Archive for January, 2020

Polaris Partners has snagged Eli Lilly vet Darren Carroll as a partner. Carroll spent 22 years at Eli Lilly before making the switch to the investment firms Boston office. Most recently, Carroll served as SVP of corporate business development at Lilly, where he oversaw the $8.1 billion acquisition of Loxo Oncology and the divestiture of animal health company Elanco. Carroll is credited with forming Lilly Asia Ventures and was the founding CEO of Lilly spinout InnoCentive.

Mirati Therapeutics a keenly watched rival to Amgen in the KRAS G12C field has made some changes in its executive team. The biotech welcomed former Spark Therapeutics exec Daniel Faga as COO and Bristol-Myers Squibb vet Benjamin Hickey as CCO. In addition, the company promoted Vickie Reed to SVP, finance and chief accounting officer and Jessica Corson as VP, business development both joined in 2013.

MBX Biosciences has tapped co-founder and board director Kent Hawryluk to run the company as president and CEO. Hawryluk hops over after a stint as CBO of Avidity Biosciences, which he also co-founded. As a partner of Twilight Venture Partners, his previous experience includes helping launch Marcadia Biotech (acquired by Roche) and MB2 (acquired by Novo Nordisk). In addition to Hawryluk, the company has brought on Greg Davis as VP, product development. Davis most recently had a stint as VP of CMC, regulatory quality at Calibrium (acquired by Novo Nordisk).

Months after stepping down as the North America president of Sobi, Rami Levinhas been appointed to be CEO at Saniona focused on the treatment of eating disorders and diseases of the central nervous system. Levin will succeed Jrgen Drejer, who will transition to the role of CSO. Prior to his 5-year tenure at Sobi, Levin headed marketing at Merck Serono.

J&J-partnered Arrowhead Pharmaceuticalshas tappedJames Hassard as the companys first CCO to begin mapping a commercial path for its RNAi therapies. Most recently, Hassard served as SVP of marketing and market access at Coherus BioSciences. Prior to that, he held stints at Medivation, Amgen and Schering Plough.

As its lead therapy clears a pivotal Phase II, bringing it closer to its first BLA,ADC Therapeutics has tapped Joseph Camardo as head of medical affairs. In his new role, Camardo will be responsible for ensuring optimal medical impact for loncastuximab tesirine (ADCT-402) among patients with B-cell non-Hodgkin lymphoma. Camardo joins the Swiss biotech after a stint as SVP of Celgenes global health, which followed positions at Forest Research Institute and Wyeth Research (now Pfizer).

After scrapping their Phase I program and having their CSO hit the exit last May, German biotech Affimedhas brought on Andreas Harstrick as CMO. Most recently, Harstrick served in the same role at Molecular Partners. Harstrick is an alumnus of ImClone, Lilly Oncology and Merck Serono.

Dyve Biosciences has named Pfizer vet Chuck Harbert as CSO following the recent clearance the company received to begin a Phase II trial for their drug, DYV-700. Harbert spent three decades at Pfizer before transitioning to his new role. During his time at the pharma giant, Harbert served as VP, US exploratory development and strategic planning and had roles at Pfizer Central Research. In addition, Harbert was the co-inventor of Zoloft.

Biocon Biologics, a subsidiary of Biocon, has appointed MB Chinappa as CFO. Chinappas appointment comes at the same time as private equity fund True Norths acquisition of 2.44% of the company in a deal worth $74 million. Chinappa makes the jump from one of Biocons other subsidiaries, Syngene, where he was president (finance) and CFO. Chinappa led the Syngenes IPO in 2015.

Momenta Pharmaceuticalshas added the title of CFO to the companys CBO Young Kwon. Kwon joined the company in 2011 and prior to that, he worked at Biogen and Advanced Technology Ventures.

AVEO which had their drug tivozanib spurned once again by the FDA two months ago has appointed Erick Lucera to the position of CFO. Prior to joining the company, Lucera served in the same role at Valeritas. Before that, he was the CFO, treasurer and secretary of Viventia Bio (acquired by Eleven Biotherapeutics and now Sesen Bio).

Candel Therapeutics focused on the development of viral immunotherapies for multiple tumor indications has brought on Genzyme vet Sandra Poole as COO. Poole was most recently COO of LogicBio Therapeutics, after servingas EVP of technical operations and commercial development at ImmunoGen. During her time at Genzyme, Poole oversaw biologics manufacturing.

Antengene, a US-China biotech backed by Celgene, has snagged one of its top execs in China. John Chin, Celgenes general manager in the country, has joined as chief business officer just a few days before former Celgene CEO Mark Alles was appointed to the board of directors. Chins resume spans Aventis, Bristol-Myers Squibb and Merck.

Rubius Therapeutics has appointed autoimmunity and translational immunology expert Laurence Turka as the biotechs first CSO, joining its mission to pioneer a new class of medicines called red cell therapeutics. Turka hops over to the company from Rheos Medicines, where he was a co-founder and CSO. Turka was an entrepreneur-in-residence at Third Rock Ventures, turning to the VC life after an academic career that put him at the head of the American Society of Transplantation and a professor at Harvard Medical School and Massachusetts General Hospital.

Abeona Therapeutics which had some good news last month when the FDA lifted its hold on the companys butterfly disease therapy is parting ways with its executive chairman Steven Rouhandeh, revealed in an SEC filing.

Eiger BioPharmaceuticals has appointed Eldon Mayer as EVP and CCO. Mayer joins just as the company has initiated an NDA for its drug ionafarnib to treat Hutchinson-Gilford progeria syndrome (HGPS or progeria) and progeroid laminopathies. Mayer had the same job at Rigel Pharmaceuticals. Previously, Mayer was the SVP of commercial operations at Questcor Pharmaceuticals (acquired by Mallinckrodt).

Cancer-focused Cellectar Biosciences has named Igor Grachev as CMO. Grachev previously served as global development leader and head of innovative clinical trials initiative, R&D for TEVA Pharmaceuticals. His prior employers include GE Healthcare, Novartis, GSK, Merck, Schering PLough, Sanofi-Aventis and BioClinica.

The immunology experts at IFM Therapeutics who brought in $55.5 million in new venture backing last month has wooedMichael Cooke from Magenta Therapeutics as CSO. BeforeMagenta, Cooke was a founding scientist at the Genomics Institute of the Novartis Research Foundation.

Anti-edema therapies-focused Aeromics has brought on Joseph Schindler as its first CMO. Schindler is an associate professor of neurology and of neurosurgery at Yale University School of Medicine, where he is the clinical chief of the division of vascular neurology. He is also the director of the comprehensive stroke program and telestroke services at Yale New Haven Hospital.

Indias Vyome Therapeutics which back in 2016 raised $14 million for its R&D work on skin diseases has named Craig Tooman COO and CFO. Prior to joining Vyome, Tooman served as the CEO of Aratana Therapeutics. In addition, Tooman has served as founder and CEO of Avanzar Medical and CFO at Ikaria and Enzon Pharmaceuticals.

Baltimore-based startup WindMIL Therapeutics spun out of John Hopkins has named Bristol-Myers vet Karen LaRochelle as SVP, corporate & business development and promoted Patrick Dougherty to SVP, strategy, planning & operations. LaRochelle previously served as CBO of PsiOxus Therapeutics and during her time at BMS served as global head of negotiations and head of business development in China. Prior to his time at WindMIL, Dougherty served as chief of staff to the SVP R&D pipeline for pharmaceuticals R&D at GSK.

Vor Biopharma the biotech co-founded by Siddhartha Mukherjee to pioneer a new type of cancer cell therapy has made two new additions to its team. Amy Mendel joins as chief legal officer and Tania Philipps joins as VP of people. Mendel was the VP & associate general counsel for Ziopharm Oncology while Philipps was the VP and head of human resources at Tango Therapeutics.

JSR life sciences company Selexis has promoted Yemi Onakunle to the position of CBO. Onakunle joined the company in 2012 from Diosynth RTP, where he was the director of commercial development. His other stints include roles at Lonza Custom Manufacturing and Bachem Americas.

Immuneering whose current pipeline focuses on diseases such as cancer cachexia and metastasis has brought on Howard Kaufman as head of research and development. Kaufman, the former president of the Society for Immunotherapy of Cancer (SITC), was most recently CMO at Replimune Group. Kaufmans hiring comes a few weeks after the appointment of Scott Barrett to CMO at Immuneering.

CAR-T-focused Innovative Cellular Therapeutics (ICT) has welcomed Christopher Ballas onboard as SVP of manufacturing. Ballas career has brought him to Rocket Pharmaceuticals, Cook Medical and WuXi AppTec.

Allurion Technologies has recruited Whitney Cypes, former senior director of marketing for Insulet Corporation, as VP of global marketing and Chris Aronson, formerly of Restoration Robotics, as VP of North American sales. In addition, Benoit Chardon was promoted to EVP of commercial.

Eliot Forster-led cancer biotech F-star Therapeutics has appointed Edward Benz, the president and CEO emeritus of the Dana-Farber Cancer Institute, and Minerva exec Geoff Race to the board of directors.

Elias Zerhouni, the former R&D head at Sanofi and ex-NIH director, has taken up a seat at Waypoint Capitals board. The Geneva firm is led by Swiss billionaire and former Serono chief Ernesto Bertarelli and devised an $832 million buyout deal to take allergy drugmaker Stallergenes Greer private.

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Eli Lilly vet jumps aboard Polaris Partners; Mirati shakes up its leadership team with new hires and promotions - Endpoints News

The prospect of using the popular genome-editing tool CRISPR to treat a host of diseases in people is moving closer to reality.

Medical applications of CRISPRCas9 had a banner year in 2019. The first results trickled in from trials testing the tool in people, and more trials launched. In the coming years, researchers are looking ahead to more sophisticated applications of CRISPR genome editing that could lay the foundation for treating an array of diseases, from blood disorders to hereditary blindness.

But although the results of clinical trials of CRISPR genome editing so far have been promising, researchers say that it is still too soon to know whether the technique will be safe or effective in the clinic.

Theres been a lot of appropriate caution in applying this to treating people, says Edward Stadtmauer, an oncologist at the University of Pennsylvania in Philadelphia. But I think were starting to see some of the results of that work.

It has only been seven years since researchers discovered thata molecular defence system called CRISPRCas9, which microbes use to fend off viruses and other invaders, could beharnessed to rewrite human genes.

Since then gene-editing has attracted attention for its potential to modify embryosan application that is ethically and legally fraught if those embryos are destined tobecome human beings. But in parallel, scientists have been testing CRISPR's much less controversial ability to disable or correct problematic genes in other cells in order to treat a host of diseases.

In 2016, Chinese researchers announced that they hadtreated the first person with a CRISPRCas9 therapydesigned to fight cancer. In cells extracted from a participant's blood, the researchers disabled the gene that codes for a protein called PD-1,which holds the immune system in checkbut can shield cancer cells in the process. The scientists then reinjected the cells.

By 2019, the US governments clinicaltrials.gov database listed more than a dozen active studies that are testing CRISPRCas9 as a treatment for a range of diseases from cancer to HIV and blood disorders.

So far, too few people have been treated in these trials to draw any firm conclusions about the safety of CRISPRCas9 therapies or how well they work. Preliminary results from two trialsone in which gene-edited blood cells were transplanted into a man to treat HIV infection, and the other in which they were transplanted into three people to treat some forms of cancershowed no signs of clinical improvement.

In both cases, the transplanted cells flourished in the bone marrow of recipients, without any serious safety concerns, but did not produce a clear medical benefit. In the man treated for HIV, the researchers attempted to use CRISPR to disable a protein that many strains of HIV use to enter cells. But only 5% of the transplanted cells were editednot enough to cure disease, the researchers reported in September. The study has been placed on hold while researchers explore ways to boost that percentage, says Hongkui Deng, a stem-cell researcher at Peking University in Beijing and a lead author of the work.

There are early hints that another trial might meet with more success. CRISPR Therapeutics in Cambridge, Massachusetts, and Vertex Pharmaceuticals in Boston, Massachusetts, have treated two people with the genetic disorders sickle-cell anaemia and -thalassaemia. Both deplete oxygen-carrying haemoglobin molecules in the blood: the idea is to use CRISPR to disable a gene that otherwise shuts off production of another form of haemoglobin. Early results suggest that the treatment might have eased some symptoms of the disorders, but the participants will need to be followed for a longer period to be sure.

Other researchers are already itching to move beyond editing cells in a dish. The challenge is in finding ways to transport the gene-editing machinery to where it is needed in the body, says John Leonard, chief executive of Intellia Therapeutics, a biotechnology company in Cambridge, Massachusetts, that is focused on CRISPRCas9 genome editing. The delivery approach is so important.

Last July, the pharmaceutical companies Editas Medicine in Cambridge, Massachusetts, and Allergan in Dublin launched a trial to treat the genetic disorder Leber congenital amaurosis 10, which can cause blindness, by editing eye cells. Researchers will inject into the eye a virus containing DNA that encodes the CRISPR genome-editing machinery, bypassing the need to guide those tools through the bloodstream to the specific tissues. The virus will be responsible for carrying the genome-editing tools into cells. It is the first trial to attempt CRISPRCas9 gene editing inside the body, and early results could be reported this year.

That would be a landmark moment for the field, and could pave the way for future trials targeting other organs, says Charles Gersbach, a bioengineer at Duke University in Durham, North Carolina. But he and others say that they hope researchers will eventually move away from using viruses to shuttle genome-editing machinery into cells. Deactivated viruses can still sometimes provoke immune responses, and can only carry a limited amount of DNA.

What's more, some gene-editing tools are currently too large to fit inside commonly used gene-therapy viruses, says chemical biologist Andrew Anzalone at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts. These include the souped-up CRISPR systems calledprime editorsthat were first reported in late 2019and might prove to be more precise and controllable than CRISPRCas9.

Intellia is looking for a way around the viruses. The company has partnered with Swiss pharmaceutical giant Novartis to develop fatty nanoparticles that can protect genome-editing molecules as they travel through the bloodstream, but also pass through the membranes of target cells.

These particles tend to accumulate in the liver, and researchers are working to develop particles that infiltrate other tissues, such as muscle or the brain. But for now, Intellia will focus on liver diseases, says Leonard, and plans to launch its first trial of the technology this year. Its crawl before you walk, so to speak, he says.

None of the technologies currently being tested is what researchers envision for the long-term applications of genome-editing, says Gersbach. The approaches that people are taking are the things that we can do today, he says, but not what we would do if we could design the ideal drug.

Leonard says that when he meets with investors, they often demand to know what medical advances will be made in the next six months. We do our best to describe that, but I always end it by saying, Can you imagine a future without gene editing? he says. I have yet to meet the person who says, yes.

This article is reproduced with permission and wasfirst publishedon January 6, 2020.

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Quest to Use CRISPR Against Disease Gains Ground - Scientific American

Bioengineering, once viewed primarily as an academic discipline, is growing up.

Our ability to engineer biology is on the verge of changing the landscape of health and health care. Tools and treatments that are engineered, not discovered CAR-T therapies for cancer, CRISPR for gene editing, stem cell therapies, and more are now making their way not just into new startups but into established industry. Just look at the first-generation CAR-T companies that have been acquired by major biopharma companies, like Bristol-Myers Squibb/Celgene acquiring Juno or Gilead acquiring Kite.

The acquirers, massive organizations built on the foundations of discovery, are now ingesting companies built with engineering DNA. These are two extremely different mindsets. For decades, biopharma companies essentially used scientists to build products, because there was no means to engineer them. The intersection of these worlds is driving us into the future.

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Here come the culture clashes.

These emerge every time major new technologies disrupt an industry. Think of the early days of oil and the evolution as the industry matured from wildcatters one man, one rig, one highly risky and unreliable process to Rockefellers and Rothschilds and a highly sophisticated engineering and discovery process that used every advanced technology and enterprise tool available.

In biopharma and health care today, the old culture of discovery the idea that science is driven by discovering new knowledge (hypothesis > test > repeat) is clashing with the new culture of engineering (design > test > iterate). This clash encompasses how everything is handled, from identifying biological targets to designing clinical trials and even to how we access health care.

Knowing that these clashes are coming will help smooth the way as the biopharma industry integrates bioengineering deeper and more broadly. I see four key clashes worth noting.

We cant yet take for granted a common understanding that we can engineer biology. In spite of bioengineering departments flourishing at revered institutions like Harvard and MIT and Stanford and Berkeley, in spite of the success of new tools like CAR-T and CRISPR, some think that bioengineering is either hype or a passing fad. Thats OK; every new field struggles with the old guard.

Bioengineering still needs to come from a place of clearly and repeatedly explaining its worth with evidence. Lets just get used to this. That said, naysayers are predisposed to cling to old-school approaches. After all, thats the value they have to offer. Ultimately, they will need to adapt to an engineering approach or get engineered out of the process.

The culture of discovery and the culture of engineering value progress differently. Discovery, for example, prioritizes the Eureka! moment above all. One of the most challenging aspects of drug development is that you cant establish a key performance indicator for such moments. Pure discovery is a lottery ticket business that exists in the biopharma industry only because of its incredibly high value and the potential to save millions of lives.

Engineering, on the other hand, values a repeatable process, one that can be stacked or adjusted the way we build with Legos, aiming for compounding results a consistent fractional improvement year over year, leading to exponential improvement over time.

Health care needs both approaches. Todays great discovery will be engineerable tomorrow (OK, maybe 50 years from now). CRISPR, for example, began with discoveries in Haloferax mediterranei, a species of salt-tolerant bacteria. That was pure scientific discovery. But using CRISPR as a tool, as a therapeutic, or as a platform for future innovations is squarely in the world of bioengineering.

The choice of staying or leaving is now at the heart of the debate about what engineering can or cant handle, and what should remain pure, unfettered empirical discovery.

The truth is that engineering can handle empirical approaches. For example, is an A/B test discovery or is it engineering? Its actually both discovery done via an engineering process with iteration. Because biology is so incredibly sophisticated and complex, there will always be discovery risk the risk that some heretofore unknown aspect of biology will lead to failure. But part of engineering is, and should be, handling discovery and failure, and discovery can and should be engineered.

Tools like artificial intelligence and machine learning allow us to introduce to the world of discovery faster throughput, faster iteration, and greater reproducibility. We need to know how and where to apply engineering and discovery frameworks, and where the two worlds meet. Is your discovery risk one where you must wait for serendipity, or can you improve your odds by engineering some part of it?

The discovery and engineering cultures speak something that sounds like the same language, but really isnt. Words like discovery and platform mean very different things in science than they do in engineering. Even success doesnt directly translate: Does it work and we know how we got there, or did we get there in a repeatable process we can tweak?

Getting lucky with a serendipitous discovery is not success in an engineering discipline, nor is getting unlucky a failure in engineering, since you can learn something valuable from failure with which to tweak the process. Like any language issue, we need to recognize the different meanings in those core concepts and know when to use which depending on the world you are in.

Integrating these cultures requires each side to understand core tools, language, and mindsets in both worlds, and knowing where to leverage the differences. Where can discovery yield new empirical information for an engineered process? Where can an engineered process increase the odds of success over a more traditional discovery route?

In health care, as more and more products and tools become engineerable, the world of discovery will need to transition toward integrating engineering. This will be bumpy and uncomfortable and lets be real, there will be blood. But there will also be many bright spots. There will be people trained in science who, when introduced to engineering, feel they can tap into a new world of possibility. There will be engineers who maybe started their careers because as kids they dreamed of engineering trains who suddenly feel they have the potential to help cure cancer.

The audacious dream of engineering biology on a molecular scale is finally being realized not just in practice but commercially if we can surmount the culture clashes.

Vijay Pande, Ph.D., is a general partner at Andreessen Horowitz, a Silicon Valley venture capital firm, and an adjunct professor of bioengineering at Stanford University. He serves on the boards of Apeel Sciences, Asimov, BioAge, Ciitizen, Devoted Health, Freenome, Insitro, Omada, and PatientPing.

