Should the FDA Have Approved Remdesivir to Treat COVID-19 Patients? – Healthline

Last week, the Food and Drug Administration (FDA) approved the antiviral remdesivir as a treatment for COVID-19 in adults and children 12 years and older, paving the way for wider use of the drug.

Dr. Lanny Hsieh, clinical professor of infectious diseases at UCI Health, said the FDAs move is very exciting.

Putting together all of the scientific evidence we have on remdesivir to date, it remains the standard of care for hospitalized patients with COVID-19, she said. Ultimately, it is our patients who would benefit from this FDA approval.

However, research so far on remdesivir is mixed, and the drug is far from a cure for COVID-19.

In May, the FDA issued an emergency use authorization (EUA) for remdesivir, marketed in the United States under the brand name Veklury. This allowed the drug to be used to treat those with severe COVID-19.

The agency broadened the EUA in August to allow for its use on all hospitalized patients with COVID-19, regardless of how severe their illness.

President Trump took remdesivir along with several other treatments when he was hospitalized for COVID-19 in early October.

The FDA based its decision on three randomized controlled trials.

One study of 1,062 participants with mild, moderate, or severe COVID-19 was published earlier in October in the New England Journal of Medicine.

Results from this trial show that remdesivir reduced the length of hospital stay by about 5 days from 15 down to 10.

Patients taking remdesivir also had a lower chance of dying after 28 days 11.4 percent compared with 15.2 percent in patients receiving an inactive placebo.

This [study], along with other trials reviewed by the FDA, has led to remdesivirs approval, Hsieh said, who is the principal investigator on the remdesivir clinical trial at UCI Medical Center.

The two other trials reviewed by the FDA had similar results. One of these also showed that a 5-day course of remdesivir worked just as well as taking the drug for 10 days.

However, preliminary results from the World Health Organization (WHO) Solidarity trial of more than 11,000 participants found that remdesivir had little effect on how long they stayed in the hospital and no effect on death.

This study was published as a preprint on medRxiv and hasnt yet been peer-reviewed, so the results should be viewed with some caution. The WHO plans to publish it in the New England Journal of Medicine.

Given the results of the WHO study, Dr. Eric Topol, a professor of molecular medicine at the Scripps Research Translational Institute, questioned whether the FDA should have granted remdesivir a full approval.

How can Remdesivir get a full [FDA] approval when there are such mixed data? Not supportive of this decision at all, he wrote on Twitter. Does it work early? Does it work late? Does it work anytime? So much unresolved.

However, Hsieh said the WHOs study had several limitations, including not comparing remdesivirs effects to a placebo, and looking at several potential treatments in the same study.

Although interesting, Solidaritys findings do not take away from the results of [the NEJM trial], she said, which is a study that is conducted with the most scientific rigor to date.

Without a COVID-19 vaccine approved in the United States, doctors are anxious for an effective treatment for COVID-19. Remdesivirs approval finally gives them something to work with.

Given the limited arsenal of effective or even marginally effective treatments for COVID-19, and the fact that we dont have a fully curative therapy or a vaccine, it is good to have more options, said Dr. Matthew G. Heinz, a hospital physician and internist in Tucson, Arizona.

But he said remdesivir is still difficult to get in some parts of the country, especially in rural areas.

And its expensive. A 5-day course of treatment can cost $3,120 for people with private insurance, reports Vox.

Remdesivir is also not without risks. In some people, it can cause elevated liver enzymes, which could be a sign of liver damage. The most common side effect, though, is nausea.

In specific situations for certain patients, I do think [remdesivir] is reasonable to use, Heinz said, because it can inhibit viral replication if given at the right time point.

Remdesivir blocks the coronavirus from replicating, so it works best if given early.

Remdesivir is likely going to be more useful for stopping serious progression of the disease, Heinz said. But to give it to someone whos already critical getting intubated or who has already been intubated may not work.

The drug is less effective in later stages of severe COVID-19, when the damage is caused more by an overactive immune response than by the virus itself.

At this point, doctors turn to other treatments that target the immune system. One of these is the corticosteroid dexamethasone, which dampens the immune response and has been shown to reduce deaths from COVID-19.

Although remdesivir isnt completely effective against COVID-19, many doctors on the front line are glad to have it as an option.

Given that its not shown to have significant safety concerns, and at least one good study does show some benefit, it is reasonable to have remdesivir as an available treatment while we wait for better ones, Heinz said.

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Should the FDA Have Approved Remdesivir to Treat COVID-19 Patients? - Healthline

Ross Prize Ceremony and Webinar on the Genetics of Neurological Disorders – The New York Academy of Sciences

New York, October 26, 2020 The Ross Prizein Molecular Medicine will be awarded to Adrian R. Krainer, PhD, St. Giles Foundation Professor at Cold Spring Harbor Laboratory, in a virtual ceremony and webinar hosted by the New York Academy of Sciences, Feinstein Institutes for Medical Research, and the journal Molecular Medicine on October 30. The webinar will be held 1 PM to 4:50 PM EDT.

The Feinstein Institutes for Medical Research has selected Dr. Krainer as the eighth recipient of the Ross Prize, which is awarded annually through the Feinstein Institutes peer-reviewed, open-access journal, Molecular Medicine.

The Ross Prize recognizes Dr. Krainer for his pioneering work in introducing anti-sense therapy in clinical use, and for its successful application to spinal muscular atrophy (SMA). The Ross Prize includes a $50,000 award.

After a brief award presentation at the start of the October 30 webinar, Dr. Krainer will discuss his work. This will be followed by a session on topics in the genetics of neurological disorders. Speakers for this session will include: Edward M. Kaye, MD, Stoke Therapeutics; Michelle L. Hastings, PhD, Rosalind Franklin University of Medicine and Science; and Timothy Yu, MD, PhD, Boston Children's Hospital, Harvard Medical School. The webinar will be held 1 PM 4:50 PM EDT.

The Ross Prize is made possible by the generosity of Feinstein Institutes board members Robin and Jack Ross. The Ross Prize recognizes biomedical scientists whose discoveries have transformed the way medicine is practiced. The awardees are midcareer researchers who have made a significant impact in the understanding of human disease pathogenesis and/or treatment. Moreover, it is anticipated that they will continue to make profound advances in the general field of molecular medicine.

The Ross Prize is a worthy tribute to the significance and impact of the fundamental and applied research conducted by my lab and our collaborators, which culminated in a disease-modifying therapy for spinal muscular atrophy, Dr. Krainer said. I greatly admire the seven previous Prize recipients, so I am humbled to join this distinguished group of scientists and clinicians.

Dr Krainer is the eighthrecipient of the Ross Prizein Molecular Medicinebecause his discoveries are revolutionizing treatment of a devastating, crippling pediatric illness, saidKevin J. Tracey, MD, president and CEO of the Feinstein Institutes and editor emeritus ofMolecular Medicine.His work enables children with spinal muscular atrophy to crawl, walk, and live a full life.

Dr. Krainer explained his work in more detail:

"My labs research has a long-standing focus on understanding RNA splicing, a fundamental cellular process. In addition, we are interested in how alterations in this key step in gene expression cause or contribute to disease. This basic research eventually led us to the development of mechanism-based therapies. Our main goals are to continue gaining novel insights into RNA-splicing mechanisms and regulation, and to translate these findings into new drugs or clinically useful methods. These are important goals, because they differ from the traditional path for drug development, and so they have the potential to yield effective solutions to intractable medical problems."

In addition to studying the mechanisms of RNA splicing, Dr. Krainer uses multidisciplinary approaches to examine the ways in which they go awry in disease, and the means by which faulty splicing can be corrected. He co-developed the first FDA-approved therapy for the genetic disorder SMA an illness that has been the leading genetic cause of infant death based on the biological process of RNA splicing. This life-saving drug is also the first approved splicing-corrective therapy.

To learn more about the Ross Prize celebration and symposium, and to register for the event, please visit http://www.nyas.org/RossPrize2020.

Past recipients of the Ross Prize are: Daniel Kastner, MD, PhD, scientific director of the National Institutes of Healths (NIH) National Human Genome Research Institute (NHGRI); Huda Y. Zoghbi, MD, professor, Departments of Pediatrics, Molecular and Human Genetics, Neurology and Neuroscience at Baylor College of Medicine; Jeffrey V.Ravetch, MD, PhD,the Theresa and Eugene M. Lang Professor and head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology at The Rockefeller University; Charles N.Serhan, PhD, DSc, director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Womens Hospital, the SimonGelmanProfessor ofAnaesthesiaat Harvard Medical School and professor at Harvard School of Dental Medicine; Lewis C.Cantley, PhD, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College andNew York-Presbyterian Hospital; John J. OShea, MD, scientific director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); and Dan R. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in theSkirballInstitute ofBiomolecularMedicine at New York University School of Medicine.

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Ross Prize Ceremony and Webinar on the Genetics of Neurological Disorders - The New York Academy of Sciences

UArizona researchers have breakthrough related to stomach cancer – Eastern Arizona Courier

TUCSON A promising new biomarker that appears in patients before stomach cancer develops may help with early detection of the disease and improve patient response to therapy, according to findings in a study led by University of Arizona Health Sciences researchers.

The biomarker can be detected through a simple blood test, saving time and lowering costs. Currently, stomach cancer diagnosis requires endoscopic collection of stomach tissue through a biopsy procedure, and then analysis by pathology.

Published in Gut, the journal of the British Society of Gastroenterology, the study was led by Juanita L. Merchant, MD, PhD, chief of the Division of Gastroenterology and Hepatology at the UArizona College of Medicine Tucson, a cancer biology program researcher at the UArizona Cancer Center and an elected member of the National Academy of Medicine.

See a video of how Drs. Juanita Merchant and Yana Zavros found a new biomarker to help diagnose stomach cancer.

The biomarker, MiR130b, is a microRNA or small non-coding RNA molecule that can play an important role in regulating gene expression, affecting disease development and progression. MiR130b can be produced by a group of immune cells called myeloid-derived suppressor cells (MDSCs), commonly associated with infections caused by Helicobacter pylori (H. pylori), a bacteria associated with ulcers. These particular cell types in the stomach correlate with early, preneoplastic changes (before a tumor develops) that can lead to gastric cancer long after an H. pylori infection has passed.

The study included collaboration with Yana Zavros, PhD, associate head for research in the College of Medicine Tucsons Department of Cellular and Molecular Medicine and the Cancer Centers shared resource director for Tissue Acquisition Cellular and Molecular Analysis.

