of these populations is far more complicated than once believed. When these folks left Africa about 100,000 years ago, there wasnt, in fact, just one kind of humanoid there.

Model of the head and shoulders of an adult male Homo heidelbergensis [H. rhodesiensis] on display in the Hall of Human Origins in the Smithsonian Museum of Natural History in Washington, D.C. Photo by Tim Evanson CC by 2.0

The study goes on to examine gene flow into the ancient ancestors of modern South Africans, and concludes that there may be links between archaic hominims and present day Africans. In fact, research suggests as many as seven percent of present day Africans may have genomes from a population that scientists have yet to identify right now, it has no known genome, hence the term ghost population. Scientists theorize this group lived somewhere between 360,000 years ago and more than one million years ago, long before the gene flow started in West Africa, about 43,000 years ago.

The new research postulates that this ghost species of early humans resembled Neanderthals, and was in Africa about 100,000 years ago. Or, scientists suggest, the archaic species was present somewhere outside of Africa, but co-mingled by interbreeding, and then returned to Africa. This theory contravenes prior scientific research, that believed that there was simply one expansion out of Africa, and man developed and evolved from there.

The scientists behind the study, five authors, have stated conclusively that they believe more research needs to be done into the genetics of early humans, both within Africa and those species from outside the continent.

Related Article: Missing Link Skeletons Finally Deciphered Show New Path of Human Evolution

They assert that the DNA of modern and early humans must be studied further if we are to finally develop a full understanding of who we are, how we evolved, and our ancestors who once travelled both inside and outside Africa. Both studies are available for viewing online at: (https://www.cell.com/cell/fulltext).

The rest is here:
Study Finds Early Humans Bred with Mysterious Extinct Species in Africa - The Vintage News

Sometimes I think there is this perception that you have to be really tough in order to be successful. I have worked with some women, that appeared to think that in order to compete with male counterparts, they have to have a hard exterior. I dont think thats true. I think you can still be yourself, even in a male-dominated field, and succeed in the industry.

I had the pleasure to interview Lesa Nelson. Lesa has worked in the field of human genetic research for the past 27 years, with the last 20+ years being in senior management positions. She directs all operational activities ofPredictive Laboratoriesand serves as the laboratory technical supervisor.

Thank you so much for doing this with us! Can you tell us a story about what brought you to this specific career path?

Iwas a biology major, and as an undergraduate student, I started working in a molecular genetics lab where I worked on projects with physicians who wanted to look at the genetics of human disease. By doing this, I gained a desire to work in applied human genetics. I was interested in doing the research, but was also interested in how it applied to actual patients. I began working with Dr. Kenneth Ward, M.D., who is currently the laboratory director atPredictive Laboratories, and we established a clinical molecular genetics laboratory at the University of Utah. We conducted research and clinical testing for patients, and together we became more entrepreneurial, which led me to move away from the university and to start working in the private sector.

Can you share the most interesting story that happened to you since you began at your company?

The most interesting thing that Ive experienced since my start at Predictive Laboratories was having the opportunity to launch genetic tests aimed to help women with infertility and endometriosis. I have been working on this research for years, so seeing it all come to fruition with the official launch of our productsARTguideandFertilityDX, this past October, has been incredibly rewarding. ARTguide identifies genetic causes of female infertility, including the risk for endometriosis and FertilityDx will provide guidance to couples struggling with infertility by identifying genetics risks to conception, pregnancy and the newborn. It has been fascinating to work on a product that can be a full solution, by leveraging everything possible in todays genetic world, across the disciplines of reproductive endocrinology and even pediatrics. Overall, its just an exciting service we are able to offer those in need!

Can you share a story about the funniest mistake you made when you were first starting? Can you tell us what lesson you learned from that?

One of the funniest mistakes that I first made in my career actually had to do with the weather! I was supposed to meet someone on a Saturday at the laboratory, and we started a job on Friday that needed to be done by Sunday. There was a 20-inch snowstorm in Salt Lake City that Saturday and I was the only one who could walk to the lab. I had to complete the job, despite never doing the procedure before, on my own while receiving guidance from another technician over the phone, while also trying to learn at the same time. Looking back, I laugh at how you can plan for everything on paper, but the weather has a mind of its own.