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Welcome to the bioengineering culture clash - STAT

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ValuEngine cut shares of Aytu Bioscience (NASDAQ:AYTU) from a buy rating to a hold rating in a report published on Tuesday, December 24th, ValuEngine reports.

Several other research firms have also recently commented on AYTU. Northland Securities started coverage on shares of Aytu Bioscience in a report on Friday, November 15th. They set a buy rating and a $5.00 price target on the stock. Zacks Investment Research lowered Aytu Bioscience from a hold rating to a sell rating in a report on Tuesday, December 17th. Finally, LADENBURG THALM/SH SH boosted their target price on Aytu Bioscience from $4.00 to $4.75 in a research note on Wednesday, September 18th.

NASDAQ AYTU traded down $0.05 during trading on Tuesday, reaching $0.85. 69,438 shares of the companys stock were exchanged, compared to its average volume of 99,631. The firm has a market capitalization of $18.59 million, a PE ratio of -0.24 and a beta of 4.61. Aytu Bioscience has a fifty-two week low of $0.65 and a fifty-two week high of $2.61. The companys fifty day simple moving average is $0.86 and its 200-day simple moving average is $1.25.

Aytu Bioscience (NASDAQ:AYTU) last posted its quarterly earnings results on Thursday, November 14th. The company reported ($0.32) EPS for the quarter, missing the consensus estimate of ($0.30) by ($0.02). Aytu Bioscience had a negative return on equity of 252.42% and a negative net margin of 390.43%. The company had revenue of $1.44 million for the quarter, compared to analyst estimates of $1.45 million. As a group, sell-side analysts expect that Aytu Bioscience will post -1.3 earnings per share for the current fiscal year.

In other Aytu Bioscience news, CEO Joshua R. Disbrow bought 55,000 shares of the stock in a transaction on Thursday, December 19th. The shares were purchased at an average cost of $0.83 per share, with a total value of $45,650.00. Also, major shareholder Armistice Capital Master Fund bought 78,788 shares of the businesss stock in a transaction on Friday, December 20th. The shares were bought at an average price of $0.90 per share, for a total transaction of $70,909.20. Insiders own 5.80% of the companys stock.

Several institutional investors and hedge funds have recently added to or reduced their stakes in the company. BlackRock Inc. acquired a new position in shares of Aytu Bioscience during the 2nd quarter valued at about $36,000. Virtu Financial LLC acquired a new stake in Aytu Bioscience in the 3rd quarter worth approximately $36,000. Bank of New York Mellon Corp acquired a new stake in Aytu Bioscience in the 2nd quarter worth approximately $75,000. Finally, Searle & CO. boosted its position in Aytu Bioscience by 24.1% during the third quarter. Searle & CO. now owns 249,848 shares of the companys stock worth $302,000 after purchasing an additional 48,601 shares during the period. Institutional investors own 27.76% of the companys stock.

Aytu Bioscience Company Profile

Aytu BioScience, Inc, a specialty healthcare company, focuses on developing and commercializing novel products in the field of hypogonadism (low testosterone), insomnia, and male infertility in the United States and internationally. The company markets Natesto, a nasal gel for the treatment of hypogonadism (low testosterone) in men; and ZolpiMist, an oral spray for the treatment of insomnia.

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Aytu Bioscience (NASDAQ:AYTU) Stock Rating Lowered by ValuEngine - Riverton Roll

SAN FRANCISCO, Jan. 8, 2020 /PRNewswire/ --Today BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) and Invitae Corporation (NYSE: NVTA) announced that Biogen (NASDAQ: BIIB), Encoded Therapeutics, Neurogene, Praxis Precision Medicines and PTC Therapeutics joined Behind the Seizure, an innovative, cross-company collaboration that aims to provide faster diagnosis for young children with epilepsy. The program will also be expanded to make no-charge testing available for healthcare providers to order for any child under the age of eight who has an unprovoked seizure.

"Behind the Seizure is one of the longest-running cross-company collaborations aimed at increasing access to genetic testing. It has been shown to decrease time to diagnosis for children experiencing unprovoked seizures by one to two years from reported averages, and as more companies have joined the program, more children have been helped," said Robert Nussbaum, chief medical officer of Invitae. "Earlier diagnosis enables clinicians to focus on providing disease-specific care sooner, which is particularly important in neurodegenerative diseases. We applaud these companies for their commitment to expanding this unique effort to help children."

Previously the program was available to children under age five. The newest companies to join Behind the Seizure include:

Behind the Seizure is supported by eight sponsors in all, including Stoke Therapeutics and Xenon Pharmaceuticals who joined in 2019.

Since the program began, thousands of children have received genetic testing through Behind the Seizure and research has shown that participants in the program were diagnosed one to two years sooner than historic averages.1 Companies that participate in the program sponsor the cost of testing using the Invitae Epilepsy Panel, which includes more than 180 genes associated with both syndromic and non-syndromic causes of epilepsy, including neurodegenerative conditions. With the expansion of the program, healthcare providers now can order the test for patients under the age of eight with unprovoked seizures. Test results are available quickly (14 days on average).

More than half of epilepsies are based in genetics. When a child presents with seizures, genetic testing can help identify more than 100 underlying, often rare conditions. Early genetic testing may be the most cost-effective, direct and accurate diagnostic tool for children, shortening years-long diagnostic odysseys. Delays in diagnosis can be devastating for children, as some genetic epilepsies are neurodegenerative and early symptoms may be subtle and easy to misdiagnose.

Participating companies provide financial support for this program, which includes testing and services performed by Invitae. Healthcare professionals must confirm that patients meet certain criteria to use the program. Third parties and commercial organizations may receive de-identified patient data and contact information for healthcare providers who use this program, but at no time do they receive patient identifiable information. Genetic testing and counseling are available in the US and Canada. Healthcare professionals and patients who participate in this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use or support any other products or services from Invitae or from third parties or commercial organizations.

About Behind the SeizureBehind the Seizure is an innovative, cross-company collaboration designed to increase access to genetic testing for children who experience unprovoked seizures in childhood in the United States and Canada. More than half of epilepsies have some genetic basis, and are often associated with rare, neurodegenerative conditions with non-specific symptoms. Early genetic testing may be the most direct, cost-effective, and accurate diagnostic tool. Participants in the Behind the Seizure program are diagnosed one to two years sooner than reported averages. The program was established by BioMarin and Invitae and now includes: Biogen, Encoded Therapeutics, Neurogene Inc., Praxis Precision Medicines, PTC Therapeutics, Stoke Therapeutics and Xenon Pharmaceuticals. To learn more about the Behind the Seizure program please visit https://www.invitae.com/en/behindtheseizure/.

About BioMarinBioMarin is a global biotechnology company that develops and commercializes innovative therapies for patients with serious and life-threatening rare and ultra-rare genetic diseases. The company's portfolio consists of seven commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visit http://www.biomarin.com.

About InvitaeInvitae Corporation (NYSE: NVTA) is a leading genetics company whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website at invitae.com.

About Encoded TherapeuticsEncoded Therapeutics, Inc. is a biotechnology company developing precision gene therapies for a broad range of severe genetic disorders. Our mission is to realize the potential of genomics-driven precision medicine by overcoming key limitations of viral gene therapy. We focus on delivering life-changing advances that move away from disease management and towards lasting disease modification. For more information, please visit http://www.Encoded.com.

About Neurogene Inc.Neurogene was founded to bring life-changing medicines to patients and families affected by rare neurological disorders. We partner with leading academic researchers, patient advocacy organizations and caregivers to bring to patients therapies that address the underlying genetic cause of a broad spectrum of neurological diseases where no effective treatment options exist today. Our lead programs use AAV-based gene therapy technology to deliver a normal gene to patients with a dysfunctional gene. Neurogene is also investing in novel technology to develop treatments for diseases not well served by gene therapy. For more information, visit http://www.neurogene.com.

About Praxis Precision MedicinesPraxis Precision Medicines is a clinical-stage genetic neuroscience company developing high-impact therapies for patients and families affected by complex and debilitating brain disorders, including rare pediatric epilepsies and neuropsychiatric disorders. These two disease areas share overlapping disease biology and genetic targets, as well as a profound need for new therapeutic options that target the underlying cause of the disease. Praxis is advancing a pipeline of breakthrough medicines with the potential to more precisely treat complex brain disorders. For more information, please visit http://www.praxismedicines.com.

About PTC TherapeuticsPTC Therapeutics is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to globally commercialize products is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need.

About Stoke TherapeuticsStoke Therapeutics, Inc. (Nasdaq: STOK), is a biotechnology company pioneering a new way to treat the underlying causes of severe genetic diseases by precisely upregulating protein expression to restore target proteins to near normal levels. Stoke aims to develop the first precision medicine platform to target the underlying cause of a broad spectrum of genetic diseases in which the patient has one healthy copy of a gene and one mutated copy that fails to produce a protein essential to health. These diseases, in which loss of approximately 50% of normal protein expression causes disease, are called autosomal dominant haploinsufficiencies. The company's lead investigational new medicine is STK-001, a proprietary antisense oligonucleotide (ASO) that has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome, a severe and progressive genetic epilepsy. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visithttps://www.stoketherapeutics.com/or follow the company on Twitter at @StokeTx.

About Xenon PharmaceuticalsXenon Pharmaceuticals is a clinical stage biopharmaceutical company committed to developing innovative therapeutics to improve the lives of patients with neurological disorders, including rare central nervous system (CNS) conditions. We are advancing a novel product pipeline of neurology therapies to address areas of high unmet medical need, with a focus on epilepsy. For more information, please visit http://www.xenon-pharma.com.

Safe Harbor StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the benefits of genetic testing and the Behind the Seizure program, including shortening the time to diagnosis and improved treatment outcomes for patients. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; the ability of genetic testing to result in faster or more accurate diagnosis; laws and regulations applicable to the company's business; and the other risks set forth in Invitae's filings with the Securities and Exchange Commission, including the risks set forth in its Quarterly Report on Form 10-Q for the quarter ended September 30, 2019. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelopr@invitae.com(628) 213-3283

1 Miller, Nicole, et al, "Behind the Seizure: A No-Cost 125-gene Epilepsy Panel for Pediatric Seizure Onset Between 24 Years". Presented at the American Society of Human Genetics Meeting: October 1620, 2018, San Diego, CA.

View original content to download multimedia:http://www.prnewswire.com/news-releases/behind-the-seizure-program-further-expands-access-to-genetic-testing-for-children-to-speed-the-diagnosis-of-genetic-epilepsy-300983302.html

SOURCE Invitae Corporation

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Behind the Seizure Program Further Expands Access to Genetic Testing for Children to Speed the Diagnosis of Genetic Epilepsy - P&T Community

Pharmacogenetics presents clinicians an attractive option to optimize drug therapy, minimize harmful effects, and contain costs; but, payers may not be taking full advantage of cost-saving potential by choosing only to cover the costs associated with interrogating a single gene.

Reports vary, but the cost of testing a single gene appears to range from $100 to $500, depending on the source. The cost of running an entire panel is a similar price.

Despite the virtually negative cost differential, payers are reluctant to cover the cost of running a full panel of tests. This common practice raises the question of why many payer organizations do not pay for running an entire test panel. Experts differ in their speculations as to why this is the case.

I dont think theyre familiar with the total body of knowledge, says Ruben Bonilla-Guerrero, MD, FACMG, FAACC, MB(ASCP), CGMBS, medical director of medical affairs at Admera Health, a leader in personalized medicine and non-invasive cancer testing in South Plainfield, New Jersey. Insurance companies consider running a pharmacogenetic test panel as experimental even though the labels on more than 200 drugs mention pharmacogenetics testing.

Related:Genetic Testing in Treatment Decision Making Goes Mainstream

Pharmacogenetic testing offers important advantages by facilitating the prescribers ability to select, initiate, and adjust a pharmaceutical drug product with a much higher level of precision than previously available with conventional dose titration. Pre-emptive testing also helps prevent adverse drug events that occur as a result of overdosing medications.

However, like many areas of healthcare, weighing the cost against the purported benefits is also critical.

Payers want to reimburse for tests that are done for a specific indication and that have evidence-based, actionable treatments based on the results, says Erin Lopata, PharmD, MPH, senior director of the Access Experience Team at Precision for Value, part of Precision Value & Health, which performs value and access consulting services for entities that may be involved in value-based contracting.

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The Benefits of Pharmacogenetic Testing - Managed Healthcare Executive

Biofidelity assay has potential to make high precision, cost-effective and non-invasive diagnosis more widely available, improving treatment and patient outcomes

Cambridge, UK, 9th January 2020 Biofidelity Ltd, a company developing high performing novel molecular assays for the detection of targeted, low-frequency genetic mutations, today announced the successful completion of a study to detect key lung cancer mutations in collaboration with Agilent Technologies, a global leader in life sciences, diagnostics, and applied chemical markets.

The collaboration, using an assay developed by Biofidelity, demonstrated an improvement in sensitivity of 50 times that achieved with current FDA-approved PCR-based diagnostics, matching that of specialized NGS assays, which require error-correction technology, while providing a dramatic simplification of workflows from more than 100 steps, to just 4 (four). Assays were performed using standard laboratory instrumentation, demonstrating the potential for straightforward adoption of Biofidelitys panels in decentralised testing laboratories around the world.

As well as extremely high sensitivity, 100% specificity was achieved in the detection of multiplexed panels of mutations from both tissue and plasma, with no false positives observed across more than 750 assays. Analysis of results is also dramatically simpler than sequencing-based assays, providing physicians a clear, simple, actionable result, with a turnaround time of less than 3 hours, making the Biofidelity assay suitable for recurrent patient monitoring.

Genetic testing for lung cancer mutations is usually carried out through invasive tissue biopsy, an expensive procedure carrying significant risk for patients with advanced disease. Up to 10% of such tests fail due to the lack of sensitivity of current testing solutions and poor sample quality.

Liquid biopsy, or testing directly from the patients blood, offers a non-invasive alternative with significant potential benefits to patients. However, its use has been limited by the lack of cost-effective, robust and rapid tests which are sufficiently sensitive to enable detection of the very small fractions of tumor DNA present in such samples.

Of the nearly 2 million new cases of non-small-cell lung cancer (NSCLC) diagnosed each year worldwide, fewer than 5% of patients receive high-sensitivity, non-invasive genetic testing. The assay developed by Biofidelity could provide a simple solution, enabling access to high-precision genetic testing for more than 1.7m new NSCLC patients every year with a test that outperforms DNA sequencing in a fraction of the time.

Work was supported by InnovateUK grant number 105202 as part of the Investment Accelerator: Innovation in Precision Medicine program.

Dr Barnaby Balmforth, Chief Executive Officer of Biofidelity, commented: Our goal is to improve patient outcomes in oncology by enabling much greater access to the highest precision diagnostic tests. This collaboration with Agilent in lung cancer has again demonstrated that Biofidelitys molecular assays dramatically increase the effectiveness and speed of diagnosis, supporting early detection of disease, better targeting of therapies and improved patient monitoring. By combining diagnostic outperformance and rapid results in a simple, cost-efficient format using existing instrumentation, we believe we have the potential to bring high precision testing to many more NSCLC patients, substantially reducing the need for invasive biopsies.

Tad Weems, Managing Director, Agilent Early Stage Partnerships, commented: As both a scientific collaborator and an investor in the company, Agilent has been impressed by the data from Biofidelitys assays, which detected a selection of NSCLC DNA mutations at extremely low frequencies in both tissue and plasma samples without the need for DNA sequencing. Biofidelitys assays are specific and sensitive, with the potential to provide improved and rapid routine cancer diagnostics.

Notes To Editors

About Biofidelity

Biofidelity has developed a molecular assay with a simple workflow and fast time-to-result which can transform the detection of genetic abnormalities within a sample by reliably detecting large panels of DNA mutations at extremely low frequencies.

This assay has a simple workflow and is suitable for routine use in diagnostics labs around the world, without the need for investment in new instrumentation or infrastructure.

Biofidelity is developing genetic panels for use in precision medicine and patient monitoring across a range of diseases including NSCLC and colorectal cancer

Located in Cambridge, UK, Biofidelity is a private company founded in 2019.

For more information, visit http://www.biofidelity.com, or follow us on LinkedIn: Biofidelity.

Issued for and on behalf of Biofidelity by Instinctif Partners.For more information please contact:

BiofidelityDr Barnaby Balmforth, CEOT: +44 1223 358652E: info@biofidelity.com

Instinctif PartnersTim Watson / Genevieve WilsonT: +44 20 7457 2020E: Biofidelity@instinctif.com

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Biofidelity and Agilent complete successful molecular assay study for rapid and accurate detection of key lung cancer mutations - BioSpace

Im fascinated by genetics, but I also find it extremely complicated and confusing. In fact, I remember genetics being one of the most intimidating topics we learned in biology back in high school. If you had told me back then that Id be writing about a genetics company all these years later for The Jerusalem Post, I might have laughed.When it comes to genetics, variables are limitless, and its mind-blowing to see how each of us, in our own unique way, essentially won the genetic lottery through the course of time and evolution.This explains why recreational genetic testing providers, such as 23andMe, Ancestry.com, and MyHeritage gained significant popularity over the years.However, it is worth noting that these services can only read a portion of our DNA data. There is so much more depth to the full picture of our DNA and gaining visibility into that data can improve health and prevent premature death, as well as identify and eliminate the risk of passing genetic disorders.The first human genome was sequenced in 2013 as part of an international project with the goal of identifying and mapping all human genes. The project took 13 years to complete and the estimated cost was a whopping $3 billion.To this day, it remains the worlds largest collaborative biological project and it has opened new frontiers in science and medicine, but also brought challenges that have yet to be fully addressed.It presently costs less than $1,000 and takes a single day to sequence the human genome. Whole genome sequencing (WGS) provides a readout of the three billion letters of an individuals entire DNA sequence. This data provides the foundation for identifying all types of disease-causing variants, or changes in an individuals DNA that cause disease.However, the biggest challenge is how to accurately (and economically) make sense of the vast amounts of data that WGS generates. I mean, there is big data and then there is this, more like astronomical data!Variantyx is a Tel Aviv-based clinically accredited genetic testing lab. Its headquarters are in Boston and it uses technology based on WGS to perform one-stop comprehensive testing for patients. The company was founded in 2014, and has raised $18 million in capital from Pitango. The analyses performed by Variantyx are carried out using an in-house developed analytical platform built and optimized for WGS data. Their proprietary algorithms identify a wide range of difficult-to-detect sequence variants, and is then presented to Variantyxs clinical team for interpretation and reporting. The potential of this technology is quite literally limitless.Variantyxs Genomic Unity is the industrys first comprehensive, all-in-one test for diagnosis of rare inherited disorders. It eliminates the need to order multiple tests, resulting in more diagnoses in a shorter period of time, and with lower overall costs. This is a big deal because rare disorders are not actually rare. With more than 7,000 rare diseases, its estimated that over 30 million people in the US and over 350 million people globally are affected. Many of these diseases are genetic in origin, and many of the individuals affected are children.THROUGHOUT THE typical diagnostic journey, a rare-disease patient will be seen by eight different physicians in less than a decade, and will spend an average of $21,000 to reach a diagnosis. They are the lucky ones. Many patients remain undiagnosed, despite multiple rounds of genetic testing. Variantyxs WGS-based Genomic Unity test is changing this.Since its introduction to the market in late 2017, the test has solved hundreds of previously undiagnosed cases for patients at many childrens hospitals worldwide. The benefits of comprehensive genetic testing extend to healthy individuals. Variantyxs Genomic Inform test has been developed to provide important information about disease predisposition risk, and carrier status. The test has applications in disease predisposition screening, newlywed carrier screening, prenatal screening and pharmacogenomics a field of precision medicine that identifies variants which influence how an individual responds to a particular prescribed drug.In terms of market demand, the overall genomic diagnostic market is valued to be greater than $20 billion, most of which is health-insurance driven. It has the potential to grow substantially as the cost of sequencing continues to decrease. In 2019, Francis deSouza, the CEO of Illumina, committed to making the $100 genome a reality. At that price, in the not so distant future, it will be possible to sequence every newborn and make their genomic data available for consultation whenever a clinical decision is made during their lifetime.Variantyx was formed as a spin-out of Tel Aviv University in 2014, and is now 45 team members strong. The idea of Variantyx actually started 10 years ago at the functional genomics lab at Tel Aviv University, headed by Prof. Noam Shomron. He and his PhD students were frustrated by the major bottleneck affecting analysis of patients exome data, as so much of the work had to be done manually. They set about developing a pipeline to more effectively process the information. To tackle the challenge of applying his teams work at the scale needed to help a larger number of patients, Noam teamed up with Tomer Jackman and Haim Neerman. Jackman had played a pivotal role at EMC, helping to develop their big data platform, and naturally wasnt daunted by the vast amounts of data that needed to be processed.Neerman, a serial technology entrepreneur in the area of IT systems and business process automation brought valuable expertise in eliminating time-consuming and error-prone manual steps. They collectively had the foresight to anticipate the shift from exome data to genome data and began building the first version of the companys analytical platform. The same platform is used today to perform its WGS-based Genomic Unity and Genomic Inform testing. The company has been growing rapidly to support the increased demand for its testing.Today, Variantyx is providing answers to rare disease patients and healthy individuals alike, and I personally cant want to see what unfolds as they prepare for a more broad population-based deployment as genome sequencing becomes more affordable, accessible, and penetrates the mainstream.