Even though you get can get rid of the bacteria, oftentimes the infection itself already has initiated a cascade of events that inevitably may lead to cancer, Dr. Zavros said. That is why early detection is so important.

A Blood Test Instead of a Procedure

The study arose out of basic science mouse models that simulated changes in the stomach similar to that caused by H. pylori. This led the researchers to identify MiR130b in the mouse models, and they also detected the same microRNA in the plasma of human patients that either had precancerous changes or those that already had progressed to cancer.

This was a retrospective study, said Dr. Merchant, who is a member of the universitys BIO5 Institute. It is very exciting because now we can begin looking at this biomarker more prospectively in different patient populations.

Although less common in the United States, the National Cancer Institute reports gastric (stomach) cancer is the third most common cause of cancer-related deaths in the world. The findings, however, could have major implications for Arizonas rural areas and Hispanic and Native American populations, which are at greater risk for developing gastric and other gastrointestinal (GI) cancers, because these diseases often are caused by dietary and environmental factors and may go undetected for long periods.

Dr. Merchants lab has a sub-project in the Cancer Centers U54 grant (Partnership for Native American Cancer Prevention) to study detection of the microRNA described in the Gut paper in members of Native American populations with H. pylori.

This molecular signature (the microRNA MiR130b) that we discovered may help us see if patients have changes in their mucosa (the membrane that lines the stomach) related to having H. pylori, Dr. Merchant said. And a blood sample would be less invasive and then could be a way to make the decision whether we need to bring a patient in for an endoscopy.

Broader Implications for Treatment

Once diagnosed, gastric cancer can be difficult to treat. Immunotherapies with proven effectiveness in treating other types of cancer are not as successful against most GI cancers, including stomach cancer. The researchers believe these new findings in gastric cancer may help to address why other GI cancers also are resistant to therapy.

The underlying mechanism by which a patient may not respond well in gastric cancer may be applicable in other organs as well Dr. Zavros said. The way the cells interact with each other to render that patient resistant to therapy may be quite similar between gastric, pancreatic and colon cancers.

Dr. Merchant added: There may be dual-purposes. We can look at it as a biomarker to help us from a diagnostic perspective, but we also can look at therapies that can be developed based on what this microRNA itself is targeting.

Another project funded by the Cancer Centers Sparking Bench-to-Bedside Team Science Project award is building from results of this study to explore therapies for pancreatic and gastric cancer. The investigators are exploring the tumor microenvironment, in particular the immune cell MDSCs, referred to previously, that appears to dampen the chemotherapeutic response to immunotherapies.

The project relies heavily on Dr. Zavros BioDroid program, which develops miniature organs in the lab with a realistic microanatomy, also known as organoids. These are used in collaboration with the Tissue Acquisition Repository for Gastrointestinal and HEpaTic Systems (TARGHETS), created by Dr. Merchant. TARGHETS is a GI/Hepatology biorepository that collects samples from patients who undergo endoscopy.

Both Drs. Zavros and Merchant are looking to the BioDroid and TARGHETS efforts to reveal additional information that will allow them to develop new approaches to address resistance of gastric cancer to immunotherapies.

We want to find a way to reprogram the cancer cells or the immune cells within that patients tumor environment to make the patient more responsive to the therapy, Dr. Zavros said. A biomarker gives us a place to start.

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UArizona researchers have breakthrough related to stomach cancer - Eastern Arizona Courier

Aviceda Therapeutics Announces Formation of Scientific Advisory Board – BioSpace

Oct. 27, 2020 12:00 UTC

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Aviceda Therapeutics, a late-stage, pre-clinical biotech company focused on developing the next generation of immuno-modulators by harnessing the power of glycobiology to manipulate the innate immune system and chronic, non-resolving inflammation, is announcing the members of its Scientific Advisory Board who will help shape ongoing development efforts.

The Aviceda Scientific Advisory Board includes Pamela Stanley, PhD; Ajit Varki, MD; Christopher Scott, PhD; Geert-Jan Boons, PhD; Salem Chouaib, PhD; and Peng Wu, PhD.

Aviceda has assembled an extraordinary multi-disciplinary team of world-class scientists and renowned researchers to join our efforts in developing the next generation of glyco-immune therapeutics for the treatment of immune-dysfunction conditions, said Mohamed A. Genead, MD, Founder, CEO & President of Aviceda Therapeutics. Each individual offers a fresh perspective and unique strategic acumen that complements and strengthens the insights of our in-house leadership development team.

Prof. Scott, Aviceda Scientific Co-Founder, is Director of the Patrick G Johnston Centre for Cancer Research and Cell Biology at Queens University Belfast. He is internationally renowned for his work in development of novel approaches in the field of antibody and nanomedicine-based therapies for the treatment of cancer and other conditions. Prof. Scott has a background in both the pharmaceutical industry and academia and was a founding scientist of Fusion Antibodies Plc. Research in his laboratory is funded by agencies such as Medical Research Council, UK charities and various industrial sources. He also held a Royal Society Industrial Fellowship with GSK from 2012 to 2015 and won the Vice Chancellors Prize for Innovation in 2015 with his groups work on developing a novel Siglec targeting nanomedicine for the treatment of sepsis and other inflammatory conditions.

The novelty of Avicedas platform technology is its potential to affect immune responses associated with a wide range of disease states, many of which are currently unmet or underserved needs. I look forward to the continued development of Avicedas core technology and moving forward to clinical trials that will pave the way for truly disruptive therapeutic strategies to enter the clinic that will significantly impact and improve patients lives in the not-too-distant future, said Prof. Scott.

Avicedas Scientific advisory chairwoman, Prof. Stanley, is the Horace W. Goldsmith Foundation Chair; Professor, Department of Cell Biology; and Associate Director for Laboratory Research of the Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York. She obtained a doctorate degree from the University of Melbourne, Australia, for studies of influenza virus, and was subsequently a postdoctoral fellow of the Medical Research Council of Canada in the laboratory of Louis Siminovitch, University of Toronto, where she studied somatic cell genetics. Prof. Stanleys laboratory is focused on identifying roles for mammalian glycans in development, cancer and Notch signaling. Among her many varied contributions, Prof. Stanleys laboratory has isolated a large panel of Chinese hamster ovary (CHO) glycosylation mutants; characterized them at the biochemical, structural and genetic levels; and used them to identify new aspects of glycan synthesis and functions. She serves on the editorial boards of Scientific Reports, Glycobiology and FASEB Bio Advances; she is an editor of the textbook Essentials of Glycobiology; and her laboratory is the recipient of grants from the National Institutes of Health. Prof. Stanley has received numerous awards, including a MERIT award from the National Institutes of Health, an American Cancer Society Faculty Research Award, the Karl Meyer Award from the Society for Glycobiology (2003) and the International Glycoconjugate Organization (IGO) Award (2003).

Working with Aviceda represents a unique opportunity to contribute to science at the cutting edge. Its pipeline contains a broad range of candidates that represents numerous first-in-class opportunities, said Prof. Stanley.

Prof. Varki is currently a distinguished professor of medicine and cellular and molecular medicine, Co-director of the Glycobiology Research and Training Center and Executive Co-director for the UCSD/Salk Center for Academic Research and Training in Anthropogeny at the University of California, San Diego; and an Adjunct Professor at the Salk Institute for Biological Studies. Dr. Varki is also the executive editor of the textbook Essentials of Glycobiology. He received basic training in physiology, medicine, biology and biochemistry at the Christian Medical College, Vellore, The University of Nebraska, and Washington University in St. Louis, as well as formal training and certification in internal medicine, hematology and oncology. Dr. Varki is the recipient of numerous awards and recognitions, including election to the American Academy of Arts and Sciences and the US National Academy of Medicine, a MERIT award from the National Institutes of Health, an American Cancer Society Faculty Research Award, the Karl Meyer Award from the Society for Glycobiology and the International Glycoconjugate Organization (IGO) Award (2007).

The Aviceda team is already building on the foundational work in the emerging field of glycobiology to develop potential therapeutics and interventional strategies. Their work could be critically important for growing the understanding of how glycobiology and glycochemistry are applicable to immunology, and more broadly, to the field of drug and therapeutic development, said Prof. Varki.

Prof. Boons is a Distinguished Professor in Biochemical Sciences at the Department of Chemistry and the Complex Carbohydrate Research Center (CCRC) of the University of Georgia (USA) and Professor and Chair of the Department of Medicinal and Biological Chemistry of Utrecht University (The Netherlands). Prof. Boons directs a research program focused on the synthesis and biological functions of carbohydrates and glycoconjugates. The diversity of topics to which his group has significantly contributed includes the development of new and better methods for synthesizing exceptionally complex carbohydrates and glycoconjugates. Highlights of his research include contributions to the understanding of immunological properties of complex oligosaccharides and glycoconjugates at the molecular level, which is being used in the development of three-component vaccine candidates for many types of epithelial cancer; development of convergent strategies for complex oligosaccharide assembly, which make it possible to synthesize large collections of compounds with a minimal effort for structure activity relationship studies; and creation of a next generation glycan microarray that can probe the importance of glycan complexity for biological recognition, which in turn led to identification of glycan ligands for various glycan binding proteins that are being further developed as glycomimetics for drug development for various diseases. Among others, Prof. Boons has received the Creativity in Carbohydrate Science Award by the European Carbohydrate Association (2003), the Horace Isbell Award by the American Chemical Society (ACS) (2004), the Roy L. Whistler International Award in Carbohydrate

Chemistry by the International Carbohydrate Organization (2014), the Hudson Award (2015) and the Cope Mid-Career Scholar Award from ACS (2016).

Aviceda is leading the field of glycoimmunology in exciting new directions. I look forward to working with the company as it pursues multiple lines of development efforts that will someday transform the way immune-inflammatory conditions are treated in the clinic, said Prof. Boons.

Prof. Chouaib is the Director of Research, Institute Gustave Roussy, Paris, where he is active in research in tumor biology. Previously, Prof. Chouaib worked at the French National Institute of Health and Biomedical Research (INSERM) where he led a research unit focused on the investigation of the functional cross talk between cytotoxic cells and tumor targets in the context of tumor microenvironment complexity and plasticity. His research was directed at the transfer of fundamental concepts in clinical application in the field of cancer vaccines and cancer immunotherapy. Prof. Chouaib is a member of the American Association of Immunologists, New York Academy of Sciences, French Society of Immunologists, International Cytokine Society, American Association for Cancer Research, International Society for Biological Therapy of Cancer and American Association of Biological Chemistry. He was awarded the cancer research prize of the French ligue against cancer in 1992 and in 2004 the presidential prize in biotechnology. He was awarded for translational research and scientific excellency by INSERM. His research has resulted in more than 310 scientific articles and several reviews in the field of human immunology, tumor biology and cancer immunotherapy; he has also been an editor for several textbooks.