What do you think makes your company stand out? Can you share a story?

I think what makes Predictive Laboratories stand out is our belief in identifying a problem and applying what we know in terms of genetic diagnosis to then develop a solution with technology. I have been lucky enough to work on projects where there is an actual discovery, and we try to find ways to turn it into something that is practical and usable. I myself was an infertility patient and I know what its like to go through that process, so I am extremely empathetic with the patients that were trying to reach and help through our diagnostic tests.

There was a recent case where a couple was going through infertility problems, a niece of theirs had developmental delay and other issues, and naturally, they wanted to know if their prospective children would be at risk and the childs parents wanted to find out what was going on. We call these situations diagnostic odysseys. The child turned 1-year-old and still no one knew what was wrong. We checked the entire coding region of the childs genome and were able to identify the mutation that ultimately caused the symptoms. It turns out it was a rare disease that only 30 people in the world had ever been diagnosed with. While there is no treatment for the disease, we were able to tell the parents the reason why this was happening. This means a lot to families.

Are you working on any exciting new projects now? How do you think that will help people?

Right now, Im excited about our focus on FertilityDX and the service it will provide to help couples navigate everything from conception to the delivery of a healthy baby. Through this service, were also able to train physicians in using genetics, so we can teach them to have a more personal approach to helping each of their patients.

Were also in the middle of an exciting time where were able to leverage all of the genetic technology out there. I would really like to see us facilitating the transfer of that genetic knowledge to different specialists and making it comprehensive. We have the ability for personalized medicine, so we need to stop thinking about a population statistic and start thinking how we can leverage technology to diagnose each individual based on their genetics.

Ok super. Thank you for all that. Lets now shift to the main focus of our interview. Are you currently satisfied with the status quo regarding women in STEM? What specific changes do you think are needed to change the status quo?

There are a lot of women in the STEM field, but you still see it kind of segregated by role. Ive noticed in my experience that most of the laboratory technicians end up being women, because the men wind up leaving for higher positions. I think it is almost historical, but I hope its changing.

A while ago, my colleagues and I interviewed third graders about what they wanted to be when they grew up. The boys who responded shared a wide variety of aspirations, while the girls mainly responded that they wanted to be teachers, actresses, nurses and moms, which are all admirable roles, but the responses did not range among the girls like they did with the boys.

I think that there is a lack of exposure to science at a young age, which is why I was involved in a local elementary school where we introduced a program to offer students the chance to do science experiments. I hope there are more and more programs that are introduced like this because I believe this is what will change the status quo. The University of Utah, for example, offers a program that takes high achieving college freshmen girls in science and provides them with a two year mentorship where they are placed in a laboratory. These women have the opportunity to spend their entire summer, prior to the start of their freshman year, exploring science with different people. I think things like this can also help get women in STEM leadership areas.

In your opinion, what are the biggest challenges faced by women in STEM or Tech that arent typically faced by their male counterparts? What would you suggest to address this?

I think we are still in a society where one of the biggest challenges that women are facing is managing work and family life. It can be challenging to work and still have a family. I think there is more pressure on women to do both and do both well. I always felt lucky because even though I worked really hard, I still had the flexibility to make time for family. Flexibility in the workplace helps and it is much easier to work remotely in the modern day, thanks to technology. Hopefully this will eventually resolve some of those issues for women who are trying to balance both.

What are the myths that you would like to dispel about being a woman in STEM or Tech. Can you explain what you mean?

Sometimes I think there is this perception that you have to be really tough in order to be successful. I have worked with some women, that appeared to think that in order to compete with male counterparts, they have to have a hard exterior. I dont think thats true. I think you can still be yourself, even in a male-dominated field, and succeed in the industry.

What are your 5 Leadership Lessons I Learned From My Experience as a Woman in STEM or Tech and why. (Please share a story or example for each.)

None of us are able to achieve success without some help along the way. Is there a particular person who you are grateful towards who helped get you to where you are? Can you share a story about that?

I am most grateful for the guidance by Dr. Ken Ward, who had worked with me almost from the start of my career in molecular genetics, as mentioned earlier. We first met when he was doing a fellowship and we immediately hit it off and worked well together.