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Israel's all-in-one test for diagnosis of rare inherited disorders - The Jerusalem Post

A doctor diagnosing a 50-year-old patient based on a blood test taken during the patients infancy would be unthinkable.

Anecdotally speaking, however, thats what Michigan State University scientists have done with corn. Using plant RNA data from 2-week-old corn seedlings, Shinhan Shiu, professor of plant biology and computational mathematics, science and engineering, has shown that farmers and scientists can improve adult crop trait predictions with accuracy that rivals current approaches using DNA, i.e. genetic data.

Traditional breeding methods take months to years, which can be saved if we can predict the desirable traits just from DNA and RNA without growing them, without having to measure the actual traits directly, said Shiu, senior author of the paper appearing in the current issue of The Plant Cell. To continue the human medicine anecdote, its like sequencing an infants RNA and analyzing what sort of traits the infant may develop later in life.

Shiu has long been fascinated with using computational approaches to resolve evolution and genome biology questions. A well-recognized grand challenge in biology is how to connect information in the DNA, or genotype, with traits, or phenotype. Solving this mystery is fundamental to understanding how genetic information is translated into outward traits in any species, Shiu said.

Since RNA is a product of DNA, one step closer to the traits DNA ultimately influences, the RNA blueprints can potentially offer better predictions. Using machine learning approaches, Shiu and his colleagues have taken a step closer to connecting DNA, RNA and the underlying traits.

This is helpful for new breeding programs and may have implications in new ways to do genetic testing, Shiu said. We found that RNA measurements provide additional information that we cannot get from DNA alone.

In terms of reproduction, for example, the team was able to make accurate flowering and yield predictions even before the plants had developed their seed or flower organisms.

Traditional methods using genetic marker-based models identified only one of 14 known genes linked to flowering time as important. However, the gene expression-based model created by Shiu and his colleagues identified five.

Even with this increased accuracy, though, Shius team isnt saying the new method should replace the old.

Our findings are complementary to genetic marker-based prediction and identifies gene expression-trait associations that are not explained by genetic markers, Shiu said. Not only does this help in selection of breeding lines with desirable traits, but also enhances our understanding of the mechanisms involved in these processes.

Future research will work to improve the models accuracy, efficiency and cost.

Additional MSU scientists contributing to the study include Christina Azodi, Jeremy Pardo, Robert VanBuren and Gustavo de los Campos. For more, seethe original paper at http://www.plantcell.org/content/early/2019/10/22/tpc.19.00332.

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Scientists improve yield predictions based on seedling data - Ohio's Country Journal and Ohio Ag Net

Coverage of our peer-reviewed research and news reporting in the healthcare and mainstream press.

Philly Voices piece, Men with testicular cancer may only need one round of chemo, study says, cited an article published onAJMC titled, When Less Is More: Halving Chemo Keeps Testicular Cancer at Bay, Study Finds. The article outlined findings from a study stating that young men who undergo chemotherapy after surgery for testicular cancer may live with side effects for decades.

Dark Daily featured an April 2019 article of AJMC titled, As DTC Genetic Testing Grows Among Consumers, Insurers Are Beginning to Get on Board. The article stated that by 2021, 100 million people will have used a direct-to-consumer genetic test, indicating its growing popularity among healthcare providers and consumers.

A September 2019 article onAJMC titled, Physician Shortage Likely to Impact OB/GYN Workforce in Coming Years, was spotlighted by MedCity News, whichreported that a womens health startup providing care by blending technology and physical clinics has pulled in $45 million to support growth.

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AJMC in the Press, January 10, 2020 - AJMC.com Managed Markets Network

As we enter the New Year, health, wellness, and resolutions to eat better and get more exercise are priorities for most of us who have not yet made them permanent fixtures in our way of life. Whether you launch into 2020 with a keto or Mediterranean diet and/or join Orangetheory, Equinox or that cult (I mean gym) CrossFitor just subscribe to the burn more calories than you take in tried and true methodwe all start off with the best of intentions. In the last couple of years, the newest health threat has been sitting too muchin our offices and homesand we have seen the emergence of stand-up desks and "how many steps have you taken today" has become a normal part of everyday conversation. But maybe the most well-accepted cause and least understood "silent killer" that we collectively do a terrible job of managing is stress.

The human body functions best when it is in a state of homeostasisin a condition of balance, harmony, and stability. Our bodies have evolved to have a number of compensatory mechanisms to maintain a balance for pH, O2/CO2, electrolytes, glucose/insulin, immune response activation/de-activation, hormone levels, and many other physiological systems. When the homeostatic state for these physiological balances is thrown off due to genetic or environmental changes over time, they may eventually experience a number of problems in their mental and physical functions. This may result in a variety of symptoms from headaches, nausea, and exhaustion to more pronounced situations, such as high blood pressure, diabetes, auto-immune diseases, and cancer.

The medical community continues to elucidate the cause and effect relationship between bacteria, viruses, toxins and our genetics and how those lead to illness. Researchers and companies continue to develop new and better drugs, vaccines, medical devices, and even gene therapy and gene-editing technology to "fix us" when we get sick. But what about our "mind-body" connection? And no, that is not just a term used by alternative medicine charlatans. The connections between our physical and mental well being are well established if still poorly understood mechanistically. Psychosomatic Disorders are a set of physical diseases that are either caused or made worse by mental factors such as anxiety or stress. According to the Cleveland Clinic, depression can be caused by chronic illness and further exacerbate the illness thereby "causing a vicious cycle to develop."

The rates for depression that occurs with other medical illnesses is quite high (national average for depression without co-morbidities is ~7-10%):

A recent article in Psychology Today explains that stress is a constant in our lives; it is always in flux and that stress and our bodies' response to it is not in and of itself a bad thing. Think "fight or flight" our evolutionary response to making sure we didn't get eaten by that annoying dinosaur. That dino-stressor kicks off a cascade of hormones that elevate our blood pressure, heart rate and increase our energy burn presumably so we can outrun that T-Rex. That's all well and good, but I don't think I will need to outrun a dinosaur or even a lion anytime soon. So what if our bodies are exposed to other non-carnivore caused periodic high-level stressors or chronic state of stress that trigger these cascades? What does that do to our bodies?

In a recent review of the physiological effects of stress, scientists and clinicians have demonstrated the negative effects on everything, including our central nervous system, cardiovascular, immune, gastrointestinal and endocrine systems. We are all familiar with stress-induced headaches, difficulty sleeping, and upset tummies, but unmanaged stress can also negatively impact a person's cardiovascular system by increasing blood pressure and heart rate which over time can lead to "stress" cardiomyopathy or increased risk of heart attack and stroke. Studies have shown impairments in memory recall, as well as cognitive processing, are also linked to chronic stress.

Let's face it, we all encounter some form of stress usually on a daily basis. We have demanding workdays, tiresome and/or tedious long commutes to our jobs, worrying about bills and the demands and responsibilities that come with raising our kids. Speaking from experience, couples will also experience stress from their relationships at times and business owners can also be stressed out about the success of their personal enterprises. While we can all expect to be stressed out over something in our lives at some point, allowing ourselves to continually remain in a state of stress could lead to serious health problems.

Healthline reports people who are stressed usually have a hard time controlling their emotions. Sound familiar to anyone? These emotional outbursts can lead to or exacerbate already existing problems with our spouse (or significant other), friends, family or co-workers. This can lead to even more stress and physical illness.

So, as you make those New Year's resolutions, let's not lose sight of how important removing or managing our stress is to our health, happiness, and well being. Resolve to try to be more self-aware of your own stress and how it is affecting you and others around you. Don't be afraid to talk to your doctor, spouse, family or friends about things that are stressing you. There is no shame in speaking up and you can take comfort in the knowledge that you are definitely not alone. Take steps to remove stressors where you can. When that is not possible, identify and try a variety of ways to cope with, manage and reduce that stress. Look, I am not an expert on what works or doesn'tdifferent things work for different people. Maybe it's a long walk, listening to music, meditating, hitting the gym, playing a video game with your kids or just giving and receiving a BIG hug from your spouse.

Life is life and we will never be stress-freebut let's resolve to reduce our stress levels in 2020 and to help those around us as well.

Originally published at erikhalvorsen.org on January 9, 2020.

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The Deadly Effects of Stress on Our Bodies - Patch.com

Note: This article was co-published with the Daily Bruinas a product of the Bridget O Brien travel grant.

Sarat Kumar Borah had been taking enzalutamide for six weeks when he told his son he wanted to give up. The medicine was helping a little with his prostate cancer symptomshis headaches were milder, some days he had more energybut he became livid whenever he thought about the price of the drug.Im drying up your funds, he told his son. I am old. What is the point of me living any longer if its going to finish everyones reserves.

Without insurance to cover the cost of the medication, Borah had relied on his son, Rupam, to help pay for the drugs. Even with the leftover box of the medicine Sarats oncologist gave him, Rupam estimates he spent around 25 thousand rupees on treatments, nearly a fourth of the average annual salary in India.

Rupam insists his father is not the type to give up.

Im going to fight this damn thing out, his father had joked just weeks earlier. Who do you think youre dealing with?

But things had changed.

Although he owns a successful design business, Rupam stopped eating out, going on vacations, and dipped far into his youngest daughters college fund, leaving him up most nights trying to piece together a plan to send her to university.

Im just trying to tell her, Finish your class 12 and hold on, lets see how we do, he says. I cant break her heart.

Even if the medicine was just a little less expensive it would help, he said. Instead, in the next couple months, the price of enzalutamide could dramatically increase.

In 2016, the patent for enzalutamide, a wonder drug for late-stage prostate cancer discovered by UCLA, was rejected by the Indian patent office, a decision many believed would make the drug less expensive.

Generic versions of the drug flooded the market, offering enzalutamide for a fraction of the cost of the name-brand drug, Xtandi. Although it still wasnt as cheap as chemotherapy, Knowledge Ecology International, a consumer advocacy group, estimated that as more generic companies joined the market, the cost of a pill could be driven down to 50 cents.

Then, just a year later, UCLA appealed the decision to the Delhi High Court and, last May, won. The court sent the patent back to the Indian patent office to evaluate anew. If the office approves the patent, the decision would outlaw the generic brands of enzalutamide, leaving only Xtandi, a medication with a daily dose that is 70 percent more expensive, costing about 2 lakhs for 112 capsules, or about $223,576 in U.S. dollars.

Liz Ketcham

In 2007, the UC system and 11 other universities signed on to a set of ethical licensing guidelines that emphasized the consideration of the needs of people in developing countries, according to the document. But to critics, the pledge was little more than a PR stunt. As it was signing its symbolic goodwill gesture, UCLA was also wrapping up the licensing agreement for Xtandi, with no provisions to ensure patients in developing countries would be able to afford the life-saving medication.

Phil Hampton, a UCLA spokesperson, says the university has since changed its licensing policies to include language that encourages licensees to consider the interests of underserved populations.

Still, Rupam Borah and countless others will not be able to afford the medication if the patent is approved. Spending a quarter of his salary on medicine is unaffordable spending 40 times his salary is impossible.

We will have to live by the reality that he will have to pass away sooner, he says. Thats it. What else can we do?

In a small lab on the southern end of UCLAs campus, Michael Jung spent most of his career as an organic chemist, developing new ways to synthesize chemicals. For 45 years he was content tinkering away at basic research questions and publishing results in journals like Tetrahedron Letters. Then on his 55th birthday, his wife pulled him aside.

What do you want to do for the rest of your life, she asked. More of the same?

Jung said he always dreamed of finding a cure for a human disease but never had the guts to try it. Some researchers worked years on developing a medication with nothing to show for it.

The day after his birthday, a colleague asked if he wanted to join a project dedicated to creating a prostate cancer drug. He took it as a sign, even though he knew almost nothing about prostate cancer. If nothing came of it, the worst people would think was that hed decided to retire early, he thought.

A couple years later, in 2009, he published a paper in Science, introducing enzalutamide, a molecule that could drastically alter the way prostate cancer was treated. While chemotherapy moves through the body quickly and indiscriminately, wiping out cancer cells and any other cells that divide quickly (like bone marrow), enzalutamide elegantly clicks into receptors on the surface of prostate cancer cells, blocking the hormones that cause them to grow.

Stephen Freedland, an oncologist at Cedars-Sinai, remembers the excitement around enzalutamide and other similar drugs.

There werent a lot of options for men. It was kind of like, Sorry, life sucks, Freedland says. Then all of a sudden we had a drug that could salvage a lot of these guys and just buy them time, a good quality of life.

Chemotherapy often leaves patients bed ridden with nausea. In contrast, patients on enzalutamide can usually maintain their normal lifestyles, only complaining occasionally about feeling a bit foggy. One of Freedlands patients said he couldnt lift as much at the gym, which is to say he, a late-stage cancer patient, was still working out.

In early clinical trials, late-stage prostate cancer patients who had already exhausted hormone therapies and chemotherapy, enzalutamide extended their lives by five months. In oncologist circles, the result was promisingusually treatments that work in late-stage cancer patients work even better for early stage patients.

Two years later, scientists stopped a clinical trial short after enzalutamide significantly reduced the risk of death in patients before they started chemotherapy, and in August, the FDA approved enzalutamide for patients before they even started hormone therapy.

Freedland thinks eventually enzalutamide could turn prostate cancer into a chronic illness something you can live with for years like diabetes or asthma.

We are in a renaissance period in the medical therapy of prostate cancer, an author of one of the clinical trials for enzalutamide said. Even at this early stage, enzalutamide is a game changer.

By weight, Xtandi is 65 times more expensive than gold. In the United States, that is 2.5 times the annual per capita income. In India, the name-brand drug costs more than 38 times the per capita income.

Rajeev Kumar, a urologist at a public hospital in Delhi, says if the patent were approved, almost none of his patients could afford the medication. Already, his patients struggle to afford the generic brands. Many of them run out of money a couple weeks into the treatment plan and stop taking the pills. Others, aware theyll inevitably exhaust their resources, refuse the prescription from the beginning.

With the patent, even his wealthiest patients would be unable to afford the medicine.

Liz Ketcham

In the United States, 80 percent of patients with insurance have a copay of less than $25 a month for Xtandi. In India, Kumar estimates less than 20 percent of his patients have insurance.If they do, their insurance policies usually cover a fixed amount of medical expenses for the entire family, which Xtandi would quickly deplete.

Rupam Borah has seen the worst of it in the hospital as he waits for his fathers appointmentschildren, mothers, and wives sobbing next to him, coming to terms with the fact that they cant afford medication.

Im still pushing for medicines and going desperate and having sleepless nights sometimes and all that but still look at people who are below us who cannot even imagine they will die, he says, shaking his head. Ive seen those kinds of people in hospitals. Ive seen them. I mean, they just cry. They are completely helpless.

Most of the men hes talked to in the hospital can scrape together enough for about a fourth of the cost of one box of enzalutamide. Sometimes he gives money to other patients at the hospital. Stretch it for as long as you can, he tells them.

If the pills became more expensive, Kumar isnt sure he would even prescribe enzalutamide to his patients anymore. A couple of months of life is only worth so much financial stress.

I know if I offered it to him he would take it and thatll end up destroying his family, he says. The next generation (will be) in debt for the next 10 years.

Even as an established doctor and professor at the most widely respected hospital in Delhi, one box of Xtandi would cost his entire monthly salary.

Would I give it all up to extend a couple of months? he says. Probably not.

Enzalutamide ultimately made the University of California more than a billion dollars. Even for the UC system, which owns the most patents of any American university, the drug generated more money than any other patent sale.

We are strategically supporting one of our essential missionsfunding and generating research with practical applications that serve the public good , Gene Block, the chancellor of UCLA, said in a university press release following the deal.

Except to many, it didnt seem as if the university was trying to serve the public good.

First, there was the billion dollars.

To R. Joseph Trojan, a pharmaceutical patent lawyer based in Los Angeles, it was simple economics: the more the UC charged for the patent, the higher pharmaceutical companies would have to price the medicine to recover what they had spent.

Where does it think the money was going to come from? he asks. It was coming out of the pockets of people who need the drug. Why are you driving up the cost of these drugs by demanding a billion dollar licensing fee upfront? That makes no sense at all.

Furthermore, although researchers used public funding from the National Institutes of Health and the U.S. Armys prostate cancer research program to discover Xtandi, UCLA was actively pursuing a patent that would make it inaccessible to the public. Meanwhile, money from the patent sale sits in a portfolio, generating $60 million dollars for UCLA every year.

Then there was the language in the licensing agreement. With no clause to protect developing countries, the agreement seemed to directly contradict the universitys own licensing guidelines, which say it should consider such public benefit and broad societal needs when developing licensing strategies.

John Mazziotta, the CEO of UCLA Health, says these ethical licensing guidelines are not always prescriptive, explaining there are a variety of complex and potentially contradictory issues that need to be taken into account when drafting such an agreement. Producing and testing medicine is expensive, Mazziotta argues. A pharmaceutical company might not agree to produce the medicine at all if there were a clause limiting the sales in developing countries.

Healthcare advocates have long been skeptical of that argument given that other companies, like the French NGO responsible for a successful gene therapy, included a reasonable pricing clause in their agreement and were still able to license the patent for millions.

Other institutions, like Harvard University, were able to include global access provisions in more than half of their pharmaceutical licensing agreements, clauses that allow generic companies in developing countries to produce their patented medications. They also allow Harvard to refuse to prosecute a patent in a developing country.

The UC created a committee in 2009 to oversee the inclusion of clauses that consider the needs of underserved people. These clauses have been included in 30 licensing agreements since 2018. Still, some argue this change was too little too late.

Without a global access provisions in the Xtandi agreement, if Medivation, a biopharmaceutical company that helped manufacture Xtandi, wanted UC to prosecute a patent that could take away medicine from thousands, the university has no legal avenue to refuse.

UC ultimately appealed the India patent decision on a technicality, claiming the patent office hadnt taken into account a piece of evidence. To argue its case, they hired Palaniappan Chidambaram, the former Union Minister of Finance in India. In October, Chidambaram was charged with corruption, forgery, and cheating by Indias Central Bureau of Investigations in October, and was granted bail in December. Chidambaram has denied wrongdoing.

Neda Ashtari, a second-year medical student at UCLA, stood on the stairs of Powell Library in October, dressed in all black.

In front of her were tens of white paper bags, each with a small plastic candle inside and a name scribbled on the front in colored marker. Students sprinkled plastic rose petals in between the bags, a sort of vigil for the lives lost as a result of UCLAs inaction to drop the patent on Xtandi, they wrote in a pamphlet.

Ashtari protested the patent appeal in India for years. In Regents meetings she stood in front of University of California leadership and demanded change.

Liz Ketcham

Can you imagine the guilt you would feel if all of your familys income went to your [medical] bills? Would you even want to live at that point? she asked. For one moment can you just step outside yourselves and imagine having to choose between the roof over your head and the (medicine) you needed to stay alive?