Dr. Wu is an Associate Professor in the Department of Molecular Medicine at Scripps Research. The current research in the Wu laboratory integrates synthetic chemistry with glycobiology to explore the relevance of protein glycosylation in human disease and cancer immunotherapy. In 2018, Dr. Wu developed a platform to construct antibody-cell conjugates for cancer immunotherapy, which does not require genetic engineering. Previously, while working as a postdoctoral fellow in the group of Professor Carolyn R. Bertozzi at the University of California, Berkeley, Dr. Wu developed an aldehyde-tag (SMARTag) based technology for site-specific labeling of monoclonal antibodies, which served as the foundation for Redwood Biosciences Inc., a biotech company co-founded by Bertozzi. In 2014, Redwood Bioscience Inc. and the SMARTag Antibody-Drug Conjugate technology platform was acquired by Catalent Pharma Solutions.

About Aviceda Therapeutics

Founded in 2018 and based in Cambridge, Massachusetts, Aviceda Therapeutics is a late-stage, pre-clinical biotechnology company with a mission to develop the next generation of glyco-immune therapeutics (GITs) utilizing a proprietary technology platform to modulate the innate immune system and chronic, non-resolving inflammation. Aviceda has assembled a world-class, cross-disciplinary team of recognized scientists, clinicians and drug developers to tackle devastating ocular and systemic degenerative, fibrotic, oncologic and immuno-inflammatory diseases. At Aviceda, we exploit a unique family of receptors found expressed on all innate immune cells and their associated glycobiological interactions to develop transformative medicines. Combining the power of our biology with our innovative cell-based high-throughput screening platform and proprietary nanoparticle technology, we can modulate the innate immune response specifically and profoundly. Aviceda is developing a pipeline of GITs that are delivered via biodegradable nanoparticles and which safely and effectively target numerous immune-inflammatory conditions. Avicedas lead ophthalmic optimized nanoparticle, as an intravitreal formulation, AVD-104, is being developed to target various immune system responses that contribute to pathology associated with age-related macular degeneration (AMD).

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Aviceda Therapeutics Announces Formation of Scientific Advisory Board - BioSpace

Remdesivir approved by FDA to treat Covid-19, but the evidence is mixed – Vox.com

The Food and Drug Administration on Thursday gave its first full approval for a drug to treat Covid-19 to the antiviral remdesivir. But some researchers say the FDA is once again promoting a Covid-19 therapy based on shaky evidence.

Developed by Gilead Sciences and marketed under the brand name Veklury, remdesivir previously received emergency use authorization (EUA) from the FDA in May, which allowed it to be used to treat patients with severe Covid-19. In August, the FDA relaxed its guidelines to allow the drug to be used in less serious cases. President Donald Trump also took the drug as part of his treatment when he was diagnosed with Covid-19 earlier in October.

Full FDA approval promotes remdesivir to the standard of care for hospitalized patients, and other potential treatments for Covid-19 will now have to be compared to it during clinical research.

Todays approval is supported by data from multiple clinical trials that the agency has rigorously assessed and represents an important scientific milestone in the Covid-19 pandemic, FDA commissioner Stephen Hahn in a statement Thursday. The FDA based its decision on three randomized controlled trials. (The largest of those looked at 1,062 hospitalized patients.) The trials results showed that remdesivir reduced the length of hospital stays in some Covid-19 patients.

However, shortly before the approval was granted, a study from the World Health Organization announced preliminary results that found the drug had no effect on mortality and unlike the FDAs findings negligible effects on how long patients were in hospitals. The study, known as the Solidarity Trial, recruited almost 12,000 patients, making it the largest Covid-19 treatment study in the world thus far. Researchers say the findings should have given the FDA pause.

I think its really inappropriate to give this a full approval because the data dont support it, said Eric Topol, a professor of molecular medicine at the Scripps Research Translational Institute. What [the FDA] should have done instead of issuing the approval was put on the brakes.

Absent a vaccine, doctors are desperate for an effective treatment for Covid-19, and the FDAs approval of remdesivir finally gives them an option. In the United States, Covid-19 case counts are rising again, with states like Wisconsin opening field hospitals to deal with a looming surge.

But the approval of remdesivir has raised concerns, not only because of the results of the WHOs trial but also because it follows a number of questionable FDA authorizations for other Covid-19 therapies that appear to have been influenced by political pressure from the White House.

Now some researchers and doctors are concerned that remdesivir could not only be less effective than promised, but that its approval could also undermine other efforts to develop better Covid-19 therapies.

Remdesivir seems to be most effective relatively early on for hospitalized patients with severe Covid-19. To help beat back the illness, it interferes with how SARS-CoV-2, the virus that causes Covid-19, makes copies of itself. The virus uses genetic instructions in the form of RNA, written in a code made of molecules represented by the letters A, U, G, and C. The drug mimics the molecule represented by A, adenosine. The fake adenosine blocks the virus from copying itself but doesnt fool human cells. The result is the virus cant reproduce as much within a patients body.

The antiviral drug was originally developed to treat the Ebola virus, and it has received a hefty investment from the US government over almost two decades, as Ekaterina Cleary, lead data analyst and research associate at the Center for Integration of Science and Industry, wrote in a piece for Stat News:

Research from the Center for Integration of Science and Industry, with which I am affiliated, determined that between gathering knowledge behind remdesivirs chemical structure and molecular target, the NIH invested as much as $6.5 billion between 2000 and 2019.

Remdesivir treatment is not without risks. It has been shown to cause some side effects in some people, such as elevated liver enzymes, which could indicate liver damage. The drug can also trigger allergic reactions, resulting in fever, shortness of breath, wheezing, swelling, low blood oxygen, and changes in blood pressure.

For a patient with private insurance, the intravenous drug can cost $3,120 for a five-day course of treatment.

Antivirals like remdesivir are most effective early on during the progression of Covid-19, when most of the damage is being done by the virus itself. Its less effective in later stages, when the problem isnt just the virus. The severe manifestations of the disease are caused by an out-of-control immune response to the infection, said Angela Rasmussen, a virologist at the Columbia University Mailman School of Public Health.

If the immune system gets riled up, it can cause a lot more destruction than SARS-CoV-2 and require more-drastic interventions like intubation, at which point another approach is needed. Thats a big reason why corticosteroids like dexamethasone, which tamp down on the immune system, are the only drugs so far reliably demonstrated to actually reduce Covid-19 mortality.

But giving a patient steroids too early in an infection could prevent the immune system from mounting an effective response against SARS-CoV-2.

Coming up with an effective treatment regimen requires delicately balancing where a patient is in the course of their coronavirus infection and how severe their illness has become. But given how murky it is to identify an infection to begin with let alone confirming the diagnosis and starting the correct treatment during the appropriate window researchers have a hard time teasing out what interventions work best.

Thats why carefully controlled, large-scale clinical trials are so important. And with mixed results coming from the studies conducted to date, some scientists dont think the evidence for remdesivirs effectiveness is enough for the FDA to grant approval.

I was really surprised when I saw that news, Rasmussen said.

The FDA has already made some controversial decisions around Covid-19 drug treatments. The agency granted an EUA for the anti-malaria drug hydroxychloroquine in March, after Trump called it a game changer. The FDA revoked the EUA in June, saying hydroxychloroquine was unlikely to be effective and could cause lead to heart problems.

Then in August, the agency granted an EUA for convalescent plasma to treat Covid-19. But the National Institutes of Health said the evidence used by the FDA was insufficient.

There is more evidence that remdesivir works compared with that of convalescent plasma, but thats not saying much. Its not as weak as the case for plasma, but thats no standard. The case for plasma is nonexistent, said Jeremy Faust, attending physician in emergency medicine at Brigham and Womens Hospital in Boston and an instructor at Harvard Medical School. There is actually randomized controlled trial data that suggests [that] for a subset of patients, remdesivir can decrease hospital length of stay.

The strongest results in favor of remdesivir show that patients who received it had a median recovery time of 10 days, compared to 15 days for those who took the placebo. Its a significant effect, but its not huge, and its certainly not a cure for Covid-19, nor a way to guarantee fewer deaths.

Faust said one of his concerns with the FDAs remdesivir approval is a phenomenon known as indication creep, in which a treatment shown to work in only a limited set of circumstances gets prescribed to more and more people. The worry here is that remdesivir, which is approved only for Covid-19 patients over 12 years old who required hospitalization, could start being used in patients with milder Covid-19 illness, or in more severe cases past the point where it could be effective.

What will happen, I guarantee, is people will start to use the medication more than they need it, Faust said. Since the course of treatment is five days, it could also extend the length of hospital stays in patients who would otherwise be discharged earlier, saddling them with unnecessary costs.

Another concern is that the approval of remdesivir, especially with such mixed evidence for its effectiveness, could undermine further research.

Topol noted that with remdesivir now as the only fully approved drug, it becomes much more difficult to conduct studies on other therapies because they now have to be compared against remdesivir, the new standard treatment, as well as a a placebo.

That raises the cost and complexity of trials, delaying results. Such comparisons are worthwhile if the standard of care is effective, but it adds unnecessary complications if its not.

It also makes it harder to recruit people for subsequent clinical trials of the drug to better validate its effectiveness. People may be more reluctant to sign up for a trial where they could get a placebo when they know they could get the actual drug.

The biggest, most serious problem is that we wont get to the truth, Topol said.

Its worth noting that remdesivir could still be a viable treatment for Covid-19, but the evidence presented so far is contradictory and more investigation is needed to clarify its effectiveness. So why did the FDA go ahead with its approval, then?

Its hard to say, but Herschel Nachlis, a research assistant professor of government at Dartmouth College, suggested the approval might be a strategic move by the agency to deflect political pressure away from the all-important Covid-19 vaccination campaign. Trump has linked a vaccine to his election prospects and blamed the FDA for holding it back. The appearance that a Covid-19 vaccine was rushed to meet political needs could make people reluctant to get vaccinated, so regulators are keen to distance themselves from the 2020 election campaign.

If, in the short term, approving remdesivir gives the President a win and alleviates some pressure on the agency from the President about vaccines, that helps buy the FDA important time, Nachlis told Vox in an email. It might be another case, like convalescent plasma, of giving up some ground in a battle to put yourself in the position to be able to win the broader war.