Despite not having a doctorate of philosophy (Ph.D) like most of the other professionals in my industry, Ken was always willing to work with me. He always saw what I was capable of and there were never any limitations of what I could do in the laboratory.

I have been working with Ken for nearly 30 years, and I came from a laboratory where as a technician, you werent going to scientific conferences or rarely were an author on a paper. At a laboratory, I worked very hard on a project and my name wasnt on the paper because I did not have my Ph.D. Since working with Ken, not having a Ph.D has never held me back, and that is super important to me. He has let me do what I wanted to on both the research and clinical side. He was always super supportive of me becoming exactly what I wanted to be. I think we are on the same wavelength and it has made me feel confident in my career and role at Predictive Laboratories. Like Ken, I too just want people to succeed. I like hearing about peoples aspirations, and I try to pass that forward as well.

How have you used your success to bring goodness to the world?

It is mostly what I said earlier, but were bringing goodness to the world and to patients by taking our research and applying it to something that affects individuals. I do not care what it is you do in the laboratory, you can always be learning from it. The ability to take something and then apply it to change someones life has been the most satisfying part of my job. What makes my heart beat the fastest is when we figure something out or help somebody with genetic testing.

You are a person of enormous influence. If you could inspire a movement that would bring the most amount of good to the most amount of people, what would that be? You never know what your idea can trigger.

I would really love to see the healthcare system be able to provide more without being governed by cost. For example, rare diseases do not get looked at because they dont generate enough revenue and Medicare doesnt want to pay for something that would cost too much. I think we could offer so much more without financial barriers. I dont mean that companies and providers of services should not have a profit, but I feel like a lot of healthcare gets caught up in the dollars. Much of it isnt driven from a patient centric point, but from a monetary one.

Can you please give us your favorite Life Lesson Quote? Can you share how that was relevant to you in your life?

I have two that I think sum up my approach to life.

One of them is that high achievement always takes place in the framework of high expectation, which was said by Charles F. Kettering, and the other is from Steve Jobs when he said, technology is nothing, what is important is that you have faith in people, that they are basically good and smart, and if you give them the tools, they will do wonderful things.

These sentiments are applicable to everything whether that be STEM or life.

Read more:
It is a myth that you have to be really tough in order to be successful with Penny Bauder & Lesa Nelson - Thrive Global

In order to contain a virus, its important to know exactly what youre dealing with and the COVID-19 coronavirus is no different.

One of the key tools to try to contain or limit transmission of infectious diseases is case identification, saysSamira Mubareka, a virologist in the University of Torontos Faculty of Medicine and at Sunnybrook Health Sciences Centre.

If you identify cases, then you can contain them. If you miss them, then you dont.

Mubareka and her colleagueRobert Kozak, both in U of Ts department of laboratory medicine and pathobiology, are part of a local working group of scientists who are researching the novel coronavirus outbreak and are developing a suite of tools to control it.

One of their current projects involves using the latest in whole-genome sequencing technology to help hospitals characterize the virus more quickly. Their work may help to track the viruss evolution and trace its spread.

If the viruss genome was a book, were going to figure out its entire story, Kozak says.

Mubareka and Kozak collected specimens of the coronavirus from the first confirmed case in Canada, an adult male who was treated and eventually discharged from Sunnybrook after returning from Wuhan, China the epicentre of the outbreak. Two more cases in Ontario have since been confirmed: the original patients wife, who accompanied him to China, and a woman in her 20s in London, Ont. who had also traveled to Wuhan.

Worldwide, there are more than 73,300 confirmed cases ofCOVID-19 as of Feb. 18. More than 1,800 have died.

Robert Kozak, pictured here in the lab, andSamira Mubareka say their teams work will enable front-line hospital staff to run a test on-site, helping to identify and triage patients more efficiently (photo by Nick Iwanyshyn)

In Canada, where there are so far seven confirmed cases, health authorities say the risk remains low. But Mubareka and Kozak are preparing for any possible scenario.

You put a smoke alarm in your house even if you hope theres no fire, says Kozak, who previously worked at the National Microbiology Laboratory in Winnipeg on Ebola and Zika.