But on that day in October, standing in front of the bags of names, she seemed quieter more defeated than angry.

The pleading, public protests, and letters to the UC presidents officeone signed by 56 civil society organizations and doctors, then another with 3,500 signatures signed by students and advocacy groups had been mostly ignored.

To her, UCLAs choice to defend the Xtandi patent is personal. Her mother was diagnosed with breast cancer when she was four years old. For 12 years, as her mothers primary caregiver, she fought with insurance companies to get medication. She lost her house, her father left under the mounting stress over the cost of treatmentsand eventually her mother.

She says the worst part wasnt saying goodbye to her mom, it was knowing the same financial nightmare would happen over and over again.

They say time heals all wounds but it hasnt, she says, her voice breaking up. I still live with the consequences of these policies every day.

In a small coffee shop on the outskirts of New Delhi, Rupam Borah flips through pictures of his dogs on his phone.

Theres Bella, who he found badly beaten on the side of the road; Phi Phi, who he rescued on the way back from his vacation on Phi Phi Island, and Coco, whose paw was run over by a car.

He has a soft spot for stray dogs. He fosters stray puppies, pays to neuter dogs, and even puts out bowls of Purina dog food on the street in front of his house.

Feeding the dogs is getting harder. Paying for everything is getting harder.

Liz Ketcham

Rupams business has been slowly declining for months. When the economy is bad, the last thing people want to do is redecorate their houses, he says. Worried about the future of his company, he started teaching his employees the skills they would need to start their own businesses.

Regardless, he tries to stay positive, especially around his fatherhes seen too many children turn cold and resentful towards their parents under the financial strain of treatment.

He coos and zooms in on the well-groomed hounds as he goes through photos, occasionally stopping to take a sip from a clay cup of chai. In one, a dog with short white fur and pink ears is flashing a soft, squinty smile at the camera. In another, Rupam nuzzles into the dogs fur as the brown-and-white mutt playfully nibbles at the hand wrapped around him.

When he tells his story, he speaks calmly and matter-of-factly. If his mother were at the table, though, he wouldnt be able to keep it together, he said.

Hes wracked with guilt over the whole situationthat his oldest daughter walks dogs to help pay for her sisters tuition, that he had to take back money from his mother to cover the cost of medication.

Rupam doesnt blame his father for wanting the medicine, but he wouldnt choose enzalutamide for himself: I would opt for euthanasia any day.

RELATED: Developers Are Attempting to Evict an Elderly Cancer Patient from Her WeHo Apartment

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Visit link:
UCLA's Fight to Patent a Life-Saving Cancer Drug Could Make the Medicine Virtually Unobtainable in India - LA Magazine

People from across the South East are joining calls from the NHS urging more men to donate blood.

There's a worry not enough male donors are coming forward which could create problems because their cells can be more effective in helping sick people.

Danielle Jinadu knows how important blood donations are.

The 23-year-old law student has the life-threatening genetic disorder sickle cell disease, and needs eight units of blood every six weeks.

Like all patients who receive multiple transfusions, Danielle relies on a safe and secure supply of blood, and male donors help ensure blood is always there.

Danielle, who is studying law at the University of Warwick, said:"For me, blood transfusions are literally the difference between life and death. Without blood transfusions I know I would not be here alive at 23 years old.

"The people that give blood are often the hidden heroes. I will never get to know their names but they are extraordinary."

The NHS is worried though because there's an imbalance in donations.

Last year, only 40% of new blood donors in our region were men.Until the end of November, almost 12,500 women started donating blood in the South East - compared to just over 8,500 men.

Ellie Hudson knows how important male donors are.

Her son Finley needed three specialist blood transfusion when he was born...

He is one of around 120 people in the UK with the condition Diamond-Blackfan anemia which means he cannot produce red blood cells.

The two-year old now has monthly transfusions at Maidstone hospital.

Ellie said: He would go in once a year or so but since Finley was born he goes as regularly as he can. We are so thankful to everyone who donates, they really are lifesavers.

The NHS wants 48% of its donations this year in the South East to be from men.

Mike Stredder, the head of donor recruitment for NHS Blood and Transplant, said:

"All our donors are amazing. But we need more men to start donating blood in the South East during the New Year. Men's blood can be used in extraordinary, lifesaving ways, but we don't have enough new male donors coming forward. This is not about recruiting as many donors as possible - it's about getting the right gender mix.

"If you can't find an appointment right away don't worry - your blood will do extraordinary things if you donate in a few weeks instead."

You can find more information about becoming a blood donor here.

More:
Urgent need for male blood donors in the South East - ITV News

Jesse Bloom, left, and Lea Starita are genetic scientists pursuing advances with the technique known as Deep Mutational Scanning, which will be the subject of a symposium and workshop at the University of Washington in Seattle on Jan. 13 and 14. (GeekWire Photo / Todd Bishop)

It has been nearly two decades since scientists accomplished the first complete sequencing of the human genome. This historic moment gave us an unprecedented view of human DNA, the genetic code that determines everything from our eye color to our chance of disease, unlocking some of the biggest mysteries of human life.

Twenty years later, despite the prevalence of genetic sequencing, considerable work remains to fulfill the promise of these advances to alleviate and cure human illness and disease.

Scientists and researchers are actually extremely good at reading genomes, but were very, very bad at understanding what were reading, said Lea Starita, co-director of Brotman Baty Institute for Precision Medicines Advanced Technology Lab, and research assistant professor in the Department of Genome Sciences at the University of Washington.

But that is changing thanks to new tools and approaches, including one called Deep Mutational Scanning. This powerful technique for determining genetic variants is generating widespread interest in the field of genetics and personalized medicine, and its the subject of a symposium and workshop on Jan. 13 and 14 at the University of Washington.

I think approaches like Deep Mutational Scanning will eventually allow us to make better countermeasures, both vaccines and drugs that will help us combat even these viruses that are changing very rapidly said Jesse Bloom, an evolutionary and computational biologist at the Fred Hutchinson Cancer Research Center, the Howard Hughes Medical Institute and the University of Washington Department of Genome Sciences.

Bloom, who researches the evolution of viruses, will deliver the keynote at the symposium, held by the Brotman Baty Institute and the Center for the Multiplex Assessment of Phenotype.

On this episode of the GeekWire Health Tech Podcast, we get a preview and a deeper understanding of Deep Mutational Scanning from Bloom and Starita.

Listen to the episode above, or subscribe in your favorite podcast app, and continue reading for an edited transcript.

Todd Bishop: Lets start with the landscape for precision medicine and personalized medicine. Can you give us a laypersons understanding of how personalized medicine differs from the medicine that most of us have encountered in our lives?

Lea Starita: One of the goals of precision medicine is to use the genomic sequence, the DNA sequence of the human in front of the doctor, to inform the best course of action that would be tailored to that person given their set of genes and the mutations within them.

TB: Some people in general might respond to certain treatments in certain ways and others might not. Today we dont know necessarily why thats the case, but personalized medicine is a quest to tailor the treatment or

Starita: To the individual. Exactly. Thats kind of personalized medicine, but you could also extend that to infectious disease to make sure that youre actually treating the pathogen that the person has, not the general pathogen, if you would. How would you say that, Jesse?

Jesse Bloom: I would elaborate on what Lea said when it comes to infectious diseases and other diseases. Not everybody gets equally sick when they are afflicted with the same underlying thing, and people tend to respond very differently to treatments. That obviously goes for genetic diseases caused by changes in our own genes like cancer, and it also happens with infectious diseases. For instance, the flu virus. Different people will get flu in the same year and some of them will get sicker than others, and thats personalized variation. Obviously wed like to be able to understand what the basis of that variation is and why some people get more sick in some years than others.

TB: Where are we today as a society, as a world, in the evolution of personalized medicine?

Starita: Pretty close to the starting line still. Theres been revolutions in DNA sequencing, for example. Weve got a thousand dollar genome, right? So were actually extremely good at reading genomes, but were very, very bad at understanding what were reading. So you could imagine youve got a human genome, its three billion base pairs times two, because youve got two copies of your genome, one from your mother, one from your father, and within that theres going to be millions of changes, little spelling mistakes all over the genome. We are right now very, very, very I cant even use enough verys bad at predicting which ones of those spelling mistakes are going to either be associated with disease or predictive of disease, even for genes where we know a lot about it. Even if that spelling mistake is in a spot in the genome we know a lot about, say breast cancer genes or something like that, we are still extraordinarily bad at understanding or predicting what effects those changes might have on health.

Bloom: In our research, were obviously also interested in how the genetics of a person influences how sick they get with an infectious disease, but we especially focus on the fact that the viruses themselves are changing a lot, as well. So theres changes in the virus as well as the fact that were all genetically different and those will interact with each other. In both cases, it really comes back to what Lea is saying is that I think weve reached the point in a lot of these fields where we can now determine the sequences of a humans genome or we can determine the sequence of a virus genome relatively easily. But its still very hard to understand what those changes mean. And so, thats really the goal of what were trying to do.

TB: What is deep mutational scanning in this context?

Lea Starita: A mutation is a change in the DNA sequence. DNA is just As, Cs, Ts and Gs. Some mutations which are called variants are harmless. You can think of a spelling mistake or a difference in spelling that wouldnt change the word, right? So the American gray, which is G-R-A-Y versus the British grey, G-R-E-Y. If you saw that in a sentence, its gray. Its the color.

But then it could be a spelling mistake that completely blows up the function of a protein, and then in that case, somebody could have a terrible genetic disease or could have an extremely high risk of cancer, or a flu virus could now be resistant to a drug or something like that, or resistant to your immune response. Or, mutations could also be beneficial, right? This is what allows evolution. This is how flu viruses of all the bacteria evolve to become drug resistant or gain some new enzymatic function that it needs to survive.

Bloom: For instance, in the case of mutations in the human genome, we know that everybody has mutations relative to the average human. Some of those mutations will have really major effects, some of them wont. The very traditional way or the way that people have first tried to understand what those mutations do is to sequence the genomes of a group of people and then compare them. Maybe here are people who got cancer and here are people who didnt get cancer and now you look to see which mutations are in the group that got cancer versus the group that didnt, and youll try to hypothesize that the mutations that are enriched in the group that did get cancer are associated with causing cancer.

This is a really powerful approach, but it comes with a shortcoming which is that theres a lot of mutations, and it gets very expensive to look across very, very large groups of people. And so the idea of a technique like deep mutational scanning is that we could simply do an experiment where we test all of the mutations on their own and we wouldnt have to do these sort of complicated population level comparisons to get at the answer. Because when youre comparing two people in the population, they tend to be different in a lot of ways, and its not a very well-controlled comparison. Whereas you can set up something in the lab where you have a gene that does have this mutation and does not have this mutation, and you can really directly see what the effect of that mutation is. Really, people have been doing that sort of experiment for many decades now. Whats new about deep mutational scanning is the idea that you can do that experiment on a lot of mutations all at once.

Starita: And its called deep because we try to make every possible spelling mistake. So every possible change in the amino acid sequence or the nucleotide sequence, which is the A, C, Ts and Gs, across the entire gene or the sequence were looking at.

Bloom: Lets say we were to compare me and Lea to figure out why one of us had some disease and other ones didnt. We could compare our genomes and theres going to be a lot of differences between them, and were not really going to know what difference is responsible. We dont even really know if it would be a change in their genomes thats responsible. It could be a change in something about our environment. So the idea behind deep mutational scanning is we would just take one gene. So in the case of Lea, she studies a particular gene thats related to breast cancer, and we would just make all of the individual changes in that gene and test what they do one by one. And then subsequently if we were to see that a mutation has some effect, if we were to then observe that mutation when we sequenced someones genome, we would have some idea of what it does.

Starita: The deep mutational scanning, the deep part is making all possible changes. We have all of that information at hand in an Excel file somewhere in the lab that says that this mutation is likely to cause damage to the function of the protein or the activity of the protein that it encodes. Making all of the possible mutations. Thats where the deep comes from.

TB: How exactly are you doing this? Is it because of advances in computer processing or is it because of a change in approach that has enabled this increase in volume of the different mutations you can look at?

Bloom: I would say that theres a number of technologies that have improved, but the really key one is the idea that the whole experiment can be done all at once. The traditional, if you were to go back a few decades way of doing an experiment like this, would be take one tube and put, lets say the normal or un-mutated gene variant in that, and then have another tube which has the mutant that you care about, and have somehow do an experiment on each of those two tubes and that works well.

But you can imagine if you had 10,000 tubes, it might start to become a little bit more difficult. And so the idea is that really the same way that people have gotten very good at sequencing all of these genomes, you can also use to make all of these measurements at once. The idea is you would now put all of different mutants together in the same tube and you would somehow set up the experiment, and this is really the crucial part of the whole thing, set up the experiment such that the cell or the virus or whatever youre looking at, how well it can grow in that tube depends on the effect of that mutation. And then you can just use the sequencing to read out how the frequencies of all of these mutations have changed. You would see that a good mutation that lets say helped the cell grow better would be more representative in the tube at the end, and a bad mutation would be less representative in the tube. And by doing this you could in principle group together tens of thousands or even hundreds of thousands or millions of mutations all at once and read it all out in one experiment.

Starita: This has been enabled by that same revolution that has given us the thousand dollar genome. These DNA sequencers that were now using, not really to sequence human genomes, but were using them as very expensive counting machines. So, were identifying the mutation and were counting it. Thats basically what were using the sequencers for. Instead of sequencing human genomes, were using them as a tool to count all of these different pieces of DNA that are in these cells.

TB: At what stage of development is deep mutational scanning?

Starita: It started about 10 years ago. The first couple of papers came out in 2009 and 2010 actually from the Genome Sciences department at University of Washington. Those started with short sequences and very simplified experiments, and we have been working over the years to build mutational scanning into better and more accurate model systems, but that are increasing the complexity of these experiments. And so weve gone from almost, Hey, thats a cute experiment you guys did, to doing impactful work that people are using in clinical genetics and things like that.

TB: When youre at a holiday party and somebody asks you what you do and then they get really into it and they ask you, Wait, what are the implications of not only personalized medicine but this deep mutational scanning? Whats this going to mean for my life?

Starita: Right now it hasnt been systematically used in the clinic, but well get phone calls from UW pathology that says, Hey, I have a patient that has this variant. We found the sequence variant and this patient has this phenotype. What does this mutation look like in your assay? And were like, Well, it looks like its damaging. And then they put all of that information together and they can actually go back to that patient and say, You are at high risk of cancer. Were going to take medical action. That has happened multiple times. Were working right now to try to figure out how to use the information that we are creating. So these maps of the effect of mutations on these very important proteins and how to systematically use them as evidence for or against their pathogenicity. Right now for a decent percentage of these people who are telling them, Well, youve got changes but we dont know what they do. We want those tests to be more informative. So you go, you get the test, they say, That is a bad one. That ones fine. That mutation is good. That ones OK. That one, though. That ones going to cause you problems. We want more people to have more informative genetic testing because right now in a decent proportion of tests come back with an I have no idea, answer.

Bloom: You can also think about mutations that affect resistance to some sort of drug. For many, many types of drugs, these include drugs against viruses, drugs against cancers and so on, the viruses and the cancers can become resistant by giving mutations that allow them to escape from that drug. In many cases there are even multiple drugs out there and you might have options of which drug to administer, but you might not really know which one. Clinicians have sort of built up lore that this drug tends to work more often or you try this one and then you try this other one, but because how well the drug works is probably in general determined by either the genetic mutations in lets say the cancer or the person or the genetic mutations in the virus or pathogen, if you knew what the effects of those mutations were ahead of time, you could make much more intelligent decisions about which drugs to administer. And there really shouldnt be a drug that works only 50 percent of the time; youre probably just not giving it in the right condition 50 perfect of the time. Wed like to be able to pick the right drug for the right condition all the time.

TB: And thats what precision medicine is about.

Starita: Yes.

TB: Deep mutational scanning as a tool.

Starita: To inform precision medicine.

Bloom: These deep mutational scanning techniques were really developed by people like Jay Shendure and Stan Fields, and Lea and Doug Fowler to look at these questions of precision medicine from the perspective of changes in our human genomes affecting our susceptibility to diseases. I actually work on mutations in a different context, which has mutations in the viruses that infect us and make us sick. These viruses evolve quite rapidly. In the case of flu virus, youre supposed to get the flu vaccine every year. The reason why you have to get it every year is the virus is always changing and we have to make the vaccine keep up with the virus. The same thing is true with drugs against viruses like flu or HIV. Sometimes the viruses will be resistant, sometimes the drugs will work. These again have to do with the very rapid genetic changes that are happening in the virus. So, were trying to use deep mutational scanning to understand how these mutations to these viruses will affect their ability to, lets say, escape someones immunity or escape a drug that might be used to treat that person.

TB: How far along are you on that path?

Bloom: Were making progress. One of the key things weve found is that the same mutation of the virus might have a different impact for different people. So we found using these approaches that the ways that you mutate a virus will allow the virus sometimes to escape from one persons immunity much better than from another persons immunity. And so were really right now trying to map out the heterogeneity across different people. And hopefully that could be used to understand what makes some people susceptible to a very specific viral strain versus other people.

TB: And so then would your research extend into the mutations in human genes in addition to the changes in the virus?

Bloom: You could imagine eventually wanting to look at all of those combinations together, and we are very interested in this, but the immediate research were focusing on right now actually probably is not so much driven by the genetics of the humans. In the case of influenza virus, like I was saying, we found that if theres a virus that has some particular mutation, it might, lets say, allow it to escape from your immunity but not allow it to escape from the immunity of me or Lea. That doesnt seem to be driven as much we think by our genetics, but rather our exposure histories. So in the case of influenza, were not born with any immunity to influenza virus. We build up that immunity over the course of our lifetime because we either get infected with flu or we get vaccinated with flu and then our body makes an immune response, which includes antibodies which block the virus. Each of us have our own personal history, not genetic history, but life history of which vaccinations and which infections weve gotten. And so, that will shape how our immune response sees the virus. As a result, we think that that doesnt really have so much of a genetic component as a historical component.

TB: Just going with the flu example, could this result in a future big picture where I go in to get my flu vaccine and its different than the one the next person might go in to get?

Bloom: What we would most like to do is use this knowledge to just design a vaccine that works for everybody. So that would just be the same vaccine that everyone could get. But its a very interesting I think at this point I would say its almost in the thought experiment stage to think about this. When you think of something like cancer, like Lea was saying, you can use these tools to understand when people have mutations that might make them at risk for a cancer, but thats actually often a very hard thing to intervene for, right? Its not so easy to prevent someone from getting cancer even if you know theyre at risk. But obviously if people are able to do that, theyre interested in spending a lot of money to do it, because cancer is a very severe thing and you often have a very long window to treat it.

Something like a flu virus is very much at the other end. If I had the omniscient capability to tell you that three days from now youre going to get infected with flu and youre going to get really sick, we could prevent that. We have the technology basically right now to prevent that, if its nothing else than just telling you to put on a bunch of Purell and dont leave your bedroom. But theres also actually some pretty good interventions including prophylactics to flu that work quite well. But the key thing is, right now we think of everyone in the world as being at risk all the time and you cant be treating everybody in the world all the time against flu. Theres just too many people and the risk that any person

Starita: Not that much Tamiflu on the market.

Bloom: Not that much, and the risk of it So I think to the extent that we could really identify whos at the most risk in any given year, that might allow us to use these interventions in a more targeted way. Thats the idea.

TB: And how does deep mutational scanning lead to that potentially?

Bloom: Yeah. So the idea, and at this point, this is really in the research phase, but the idea is if we could identify that say certain people or certain segments of the population, that because of the way their immunity, lets say, is working makes them very susceptible to the viral mutant that happens to have arisen in this particular year, we could then somehow either suggest that theyre more at risk or, as you suggested, design a vaccine thats specifically tailored to work for them. So thats the idea. I should make clear that that is not anywhere close to anybody even thinking of putting it into economic practice at this point because even the concepts behind it are really quite new. But I do think that theres a lot of potential if we think of these infectious diseases not so much as an act of God, where you just happened to someone sneezed on you as youre walking down the street, but actually a complex interaction between the mutations in the virus and your own either genetics or immune system, we can start to identify who might be more at risk for certain things in certain years, and that would at least open the door to using a lot of interventions we already have.