Whether Nachliss hypothesis is correct isnt yet known. But what is clear is that the evidence on remdesivirs effectiveness appears to be mixed, which is why it would have been helpful for the FDA to have held a public advisory committee meeting to discuss the evidence, a step it typically takes for full pharmaceutical approvals.

Since it may be months before a vaccine for Covid-19 is available, treatments are still urgently needed and other approaches are being studied. Trump, for example, also underwent a course of an experimental monoclonal antibody therapy from the company Regeneron when he was treated for Covid-19. There are multiple clinical trials of these drugs underway, but now they have competition.

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Remdesivir approved by FDA to treat Covid-19, but the evidence is mixed - Vox.com

FDA Approves New FoundationOneLiquid CDx Companion Diagnostic Indications for Three Targeted Therapies That Treat Advanced Ovarian, Breast and…

FoundationOne Liquid CDx analyzes the largest genomic region of any FDA-approved comprehensive liquid biopsy test and was approved in August to provide tumor mutation profiling in accordance with professional guidelines for patients with any solid tumor. Concurrently, it was approved as a companion diagnostic for a poly (ADP-ribose) polymerase (PARP) inhibitor approved by the FDA for the treatment of metastatic castration-resistant prostate cancer patients with qualifying BRCA1/2 alterations, and for three first-line EGFR tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer patients.

FoundationOne Liquid CDx offers oncologists an important and minimally invasive tool to consider when making treatment decisions for their patients, regardless of the type of cancer they have, said Brian Alexander, M.D., M.P.H., chief medical officer at Foundation Medicine. These three additional companion diagnostic claims expand the tests clinical utility into breast and ovarian cancer, demonstrating our commitment to bringing precision medicine to more patients, and we plan to continue working with our biopharma partners to increase that reach.

Todays approval expands FoundationOne Liquid CDxs companion diagnostic indications to include the following targeted therapies:

PIK3CA is the most commonly mutated gene in HR+/HER2- breast cancer; approximately 40% of patients living with HR+/HER2- breast cancer have this mutation.1

An estimated one in four women with epithelial ovarian cancer have a mutation of the BRCA1 or BRCA2 gene.2

Using a blood sample, FoundationOne Liquid CDx analyzes over 300 cancer-related genes for genomic alterations. FoundationOne Liquid CDx results are delivered in an integrated report that identifies alterations matched to FDA-approved therapies. It also enables accelerated companion diagnostic development for biopharma companies developing precision therapeutics.

As a laboratory professional service which has not been reviewed or approved by the FDA, the FoundationOne Liquid CDx report delivers information about the genomic signatures microsatellite instability (MSI) and blood tumor mutational burden (bTMB), as well as single gene alterations, including NTRK fusions, to help inform the use of other therapies including immunotherapies. Also, as a laboratory professional service, the report provides relevant clinical trial information and includes interpretive content developed in accordance with professional guidelines in oncology for patients with any solid tumor.

About FoundationOne Liquid CDx

FoundationOne Liquid CDx is a qualitative next generation sequencing based in vitro diagnostic test for prescription use only that uses targeted high throughput hybridization-based capture technology to analyze 324 genes utilizing circulating cell-free DNA (cfDNA) isolated from plasma derived from anti-coagulated peripheral whole blood of advanced cancer patients. The test is FDA-approved to report short variants in over 300 genes and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies (listed in Table 1 of the Intended Use) in accordance with the approved therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Patients who are negative for companion diagnostic mutations should be reflexed to tumor tissue testing and mutation status confirmed using an FDA-approved tumor tissue test, if feasible. For the complete label, including companion diagnostic indications and complete risk information, please visit http://www.F1LCDxLabel.com.

About Foundation Medicine

Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patients cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicines molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit http://www.FoundationMedicine.com or follow Foundation Medicine on Twitter (@FoundationATCG).

Foundation Medicine and FoundationOne are registered trademarks of Foundation Medicine, Inc.

PIQRAY is a registered trademark of Novartis AG.

RUBRACA is a registered trademark of Clovis Oncology, Inc.

ALECENSA is a registered trademark of Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.

Source: Foundation Medicine

1 The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.2 Pennington et al, Clin Cancer Res. 2014; 20(3):764-7753 Dearden et al. Ann Oncol. 2013 Sep; 24(9): 23712376.

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How Many Have Recovered From Covid-19 Cases? No One Knows. – msnNOW

Gabriela Bhaskar for The Wall Street Journal Coronavirus recoveries are undercounted in public-health statistics.

Health researchers collect various pieces of Covid-19 data to get a handle on the spread of the new coronavirus, but one metric has proven tough to pin down: how many infected people have recovered.

Among the 8.8 million coronavirus cases reported in the U.S. so far, some 3.5 million have recovered, according to Johns Hopkins University, which tracks the pandemic.

Yet the tally of recovered Covid-19 patients misses the mark, health experts say, while also failing to capture the many people who are struggling with lingering medical issues from their cases.

The data are so spotty, public-health authorities say they dont know what the true count is. The national figure displayed on trackers likely misses the true count by millions, estimates Ashish Jha, dean of the Brown University School of Public Health.

The spottiness stems from the absence of both an agreed-upon definition for a coronavirus recovery and a standardized way to track the numbers of patients, the health experts say. What constitutes recovery is so nebulous that some states dont even track it, and those that do probably undercount the true number.

Im not aware of anyone using the recovery figures, said Marcus Plescia, chief medical officer of the Association of State and Territorial Health Officials. Ive seen that data, and Ive not paid attention to them.

The lack of clarity means the popular picture of Covid-19s toll misses a datapoint indicating that most infected people have overcome the illness. And it highlights the challenges in assembling data that would help health authorities track the virus and help people fight it.

Like a lot of these issues with data reporting for Covid, theres really not a clear standard for how to do it, said Lauren Gardner, a Johns Hopkins University associate engineering professor who leads the team that built the schools widely cited Covid-19 dashboard.

Both the general public and many health professionals tend to consider patients recovered if they feel the way they did before they became ill. Yet many states define coronavirus recovery differently.

These states count a Covid-19 case as a recovery simply because time has passed since a person developed symptoms or was discharged from the hospital.

Michigan defines recovered cases as the number of people with a confirmed Covid-19 diagnosis who are alive 30 days after getting symptoms. Texas estimates recoveries under a complex formula that subtracts deaths and certain other cases, and assumes it takes 32 days for hospitalized patients to recover and 14 days for nonhospitalized patients.

Such measurements might indicate how many people who tested positive for the coronavirus didnt die, but might miss those who never displayed symptoms and didnt undergo testing.

The metrics also miss the viruss individual impact, according to health experts. While some patients bounce back quickly, others can struggle with side effects for weeks or even months.

There is a variable path after people get sick, said Eric Topol, a cardiologist and professor of molecular medicine at the Scripps Research Institute. There are people who are still ill months after they get sick. We know those symptoms can be very severe, and people can be debilitated.

Given the complexities, some states dont try to count how many have recovered from Covid-19.

The California Department of Public Health said assessing who is recovered is too subjective, and the persistence of side effects in a subset of Covid-19 patients known as long-haulers makes it hard to get a good count.

The Florida Department of Health also doesnt provide a specific recovery metric. It said relying on hospital discharges or estimating length of illness doesnt capture recovery.

Without data from every state and accurate figures from states reporting data, the recovery numbers given by Covid-19 trackers available online are useless for assessing how many people have recovered, said Jennifer Nuzzo, an epidemiologist and senior scholar at the Johns Hopkins Center for Health Security.

Dr. Nuzzo said she doesnt know what the true number of recovered patients is.

Covid-19 trackers get their recovery figures from states that are reporting the numbers. Alexis Madrigal, a founder of the widely cited Covid Tracking Project, said he has sometimes wanted to stop recording recoveries because of too much imprecision in what constitutes a recovery and in tallying them.

Most recovery definitions are not what they purport to be or what people expect, said Mr. Madrigal, who is also a staff writer at The Atlantic magazine.

Donna Bourne, of Shelby, Ohio, got sick and tested positive for Covid-19 in late March. Seven months later, she said, she still struggles with fatigue and severe shortness of breath climbing the stairs in her home. She uses her asthma inhaler every day, as opposed to once a week before getting Covid-19. She now also has an irregular heartbeat, recall problems and sometimes drools because the lower part of her face is partially paralyzed.

Despite her continued health issues, she fits the description of presumed recovered in Ohio, because she is still alive more than 21 days since she first developed symptoms.

Your body just does not recover from Covid the way it would from the flu, said Ms. Bourne, 55 years old, who was recently furloughed from her job assisting workers with disabilities. Its really, really hard on you.

Many state and local health departments ignore recovery tallies in gauging the progress of the pandemic.

Without a standard definition of Covid-19 recovery, there isnt a way to compare data between counties or cities, or to tell how well people living in these places are recovering, said Oscar Alleyne, chief of programs and services for the National Association of County and City Health Officials.

What health authorities could use is a figure capturing how people infected with Covid-19 are faring over time, Dr. Alleyne said. Armed with such data, public-health departments would be better equipped to write guidelines for treatment and allocate the resources that doctors and patients need, he said.

Write to Sarah Toy at sarah.toy@wsj.com

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COVID-19 in the continent’s children: UK award supports new research – University of Cape Town News

Professor Heather Zar, the chair of the Department of Paediatrics and Child Health and the director of the South African Medical Research Council Unit on Child and Adolescent Health at the University of Cape Towns(UCT) Faculty of Health Sciences, is spearheading a research project that is one of 12 globally to receive a recent COVID-19 grant.

The National Institute for Health Research / United Kingdom Research and Innovation Global Effort on COVID-19(NIHR/UKRI GECO) grant is a collaborative funding opportunity. Under Professor Zar as the project leader, the study will offer a unique opportunity to understand the determinants of severe acute respiratory syndrome coronavirus2(SARS-CoV-2) infection and coronavirus disease(COVID-19) in children in Africa in a low-middle-income country(LMIC) context. The award will enable Zar and her team to undertake a study titled Spectrum, determinants and long-term outcome of SARS-CoV-2 infection and disease in African children.

The reasons children typically develop mild illness or have asymptomatic infection are poorly understood. In LMICs, where children make up a large proportion of the population, risk factors such as malnutrition, HIV exposure, tuberculosis or prior infection with endemic coronaviruses may have an impact on the risk of infection and development of COVID-19.

This project aims to investigate the spectrum of illness in African children, the risk factors for infection or disease, and the immune or inflammatory factors protecting children against SARS-CoV-2 infection or severe COVID-19 disease.