Part of the teams work involves developing a test that will speed up the characterization of the virus. Currently, patient samples in Ontario are sent from local hospitals by courier to the Public Health Ontario lab in downtown Toronto for testing, and to the national lab in Winnipeg for confirmation.

The process can take a few days, depending on the hospitals distance from the labs and test volumes.

Mubareka and Kozak say their teams work in collaboration with McMaster University and infectious disease expert Allison McGeer of U of Ts Dalla Lana School of Public Health, Faculty of Medicine and Mount Sinai Hospital will enable front-line hospital staff to run a test on-site, helping to identify and triage patients more efficiently. The test involves using swabs from a patients nose and throat to do genomic testing to sequence the virus.

If theyre negative, you can take them [the patients] out of precautions and maybe even send them home, Kozak says. If theyre positive, then you can again take the appropriate precautions to isolate them and do everything else that needs to be done.

The researchers hope they can adapt the approach for mini-sequencers the size of a cell phone, so it can be used more widely.

Vivek Goel,U of Ts vice-president, research and innovation, and strategic initiatives,says the university worked quickly to mobilize support for the project.

With its cross-disciplinary expertise and close relationships with area hospitals, the university recognizes that its uniquely positioned to play a leadership role when it comes to these sorts of global health issues, Goel says.

We also have the benefit of having experienced the SARS outbreak in Toronto in 2003, so we know first-hand how important this sort of research can be.

The genomic testing being performed by the U of T-led group could also help researchers get a fuller picture of the mysterious illness.

Although genomic sequences of the virus were published and shared in public databases, many were deposited soon after the first cases were identified in Chinas Hubei province, according to Mubareka.

The problem is that was early on before it started going from person to person-to-person, she says, noting that viruses mutate.

There are only about 50 sequenced genomes of the virus, adds Kozak for about 48,000 confirmed cases.

Youre not getting a great snapshot, he says. Its tough to really understand a lot about the virus.

Among the nagging questions about COVID-19 that U of T and Sunnybrook researchers hope to answer are how long patients remain contagious and if the amount of the virus present in respiratory secretions is proportional to its severity.

Their work may help others understand how the virus spreads from point A to point B, and if its changing in ways that make it more dangerous.

The research team includes U of T students likeNatalie Bell, a second-year masters student in laboratory medicine and pathobiology who is also working with Mubareka on a project related to influenza from swine.

Its really interesting to see science happen in real time, especially being part of Sams lab [and] to see her involvement and the movement from lab to policy work, and how it impacts public health, Bell says.

Mubareka and Kozak plan to upload the sequencing data to public servers and share it with the world to help with epidemiological studies and vaccine design.

We will build global capacity any way that we can, Kozak says.

Mubareka and Kozak say their work was made possible thanks in part to the McLaughlin Centre, which provided emergency funding for the project. We have no shortage of ideas of things we can do to hopefully make a difference, Kozak says, but you always need someone to provide the resources to do it.

Stephen Scherer, the director of the McLaughlin Centre at U of T and a University Professor in the department of molecular genetics, says the centre wanted to make sure the researchers had the necessary funds to do their work in time.

Nobody is busier right now than this group, so we wanted to make the process as easy as possible for them, Scherer says. We also wanted these researchers to know the rest of us value their efforts to keep us safe.

Go here to read the rest:
U of T and Sunnybrook virologists work on tools to combat coronavirus outbreak - News@UofT

MedicalResearch.com Interview with:

Robert E. Dudley, Ph.D.Chairman, Chief Executive Officer and PresidentClarus Therapeutics

Dr. Dudley discusses the recent announcement that Clarus Therapeutics, Inc. has launched JATENZO (testosterone undecanoate) capsules for the treatment of appropriate men with testosterone deficiency (hypogonadism):

MedicalResearch.com: What is the background for this announcement?

Response: JATENZOis the first and only oral softgel testosterone undecanoate and the first oral testosterone product approved by the U.S. FDA in more than 60 years.JATENZO is indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone.

The launch of JATENZO means that physicians and men living with testosterone deficiency due to genetic or structural abnormalities finally have a safe and effective oral testosterone replacement therapy. We are proud to commercially launch this unique oral formulation to healthcare providers and the appropriate patients who they treat. JATENZO is now available at pharmacies across the country.