Starita: The first year was three years ago, and some very enthusiastic graduate students started it. Basically, it was almost like a giant lab meeting where everybody who is interested in this field came. Somebody tweeted it out and then all of a sudden people from UCSF were there and were like, What the heck? It was great and we all talked about the technology and how we were using it. The next year, the Brotman Baty Institute came in and were like, OK, well, maybe if we use some of this gift to support this, we can have a bigger meeting. And then it was 200 people in a big auditorium and that was great. And now this year, its a two-day symposium and workshop, and its also co-sponsored by a grant from the National Human Genome Research Institute. But now weve got hundreds of people, so about 200 people again, but now flying in from all over the world. Weve got invited speakers, and the workshop, which is Tuesday, is a more practical, If youre interested in this, how do you actually do these experiments?

TB: Whats driving the interest in deep mutational scanning?

Bloom: We are starting to have so much genetic information about really everything. It used to be, going back a couple of decades, a big deal to determine even the sequence of a single flu virus. It was totally unthinkable to determine the sequence of a human genome, right? If you dont know what mutations are there, you dont really care that much what they do. Now we can determine the sequence of tens of thousands of flu viruses. I mean, this is happening all the time, and we can determine the sequence of thousands, even tens of thousands of human genomes. So now it becomes, as Lea said, really important to go from just getting these sequences to understanding what the mutations that you observe in these sequences actually will mean for human health.

See this site for more on the Brotman Baty Institute for Precision Medicine and the Deep Mutational Scanning Symposium and Workshop, Jan. 13 and 14 in Seattle. The symposium is free to attend if youre in the Seattle area, and it will also be livestreamed, with archived video available afterward.

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Scientists pursue new genetic insights for health: Inside the world of deep mutational scanning - GeekWire

Ultragenyx Pharmaceutical saw its shares jump around 27% in trading Friday after announcing positive top-line data out of its gene therapy trial.

Its a small number, just three patients that form part of a third cohort for the phase 1/2 study, as well as another small test but a longer-term look from the second cohort.

In cohort three testing the biotechs drug DTX301, an adeno-associated virus gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency, there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status.

The Art of Recognizing Clinical Supply Risk Factors and Applying Proactive Measures to Avoid Study Delays and Disruptions

No two studies are the same and each clinical supply project carries unique risks. But what characteristics are most likely to raise a flag that issues are ahead? Are there certain types of clinical sponsors and studies that are at greater risk of experiencing supply challenges? And how do clinical sponsors know what is important to focus on and what is not? Join us for this webinar as we attempt to answer these questions.

Meanwhile, in cohort two, one female patient saw a new response after a year. The biotech added that the two previously disclosed responders in cohort one and two also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response, it said in a statement.

RELATED: BIO: In conversation with Emil Kakkis, Ultragenyx CEO

OTC deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme OTC. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood,

According to the National Organization for Rare Disorders, the severity and age of onset of OTC deficiency vary from person to person, even within the same family. A severe form of the disorder affects some infants, typically males, shortly after birth (neonatal period). A milder form of the disorder affects some children later in infancy. Both males and females may develop symptoms of OTC deficiency during childhood. Most carrier females are healthy, but may be prone to severe headaches following protein intake.

Analysts at Jefferies said the data looked better than expected and could be a positive spark to help turn the stock heading into 2020 events. It certainly did in the immediate term, with the biotechs shares up by 27% in mid-morning trading Friday.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, said Eric Crombez, M.D., chief medical officer of the Ultragenyx Gene Therapy development unit.

We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

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Ultragenyx shares jump on 'better than expected' gene therapy data - FierceBiotech

A B.C. transgender teens bid to obtain hormone therapy was legal, B.C.s Court of Appeal ruled unanimously Jan. 10 in supporting a lower court decision.

The child A.B. is able to assert his rights, and has done so in accordance with the law, Chief Justice Robert Bauman and Justice Barbara Fisher wrote in the decision.

The 15-year-old A.B. was born female but wanted to pursue therapy, a move approved by his mother, E.F., but not by his father, C.D. The parents are separated but share parenting duties.

Doctors found A.B. sufficiently mature to make the treatment decision on his own, and C.D. began legal action.

The appeal court had to examine three Supreme Court of BC orders before arriving at its conclusion that ABs consent to that treatment is valid, and no further consent from his parents, in particular CD, is required in that regard.

A February 2019 order declared A.B. validly able to consent to treatment, and that referring to A.B. as a girl or attempting to convince him to halt treatment would be considered family violence under the Family Law Act.

An April 2019 protection order restricted the fathers ability to speak with others, including media outlets and A.B., about his decision to receive therapy.

And, a July 2019 order dismissed C.D.s action initiated by C.D. as vexatious and an abuse of process.

The father appealed.

He claimed the orders violated his Charter-protected freedoms of belief and expression and what he terms parental rights, were procedurally unfair, and not in his childs best interests.

A.B., however, said the decisions were Charter-compliant and in his best interests as well as the statutory right of mature minors to make their own medical decisions.

His mother supported that claim.

The decision said A.B. has identified as male since he was 11 years old and began socially transitioning at 12, enrolling in school under a chosen male name and using male pronouns with his teachers and peers.

Around 13 years of age, after two years of consistently identifying as male, ABs persistent discomfort with his body led him to want to take steps to appear more masculine, the court said.

He was soon diagnosed with gender dysphoria, a recognized medical condition where a person experiences significant distress because the gender identity they experience differs from their genetic or biological gender, and how others perceive them, the court said.

A doctor said he could be a good candidate for treatment and another found such treatment was reasonable and in his best interests.

The process stopped once doctors found out about C.Ds opposition.

Doctors explained to C.D. that minors are permitted to consent to their own medical treatment under a section of the Infants Act.

One doctor asked for an opinion from the Provincial Health Services Authority Ethics Service, which agreed that A.B. demonstrated capacity to understand the treatment.

The teen was further referred to the B.C. Mental Health Centre, which found that he demonstrated detailed understanding of the risks and benefits of the treatment, and that he displayed reasonable judgment and insight.

C.D. filed suit to stop treatment in late 2018. Treatment was ordered stopped until the case could be heard.

The court said where a child has consented to health care under the Infants Act, the Family Law Act doesnt provide authority to start consideration of the childs best interests over medical treatment.

The court said the father continually disrespected his childs choices and in seemed oblivious to the effect of his behaviour on A.B. But, the court added, such effects did not rise to the level of family violence.

The court said C.D.s claims he parental rights under the Charter had been violated had no merit.

jhainsworth@glaciermedia.ca

@Jhainswo

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Trans teen can decide on hormone therapy, court rules - The Tri-City News

INTRODUCTION

Congenital defects are a leading cause of morbidity worldwide, accounting for the deaths of 330,000 newborns every year. Brain malformations, including microcephaly and holoprosencephaly (HPE), are the most common congenital anomalies and place a heavy burden on the affected individuals and the health care system (13). HPE is a structural anomaly of the developing forebrain affecting 1:250 embryos and 1:16,000 live-born infants. Clinically, HPE encompasses a continuum of brain malformations and is accompanied with a spectrum of craniofacial defects in 80% of the cases; microcephaly and eye defects are among the most common features in affected individuals (4). In the majority of cases, the underlying cause remains uncertain due to the high complexity and the multigenic origin of these anomalies (5, 6). Lately, it has become clear that HPE is caused by a malfunction in key signaling pathways in the early embryo, leading to developmental defects in the organizing centers and midline structures (7). The defects involve a sequence of developmental steps that begin with Nodal signaling to establish the midline progenitors in the developing primitive streak (PS). It then continues with the proper positioning of the forming prechordal plate beneath the neuroectoderm and activation of midline Hedgehog signals to maintain the anterior identity of the forebrain. However, the restriction of HPE genetic determinants to a handful of NODAL and Sonic hedgehog (SHH) pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Expansion of this genetic repertoire has become a necessity to develop therapeutic options and improve molecular diagnosis of HPE.

Genes encoding transcription factors (TFs) and epigenetic regulators are relevant etiological candidates given their central role in integrating signaling cascades and orchestrating multiple biological processes. Deficiency in their function can disturb entire transcriptional programs, involving numerous genes and molecular pathways, leading to a complex pathological outcome. Consistent with this hypothesis, we have recently identified a loss-of-function (LOF) mutation in the transcriptional regulator PRDM15 in patients with a syndromic form of HPE. Here, we combine mouse genetics and epigenomic approaches to uncover the role of this TF in congenital brain malformations. Our findings establish PRDM15 as a key regulator of NOTCH and WNT/PCP pathways in the developing embryo, implicating them in regulation of anterior/posterior (A/P) patterning and forebrain development. In addition, we uncover new genetic variants in key components of these signaling pathways in patients with HPE. Collectively, our findings refine the molecular mechanisms governing forebrain development and set the stage for the identification of new HPE candidate genes.

Homozygosity mapping and whole-exome sequencing on patients with steroid resistant nephrotic syndrome (SRNS) identified three recessive mutations in PRDM15 (NM_001040424.2). These mutations are located in the sequences coding for the PR domain (c.461T>A; p.Met154Lys-M154K and c.568G>A; p.Glu190Lys-E190K) and the 15th zinc finger (c.2531G>A; p.Cys844Tyr-C844Y), respectively (Fig. 1A). Of particular interest, in four consanguineous families that have the variant encoding PRDM15 C844Y, the affected probands exhibited a syndromic form of SRNS consistent with the Galloway-Mowat syndrome (8). Besides renal defects, the patients displayed facial (narrow forehead, microcephaly, abnormal cerebral gyration, and ophthalmic abnormalities) and extracranial defects (heart malformations and postaxial polydactyly) (9).

(A) Schematic representation of the PRDM15 mutation positions and the affected domains. (B) Alkaline phosphatase (AP) staining of ESCs; the respective genotypes are indicated in the lower panel. Data are average of four independent cell cultures (n = 4) SD. Statistical tests were applied on differences observed in the percentage of completely undifferentiated colonies. Students t test (two sided) was used to determine significance. (C) Heat map of differentially expressed genes in ESCs upon the indicated genetic manipulations. (D) mRNA levels of Rspo1 in ESCs; the respective genotypes are indicated by color code. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Data shown are from three independent experiments (n = 3). (E) Enrichment of PRDM15 binding on promoter regions of the target gene (Rspo1) in ESCsrespective genotypes are indicated by color codeas measured by ChIP-qPCR. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) to (E), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15 (hPR15). In (D) and (E), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

We have recently demonstrated that PRDM15 regulates the transcription of Rpso1 and Spry1, two key components of the MAPK (mitogen-activated protein kinase)/ERK (extracellular signalregulated kinase) and WNT pathways, to maintain nave pluripotency of mouse embryonic stem cells (mESCs) (10). To evaluate the effects of these mutations on PRDM15 function, we ectopically expressed the three identified human variants in Prdm15-deficient embryonic stem cells (ESCs) (Prdm15/). Only hPR15-C844Y, which is associated with brain defects in humans, failed to restore ESC self-renewal (Fig. 1B), and most importantly, the global changes in gene expression, induced by loss of endogenous PRDM15 (Fig. 1C and table S1 (A to E)]. These data strongly suggest that hPR15-C844Y is a LOF mutation. While hPR15-M154K and hPR15-E190K rescued Rspo1 expression at levels comparable to the wild-type (WT) human PRDM15 (hPR15-WT), hPR15-C844Y failed to restore its transcript levels [quantitative polymerase chain reaction (qPCR)] and to activate its transcription in a luciferase reporter assay (Fig. 1D and fig. S1A).

To gain further insights into the impact of these mutations on PRDM15 function, we tested the stability of the encoded proteins and their cellular localization. Immunofluorescence staining, in a Prdm15/ background, showed that none of the mutations affected the nuclear localization of PRDM15 (fig. S1B). On the other hand, all three mutants encoded less stable proteins (fig. S1C). We have previously shown that the zinc finger domains are required for DNA binding and transcriptional activity of PRDM15 (10). Thus, we sought to test the ability of the various mutants to bind to chromatin. Consistent with an LOF of the zinc finger mutant, chromatin immunoprecipitation (ChIP)qPCR analysis revealed reduced enrichment of hPR15-C844Y at the promoter region of Rspo1 (Fig. 1E), a result compatible with its inability to promote its transcription (Fig. 1D and fig. S1A).

To gain molecular insights on the effects of PRDM15 LOF during mammalian development, we intercrossed Prdm15lacZ/+ heterozygous mice, which are healthy and fertile. A description of all the Prdm15 alleles and deleter strains used in this study is summarized in fig. S2A. Consistent with a fundamental role of PRDM15 during embryonic development, we obtained no homozygous mutant [Prdm15lazZ/lacZ knockout (KO)] pups (Fig. 2A), while of the hundreds Prdm15lacZ/+ embryos that were dissected at various stages of development, none showed any defects. Timed matings revealed the embryonic lethality of Prdm15lazZ/lacZ (KO) embryos occurs between embryonic days 12.5 (E12.5) and E14.5 (Fig. 2A). Notably, at E12.5, KO embryos were smaller and showed a spectrum of brain malformations affecting predominantly the anteriormost structures of the head, including the eyes (Fig. 2B), consistent with the brain and facial features observed in patients with the C844Y mutation. Coronal sections of the brain at this stage confirmed that the lateral and medial ganglionic eminences were underdeveloped. Furthermore, we noted an abnormal separation of the cerebral hemispheres, reminiscent of HPE (Fig. 2C). Classic HPE encompasses a continuum of brain anomalies caused by neural tube patterning defects that affect the anteriormost structures and is often accompanied by craniofacial defects involving the eyes (4, 11, 12).

(A) Genetic distribution of embryos from Prdm15+/LacZ intercrosses, indicating lethality between E12.5 and E14.5. (B) Phenotypic continuum of brain defects in E12.5 Prdm15lacZ/lacZ KO embryos. (C) Hematoxylin and eosin (H&E) staining of serial coronal sections of E12.5 brains from Prdm15+/+ WT (upper panel) and Prdm15lacZ/lacZ KO (lower panel) embryos. The mutants lack the complex organization of the anterior forebrain, including the lateral (LGE) and medial ganglionic eminences (MGE), the epithalamic and dorsal thalamic neuropeithelium (NE), and eyes. (D) Nestin-Cremeditated deletion of Prdm15 in neuronal precursors does not affect brain development. Representative images are shown in (B) to (D). LGE/MGE, lateral and medial ganglionic eminences; NE, neuropeithelium; NCX, neocortex; E, eye; LV, lateral ventricle; V, ventricle; TOT, total. (B and D) Photo credit: Messerschmidt and Mzoughi.

These results prompted us to delete Prdm15 specifically in the developing brain by crossing Prdm15fl/fl mice to the Nestin-Cre deleter strain. This Cre recombinase is active at ~E11 in neural stem cells/progenitors and would reveal whether PRDM15 is essential for the process of neurogenesis. The resulting Prdm15/::Nestin-CRE embryos did not show any apparent defects at E12.5 (Fig. 2D), were born at the expected Mendelian ratios, and developed into healthy adults (fig. S2B). This suggests that PRDM15 is required at earlier time points of forebrain specification.

Defects in Prdm15 KO embryos are apparent before the onset of neurulation, as mutants were markedly smaller and had an abnormal morphogenesis by E7.5 (fig. S3A). Between E6.5 and E7.5, two signaling centers act sequentially to pattern the forebrain in the mouse embryo (Fig. 3A) [reviewed in (1315)]. The first resides within the extraembryonic lineages and is called the anterior visceral endoderm (AVE). The AVE imparts anterior identity to the underlying epiblast, thereby restricting the site of gastrulationthe PSto the posterior epiblast. During gastrulation, a second specialized population of cells, known as the AME, emerges from the anterior PS (APS). These cells migrate anteriorly, giving rise to the anterior definitive endoderm and prechordal plate mesoderm. Their role is to produce secondary inductive cues that reinforce anterior identity in the overlying neural plate (Fig. 3A).

(A) Schematic of the signaling centers governing A/P patterning in the mouse embryo. (B) At E6.5, Foxa2 is expressed in the AVE (red line) and APS (red asterisk). At E7.5, Lhx1 transcripts label the visceral endoderm (VE) overlying the epiblast including the AVE as well nascent mesoderm and midline axial mesendoderm. In Prdm15 mutants (mut), Foxa2 expression is confined to the distal VE, with little enrichment in the prospective AVE. Lhx1 is detected in the VE and mesoderm of the middle Prdm15 mutant, but only in the VE of the one on the right. (C) Expression of T, Lefty2, Foxa2, Chordin, and Shh in WT and Prdm15lacZ/lacZ embryos at E7.5. In Prdm15 mutants, T is expressed normally in the PS; Lefty2 transcripts are down-regulated in nascent mesoderm; Foxa2 and Chordin expression remains high distally in the region of the APS (angled black-dashed line) but does not extend anteriorly in the midline axial mesendoderm (am); and Shh expression is similarly weak in the anterior midline (asterisk). n, node. (D) Expression of Six3/Shh or Otx2/Shh in WT (upper) and Prdm15lacZ/lacZ KO (lower) embryos at E8.5. Six3 and Otx2 expression highlights the reduction in anterior forebrain (fb) development (angled black dashed lines) in Prdm15lacZ/lacZ KO mutants. no, notochord; mb, midbrain; DVE, Distal Visceral Endoderm. Representative images are shown in (B) to (D). (C and D) Photo credit: Dun and Ong.

We reasoned that loss of PRDM15 might impair forebrain specification during the earliest events of anterior patterning and therefore examined the expression of a panel of marker genes diagnostic for defects in either the AVE or AME in Prdm15 KO embryos. Foxa2 is a marker of both, AVE and APS, in early PS stage embryos at E6.5. In Prdm15 KO embryos, in situ labeling shows expression in the distal visceral endoderm overlying the epiblast in a pattern typically observed 1 day earlier in WT embryos (Fig. 3B) (16). We conclude that Prdm15 KO embryos are developmentally delayed even before gastrulation. At E7.5, Lhx1 is expressed in the nascent mesoderm and anterior midline mesendoderm. In the smaller, delayed Prdm15 KO littermate embryos, Lhx1 is expressed normally throughout the visceral endoderm, including the AVE, as well as in the nascent mesoderm (Fig. 3B) (17, 18). Both FOXA2 and LHX1 are required for the formation and function of the AVE, and their activation provides evidence that the initial specification of the primary anterior-posterior axis by the AVE is normal in Prdm15 KO embryos.

We next examined the expression of PS (T and Lefty2) and AME (Foxa2, Chordin, and Shh) marker genes. By E7.5, Prdm15 KO embryos are easily recognizable due to a characteristic ruffling in the extraembryonic visceral endoderm, with a fully extended PS that expresses both T and Lefty2 (Fig. 3C). At this stage, Foxa2 is expressed in the node, which marks the anterior end of the PS, and the AME that extends rostrally in WT embryos. In contrast, in Prdm15 KO embryos, Foxa2 transcripts are present distally but do not extend anteriorly (Fig. 3C). A similar pattern is observed with Chordin, which also labels the node and AME in WT embryos but is confined to the APS in Prdm15 KOs (Fig. 3C). Shh expression is also diagnostic for the node and AME, but in KO embryos, only a few Shh-positive cells are observed along the anterior midline (Fig. 3C). Together, these results show that loss of PRDM15 specifically affects the production of the anterior AME. Consequently, the crucial refining signals produced by these cells that orchestrate the continued patterning and morphogenesis of the anterior neuroectoderm are lost, resulting in anterior truncations that are evident by diminished forebrain expression of Six3 and Otx2 in Prdm15 KO mutant embryos at E8.5 (Fig. 3D). To further corroborate these findings, we deleted Prdm15 specifically in the epiblast, using the Sox2-Cre transgene (fig. S3B) (19), while maintaining WT extraembryonic tissues. Consistent with an essential role for PRDM15 in the PS-derived AME and not AVE specification, Prdm15/::Sox2-CRE embryos died in utero starting at E12.5 (fig. S3C) and exhibited a spectrum of brain defects similar to those observed in Prdm15 KO embryos (fig. S3D).