Zar is collaborating with partners at the universities of Western Australia and Southampton in the United Kingdom for this research.

COVID-19 infection in African children

This funding provides a wonderful opportunity to better understand COVID-19 in African children in an LMIC context, she said.

This is particularly relevant because of the high burden of pneumonia, which continues to be the major single killer of children under five years of age, due to factors such as malnutrition, smoke exposure and the high burden of infectious disease in these settings.

Understanding why children are only mildly affected may be key to developing new strategies to prevent or ameliorate illness.

However, this hasnt occurred with COVID-19, said Zar, who is an affiliate member of the Institute of Infectious Disease and Molecular Medicine(IDM) at UCT. Surprisingly, children in LMICs and globally are predominantly only mildly affected by COVID-19, with relatively few severe cases or deaths occurring in young children. The current project will investigate whether prior infection with other organisms (including seasonal coronaviruses) protects children against severe disease through development of immunity.

Understanding why children are only mildly affected may be key to developing new strategies to prevent or ameliorate illness, said Zar.

Drakenstein Child Health Study

Whitney Barnett, the projects programme manager, said that this funding will offer researchers the additional focus of investigating COVID-19 across different settings, ranging from communities to hospitals. SARS-CoV-2 infection will be investigated in children who are hospitalised with pneumonia as well as in children who are part of the population-based Drakenstein Child Health Study(DCHS), anovel African birth cohort study, which is led by Zar.

The DCHS has comprehensively investigated the early-life determinants of child health, and developmental pathways to health or disease from pregnancy through childhood so it provides a unique platform to study COVID-19 in children, and the impact of the pandemic on child health.

It is especially important to be able to do this study here because children make up a high proportion of the population.

The DCHS also bridges the intersection of infectious diseases and the emergence of non-communicable diseases, Zar said.

It is especially important to be able to do this study here because children make up a high proportion of the population, and risk factors such as malnutrition, pollution, poverty and a high burden of infections may contribute to their vulnerability to developing illness.

She added that the context of the DCHS offers further understanding of COVID-19-related childhood illness, including the protective or risk factors for infection or disease that have been carefully measured from the antenatal period through childhood, and the role of inflammation.

As a child health specialist in respiratory illness, Zar said that this will inform future research and healthcare approaches and provide a unique opportunity to generate new knowledge, identify risk factors for illness and develop novel strategies for prevention and treatment.

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COVID-19 in the continent's children: UK award supports new research - University of Cape Town News

FoundationOneCDx Receives FDA-Approval as a Companion Diagnostic for VITRAKVI(larotrectinib) to Identify Patients with NTRK Fusions Across All Solid…

Foundation Medicine, Inc. today announced that it has received approval from the U.S. Food and Drug Administration (FDA) for FoundationOneCDx to be used as a companion diagnostic for VITRAKVI (larotrectinib), which is currently FDA-approved for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. FoundationOne CDx, the only FDA-approved tissue-based comprehensive genomic profiling (CGP) test, is now approved to detect NTRK1/2/3 fusions across all solid tumor types and identify patients who may be appropriate for treatment with VITRAKVI.

NTRK fusion positive cancer occurs when a piece of the chromosome containing the NTRK gene breaks off and binds to another chromosome. These NTRK gene fusions produce TRK fusion proteins, which may cause cancer cells to grow.1 NTRK fusions are more commonly found in rare cancer types, such as secretory carcinoma of the breast or salivary gland and infantile fibrosarcoma, but they can also occur across many more common cancer types including glioma, melanoma and carcinomas of the lung, thyroid and colon.2

"Taking a comprehensive and validated approach to genomic testing is critical for all advanced cancer patients, but especially for those harboring rare mutations that can be missed with alternative testing methods," said Brian Alexander, M.D., M.P.H., chief medical officer at Foundation Medicine. "Not only will this approval improve access to genomic testing and reinforce the role it plays in rare cancers, but it also confirms the incredible progress made toward tumor-agnostic cancer care. We're proud of the impact this will have on NTRK fusion positive cancer patients."

FoundationOne CDx is the first FDA-approved broad companion diagnostic that is clinically and analytically validated for solid tumors. The tissue-based comprehensive genomic profiling test is currently approved as a companion diagnostic for more than 20 targeted therapies.

"Many patients with rare conditions, like NTRK fusion positive cancer have limited treatment options and poor access to targeted therapies," said Susan Spinosa, co-chair and patient founder of the NTRKers. "This companion diagnostic approval is a critical step forward in addressing this challenge as it provides this patient population with broader access to comprehensive genomic testing and appropriate treatment options."

The approval of VITRAKVI was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate (ORR) and response duration, as determined by a blinded independent review committee according to RECIST 1.1. The clinical validation to support the FoundationOne CDx NTRK companion diagnostic approval was then achieved through a clinical bridging study between the local clinical trial assays and FoundationOne CDx.

About FoundationOne CDx

FoundationOne CDx is a next-generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. FoundationOne CDx is for prescription use only and is intended as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with their approved therapeutic product labeling. Additionally, FoundationOne CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy. For a full list of targeted therapies for which FoundationOne CDx is indicated as a companion diagnostic, please visit http://www.foundationmedicine.com/genomic-testing/foundation-one-cdx.

About Foundation Medicine

Foundation Medicine is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patient's cancer and match them with relevant targeted therapies, immunotherapies and clinical trials. Foundation Medicine's molecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visit http://www.FoundationMedicine.com or follow Foundation Medicine on Twitter (@FoundationATCG).

Foundation Medicine and FoundationOne are registered trademarks of Foundation Medicine, Inc.

Vitrakvi is a registered trademark of Bayer

Source: Foundation Medicine

1 National Cancer Institute. "NTRK Gene Fusion." https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ntrk-gene-fusion

2 "Annals of Oncology. "Identifying patients with NTRK fusion cancer" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859817/

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FoundationOneCDx Receives FDA-Approval as a Companion Diagnostic for VITRAKVI(larotrectinib) to Identify Patients with NTRK Fusions Across All Solid...

The body fires ‘blobs of fat’ packed with toxic proteins to fight bacteria – Live Science

The human body uses many tactics to fight invaders. Scientists just found another weapon in its arsenal: tiny fat blobs packed with toxic proteins that are fired at the enemy.

Complex organisms including fungi, plants and animals are made up of eukaryotic cells that contain subcellular structures called organelles. These organelles all work together to keep the cells functioning; the nucleus, for example, is the brain of the cell and lipid droplets (LDs) are teeny blobs of fat that store and provide fuel for the cell when needed.

Lipid droplets are usually attached to the mitochondria an organelle that generates most of the cell's energy and serve as a source of fuel when needed. Previous research has found that certain parasites, viruses and bacteria steal these droplets and also use them to fuel growth. So until now, scientists thought that these lipid droplets supported infection, the authors wrote in a new study published Oct. 15 in the journal Science.

Related: 5 ways gut bacteria affect your health

"It was previously thought that bacteria were merely using the lipid droplets to feed on, but we have discovered these fatty droplets are involved in the battle between the pathogens and our cells," co-author Robert Parton, head of the cell biology and molecular medicine division of the University of Queensland's Institute for Molecular Bioscience in Australia, said in a statement. Previously, scientists found that exposing fruit flies to a microbe induced formation of lipid droplets with antimicrobial activity, according to an accompanying commentary in the journal Science.

Parton and his team wanted to see whether this strange battle technique also existed in mammalian cells. They injected mice with lipopolysaccharide, a toxin that's produced by bacteria. The toxin spurred threatened cells in the mice's liver to produce more lipid droplets and increase the size of existing ones, according to the study.

In cells infected with the toxin, threatened cells packed lipid droplets with hundreds of antiviral and antibacterial proteins.The scientists also found that the droplets detached from the mitochondria and moved toward the bacterial toxin.

"Fat is part of the cell's arsenal cells manufacture toxic proteins, package them into the lipid droplets, then fire them at the intruders," Parton said. "This is a new way that cells are protecting themselves, using fats as a covert weapon, and giving us new insights into ways of fighting infection."

The researchers also saw a similar response when they exposed human macrophages a type of white blood cell that helps detect and destroy pathogens and problem cells to the bacterial toxin in the lab. Now, Parton and his team hope to figure out how the lipid droplets actually target the bacteria, he said in the statement. "By understanding the body's natural defenses, we can develop new therapies that don't rely on antibiotics to fight drug-resistant infections."

Though scientists are just discovering this defense strategy now, these droplets were first discovered more than 130 years ago, and they are present in all types of eukaryotic cells, according to the commentary.

"There is great and justifiable excitement regarding the functions of LDs and other membraneless organelles," and how they change in many cellular processes, Douglas Green, the chair of the immunology department at St. Jude Children's Research Hospital in Tennessee, wrote in the accompanying commentary. "We have much to learn about these drops of oil in cells."

Originally published on Live Science.

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The body fires 'blobs of fat' packed with toxic proteins to fight bacteria - Live Science

Study shows a molecular dance that keeps your heart beating – WSU News

A microscope photograph of a heart muscle cell. The regular green patterns show stained actin filaments.

By Tina Hilding, Voiland College of Engineering and Architecture

It might look like a little game at the molecular scale.

Filament-like proteins in heart muscle cells have to be exactly the same length so that they can coordinate perfectly to make the heart beat.

Another protein decides when the filament is the right size and puts a wee little cap on it. But, if that protein makes a mistake and puts the cap on too early, another protein, leiomodin, comes along and knocks the cap out of the way.

This little dance at the molecular scale might sound insignificant, but it plays a critical role in the development of healthy heart and other muscles. Reporting in the journal, Plos Biology,a WSU research team has proven for the first time how the mechanism works.

The finding could someday lead to improved diagnostics and medical treatments for serious and sometimes devastating hereditary heart conditions that come about from genetic mutations in the proteins. One of these conditions, cardiomyopathy, affects as many as one in 500 people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects skeletal muscles throughout the body with often devastating consequences.

Mutations in these proteins are found in patients with myopathy, saidAlla Kostyukova, associate professor in the Gene and LindaVoiland School of Chemical Engineering and Bioengineeringand leader of the project. Our work is to prove that these mutations cause these problems and to propose strategies for treatment.

Heart muscle is made of tiny thick and thin filaments of proteins. With the help of electrical signals, the rope-like filaments bind and unbind in an intricate and precise architecture, allowing heart muscle to contract and beat.