MedicalResearch.com: What are the main findings of the underlying studies?

Response: JATENZO was evaluated in a Phase 3 pivotal trial among 166 adult, hypogonadal men in a 4-month, open-label study with a topical testosterone comparator arm. The starting dose was 237 mg twice daily (BID) with meals. Dose adjustments (minimum 158 mg BID; maximum 396 mg BID) were made roughly 3 and 7 weeks after initiation of JATENZO based on average circulating testosterone concentration levels. 87% of JATENZO patients reached testosterone levels within the normal eugonadal range at the end of the study; peak testosterone levels were in close alignment with FDA targets.

Across all Phase 2 and Phase 3 trials combined, the safety of JATENZO has been evaluated in 569 patients who were treated with JATENZO for up to two (2) years. Liver toxicity was not observed with JATENZO in clinical trials.

Mild gastrointestinal adverse events observed with JATENZO were transient, manageable and did not lead to discontinuation.Decreased HDL cholesterol and increased hematocrit were associated with JATENZO use but did not lead to discontinuation of JATENZO. Only three of the 166 patients (1.8%) in the 4-month study experienced adverse reactions that led to premature discontinuation from the study, including rash (n=1) and headache (n=2). JATENZO was associated with an increase in systolic blood pressure. A boxed warning about the potential risks associated with elevated blood pressure appears on JATENZO labeling. Patients on JATENZO should have their blood pressure monitored.

Among the 569 patients who received JATENZO in all Phase 2 and 3 trials combined, the following adverse reactions were reported in >2% of patients: polycythemia, diarrhea, dyspepsia, eructation (i.e., burping), peripheral edema, nausea, increased hematocrit, headache, prostatomegaly (i.e., enlarged prostate), and hypertension.

MedicalResearch.com: How doesJATENZO differ from other treatments for testosterone deficiency?

Response: The launch of JATENZO is an important step forward in testosterone replacement therapy. The only other oral testosterone replacement therapy product ever approved by the FDA is methyltestosterone (an alkylated androgen) that has been associated with serious liver toxicity and is rarely, if ever, used today. Because JATENZO is formulated as a lipophilic prodrug, it bypasses the first-pass hepatic metabolism. No liver toxicity-related events were observed in clinical studies of JATENZO including in patients who took JATENZO at higher doses than recommended in current product labeling for two (2) years.

We believe JATENZO addresses a long-standing need for a safe and effective oral testosterone replacement product that meets current day FDA safety and efficacy standards. JATENZO enters a market where the vast majority of hypogonadal men are treated with injectable or topical testosterone products. JATENZO avoids administration challenges seen with these non-oral treatments it presents no injection site pain, no transfer risk, no mess, no skin irritation and no surgical procedure. Therefore, we believe a significant number of hypogonadal men will prefer JATENZO as an alternative to other forms of testosterone therapy.

MedicalResearch.com: How are men tested to determine ifJATENZO therapy is appropriate for them?

Response: According to the American Urological Association and Endocrine Society clinical guidelines, diagnosis of hypogonadism is determined by both the identification of symptoms and/or signs consistent with hypogonadism and blood test measurement of low morning total serum testosterone concentration (defined as <300 ng/dL, on two separate days). Healthcare providers should assess each patient individually for the appropriateness of JATENZO to treat their clinical hypogonadism.

MedicalResearch.com: What else should readers take away from your report?

Response: Clinical hypogonadism can be more complex than most people realize and left untreated, can have a profound negative impact for the individual. Men with the symptoms of hypogonadism have a real medical need that deserves appropriate diagnosis and treatment.

Any disclosures?

Pleaseclick herefor full Prescribing Information, including BOXED WARNING on increases in blood pressure.

Citation:

CLARUS THERAPEUTICS ANNOUNCES COMMERCIAL LAUNCH AND AVAILABILITY OF JATENZO (TESTOSTERONE UNDECANOATE) CAPSULES, CIII FOR THE TREATMENT OF HYPOGONADISM

We respect your privacy and will never share your details.

Feb 19, 2020 @ 12:05 pm

The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.