To examine the impact of PRDM15 depletion on early embryonic processes, namely, A/P patterning, we sequenced the transcriptome of WT versus Prdm15 KO E6.5 embryos. We reasoned this could be the most critical stage for AME specification as AME cells emerge less than 24 hours later. Unbiased clustering of global gene expression separated WT versus Prdm15 KO embryos into distinct groups, indicating marked transcriptional differences (Fig. 4A and table S1F). Gene ontology (GO) analysis of the significantly down-regulated genes identified Pattern specification process, Head development, and Neural tube development among the enriched terms. Among these genes, several are important regulators of forebrain development and A/P patterning (Fig. 4B and fig. S4A, and table S1, G to H). We noted a striking reduction in the expression of key components of three signaling pathways: WNT, NOTCH, and SHH (Fig. 4C, fig. S4B, and table S1, I and J).

(A) Unbiased clustering heat map of the entire transcriptome in WT (n = 8) versus Prdm15lacz/lacz KO (n = 10) E6.5 embryos, analyzed by RNA sequencing. Heat maps of differentially expressed genes from the indicated GO categories (B) and KEGG pathway (C) identified as top hits in the RNA sequencing. Light and dark blue rectangles on the right side indicate genes whose promoter region is directly bound by PRDM15 in ESCs only or both in ESCs and E6.5 embryos, respectively. (D) Snapshots of representative PRDM15 ChIP tracks (UCSC genome browser). Examples of conserved target genes (binding sites) between E6.5 embryos (blue) and ESCs (orange) are shown.

We have recently shown that PRDM15 recognizes a defined DNA motif present at promoters or enhancers of target genes (10). To define the set of direct PRDM15 transcriptional targets, we performed ChIP sequencing (ChIP-seq) on mESCs and WT E6.5 embryos (table S1, K and L). Despite the limited biological material available from the pre-gastrula embryos, we identified 58 high-confidence promoter-bound targets, the majority of which (~84%) were also bound by PRDM15 in ESCs (Fig. 4D, fig. S4C, and table S1M). In addition, identification of the same PRDM15 consensus binding motif in both systems implies a conservation of its targets. We therefore chose to consider PRDM15-bound promoters identified in ESCs as relevant for our follow-up analyses. Among these, a handful of PRDM15 targets, including Rbpj, Notch3, Maml3 (NOTCH), Vangl2, Wnt5b, Gpc6, Nphp4 (noncanonical WNT), and Gas1 (SHH), were of particular interest as they are significantly down-regulated in the mutant embryos (fig. S4D). Collectively, these data indicate that lack of PRDM15 leads to transcriptional down-regulation of key regulators of developmentally important signaling pathways (NOTCH, noncanonical WNT, and SHH).

These results prompted us to perform a targeted analysis of the down-regulated PRDM15 target genes in a large cohort of patients with HPE (132 trios and 188 singletons). We found heterozygous variants in 99 genes, ~17% of them were likely to be damaging (table S2A). To gain insights on potential functional interactions between these genes, we generated functional protein association networks using STRING. Although the majority of the proteins did not seem to be functionally related, two main networks representing NOTCH and WNT/PCP signaling formed (Fig. 5A and table S2B), supporting their potential involvement in HPE pathobiology.

(A) Functional groups identified by protein association network analysis of PRDM15 target genes mutated in patients with HPE using STRING. (B) mRNA levels of the indicated genes in ESCs; the respective genotypes are indicated in the lower panel. Expression levels were normalized to Ubiquitin (Ubb), and Prdm15fl/fl (empty vector) was used as reference. Rspo1 expression levels were used as positive control in Fig. 1D. Data shown are from three independent experiments (n = 3). (C) Enrichment of PRDM15 binding on promoter regions of the indicated target genes in ESCsrespective genotypes are indicated in the lower panelas measured by ChIP-qPCR. ChIP on the Rspo1 promoter was used as a positive control for PRDM15 binding. Depicted is the average enrichment [data from three independent cell cultures (n = 3)] over percent of input. In (B) and (C), the endogenous mouse Prdm15 has been deleted by the addition of OHT (50 nM) after ectopic expression of WT or mutant human PRDM15. In (B) and (C), center values, mean; error bars, SD. Students t test (two sided) was used to determine significance.

To assess the ability of the PRDM15 mutants to regulate the expression of critical components of both pathways, we took two approaches. First, we performed rescue experiments in Prdm15/ ESCs by reintroducing WT or mutant PRDM15 expression constructs. While hPR15-M154K and hPR15-E190K restored the expression of target genes at levels comparable to the WT human PRDM15 (hPR15-WT), none were significantly rescued by hPR15-C844Y (Fig. 5B and fig. S5A). In addition, ChIP-qPCR analysis confirmed a reduced enrichment of hPR15-C844Y at the promoter regions of these target genes (Fig. 5C and fig. S5B), which is consistent with the failure to promote their transcription (Fig. 5B). Second, to confirm that the C844Y mutation in humans is indeed an LOF mutation, we introduced the corresponding homozygous mutation (C842Y) in mESCs using CRISPR-Cas9 technology (fig. S5, C to E). Although the C842Y knock-in allele did not affect Prdm15 transcript levels, the resulting protein was unstable and less abundant (fig. S6, A and B). qPCR confirmed that Prdm15C842Y cells express PRDM15 target genes (i.e., Rbpj, Notch3, Vangl2, etc.) at lower levels compared with WT (fig. S6C) and that endogenous PRDM15C842Y protein is unable to bind (ChIP-qPCR) to its target promoters (fig. S6D).

Our findings call for a future functional characterization of the NOTCH and PCP gene variants and should motivate targeted genetic mapping for new HPE candidates in regulators of both pathways.

We have identified new mutations in the PRDM15 gene in patients with SNRS. Although the mutations affecting the PR domain of the protein (M154K and E190K) are associated with isolated SRNS cases only, the zinc finger mutation (C844Y) causes a syndromic form of HPE. In our in vitro ESC system, these PR domain mutations reduced the stability of the encoded protein but rescued considerably the phenotypic and molecular changes induced by loss of the endogenous protein. This is consistent with the fact that these mutations in humans cause isolated SRNS only and could imply a context-dependent requirement for the PR domain. Alternatively, the differential impact of the PR versus ZNF mutations on protein stability may support a threshold model, where different levels of PRDM15 expression are required for the development of specific organ systems. On the other hand, the ZNF mutation (C844Y) had marked effects on PRDM15 function in both settings, which we attribute here to impaired binding of the mutant protein to regulatory regions of its transcriptional targets.

Similar to the LOF mutation in humans, genetic deletion of Prdm15 in mice leads to a broad spectrum of brain defects, affecting predominantly the anteriormost structures including the eyes. Such phenotypic continua are commonly assigned to allelism, polygenic origin, and the action of modifier genes. Yet, here we report that perturbation of a single transcriptional regulator can indeed affect an entire transcriptional network, relevant to both normal development and pathological manifestations.

Our findings show that PRDM15 promotes transcription of several regulators of the NOTCH and WNT/PCP pathways to orchestrate formation of midline structures. Perturbation of these transcriptional programs, upon PRDM15 depletion, disrupts forebrain development due to impaired AME specification and lack of SHH signaling, consistent with the sequence of developmental defects associated with HPE pathobiology (7).

Of note are the prominent phenotypic similarities between Prdm15 null embryos and genetic (or microsurgical) modulation of the Nodal signaling pathway in mouse. That is, Nodal hypomorphic alleles, assorted combinations of mutations in Smad2 and Smad3, as well as the mutations in the downstream effectors Foxh1 and Foxa2, all result in embryos with defective AME production and compromised anterior forebrain development (2023).

On the other hand, the characteristic ruffling of the visceral endoderm observed in Prdm15 KO embryos at E7.5 has been observed in other mutants where extraembryonic mesoderm (ExMeso) production during gastrulation is impaired, such as in loss of Smad1 (24), combined loss of Smad2 and Smad3 in the epiblast (21), or Otx2 (chimeric analysis) (25). It is, however, important to emphasize that epiblast-specific deletion of Prdm15 (Prdm15/::Sox2-CRE embryos) equally results in smaller embryos with defects in the formation of anterior structures (fig. S3). It is additionally possible that the developmental delay we observed in Prdm15 KO embryos disproportionally affects some parts of the gastrulating embryo, rather than an overall delay in epiblast proliferation before gastrulation.

On the basis of our molecular analysis, we conclude that like modulation of the Nodal signaling pathway, loss of Prdm15 specifically affects AME specification. Given the requirement of this critical signaling center in providing reinforcing anterior patterning signals, we favor a model in which its lack or dysfunction underlies the Prdm15 phenotype, rather than a paucity of mes(endo)derm produced during gastrulation by a mutant embryo experiencing developmental delay.

The restriction of HPE genetic determinants to a handful of NODAL and SHH pathway regulators stems from our limited understanding of the molecular events governing specification of early and late midline structures. Recent studies have implicated components of the WNT/PCP pathway in regulating polarity of the node along the A/P axis and linked their deregulation to structural anomalies of this critical organizing center (2629). Thus, it is not unexpected that perturbation of the WNT/PCP pathway affects the specification of APS derivatives, namely, the AME and node (29). In addition, while the links between mutations in PCP signaling and neural tube defects are well established (6, 3032), their involvement in HPE remains uncharted. NOTCH signaling, on the other hand, has been implicated in HPE only recently (33). Besides its established neurogenic role in the developing mouse telencephalon, growing evidence supports the involvement of key NOTCH regulators (for example Dll1 and Rbpj) in node morphogenesis and midline truncations (34, 35).

Our findings prompted us to perform a targeted search for mutations in a large cohort of patients with HPE. Our analysis of exome sequencing data from 132 trios and 188 singletons revealed multiple rare heterozygous variants in PRDM15 transcriptional targets involved in forebrain development. In silico protein association network analysis of these variants identified two major functional groups regulating the NOTCH and WNT/PCP pathways. We expect that our findings will encourage validation of the reported variants/mutations as well as further mining for additional HPE candidates in both pathways.

PRDM15 KO-first mice that harbor the Prdm15lacZ allele were obtained from the European Conditional Mouse Mutagenesis Program. Hemizygous (Prdm15lacZ/+) animal intercrossings were performed to obtain homozygous (Prdm15lacZ/lacZ) embryos. Further details on these animals and the conditional Prdm15fl/fl strain can be found in (10). To generate epiblast-specific Prdm15/ embryos, Prdm15fl/fl mice were first crossed to heterozygous Sox2-CRE transgenic animals [B6.Cg-Edil3Tg(Sox2-cre)1Amc/J; JAX Laboratory] (36). The resulting males (Prdm15/+::Sox2-CRE) were then crossed again to Prdm15fl/fl females. In this generation, a quarter of the progeny is expected to be Prdm15/::Sox2-CRE. The Sox2-CRE transgene was always propagated through male animals. A similar breeding strategy, using Nestin-CRE [B6.Cg-Tg(Nes-cre)1Kln/J; JAX Laboratory] transgenics, was followed to generate Prdm15/:: Nestin-CRE mice. All mice-related procedures were approved by the local Institutional Animal Care and Use Committee (IACUC) and performed in compliance with the respective guidelines (IACUC nos. 151042 and 18/10EGDM/90).

E12.5 embryos were fixed in 4% PFA (paraformaldehyde) for 48 hours before being mounted in OCT (Optimal Cutting Temperature) embedding compounds. Then, serial coronal sections of the brains (anterior-posterior) were made using a cryostat and immediately thaw mounted on poly-l-lysinecoated histological slides for hematoxylin and eosin staining.

Prdm15fl/fl; ROSA26-CreERT2 ESCs have been described in (10). For all experiments, ESCs were cultured in the conventional [serum + Lif (Leukemia Inhibitory Factor) (SL)] medium unless otherwise stated. OHT (4-Hydroxytamoxifen) (50 nM; SIGMA-H7904) was added to the culture medium overnight (O/N) to generate Prdm15/ cells.

Embryos were isolated between E6.5 and 8.5, genotyped, then processed for whole-mount in situ hybridization as described in (37) with the following probes: Foxa2, Lhx1, T, Lefty2, Chordin, Shh, Otx2, and Six3.

Full-length human PRDM15 cDNA (NM_001040424.2) was subcloned into the PiggyBac vector (DNA2.0, PJ549). Clones encoding the various PRDM15 mutations were generated using the QuickChange II XL Site-directed Mutagenesis Kit (Agilent Technologies). The sequence of primers used can be found in table S3.

To introduce the hC844Y/mC842Y point mutation, mESCs were transfected with PX458 [pSpCas9 (BB)-2A-GFP] vector expressing a guide RNA targeting the site to be mutated, along with a single-stranded oligonucleotide containing the target point mutation, to serve as a DNA repair template. Additional eight silent mutations have been introduced to avoid editing of the template by the CAS9 protein. Single clones were sorted and expanded in 2i medium. Genomic DNA was used for screening by digestion with XMN I restriction enzyme. DNA from potential mutants was cloned into the pCR 4-TOPO TA vector following the manufacturers instructions, and 5 to 10 colonies were sequenced. Details of the strategy and the sequence of the oligonucleotides used are described in fig. S5 and table S3.

To assess protein stability, Prdm15/ ESCs expressing either wild or mutant PRDM15 were treated with cycloheximide (CHX; 150 g/ml) (Sigma, no. C-7698), and then collected at different time points (2, 4, and 6 hours) for protein extraction and analysis by Western blotting. Samples collected immediately before treatment with CHX (t = 0) served as reference. Antibodies and dilutions used were PRDM15 (in house, 1:3500) and TUBA (Alpha-TUBULIN) (Sigma T5168, 1:10,000).

To assess ESC self-renewal/differentiation, cells were stained with alkaline phosphatase staining solution (AP detection kit, Millipore, SCR 004). In brief, 500 cells per well (12-well plates) were seeded in triplicates and cultured for 5 days with daily change of medium before being stained as per the suppliers recommendations.

ESCs were seeded on gelatin-coated eight-well glass slides (Millipore, PEZGS0816), at 3 103 per well, and cultured in 2i medium. Three days later, cells were fixed in 4% PFA at room temperature, permeabilized with 0.5% Triton X-100, and then blocked using 2% bovine serum albumin (BSA) for 1 hour at room temperature before O/N staining with anti- PRDM15 (in house, 1:100) at 4C. The next day, slides were washed with phosphate-buffered saline (PBS) (three times) and stained with Alexa Fluorconjugated secondary rabbit antibody at 37C (30 min). Last, slides were washed with PBS (three times) before they were mounted with a DAPI (4,6-diamidino-2-phenylindole)containing mounting medium (VECTASHIELD, Vector Laboratory H1200).

Total RNA from cells was isolated using PureLink RNA Mini Kit (Ambion, 1283-018A) according to the manufacturers instructions. RNA was retrotranscribed into cDNA using Maxima First Strand cDNA Synthesis Kit (Thermo Scientific, K1642) and subjected to quantitative real-time PCR (qRT-PCR) on an ABI PRISM 7500 machine. qPCRs (20 l) contained 10 l of SYBR Green PCR supermix (2), 4 l of a forward and reverse primer mix (final concentration, 200 nM), and 6 l of cDNA (20 ng). Primers sequences are listed in table S4.

The detailed procedure for ChIP experiments has been described previously (38); all steps were performed at 4C and protease inhibitor was added, unless stated otherwise. In brief, 20 to 40 million ESCs were fixed in 1% formaldehyde for 10 min at room temperature before quenching with 0.125 M glycine (5 min at room temperature). Cells were then washed in PBS and harvested in lysis buffer before freezing at 20C O/N. The following day, cells were pelleted by centrifugation, resuspended in ice-cold ChIP buffer, and sonicated for six cycles (30-s ON/30-s OFF) using a BRANSON Digital Sonifier (no. S540D). Lysates were then precleared for 2 hours in Sepharose A beads (blocked in 5 mg/ml BSA) before O/N incubation with PRDM15 antibody (4C). The next day, Protein A beads were added for 4 hours before washing then de-cross-linking in 1% SDS and 0.1 M NaHCO3 (65C, O/N). Last, DNA was eluted in T-buffer (pH 8) using QIAquick PCR Purification Kit, QIAGEN. Sequences of primers used in ChIP-qPCR are listed in table S4. For the E6.5 ChIP, approximately 40 to 50 embryos per experiment were pooled together and fixed immediately after isolation.

TruSeq ChIP Sample Prep Kit (IP-202-1012) was used for DNA library preparation. Sequencing was performed in the Illumina HiSeq 2000 and NextSeq 500 at the Genome Institute Singapore. Details of the bioinformatics analysis can be found in (10). In brief, the sequenced reads were aligned to the mm9 genome assembly using bowtie version 2. Peak calling was done using MACS 2.1.1 (https://github.com/taoliu/MACS). Peaks were then annotated using the ChIPpeakAnno package in Rpromoters were defined to be 5 kb upstream and 1 kb downstream of the transcription start site. Motif discovery was done using MEME-ChIP in the MEME Suite (http://meme-suite.org).

For E6.5 embryo transcriptome analysis, RNA was extracted from 8 WT and 10 Prdm15lacZ/lacZ littermates. RNA from ESCs was collected 3 days after ethanol/OHT treatment. Library preparation was performed following the TruSeq RNA Sample preparation v2 guide (Illumina). The sequenced reads were mapped to mm9 build of the mouse genome using STAR version 2.4.2a. Differential expression analysis was performed using the DESeq2 package in R. Only genes with an average FPKM (Fragment Per Kilobase Million) >1 are considered expressed. Enriched GO terms and KEGG pathway were identified using Metascape. Genes used for GO analysis were filtered based on statistical significance (P < 0.05) and fold change (log2 fold change of 0.322) in E6.5 embryo RNA sequencing. Heatmaps of gene expressions (FPKM) were generated with in-house scripts with R.

To identify potential new candidate genes associated with HPE, we searched for genetic variants in genes/proteins acting downstream of PRDM15. Exome sequencing data from a cohort of 320 patients with HPE (132 trios and 188 singletons) were evaluated. Filter criteria are as follows: allele frequency <0.0001 in ExAC database (39) de novo (if trio available); synonymous changes were omitted; and benign changes by ACMG 2015 (40) criteria were removed. To identify protein networks and functional groups, genes with potential HPE variants were subjected to protein association network analysis using STRING database (https://string-db.org).

All experiments were repeated at least three times with similar results. Each biological repeat was done in at least two to four technical replicates/independent cell cultures, where applicable. Normal distribution was assumed for all statistical analyses. Unpaired Students t test (two sided) was applied using GraphPad Prism (version 7.0) to determine the statistical significance of the observed differences. Changes were considered statistically significant when P < 0.05.

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PRDM15 loss of function links NOTCH and WNT/PCP signaling to patterning defects in holoprosencephaly - Science Advances

How do I get stronger on the bike? you ask. Its that time of year: your races are done and you know where you stand performance-wise. You might find yourself wondering how some girls are so strong on the bike. How some guys ride by you as if youre standing still. Theres at least one explanation: strength. They have more of it than you (at present).

By Adam Johnston

If youre wondering what you can do this winter to improve your cycling (and your running and swimming, by the way), consider adding a regular strength training program to your routine (if youre not already doing so).

The majority of adult age group athletes are not limited by their muscular endurance. Theyre fond of their long training rides. They bump up to their competitive distances (whether it be standard, half or full) as quickly as they can. The ability to perform repeated muscular contractions at low levels of force is not what limits most athletes. Rather it is their muscular strength the ability to contract their muscles forcefully and/or against heavy resistance.

When most people start they typically improve almost regardless of what training they perform. Beginner and intermediate athletes get better quite simply by accumulating miles on the bike, running and in the pool. But once the initial break-in period has come and gone the next step is to focus on muscular strength.