The thin filaments are made of actin, the most abundant protein in the human body. Tropomysin, another protein, wraps itself around the actin filaments. Tropomyosin together with two other proteins, tropomodulin and leiomodin, at the end of the actin filaments act as a sort of cap and determine the filament length.

Its beautifully designed, said Kostyukova, whose research is focused on understanding protein structures.

And, tightly regulated.

To keep heart muscle healthy, the actin filaments, which are about a micron long, all have to be the exact same length. In families with cardiomyopathy, genetic mutations result in formation of filaments that are either too short or too long. Those affected can have significant heart problems that cause disability, illness and death.

In a project that spanned seven years, the researchers proved that leiomodin attaches to the end of the actin filament and kicks out the other protein, tropomodulin, to assure the actin filaments proper length.

This is the first time that this has been shown with the atomic-level precision, said Dmitri Tolkatchev, research assistant professor in the Voiland School and lead author on the paper. Previously, several laboratories attempted to solve this problem with very little success. With our data we finally have a direct proof.

The researchers used state-of-the-art approaches to make the key proteins and study them at the molecular and cellular level. The work entailed designing the molecules, constructing them at the gene level in a plasmid, and then producing them into bacterial or cardiac cells. The researchers used nuclear magnetic resonance, which works on the same physical principle as Magnetic Resonance Imaging (MRIs), to understand the proteins binding at the atomic level. They also used molecular dynamic simulation to model them.

The probability of being able to show this mechanism was not high, but the impact of the discovery is, said Tolkatchev, an expert in nuclear magnetic resonance. This was a very important problem to study and could have a significant impact in the field of muscle mechanics.

The researchers hope to continue the work, identifying additional components and molecular mechanisms that regulate thin filament architecture, whether diseased or healthy.

The multidisciplinary group included researchers from the University of Arizona led by Carol Gregorio, director of the Cellular and Molecular Medicine Department. WSUs group has expertise in protein structure, structural biochemistry, and properties of actin filaments and regulatory proteins, and UAs group has expertise in molecular, cellular and developmental biology of muscle assembly. The collaborative work was funded by the National Institutes of Health.

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Invitae CEO on how COVID-19 testing could have a positive impact on the future of genetics testing – Report Door

Invitae CEO Sean George joins Yahoo Finances on the move to talk about how Invitae is bringing genetic testing and information into mainstream discussions.

JULIE HYMAN: Im watching shares of Invitae, which have just about tripled this year. We are joined now by the CEO, Sean George, from San Francisco. Sean, thanks for joining us. You guys do diagnostic testing and you dont do it for COVID specifically, but you do it for a host of other diseases. And weve obviously seen COVID-19 testing really expand. You can drive up and get it in places. There are now going to be at-home tests that are going to be introduced. Do you think that this then gets people more comfortable with testing for a range of different diseases? Or are you hoping that it does?

SEAN GEORGE: Well, I think it does. And I think in general, trend of the last decade or so is people are starting to understand that this diagnostic information is very useful in advance of when theres an actual problem. Obviously, people are now getting very familiar with COVID testing, what it could have done prior to, and certainly during an outbreak and to manage it.

And when you think about how fundamental in an individuals genomic information is for their health, the idea is starting to catch hold with more and more people, especially generalists, and the idea that genetic information used at the right time, ahead of time, at every stage in life, has profound implications on an individuals health.

ADAM SHAPIRO: So these kinds of tests, we keep hearing in relation to COVID, the issue of false positives. But putting that to the side, in the traditional diagnostic models, whats an accepted, if there is, metric, for when youre going to get a false positive or false negative? How does the industry deal with that issue?

SEAN GEORGE: Right, and especially in medical genetics, that threshold is very, very, very, very tight. Its exacting on 99 and a few nines of how the percentage of sensitivity and specificity these tests need to have because of the profound implications of genetics. Whether its dealing with cancer, cardiovascular disorders, pediatric disorders, battling cancer as 45 million people are per year in the markets we serve, and to answer those fundamental questions and then take concrete medical next steps. The sensitivity specificity, the precision of the tests need to be extraordinarily high.

Story continues

BRIAN CHEUNG: Hey, Sean, Brian Cheung here. So for those that maybe arent that well versed in this type of science, explain to us exactly where you fit in the business world of things that might be tangentially related to genetic testing. I mean, do you guys work with say CRISPR firms or types of, I guess, diagnostic or treatment relative to businesses in that space? Where does your business fit in that universe?

SEAN GEORGE: I think the way to think about it, the people who, certainly anybody who has had an introduction or a brush with genetics and the health care, their clinician, were the number one brand in medical genetics around the globe. Their clinician certainly knows us and has been working with us for many years. And again, whether thats to diagnose any number of 1,000 rare disorders, to help an individual understand their prognosis and next best steps for cancer treatment.

Certainly around reproductive health. You may have heard carrier screening or non-invasive prenatal screening. Those are the kind of tests that we do. And we primarily do it with your clinician. Certainly up until now, mostly the specialists of the world, the medical genetics, the various conditions. Like I said, there are thousands. Ever increasingly, as we have dramatically driven down the price of the, weve driven down the cost of this testing by almost two orders of magnitude over the last 10 years.

And ever increasingly, generalists are starting to use this information. Theyre becoming more comfortable with it. We have tools and front end capabilities to allow clinicians to use the information without the deepest of knowledge around each individual gene, around each individual condition. And have tools online to follow the patients, follow up on their results, make sure they understand what the next best step is, and really support the clinician, the patient with the use of genetics in mainstream medical care.

JULIE HYMAN: And Sean, when were talking about genetics testing, is it mostly probability testing, particularly for cancers when you talk about carrier testing that youre at X percent risk for developing a certain disorder? Or is genetics testing also increasingly being used for actual diagnosis?

SEAN GEORGE: The kind of testing we specialize, the kind of testing put into play by most clinicians, medical geneticists, is a little more precise than just a very slight probability increase over average risk. These are, carrier screens, you mentioned, this will tell you whether you and your partner are carrying different conditions. It will tell you what are the odds specifically of having a child who might be affected by the condition. Or if you were to have a child, what would the odds be.

Ill take, for example, some of the cardiovascular diseases or cancer genetic diseases. If you have some of these genes that are affected, your risk is 30 to 80 times the population average risk of these conditions. So its quite prognostic. Now like I said, when you do get an answer, it really helps to diagnose the condition far earlier than you would otherwise be able to without the use of genetics.

And then depending on the disease, there are a variety of next steps, all the way from preventive approaches to therapies. And we work with over 100 biopharmaceutical partners too, who have therapies that are specifically targeted against genetic conditions that we can introduce our patients to as early as possible.

JULIA LA ROCHE: Sean, this is such a fascinating discussion, what youve been bringing up, and youre talking about the next best action. And its such an interesting way to look at health care, especially looking at it from preventative as well, or even just having a better understanding of your genetics and what it could mean or what the outcomes can be. I guess for you, if we could just kind of step back, what is the moonshot for you when it comes to your business and the broader health care system?

SEAN GEORGE: And in fact, were kind of, Im not sure at what inning we are in of that moonshot, I think its probably early, first or second. But the real idea, and when we founded the company, it was a simple idea. Genetics is so impactful for health care on an individual basis, yet is sparingly used at all in modern health care around the globe. The moonshot is really to have an individuals genome available, managed on their behalf, so that information can be put into play at the right point, at the right time, with all of the people around them that can help put that information to use for their health.

So for example, upon birth. 3% of live births end up in the NICU or the PICU because of genetic conditions. Having that information instantaneously would dramatically improve the outcome of the children in that situation. Some 20% to 30% of populations primary health care complaint over their lives will be genetic in nature.

Knowing that ahead of time instead of after years and years and years of symptoms kind of popping up and then getting worse over time and finally getting diagnosed, knowing ahead of time can greatly improve the preventive measures taken. I think we will in five to 10 years, we will look back in horror thinking that women had children, started families without accessing the fundamental genetic information that can introduce so much risk along the way, either for the women themselves during carrying to term, and then certainly upon delivery.

And I think cancer is another example. Its one of the more advanced conditions when considering molecular medicine. I think again, in 10 years well look back, and the idea that we didnt access the fundamental information about a persons genetic background and the genomics of the cancer itself to precision tailor treatment to them, I think well look back and wonder why we didnt do it faster.

But again, a big problem with that has been cost in the past, and weve taken care of that and are continuing to work on it. So I think across all stages in life, were about to see here in the next decade this genetic information to be used almost as a medical utility. Again, and our aim is, the moonshot is to across all stages of life, all the way from birth until youre dealing with aging and senescence.

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Invitae CEO on how COVID-19 testing could have a positive impact on the future of genetics testing - Report Door

Researchers Unravel the Network of Molecules That Influence COVID-19 Severity – SciTechDaily

Evgenia Shishkova, assistant staff scientist from the Coon Lab. Credit: Morgridge Institute for Research

While most COVID-19 cases are asymptomatic or mild, severe complications associated with acute respiratory distress have led to more than one million deaths worldwide in just several months.

Researchers from the Morgridge Institute for Research, the University of Wisconsin-Madison, and Albany Medical College sought to better understand the molecular factors that drive the severity of COVID-19, and offer insight into treatment options for those with advanced disease.

The collaborative study published online in Cell Systems identified more than 200 molecular features that strongly correlate with COVID-19 severity.

To my knowledge, this the largest outcome study, says Dr. Ariel Jaitovich, a pulmonary and critical care physician at Albany Medical Center. I know that there are some large studies focused on the diagnostics (infected versus non-infected). We have a large group of just COVID patients, but with a very granular difference in terms of severitythat is something that I hadnt seen.

The team analyzed 102 blood samples from patients diagnosed with COVID-19, and 26 samples from patients with acute respiratory distress syndrome (ARDS) but negative for COVID-19 as controls.

I felt like we had a unique opportunity with Ariels cohort that he had recruited. It was very early in the COVID epidemic here in the United States, so he was really out on the forefront of getting these types of samples from the clinic, says Josh Coon, Morgridge metabolism investigator and professor of biomolecular chemistry at the UW-Madison School of Medicine and Public Health.

Using methods in mass spectrometry, RNA sequencing, and machine learning, the researchers explored a database of more than 17,000 different proteins, metabolites, lipids, and RNA transcripts associated with clinical outcomes.

They identified 219 molecules and genes that influence blood coagulation, vessel damage, inflammation, and other biological process reported to play a role in severe disease.

We had to think hard about how to actually compare it to the existing data, says Ron Stewart, Morgridge investigator and associate director of bioinformatics whose team was tasked with analyzing the transcriptome data. What weve largely found is we recapitulated prior work, which is good.