The rest is here:
Clarus Therapeutics Lauches JATENZO - Oral Testosterone Replacement Therapy - MedicalResearch.com

One of the more underrated horror-thrillers is Warner Bros./Dark Castles 2009 Orphan, directed by Jaume Collet-Serra and starring a young Isabelle Fuhrman as Esther, an adopted9-year-old girl who is not nearly as innocent as she claims to be.

As its revealed, Esther is actually a 33-year-old woman named Leena Klammer. She has hypopituitarism, a rare hormonal disorder that stunted her physical growth and caused proportional dwarfism, and has spent most of her life posing as a little girl. (Wiki)

In an interesting turn, Sierra/Affinity is launching sales at the EFM in Berlin on Esther, a prequel to Orphan that will be directed by William Brent Bell (The Devil Inside, The Boy, Brahms: The Boy II), reports Deadline.

In it, Lena Klammer orchestrates a brilliant escape from a Russian psychiatric facility and travels to America by impersonating the missing daughter of a wealthy family. But Lenas new life as Esther comes with an unexpected wrinkle and pits her against a mother who will protect her family at any cost.

Orphans big selling point was the shocking twist that changed the way you viewed the intense and immensely uncomfortable events of the film. It will be interesting to see if the prequel can conjure up the same kind of suspense with the audience already being in on the Esthers secret. Its unclear if Fuhrman will return, although its extremely unlikely.

The prequel, expected to start in the third quarter, is written by David Coggeshall.

Dark Castle Entertainments Alex Mace, Hal Sadoff and Ethan Erwin will produce with James Tomlinson. David Leslie Johnson will serve as an executive producer and Jen Gorton and Josie Liang will oversee for eOne.

Here is the original post:
'Orphan' Prequel to Tell the Origins of 'Esther' - Bloody Disgusting

]]> 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.

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

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

Sorry, but your browser does not support the video tag.

(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

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

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.

Read the original post:
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.

For More Info, Get a Sample[emailprotected]https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-stem-cell-banking-market

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.

Few Of The Major Competitors Currently Working In The Global Stem Cell Banking Market AreNSPERITE N.V, Caladrius, ViaCord, CBR Systems, Inc, SMART CELLS PLUS, LifeCell International, Global Cord Blood Corporation, Cryo-Cell International, Inc., StemCyte India Therapeutics Pvt. Ltd, Cordvida, ViaCord, Cryoviva India, Vita34 AG, CryoHoldco, PromoCell GmbH, Celgene Corporation, BIOTIME, Inc., BrainStorm Cell Therapeutics and others.

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.

One of the important factors in the global Stem Cell Banking market report is competitive analysis. The report covers all of the key parameters, such as product innovation, market strategies of the key players, market share, revenue generation, the latest research and development and market experts views.

Inquire More or Share Questions if Any before the Purchase on This Report @https://www.databridgemarketresearch.com/inquire-before-buying/?dbmr=global-stem-cell-banking-market

The report focusses on weaknesses and strengths of the global Stem Cell Banking market with a competitive landscape that includes information on some market vendors. Information presented in the report is gathered from primary and secondary research methods. The report also presents recent trends and opportunities of the market helping players strive for the lions share in the market.

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.

Supply Side: Product Managers, Marketing Managers, C-Level Executives, Distributors, Market Intelligence, and Regulatory Affairs Managers among others.

Reasons to Purchase this Report

Get Direct Order of this Report @https://www.databridgemarketresearch.com/checkout/buy/enterprise/global-stem-cell-banking-market

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..

Browse Complete Tables and Figures:https://www.databridgemarketresearch.com/toc/?dbmr=global-stem-cell-banking-market

About Data Bridge Market Research:

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

Contact Us:

Data Bridge Market Research

US: +1 888 387 2818

UK: +44 208 089 1725

Hong Kong: +852 8192 7475

Email:[emailprotected]

Read the original post:
Stem Cell Banking Market 2020 Climbs on Positive Outlook of Booming Sales|NSPERITE NV, Caladrius, ViaCord, CBR Systems, SMART CELLS PLUS, LifeCell...

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.

View post:
Seeing through a forest of SCN2A gene variation - SFARI News