Reams of information are available for the endurance athlete on strength training. This article isnt intended to regurgitate the research and advice thats readily available elsewhere. Rather, its meant to get you thinking of a few strength-related concerns and to consider a few things that you might not have anticipated when it comes to strength training for the endurance athlete.

Consider the following 10 strength training tips:

Be smart, be consistent, and get stronger for 2020.

Adam Johnston is the owner of WattsUp Cycling in Toronto. WattsUp Cycling offers an endurance athlete-specific strength training program on site. Visit http://www.wattsupcycling.ca to find out more.

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10 Ways to Get Stronger on the Bike - Triathlon Magazine Canada

One of the nerve-racking parts of living with severe allergies is having to make the call about if and when an allergic reaction is anaphylaxis. A shot of epinephrine can save a life, but having to inject ourselves or our child with a needle is something we did not sign up for.

However, mistakes in the critical areas of recognizing and responding to anaphylaxis can mean the difference between life and death. Plus, studies are showing that prompt administration of epinephrine can simply reduce the chance that a food allergy reaction moves from relatively mild to severe anaphylaxis.

Over the years, Allergic Living readers have raised many questions related to epinephrine: from when to give it, to when a person needs a second dose, to issues such as how much heat or cold an epinephrine auto-injector can take, whether antihistamines mask anaphylaxis symptoms and more.

We asked Gina Clowes, the nationally known food allergy educator and parenting coach and consultant at AllergyMoms.com, to help us create a go-to epinephrine resource with answers to these vital questions.

Ginareached out to Dr. Julie Brown, anemergency medicine physician at Seattle Childrens Hospital, for her expertiseon the topic. Dr. Brown works closely with the food allergy community and has acontinuing research interest in epinephrine, auto-injectors and anaphylaxis. AsGina says, Were so grateful to Dr. Brown for agreeing to answer commonepinephrine questions. I find her insights and answers fascinating, and knowtheyll be helpful to a lot of people.

Following you will find written answers about epinephrine in a handy Q&A format. Plus, we include a podcast featuring Gina and Dr. Brown that offers further elaboration on some of the key answers.

Allergic Livings Epinephrine Q&A

Dr. Brown explained that epinephrine is adrenaline, the same hormone that is formed in the body in the fight or flight response. But it also has a very important role, probably by design, in turning off allergic reactions.

In the allergy context, she says epinephrine acts on a number of different receptors on cells in the body, and seems to reverse fairly pointedly all of the things that are happening in allergic reactions.

The reason is, the earlier you give epinephrine, the better outcomes are, says Dr. Brown. The longer one waits, the more likely the reaction is to progress and require multiple doses of epinephrine.

If we wait, were more likely to get sicker and have much more significant symptoms, she says. We are more likely to need multiple doses of epinephrine or need to stay in the hospital.

She reminds us that patients can start off having very mild symptoms, and then turn very quickly to getting very sick. What we want to do is to treat before things get serious. Sadly, most patients who have died from anaphylaxis had delayed treatment with epinephrine.

Dr. Brown generally recommends between 5 and 15 minutes as a reasonable timeframe between doses to determine if the epinephrine has taken effect. She says that if you have someone who looks like they are not breathing, they are turning blue, they are passed out, you would shorten the time window.

In such a case she says it may be reasonable to give a second dose, just to make sure that youve got a good amount of epinephrine circulating while awaiting an ambulance.

All About Epinephrine Podcast with Dr. Julie Brown and Gina Clowes

After the death of a U.K. teenager, whosecase involved getting two injections of epinephrine in the same thigh, therewas some suggestion that a second dose should have been given in the oppositethigh.

Thesuggestion was that this might increase the circulation of epinephrine in thebody. However, Dr. Brown does not seea concern with injecting a second dose in the same thigh. As this is such a largemuscle, she says you are highly unlikely to inject in the exact same location.

However, she agrees that there is no problem with injecting a second dose in the opposite thigh (to the first dose) if there is no barrier to doing so.

Ina severe anaphylactic reaction, Dr. Brown says there is a lot of fluid leakage fromthe blood vessels internally, which makes it hard for your body to pump enoughblood through your heart. Its often helpful for a person to lie down with feetelevated when suffering from a serious reaction.

Youare helping them to circulate their blood the best if theyre lying down,she says. And after youve given epinephrine, youre helping to circulatethat epinephrine the best if theyre lying down.

Shediscussed U.K. research into cases of patients who had died from anaphylaticshock. Some patients worsened after they stood up quickly or were propped up duringtheir extreme reactions. The lack of blood flow to the heart may have led to aheart attack, which contributed to the fatal outcome.

Dr.Brown recommends that patients experiencing active anaphylactic symptoms shouldlie down, if possible. However, I certainly see lots of kids who aresitting comfortably for hours in our emergency department, and they dont allneed to be lying down. She says this recommendation is probably mostimportant when a patient feels faint or light-headed or early in a reactionthat is progressing rapidly.

Importantly, she says, not everybody is going to be best off lying down. Dr. Brown gives the example of someone whos having respiratory distress as a symptom. If its upper airway difficulty, with what we call stridor the kind of noise where youre having trouble breathing in that person often needs to be sitting up and leaning forward. This is a position that allows your airways to be the most open.

In addition, she says that individuals who are vomiting should be lying on their side to reduce the chances of choking.

This is an issue of concern particularly in schools. The teacher should never send a kid in school on their own to the nurses office, says Dr. Brown. You dont know how the disease is going to progress between the classroom and the nurses office.

She recommends sending someone with the student, at a minimum, so they can monitor and advocate for the child or teen if needed. If the child is feeling faint, then help should be brought to the child, rather than sending the child to get help.

According to Dr. Brown, studies have shown there is epinephrine in your system for at least 6 hours. Its at a higher level for about an hour, and it peaks around 5 minutes. Theres a pretty decent amount [circulating] for 40 minutes.

Shesays people often think epinephrine only lasts 15 minutes because thats whenyoure suggested to take a second dose if needed. But it doesnt mean that thereisnt medication still on-board from the first dose.

Evidenceshows most people only need one dose of epinephrine, says Dr. Brown. One reasonis that it lasts for the duration of most reactions. A second reason is thatepinephrine stabilitizes mast cells, making them less twitchy, aneffect that may last even after the epinephrine is gone.

She says a third factor is that, even for patients who dont get epinephrine, a lot of these reactions will burn out on their own. Thank goodness for that, because everybody [with food allergies] has a first reaction where they arent carrying epinephrine! she says. Of course, you never want to count on it burning out on its own, so you should always treat anaphylaxis early with epinephrine.

Thegood news is: There are a number of studies that have looked at what happenedto epinephrine when you freeze it. Theyve shown that both refrigerating andfreezing epinephrine does not degrade epinephrine. So it maintains high levelsof epinephrine.

Dr. Brown and colleagues have further investigated what happens to auto-injector devices when frozen. Dr. Brown was senior author of a study [by Alex Cooper et al] in which 104 EpiPens were frozen for 24 hours, then thawed while their mates [from EpiPen 2-Pak cartons] were left at room temperature. The frozen-then-thawed devices fired a similar amount of epinephrine to their never-frozen paired device. When another 104 frozen-thawed devices were opened unfired, there was no damage to the syringes or other device parts.

This research didnt find any evidence of adverse effects to the device of having been frozen for 24 hours. It looks like freezing has pretty minimal effects on EpiPens, said Dr. Brown. She cautions that this research looked only at EpiPens, not other auto-injectors, and the impact on other devices could be different.

Dr. Brown explains that heat is much more problematic than cold. Previous research has shown that you can definitely see the degradation of epinephrine itself with high heat. She says temperatures in a car on a hot, sunny day can exceed 194 degrees F, and a device exposed to this sort of heat could have degradation of the epinephrine.

The device itself can also be negatively impacted by heat. Her teams ongoing research [lead investigator Samuel Agosti] is examining the impact of high heat, and exposing EpiPens and EpiPen Jrs to 183 degrees F for 8 hours. In this study, Dr. Brown reports, were seeing differences in the amount of epinephrine fired from heated-then-cooled devices compared with their unheated pairs [from EpiPen 2-Paks]. We are also having trouble getting some devices out of the cases.

Sherecommends replacing a device that has had significant heat exposure. Shecautions if it feels hot to the touch, I would say thats pretty suspect that thedevice is not reliable anymore. Theres a risk there.

Dr. Brown doesnt think so. She says that in the United States, we have safe devices that have really maximized needle lengths for serving a wide range of population and different-sized people. Longer needles might be more suitable for some extremely large patients, but those longer needles might be long enough to reach bone in many normal-weight patients.

She notes that the goal is to get the medicine into the thigh muscle, and the device mechanism that pushes the drug out also plays a role. So needle length isnt the only factor. Although there will always be challenges to meet every patients needs, Dr. Brown believes the options available the devices in the U.S. are probably doing a reasonable job, all things considered. She notes there is even a third dose option now, the Auvi-Q device for infants.

Dr. Brown had no concerns about airport scanners. Shes not aware of any specific research in this area, but doubts an airport scanner would have any ability to impact your dose of epinephrine or the functioning of the device.

Her team [led by investigator Andrew McCray] has researched this easy mistake to make and the news is not good for an EpiPen that has gone through the laundry. While prescribing information does not address what to do if the device is submerged in water, the EpiPen website says the carrier tube is not waterproof and that a submerged device should be replaced. However, Dr. Brown said: I still thought that they would do pretty well because it looks like a robust device that was based on a design developed for the military. But our results are not encouraging.

She reports that water gets lodged in the outer layer of the device, and more importantly the amount of drug that fires appears to be impacted. She recommends following the advice to replace an auto-injector that has gone through the washing machine.

Epinephrinedevices do continue to maintain a high level of the labeled dose of epinephrineas they age. While Dr. Brown recommends keeping current, unexpired deviceswhenever possible, she has little concern about the four-month expiration dateextension that the FDA issued on certain lot numbers during periods of shortage.

However, as Dr. Brown explains, the amount of epinephrine is only part of the story. There are epinephrine metabolites that occur as the medication ages. The safety or toxicity of these metabolites in the body in expired medication is unknown. While the theoretical risk of these metabolites shouldnt prevent use of a potentially life-saving medication in an emergency, it is a good reason to keep a current device on hand.

Shes aware that many allergy families keep older auto-injectors in case of emergency, but cautions that the level of epinephrine is getting pretty low after two years, and the level of metabolites is probably getting fairly high. Two years is probably a reasonable limit for keeping back-up devices. After that, its really time to just toss them in your med recycling bin.

With heat, light exposure or over time after expiration, epinephrine is degraded and metabolites begin to increase. Epinephrine metabolites can exceed FDA recommended levels well before the medication shows any discoloration, says Dr. Brown. However, some pharmacists still perpetuate the notion that as long as the medication is clear, its OK to use.

If the epinephrine has been exposed to heat, it can have a fairly significant increase in epinephrine metabolites and not be discolored. You cant rely on color tell you whether or not your device is safe to use, she cautions.

If it is discolored, it is unsafe. But if it was exposed to heat and is clear, it could still have significant degradation.

Although Dr. Brown acknowledges the concern of Benadryl masking anaphylaxis, she says that is giving antihistamines way more power than they have in allergic reaction. Her view is that if a reaction is going to be an anaphylactic one, an antihistamine wont stop it. There is no argument that epinephrine is the drug of choice to treat anaphylaxis, a life-threatening allergic reaction. But for a mild symptom, such as a mild runny nose or slight rash, she says its fine to give an antihistamine. Youre not going to mask anything. As long as youre still keeping a watchful eye for symptom progression.

She shares two caveats, though. Dr. Brown is among a growing number of experts who prefer a non-sedating antihistamine, such as Zyrtec, rather than Benadryl, as the latter is more sedating. She recommends this to avoid confusion between drowsiness from the medication and drowsiness related to anaphylaxis.

The second caveat is that if an antihistamine has been given for a single symptom, such as hives, you would still count that symptom as one system affected, even if the symptom resolves. She explains that if youve treated hives with an antihistamine and theyve improved, but half an hour later you go on to start vomiting, now youve hit two systems. According to most care plans, you would meet criteria for using epinephrine.

Interestingly, research shows conflicting benefits of corticosteroid medication in anaphylaxis. First, Brown explains there is a misconception that steroids take a long time to work, but theres some evidence that steroids actually can work within 30 minutes.

However, research from Canada suggests that steroids given prior to admission into the hospital increased intensive care admissions. She notes that its unclear if that truly was an effect of the steroids, or if perhaps steroids were being used instead of epinephrine.

There is also a notion that steroids decrease the risk of a biphasic or secondary reaction. But a review of cohort studies suggests that steroids are not having an impact on biphasic reactions. Brown concludes that theres really not a lot of great evidence to support that steroids are doing anything in anaphylaxis.

There are many other drugs and supports that can help a patient recover from an anaphylactic reaction such as fluids, oxygen, antihistamines, albuterol and other asthma medications. The additional drugs and monitoring available are why it is so important to seek medical care during an anaphylactic reaction.

Thefirst thing to remember is that [patient emergency anaphylaxis] care plans havea very low threshold for giving epinephrine. Often you are giving epinephrinebecause you meet this two-system criteria for giving epinephrine, Dr. Brownexplained.

Thatthreshold for using epinephrine by a lay person, who is not in a medicalsetting, is lower than it would be in a hospital. In the emergency departmentBrown notes:

The physician has the advantage of having you on monitors, of knowing your vital signs, what your exam is like, what kind of a timeframe were talking about. Time is very important in anaphylaxis, and thats not something that is incorporated into emergency care plans. The doctors will incorporate all that information into the decision-making about whether or not its appropriate to give more epinephrine at that time, whether or not they want to do something else, or whether they just want to watch further.

All of those may be safe and appropriate options in the emergency department setting, while you might make very different decisions if youre in the community and following your care plan.

Dr. Brown cautions that its important to understand that there is no rhyme or reason to food allergy reactions and that any reaction can become the bad reaction. You can have had very mild reactions all of your life, and then your next one can be really severe.

At the same time, it is wise to be aware that if youve had very life-threatening reactions in the past, then that may increase your chance of having one again, she says.

While our individual histories are things we cant necessarily change or impact, co-factors are things that we can be aware of. Dr. Brown explains that co-factors are things like exercise, heat, alcohol consumption, illness and menstruation. All of those can exacerbate your allergic reaction.

So if youre having a mild allergic reaction and you go out for a jog, that may really flare up that reaction. Or if youre having a bit of a reaction and you go take a hot shower, that may really activate all your masts cells and you may come out of the shower just covered in hives. Some people are exacerbated by cold, so they might go out on a very cold day and find that that sets them off. Illness certainly decreases peoples threshold for reaction. So they may find that they can tolerate a food pretty well most of the time, and then when they are ill have a decreased threshold for reacting to that food. Some women find around their menstruation theyre much more likely to react to certain foods, she says.

Dont be afraid of epinephrine. It is unfortunately so hard for so many people to get past the mental idea of giving themselves [or a child] a shot, but it invariably makes you feel so much better when youre having an allergic reaction, says Dr. Brown. It only does good things, it only keeps you safe. It really is a wonder drug in anaphylaxis.

She puts it succinctly: Dont be afraid to use it yourself. Dont be afraid to use it for your child. Youre only going to make things better.

Allergic Living and Gina Clowes extend our appreciation to Dr. Julie Brown for her generous time in helping to create this go-to resource for the food allergy community. Dr. Brown is an emergency medicine physician and co-director of emergency medical research at Seattle Childrens Hospital, with study interests in epinephrine, auto-injectors and anaphylaxis. Gina is the founder of AllergyMoms.com.

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All About Epinephrine: What It Does in a Reaction, How Long It Lasts, When It Gets Hot or Cold - Allergic Living

Does Wanting A Lot of Sex Mean Youre Addicted? Experts Explain

You might be familiar with the statistic that claims men think about sex every seven seconds.

That statement has garnered plenty of skepticism from gentlemen thatve heard it, and not just because theres no research to back it up. After all, its difficult to see how someone could get anything accomplished if they thought about getting it on 500 times an hour (thats 8,000 times a day).

RELATED: Dealing With Porn Addiction

So lets ask the question on everyones mind: Is it normal to think about sex all the time?

According to a 1995 survey conducted by the Kinsey Institute, 54 percent of men said they think about sex several times a day, and 43 percent said its on their mind a few times per week or just a few times per month. Only 4 percent reported thinking about it less than once a month. Its worth noting that the Kinsey Institute survey included men of all ages, meaning their sex drives varied.

But when it comes to thinking about sex, at what point do all of those racy thoughts become problematic, going as far to interrupt your regular day-to-day routine?

The line between a typical horny guy and sex addict can get pretty blurry. To figure this out, AskMen spoke with three experts to clarify the difference.

Dr. Joshua Klapow, clinical psychologist and host of The Kurre and Klapow Show, asserts that sex drive can vary greatly among men, with age being one of the key factors that impact it. Still, even within the same age range, its very difficult to define whats normal.

Younger men (17-30), with more testosterone production on average will have stronger sex drive than older men, he explains. However, environmental and biological factors can impact that significantly. We see men in their 20s with moderate drive and men in their 50s with a strong drive. Sexual experience, social norms, learning history and expectations (i.e. how much sex theyve had in the past) all affect the degree of sexual drive.

Klapow also notes that life circumstances can have an effect on sex drive. For example, stress, grief, anxiety, and sleep deprivation can all come into play in terms of your sexual interest and activity.

Dr. Dawn Michael, clinical sexologist founder of TheHappySpouse.com, states that every man has his own unique sex drive.

Sex drive can be dependent on a mans pattern of masturbation and sexual release (orgasm), she says. If a man orgasms every day, his body gets used to that pattern.

Given that the Kinsey Institute study included participants within such a wide age range, its difficult to discern any norms for particular groups from the findings. However, Dr. Leslie Beth Wish, licensed clinical psychotherapist, relationship expert and author of Training Your Love Intuition, points at a 2016 study from Ohio State University as a more reliable source due to its focus on men between the ages of 18 to 25.

Researchers gave participants a counting machine, which they used to track their thoughts about sex. On average, participants had explicit thoughts about 19 times per day (or once every 1.26 hours). This may come as no surprise, but the men thought about food almost just as often (18 times per day).

In other words, even if youre thinking about sex about once every hour or two, youre right in line with the average for young men. How do you know if its becoming a problem? According to Klapow, if youre preoccupied with thoughts of sex to the point that they interfere with your ability to work, study, maintain relationships or have a social life, thats a red flag.

Experts agree that the definition of sex addiction is nuanced and delicate in fact, theres no official medical diagnosis for it.

We have to be careful to label someone as having a sex addiction, says Michael. The label sex addiction is very complicated and misused often. Some men are labeled sex addicts by their partners who may simply not have the same sex drive.

That said, there are some tell-tale signs that can suggest youre experiencing compulsive sexual behavior. Below, youll see some of the most common indicators of addiction via Klapow and Wish:

Wish states that sex addiction is often marked by a constant need to expand your sexual activities. Its not unlike a drug addiction, where you need to continually increase your dosage of the substance to experience the same pleasurable effects. For example, you might feel compelled to incorporate more elements of danger into your sex life for more of a thrill, or need to seek out increasingly hard-core pornography in order to reach an orgasm.

Our brain and body like variety, she adds. Imagine if you had to eat your favorite meal three times a day, every day. This loss of pleasure creates a compulsion for something new. Regardless of the next choice, that choice, too, most likely will stop being as satisfying, and, as a result, men get trapped in an endless cycle.

Even if some of the aforementioned signs sound familiar, all experts agree that sex addiction isnt something that should be self-diagnosed.

Wish points out that you could be overlooking a medical issue, such as a mental health disorder or hormone imbalance, at the root of your addiction. Additionally, Michael notes that past traumatic experiences may be contributing to this behavior, and those are best worked through with a professional such as a licensed counselor or therapist.