One particularly unique aspect to the study, which contributed to the robust dataset, was the teams use of plasma samples.

Most of the research done in proteomics, the blood samples use the serum fraction that doesnt have the clotting factors, says Jaitovich. This is very important because patients with COVID-19 have accelerated clotting activity.

A metabolite called citrate is used as a therapeutic anticoagulant to decrease the likelihood of developing clotting. Yet the study revealed that the presence of metabolic citrate decreased as patients presented with more severe illness.

The fact that citrate is reduced in these patients will potentially indicate that the reduction facilitates the hypercoagulation phenotype that we found in these patients, says Jaitovich.

Another molecule possibly contributing to hypercoagulation in severe COVID-19 is a protein called gelsolin, which is normally released as a response to inflammation due to cellular injury or infection. Gelsolin was also reduced in the plasma samples from people with severe disease.

In addition to biomarkers associated with hypercoagulation, the team also identified a cluster of proteins involved with blood vessel damage, with higher abundance in severe COVID-19 samples.

There are all these factors upstream of the process that are actually being changed, that you need to address as much as just the process of clotting in order to manage this phenotype, says Evgenia Shishkova, assistant staff scientist in the Coon Lab.

The analysis also revealed increased levels of proteins and upregulated genes involved in neutrophil degranulation, which has been associated inflammation, thrombosis, and the development of ARDS.

So it seems like theres this really strong interplay between the inflammatory response and probably these thrombotic events, which are also being seen in the COVID patients, saysKatie Overmyer, associate director of theLaboratory for Biomolecular Mass Spectrometry at UW-Madison.

Finally, the multi-omic analysis revealed a network of high-density lipoproteinsthe proteins APOA1 and APOA2, and a group of lipids known as plasmalogens which act as antioxidants were all lower in the severe COVID-19 cases.

These aspects were not on our radar, says Jaitovich. The ability to merge these dimensions in one single unifying narrative allowed us to make sense of stuff that was completely obscured to us.

And by identifying these various molecules, it opens up the potential for developing targeted therapeutics that may help alleviate disease.

We can offer hard data for people who are specialists in all these different areas to go and maybe learn about the prospects that what theyre thinking might have an impact on COVID, says Coon.

The researchers made the data publicly available through an interactive web tool, covid-omics.app, where the scientific community has been comparing and analyzing the data along with their own workflows.

Coon adds, I think weve tried to do our best to highlight vignettes that we think are important, but the bigger impact is probably going to come from the community being able to dig into this.

Reference: Large-scale Multi-omic Analysis of COVID-19 Severity by Katherine A Overmyer, Evgenia Shishkova, Ian Miller, Joseph Balnis, Matthew N. Bernstein, Trenton M. Peters-Clarke, Jesse G. Meyer, Qiuwen Quan, Laura K. Muehlbauer, Edna A. Trujillo, Yuchen He, Amit Chopra, Hau Chieng, Anupama Tiwari, Marc A. Judson, Brett Paulson, Dain R. Brademan, Yunyun Zhu, Lia R. Serrano, Vanessa Linke, Lisa A. Drake, Alejandro P. Adam, Bradford S. Schwartz, Harold A. Singer, Scott Swanson, Deane F. Mosher, Ron Stewart, Joshua J. Coon and Ariel Jaitovich, Accepted 5 October 2020, Cell Systems.DOI: 10.1016/j.cels.2020.10.003

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Researchers Unravel the Network of Molecules That Influence COVID-19 Severity - SciTechDaily

Curing the incurable: teaching an old drug new tricks to fight ovarian cancer – The Guardian

In May, PhD students who are funded by the Medical Research Council (MRC) were invited to enter the Max Perutz science writing award 2020 and to tell the general public why your research matters. From the many entries received, the 10 that made the shortlist covered diverse topics, including motor neurone disease, self-harm, babies experiences of pain, and bone loss resulting from space travel.

The essays were judged by the Observers Ian Tucker, the Science Museums Roger Highfield, Prof Fiona Watt from the MRC, Bristol Universitys Andy Ridgeway and the journalist and broadcaster Samira Ahmed.

At a virtual ceremony last Tuesday, the 1,500 prize was presented to the winner, Sarah Taylor from the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh for her article about her research into the influence of proteins on the effectiveness of chemotherapy.

Here we publish the winning article, described by Samira Ahmed as a terrifically told and intriguing story.

She sits in the small consulting room once again, waiting to hear the news of her latest scan. It has been a difficult journey since the last time she sat in this chair, before her most recent round of treatment began. Over a month of exhaustion, vomiting, soreness, sleepless nights and the inevitable hair loss. But this time, the chemotherapy has not been successful. After all the side effects, all the pain that she has endured, her tumour is still growing, a dark mass on her ovary. Where does she go from here? What can she do when the treatment shes pinned all her hopes on just stops working?

This situation is all too common for women with high grade serous ovarian cancer (HGSOC), a devastating form of ovarian cancer. Only 35% survive longer than five years following their diagnosis. While chemotherapy and surgery are highly effective at initially shrinking tumours, the cancer continues to fight back. Over time the tumour changes, with cells that survive treatment prevailing and replicating, passing on the protective traits that give them that survival edge. The tumour becomes completely resistant to chemotherapy, and no barrier remains to stop it from growing out of control and overwhelming the body.

However, there are groups of patients whose cancers are much more sensitive to chemotherapy treatment than others, who can be completely cured by chemotherapy. One key to this is DNA repair proteins, the tools that all cells use to protect their DNA from damage. Think of this DNA as the instruction manual for a cell, detailing how to build all the proteins the cell requires to live and carry out different functions. Cancer cells often have defective DNA repair proteins, as this allows them to adapt and grow rapidly. Strange as it may sound, this can be a good thing from our perspective! Chemotherapy kills cancer cells by attacking their DNA, and those which lack DNA repair proteins essentially forgot to bring a first aid kit they cannot fix themselves up and keep going. This means that the chemotherapy can completely kill off the cancer, so the patient will survive. This reveals gaps in the armour of this cancer, which we can exploit to help the women who need it most.

No two cancers are quite the same, even within a specific type like HGSOC. Some have completely functional DNA repair proteins. Some have defective proteins initially but can adapt and fix these. Others can make excessive amounts of the proteins to combat the effects of chemotherapy and survive. I hope that by learning what happens to these proteins as a cancer cell becomes resistant to chemotherapy, I can make new drugs to prevent the crucial DNA repair proteins from functioning, which will enable the chemotherapy to kill cancer cells more effectively.

The first question that I asked was which, if any, of these proteins are actually important for the way HGSOC reacts to chemotherapy. I used cells taken from HGSOC patient tumours and adapted to grow easily in the lab, called cell lines, which have similar properties to an actual tumour in a patient. By using cell lines taken from a selection of patient tumours, scientists can build up a picture of the similarities and differences between patient tumours. I started by assessing the growth of various cell lines when treated with a drug called carboplatin, the standard chemotherapy used to treat HGSOC. The slower the cells grow, the more effective it is as a treatment. I found that there was a lot of variation in sensitivity to carboplatin between the different cell lines unsurprising really since one of the main challenges in cancer research is how many differences there are between individuals tumours, and even between different parts of the same tumour.

Next, I set out to find the reason for these differences, looking for changes in the DNA repair proteins. I studied a database of ovarian cancer patients looking for clues on what could be going on, and found that it is common for the tumour cells to produce either abnormally high or low amounts of certain DNA repair proteins. So, I decided to measure the amount of repair proteins produced by my cell lines. I found that in the cell line that was most sensitive to chemotherapy, one of these repair proteins was almost entirely missing! This is a really good indicator that this protein could be an important factor behind repairing the damage caused by chemotherapy.

So, I had identified a protein potentially involved in chemotherapy effectiveness. What next? I wanted to confirm that this protein acts in the way I suspected within the cancer cells. I blocked the cell lines from producing the protein I was interested in, and again looked to see how sensitive to chemotherapy the cancer cells were. This confirmed my initial suspicions removing the protein made the cancer cells much more susceptible to chemotherapy!

As I am only in my first year of working on this project, there is still much to be done, but this is an exciting starting point. I certainly find it very exciting! I plan to study the mechanism used by these cancer cells to alter the amount of this repair protein, and see how smart the cancer cells are are they cheating the chemotherapy by producing more of this protein to prevent the cells from being killed? Does this result in a chemotherapy-resistant tumour? Most importantly, I would like to identify patients whose cancers have high levels of this repair protein, for whom conventional chemotherapy might be less effective, and focus on how I can help them. To tackle this problem, I would like to test drugs that block this protein from carrying out DNA damage repair, leaving the cancer powerless, unable to repair the damage inflicted by chemotherapy. My dream is that one day this will help more women to leave that consulting room feeling victorious, having beaten the odds, and able to shut the door for good on their way out.

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Curing the incurable: teaching an old drug new tricks to fight ovarian cancer - The Guardian

IBCN 2020: IBCN 2020: Molecular Correlates of Cisplatin-Based Chemotherapy Response In Muscle-Invasive Blad… – UroToday

(UroToday.com) While cisplatin-based chemotherapy is a mainstay for neoadjuvant and adjuvant treatment of patients with muscle-invasive bladder cancer (MIBC), and none of the reported biomarkers for predicting response have been implemented in the clinic thus far.

Dr. Ann Taber presented data from researchers at the Aarhus University Hospital, Denmark, where they performed comprehensive genomic, transcriptomic, epigenomic, and proteomic analysis of 300 MIBC patients treated with cisplatin-based chemotherapy to identify molecular changes associated with treatment response. Based on mutational signatures, they identified two patient groups: those characterized by mutations in a tri-nucleotide signature 5 context (SBS5) that are related to ERCC2 mutations, and those related to APOBEC mutations.

Expression data identified the basal/squamous gene expression subtype to be associated with poor cisplatin-based treatment response. Immune cell infiltration and high PD-1 protein expression was also significantly associated with treatment response; they identified a unique subset that corresponds to an immune desert, which was associated with poor treatment response (Figure 1).

Figure 1: Association of immune cell infiltration and cisplatin-based treatment response.

The authors then assigned patients to high and low genomic instability groups based on SBS5 mutations, indels, allelic imbalance and BRCA2 mutation status. Patients with high genomic instability had a response rate of 71% versus 49% for patients with low genomic instability (p = 0.007). Through further integration, they identified a group of patients with a very high response rate (80%) characterized by high genomic instability and non-basal/squamous gene expression subtype and a group of patients with a very low response rate (25%) characterized by low genomic instability and basal/squamous gene expression subtype (p<0.001, Figure 2).