Ideally, consult a mental health professional who specializes in sexual addictions, advises Klapow. The key is to recognize that if you see yourself as having a sexual addiction, you are not likely to be able to modify your behavior on your own. Its important to contact a mental health professional as sexual addiction is not by itself a diagnosis and often is a problem that presents with other psychiatric problems (i.e. bipolar disorder, OCD, mania, etc.)

If you cant find a licensed professional who specializes in sexual addictions in your area, contact a licensed mental health professional, or talk to your primary care physician.

The bottom line? If your sexual thoughts and activities are negatively impacting your life in any way, then it may be time to figure out what you can do to address those compulsions. If they arent, take a deep breath and know that those frequent naughty thoughts are totally normal in fact, its just points at a healthy, active sex drive.

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Is It Normal to Want Sex All the Time? How to Tell If You're an Addict - AskMen

Its well known that most industries are still overwhelmingly dominated by men. For instance, Wall Street, tech, construction, and engineering are only a few of the industries in which women are underrepresented, holding only 9 percent and 6 percent of the senior roles in venture capital and private equity. However, no one needs those statistics to confirm what we already know: There are specific fields in which women havent yet broken the infamous glass ceiling.

The most significant mistake analysts tend to make when discussing male-dominated industries is that they focus on the inequality itself. However, it can be far more fruitful to consider the advantages women bring to the table, both for themselves and for the industries involved.

The outcome of equal female representation in the workforce was summarized quite succinctly by management consulting giant McKinsey in 2018. They found that even though women make up around half of the worlds working-age population, they tend to be underrepresented, especially in the top roles of the workforce. Yet McKinsey estimates that women working at their full potential can add up to $28 trillion in additional global GDP by 2025. On a more micro level, an MIT study on workplace diversity has shown that splitting offices along gender lines drastically boosts productivity.

That gender diversity offers a workplace many benefits has been well covered, but what about the inclusion of women in a companys ranks boosts productivity and propels the business forward?

While there is abundant evidence showing women to be excellent communicators, multitaskers, and critical thinkers, psychological evidence also shows that men and women think slightly differently. Sometimes referred to as the battle of the hormones, there exists a phenomenon in which women and men bring different perspectives to the table due to their different genetic makeup and inherently opposing strengths and weaknesses. In other words, they complement each other in the workplace, joining forces to tackle obstacles neither gender would be able to face alone.

As the CEO of a tech company in the logistics industry, one of the most masculine industries imaginable, I have personally witnessed the wonders women can offer a world traditionally shaped by the minds of men. For example, I have observed how womens creativity improves specific processes inside companies thanks to their innovation, and how women who come from very little strive to achieve greatness, not just for themselves but for their companies, taking nothing for granted. And thats precisely it -- because women are aware that, despite the tremendous progress made in the fight against inequality, they are still afforded less professional opportunities than men, they know they have to work just a little harder. Armed with the mentality of fighting for every inch of progress, its hard to fail.

I also noticed this schism during my time in the Israeli Defense Forces, where I was rewarded for my hard work by perhaps the least likely of fans. Between 1999 and 2001, I served as an instructor of an infantry artillery unit, and afterward as an officer. Yes, the Israeli army has a reputation for gender diversity (as of 2011, 88-92 percent of all roles in the IDF were open to women), but military culture has been shaped by masculinity for thousands of years before any position was open to women, in any military. Also, some units are less used to having a woman around than others.

Units that absorb religious soldiers, for example, are bastions of gender bias because both religion and army culture have historically been patriarchal. And yet, even in these environments, there isnt a gap that cant be closed with a demonstration of knowledge and leadership.

During my time as an artillery training instructor, I trained a group of Yeshiva students -- deeply religious Jewish men who study Torah part-time while serving in the army. In other words, my trainees were accustomed to strict religious rules regulating the interactions between men and women. Every time I entered the infantry fighting vehicle (IFV) to train them, the soldiers backed up out of shock. It wasnt out of malice; its just that the religious rules they live by dont allow them even to touch a woman that is not their wife. Suddenly, they were expected to be trained by a woman soldier within the confined space of an IFV (for those not as familiar, they are quite small).

However, the initial feeling of confusion quickly transformed into mutual respect between the religious soldiers and me. By the end of the month-and-a-half training program, we had grown so close that they gave me a customized helmet and dog tag, with my name engraved on each. They so appreciated my professional contribution to our training sessions together that it changed their view on serving alongside a woman. It probably opened their minds in general.

Psychology is a useful tool and one that shouldnt be limited to individuals in need of guidance. The different perspectives diversity can offer industries such as cryptocurrency, blockchain, finance, and logistics, should be embraced as tried and true tools for propelling those industries forward. Since psychology teaches us about the secrets behind the ways men and women think, one of its central themes is that positivity is more effective than negativity. If were going to break bulletproof glass ceilings in boys-club industries, were going to have to explain why they would benefit from a womans touch once the shattered glass settles on those polished corporate tiles.

Hagar Valiano Rips is the CEO of Ladingo, and an entrepreneur and dynamic professional with more than 14 years of executive experience in business and product development across various industries. She started her first company at the age of 23 and sold it at 25. Valiano Rips also served as a commanding officer of an infantry unit in the Israeli Defense Forces.

Link:
Why Male-Dominated Industries Could Use a Woman's Touch: A Perspective from a Current CEO and Former Soldier - TechDay News

Every holiday, and on Black Friday and Cyber Monday and Random Discount Wednesday and Oh God Buy Stuff The High Street Is Dying Thursday, a load of miserable Opinions-For-Hire types churn out diatribes about why you absolutely should not buy anyone, including yourself, a DNA test in the sales or otherwise. And I'm here to tell you why they're wrong.

Before we get to why DNA tests are officially a good thing, let's run through some of the downsides those op-eds always bring up.

Yes, some people have found unexpected skeletons in their cupboards and sparked giant, multigenerational family arguments. But that's very rare most of us, for better or worse, don't have family histories that'd make a good daytime soap. And even if it does happen, wouldn't you rather know the truth? Where you really come from, and why you were lied to about it? It could have enormous impacts on your life choices.

Another concern is data security. Doom-mongers envisage a future where your genetic information is sold to health insurance companies, who jack up your premium as a result but that's much more of a concern for countries like the US than the UK, which still (at the time of writing, at least!) has a National Health Service. The NHS itself is on board with genetic testing, getting ready to offer a service of its own in return for contributing your anonymised data to lifesaving research.

Image: Nosha via Flickr CC

It's worth noting, too, that not all DNA testing is created equal. Some services are more geared towards looking at your ancestry and ethnicity information, while others only give surface-level results like "may be slightly more likely to have [X]", in which X can be anything from Alzheimer's to asparagus-scented wee. So depending on which service you've gone for, the information might be all but useless unless someone's trying to prove you ticked the wrong box on the ethnicity form when you applied for your job.

OK, so maybe not insurance companies, but what about your test results getting into other bad actors' hands? Well, yes, every damn company holding sensitive data has security issues, it seems the NHS very much included. However, I'm not overly worried that someone's going to download my info, insert it into some kind of biological 3D printer and start creating counterfeit versions of me. Even if that were possible, they'd needwaymore information than they'd get from a home DNA test.

The idea that your DNA test results constitute the source code for everything you are is a misconception. For starters, the tests only look at a tiny fraction of the human genome, but even if they didn't that's not how genes work. Yes, some problems and tendencies are genetic, but many are only influenced by your genes (often more than one), and some have absolutely sod-all to do with DNA whatsoever, being entirely caused by environmental factors. When you get the flu, does your DNA suddenly say "this person has the flu"? No. Is there a gay gene? No. Nobody's going to post your base pairs on Pastebin and recompile you.

As someone who's done many of these tests, I don't feel that my DNA is some kind of proprietary code I need to defend; in fact I'd open-source it if it meant we could work together on debugging some of the shit bits. Heck, maybe we can even fork me into a better person.

DNA data getting into evildoers' hands is one of those possibilities that sounds awful in theory, and it might well be awful in a few years when the whole system is more refined, but right now it would amount to "the terrorists have found out that you... HAVE A MODERATE CHANCE OF BEING BLUE EYED!" Not such a great Bond movie, is it?

You might also have seen some outcry when a popular DNA site was acquired for the purposes of solving crime, but assuming you and yours aren't massive criminals, that's probably not a huge worry either. In fact, DNA testing of relatives and descendants of suspects has solved a surprising number of cold cases in the US alone in the last few years, as well as identifying quite a few nameless bodies. Surely we can all agree that's a good thing.

While most of the worries about DNA testing are premature or arguable at this point, there are benefits that are real and tangible.

In my case, since my father is dead and I have no contact with my mother, a lot of the information I've found through DNA testing just wasn't available to me in other ways. There are plenty of people in similar situations folks who don't know who their birth parents were, have no contact with them, or aren't able to talk to them about matters of health and ancestry for one reason or another, for instance. DNA testing gives us a way to make family connections, in both the data and the relationship sense.

Last month, someone I share DNA with added me on Facebook. For some people, that might be strange and unnerving (in which case I'd say don't make your name public on your DNA profile I did because I wanted to find relatives), but for me it was wonderful. Being estranged from part of my immediate family means these connections mean more to me, and it's fascinating to look at the surnames, traits and lives of people all over the world who share my DNA segments.

For instance, until I had my DNA tested and analysed, I had zero idea about my considerable Jewish heritage. That led to a lot of genealogical research, ultimately helping me trace my family tree back to the 1700s. Now, when a new DNA relative contacts me (and they do, often it's like having email penpals), we can frequently figure out where our family trees connect, and fill each other in on cool details about our ancestors.

The health information can be life-changing too. In my case, I carry two genetic diseases that would make having a biological child pretty unwise. I already knew this from trying to donate my eggs a few years prior to the first test, and I don't want kids anyway, so it wasn't a nasty surprise but if I'd been planning babies, it would have been invaluable information. From this viewpoint, it seems almost crazy that most people go ahead and mix their genes with no idea what they might contain.

Of course, someone else with my results might have been devastated, but I would still argue it's better to know what you're facing. The same goes for the more serious heritable conditions that DNA tests can show. Yes, it's scary to think you might have a higher chance of getting a particular type of cancer, but it's not a certainty, and it might help you make those lifestyle changes you swear to every January. Or at least start living like you're not immortal, because newsflash: you're not.

In any case, the limited information you can get from home testing services can only give you clues, not the full picture, and some services are more accurate than others. As I mentioned, there's a lot besides raw DNA that makes a difference to how you turn out (see the whole field of epigenetics, for instance). Over time, we'll likely get more sophisticated information, which might one day mean we can start patching ourselves or at least developing medicines and treatments that interact with our unique makeup. But that's a long way off yet.

For now, there's a lot of valuable and fascinating data to be gleaned from testing your DNA, and a relatively low chance you'll ruin the next family reunion. Only you can decide what makes the most sense for you, and no test or article can tell you that.

Main image: Andy Leppard via Flickr CC

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Home DNA Tests Are Not the Devil - Gizmodo UK

More uniform response in Cohort 3 with two confirmed responders and one potential responder

New female responder in Cohort 2 for a total of three confirmed female responders across all cohorts

Up to six responders across all nine patients dosed in study

Prophylactic steroid cohort to begin in first half 2020; data expected in second half 2020

Ultragenyx to host conference call today at4:30 p.m. Eastern Time

NOVATO, Calif., Jan. 09, 2020 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, today announced topline positive safety and efficacy data from Cohort 3 and longer-term data from Cohort 2 of the ongoing Phase 1/2 study of DTX301, an investigational adeno-associated virus (AAV) gene therapy for the treatment of ornithine transcarbamylase (OTC) deficiency. In Cohort 3 (n=3), there were two confirmed female responders as well a third potential male responder who requires longer-term follow-up to confirm response status. In Cohort 2, one female patient has newly demonstrated a response starting at Week 52 which was confirmed at Week 78. The two previously disclosed responders in Cohort 1 and Cohort 2 also remain clinically and metabolically stable at 104 and 78 weeks, respectively. Across all nine patients dosed in the study, up to six patients have demonstrated a response.

We are encouraged to see a more uniform response at the higher doses including three female responders. To date, three patients in the study have discontinued alternate pathway medication and liberalized their diets while remaining clinically and metabolically stable, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. We are moving to prophylactic steroid use in the next cohort as we believe this could further enhance the level and consistency of expression that we have demonstrated so far.

Cohort 3 Efficacy Summary (as of December 9, 2019 cutoff date): One complete responder, one responder, and one potential responder

Patient 7 (complete responder, female): Patient 7 demonstrated a clinically meaningful 79 percent change in rate of ureagenesis, from a low of 24 percent of normal at baseline to the 51 to 64 percent range, and staying at 44 percent of normal at Week 52. During this period, she reported feeling significantly better and discontinued her alternate pathway medications and liberalized her protein-restricted diet. She has remained clinically and metabolically stable without a rise in ammonia.

Patient 8 (responder, female): Patient 8 demonstrated a significant and consistent 90 percent reduction in ammonia levels, time-normalized over a 24 hour period, from a high of 184 umol/L at baseline to 19 umol/L at Week 24, which is within the normal range. Potentially aberrant high baseline ureagenesis values inconsistent with her known more severe clinical status make her ureagenesis results uninterpretable. This patient was on a tapering course of steroids at the time of last assessment and has not yet discontinued alternate pathway medications or liberalized her diet. The investigator reported that her family says her health is the best it has ever been.

Patient 9 (potential responder, male):Patient 9 showed a 123 percent increase in rate of ureagenesis, from 25 percent of normal at baseline to 56 percent of normal at Week 12 while still on a steroid taper. Steroids have been shown to suppress rate of ureagenesis in other study patients. This patient has not yet discontinued alternate pathway medications or liberalized his diet. His ammonia levels have remained in the normal range and response status will be confirmed after additional follow-up.

Cohort 2 Efficacy Summary: Two responders including new responder and previously-disclosed male complete responder

Patient 6 (new responder, female):Patient 6 has now shown a 218 percent improvement in rate of ureagenesis, from 20 percent of normal at baseline to 61 percent at Week 52 and maintained at 64 percent at Week 78. In addition, she has shown a significant 74 percent reduction in ammonia levels from 156 umol/L at baseline to 40 umol/L at Week 78. She has started to taper her alternate pathway medications and liberalize her diet. With this new responder, there are two confirmed responders in cohort 2 out of three total patients.

Story continues

Safety SummaryAs of the data cutoff date, there have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All adverse events have been Grade 1 or 2. All three patients in Cohort 3 had mild, clinically asymptomatic elevations in ALT levels, similar to what has been observed in other programs using AAV-based gene therapy. All three patients have been responding to reactive tapering courses of steroids, and all patients remain clinically stable.

Initiating Prophylactic Steroid Cohort As previously disclosed, a fourth cohort will enroll three patients at the 1.0 10^13 GC/kg dose, using prophylactic steroids. Patients will receive an 8-week tapering regimen of prophylactic steroids, starting at least 5 days prior to dosing with DTX301 at a starting steroid dose of 60 mg/day. The first patient is expected to be enrolled in the first half of 2020, and data from the prophylactic steroid cohort are expected in the second half of 2020.

Potential Phase 3 Study DesignUltragenyx is continuing discussions with the U.S. Food and Drug Administration (FDA) regarding the potential Phase 3 study design. Ammonia is expected to be a primary endpoint based on direct FDA feedback to date, with ureagenesis as a measure of biologic activity that supports the decision for patients to discontinue alternate pathway medications.

Conference Call and Webcast InformationUltragenyx will host a conference call today, Thursday, January 9, 2020, at 4:30 p.m. ET/ 1:30 p.m. PT during which Emil D. Kakkis, M.D., Ph.D., the company's Chief Executive Officer and President, will discuss the new data from the ongoing DTX301 Phase 1/2 Study. The live and replayed webcast of the call and slides will be available through the companys website at http://ir.ultragenyx.com/events.cfm. To participate in the live call by phone, dial (855) 797-6910 (USA) or (262) 912-6260 (international) and enter the passcode 5583103. The replay of the call will be available for one year.

About the OTC Phase 1/2 Study (DTX301)The Phase 1/2 study evaluates the change in the rate of ureagenesis, ammonia levels, neurocognitive assessment, biomarkers, and safety of DTX301 in patients with OTC deficiency. Three patients have been dosed in each of three dose cohorts of 2.0 10^12 GC/kg (Cohort 1), 6.0 10^12 GC/kg (Cohort 2), and 1.0 10^13 GC/kg (Cohort 3). Patients in the first three cohorts received steroids to reactively manage ALT elevations. In the fourth cohort, three patients will receive a 1.0 10^13 GC/kg dose and will all receive a prophylactic tapering course of steroids.

About OTC DeficiencyOTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 patients are affected by OTC deficiency worldwide, of which approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

About DTX301DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug Designation in both the United States and Europe.

About Ultragenyx Pharmaceutical Inc.Ultragenyx is a biopharmaceutical company committed to bringing to patients novel products for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyxs strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the Company's website atwww.ultragenyx.com.

Ultragenyx Forward-Looking Statements Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations regarding the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical drug development process, including the potential for substantial delays and the risk that earlier study results may not be predictive of future study results, the lack of predictability in the regulatory approval process, the timing of regulatory filings and approvals (including whether such approvals can be obtained), and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations and the availability or commercial potential of our products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 6, 2019, and its subsequent periodic reports filed with the Securities and Exchange Commission.

Contact Ultragenyx Pharmaceutical Inc.Investors & MediaDanielle Keatley415-475-6876

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Ultragenyx Announces Positive Topline Cohort 3 Results and Improved Longer-Term Cohort 2 Results from Phase 1/2 Study of DTX301 Gene Therapy in...

What happened

Shares of CRISPR Therapeutics (NASDAQ:CRSP) rose over 113% last year, according to data provided by S&P Global Market Intelligence. The pharma stock built momentum throughout much of the year, but surged in October ahead of an important data presentation that ultimately lived up to the hype. That allowed the gene-editing stock to easily outperform the 28.8% gain of the S&P 500 in 2019.

The end-of-year rally was driven by promising clinical results for its lead drug candidate. The first two individuals, one with sickle cell disease (SCD) and one with transfusion-dependent beta thalassemia (TDT), dosed with CTX001 achieved functional cures after receiving an initial dose of the gene-editing product. The results need to be proven durable and replicated in a larger number of patients, but the update was about as good as investors could have hoped for at the current stage of development.

Image source: Getty Images.

Both SCD and TDT are caused by structural abnormalities in red blood cells. But these are one of the few cells in the human body that don't contain DNA. That means CRISPR Therapeutics has to harvest stem cells from the bone marrow of patients, apply gene editing to those extracted cells, and then inject the engineered stem cells back into patients (the ex vivo method). If the therapy works, then the engineered stem cells should produce functional red blood cells and potentially result in a cure.

In the early study, the ex vivo approach of CTX001 appeared to do just that. The TDT patient required an average of 16.5 blood transfusions per year in the two years before the clinical trial. Nine months after receiving the gene-editing treatment, the individual was transfusion independent (compared with an expected 12 transfusions) and expressed working copies of hemoglobin on 99.8% of red blood cells.

The SCD patient experienced an average of seven vaso-occlusive crises (painful blockages of blood vessels caused by abnormally shaped red blood cells) per year in the two years before the clinical trial. Four months after receiving the gene-editing treatment, the individual reported no vaso-occlusive crises (compared with an expectation for two such episodes) and expressed working copies of hemoglobin on 94.7% of red blood cells.

The early success of CTX001 bodes well for the ex vivo approach of CRISPR Therapeutics and its partner Vertex Pharmaceuticals(NASDAQ:VRTX), but investors should be careful not to extrapolate the results too broadly. Gene-editing tools that are applied inside the body (in vivo) face significantly steeper obstacles, such as the difficulty of delivering gene-editing payloads to specific tissue types inside the body. There's also the elephant in the room: Scientists are beginning to realize that current-generation CRISPR gene-editing tools don't work all that well.

Nonetheless, CRISPR Therapeutics is the top CRISPR-based gene-editing stock on the market. It has the cash, the partnerships, and the early results to back up its claim to that label.

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Here's Why CRISPR Therapeutics Stock Jumped 113.2% in 2019 - Motley Fool