Figure 2: Patient subclassification based on genomic instability and basal/squamous gene expression subtype.

The results highlight several molecular correlates of chemotherapy response. These findings are now the basis of a new clinical trial for the treatment of metastatic bladder cancer following radical cystectomy.1

Presented by: Ann Taber, Ph.D., Department of Molecular Medicine (MOMA), Aarhus University Hospital, Denmark.

Written by:Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh,at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.

References:1. Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy (TOMBOLA). ClinicalTrials.gov identifier NCT04138628.

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IBCN 2020: IBCN 2020: Molecular Correlates of Cisplatin-Based Chemotherapy Response In Muscle-Invasive Blad... - UroToday

Treadwell Announces Initiation of New Clinical Trial of CFI-400945 in Patients with Metastatic Castrate-Resistant Prostate Cancer (mCRPC) – BioSpace

NEW YORK--(BUSINESS WIRE)-- The Canadian Cancer Trials Group (CCTG) today announced the commencement of a new sub-study evaluating CFI-400945, an oral, first-in-class inhibitor of Polo-like Kinase 4 (PLK4), in patients with metastatic castrate-resistant prostate cancer (mCRPC).

We are very excited to see the initiation of this trial, that builds on preclinical work demonstrating an association between loss of the tumor suppressor PTEN, a common alteration in this disease setting, and response to CFI-400945, says Dr. Mark Bray, Treadwell Chief Scientific Officer and Co-Founder.

This is the first trial that evaluates a precision medicine approach for patients with advanced prostate cancer using liquid biopsies for genomic testing. This innovative trial design, which incorporates liquid biopsy-based biomarker evaluation, helps meet the urgent need to identify more effective therapies for men with advanced prostate cancer, said Dr. Lesley Seymour, CCTGs Director, Investigational New Drug Program and a Medical Oncologist in the Department of Oncology at Queens University.

The study is supported by the Canadian Cancer Society, Prostate Cancer Canada and the Movember Foundation through a Translation Acceleration Grant to Tak Mak (The Princess Margaret Cancer Centre), the Canadian Clinical Trials Group and a team of co-investigators from across Canada.

Our understanding of the molecular drivers of prostate cancer is increasing, and for some of these molecular variations we have few therapeutic options, says the trail study chair Dr. Aaron R. Hansen, GU Medical Oncology Site Lead Division of Medical Oncology at Princess Margaret Cancer Center. The innovative trial design of IND234 will match men with metastatic castration resistant prostate cancer with agents designed to target their specific molecular abnormalities, in order to improve their outcomes.

This sub-study is part of the IND.234 - Prostate Cancer Biomarker Enrichment and Treatment Selection (PC-BETS) Study. The primary endpoint is clinical benefit rate defined as proportion of patients who had PSA decline 50%, complete or partial objective response, or stable disease for 12 weeks.

The CCTG IND234 trial will be open at sites across Canada, for a full list of participating centers and for additional information about the study, please visit http://www.clinicaltrials.gov.

About CFI-400945

CFI-400945 is a first-in-class, oral selective and potent inhibitor of Polo-like Kinase 4 (PLK4), which regulates centriole duplication and thus mitotic progression. PLK4 is overexpressed in a variety of solid tumors and elevated expression is associated with poor clinical outcomes. Depletion of PLK4 expression in cancer cells by RNA interference leads to mitotic defects and cell death. PLK4 was identified as a drug target based on functional screening to identify vulnerabilities of genomically unstable breast cancers.

Anti-tumor activity of CFI-400945 has been shown in mice bearing human cancer xenografts, including robust tumor growth inhibition and durable tumor regression in primary tumor xenografts from breast cancer.

About Treadwell Therapeutics

Treadwell Therapeutics is a clinical-stage oncology company exploiting cancer cells vulnerabilities to develop first-in-class and best-in-class small molecules to address unmet needs in patients with cancer.

The Companys robust, internally developed pipeline includes a first-in-class PLK4 kinase inhibitor, CFI-400945 and a potentially best in class TTK inhibitor, CFI-402257 in Phase 2 studies, and CFI-402411, an oral immunomodulatory kinase inhibitor with activity toward HPK1, in Phase 1/2 studies. For more information, please visit http://www.treadwelltx.com.

About Canadian Cancer Trials Group (CCTG)

Celebrating its 40th year, the Canadian Cancer Trials Group (CCTG) is a cancer clinical trials research cooperative that runs phase I-III trials to test anti-cancer and supportive therapies in over 80 institutions across Canada and internationally. From its operations centre at Queens University, CCTG has led and participated in over 500 trials in over 40 countries aimed at improving survival and quality of life for all people with cancer. CCTG is a national program of the Canadian Cancer Society that provides core funding for the Group. To learn more about the CCTG, go to http://www.cctg.ca

View source version on businesswire.com: https://www.businesswire.com/news/home/20201019005662/en/

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Treadwell Announces Initiation of New Clinical Trial of CFI-400945 in Patients with Metastatic Castrate-Resistant Prostate Cancer (mCRPC) - BioSpace

Prop. 14: In the COVID age, can California still afford its stem cell research program? – CALmatters

In summary

Proposition 14 asks voters to spend nearly $8 billion to continue the stem cell research program at a time when the coronavirus pandemic has decimated the state budget.

For the second time in 16 years, California voters will decide the fate of the states multi-billion dollar stem cell research program that established the state as a worldwide leader.

How the times have changed.

In November, as the pandemic drags on, Proposition 14 asks voters to spend nearly $8 billion to continue the program during a period when the research environment has significantly evolved and coronavirus has battered the states budget.

The bond measure would approve $5.5 billion in bonds to keep the states stem cell research agency running and grants flowing to California universities and companies.

At least $1.5 billion would be earmarked for brain and central nervous system diseases like Alzheimers and Parkinsons. The overall cost of the bonds and their interest totals about $7.8 billion, according to the state legislative analyst. The state would pay about $260 million annually for 30 years, or about 1 percent of Californias annual budget.

Proposition 14 is essentially a repeat with a bigger price tag and a few tweaks of Proposition 71, which California voters approved in 2004 after then-President George W. Bush prohibited, on religious grounds, all federal funding of any stem cell research using human embryos.

The bond measure would approve $5.5 billion in bonds to keep the states stem cell research agency running and grants flowing to California universities and companies.

That groundbreaking measure authorized $3 billion in state bonds to create the states stem cell research agency, the California Institute for Regenerative Medicine, and fund grants for research into treatments for Alzheimers disease, cancer, spinal cord injuries and other diseases.

The institute has nearly used up its original funding, so Prop. 71s author, real estate investor and attorney Robert N. Klein II, led a new effort to get Prop. 14 on the November ballot.

This time, embryonic stem cell research is in a much different place, with federal funding no longer blocked and more funding from the biotech industry.

Voters will want to consider what Californias previous investment in stem cell research has accomplished. Its a nuanced track record.

While many scientific experts agree that Prop 71 was a bold social innovation that successfully bolstered emerging stem cell research, some critics argue that the institutes grantmaking was plagued by conflicts of interest and did not live up to the promises of miracle cures that Prop. 71s supporters made years ago. Although the agency is funded with state money, its overseen by its own board and not by the California governor or lawmakers.

The agency had done a very good job of setting priorities for stem cell research, including research using human embryos, and doling out $300 million annually to build up California as a regenerative medicine powerhouse, according to a 2013 evaluation by the National Academies of Science, Engineering and Medicine.

But the report also found that because the institutes board is made up of scientists from universities and biotech firms likely to apply for grants, board members had almost unavoidable conflicts of interest.

Because human stem cells can develop into many types of cells, including blood, brain, nerve and muscle cells, scientists have long looked to them for potential treatments for currently incurable diseases and injuries. Researchers use two types of stem cells: embryonic stem cells, derived from unused human embryos created through in vitro fertilization, and adult stem cells, which are harder to work with but in some cases can be coaxed in a lab into behaving more like embryonic stem cells.

From the start, stem cell research has been ethically charged and politically controversial because human embryos are destroyed in some types of studies. Federal restrictions on the research have waxed and waned, depending on which political party holds power. While former President Bush restricted federal money for embryonic stem cell research, former President Obama removed those restrictions.

The Trump administration has restricted government research involving fetal tissue but not embryonic stem cells. However, anti-abortion lawmakers have called on the President to once again end federal funding for embryonic stem cell research.

California-funded research has led to one stem cell treatment for a form of Severe Combined Immunodeficiency known as the bubble baby disease. Children with the rare disease dont make enough of a key enzyme needed for a normal immune system. Without treatment, they can die from the disease if not kept in a protective environment. The U.S. Food and Drug Administration is now reviewing the treatment but has not yet approved it for widespread use.

Although many of the agencys early grants were for basic science, the institute also has supported 64 clinical trials of treatments for many types of cancer, sickle cell disease, spinal cord injuries, diabetes, kidney disease and amyotrophic lateral sclerosis, commonlyknown as Lou Gehrigs disease.

A June 2020 analysis by University of Southern California health policy researchers estimated that taxpayers initial $3 billion investment in the research institute helped create more than 50,000 jobs and generated $10 billion for the states economy.

Gov. Gavin Newsom has endorsed Proposition 14, and other supporters include the Regents of the University of California, the California Democratic Party, the Juvenile Diabetes Research Foundation, patient advocacy groups like the March of Dimes, and some local politicians and chambers of commerce.

Supporters have raised more than $8.5 million, including about $2 million from billionaire Dagmar Dolby, to pass the measure, according to California Secretary of State campaign finance reports.

The passage of Proposition 71 helped save my life, Sandra Dillon, a blood cancer patient, wrote in a San Diego Union-Tribune commentary supporting Proposition 14. She wrote that she had benefited from a drug developed with Institute-funded research that has been designated by the FDA as a breakthrough therapy.

It is unimaginable to think that Californians would vote to discontinue this amazing effort I dont know where I would be or what condition I would be in if it wasnt for the investment Californians made nearly two decades ago.

I think the agencys done good work, but this was never planned to be funded forever with debt.

Lawrence Goldstein, a UC San Diego professor of cellular and molecular medicine and stem cell researcher, said the grants were instrumental in furthering his research on treatments for Alzheimers disease and that Prop. 14 will help create new jobs. The agency has funded a great deal of very important stem cell medical research thats already produced terrific results and has the prospect of saving many more lives in the decade to come, he said.

Opponents include one member of the institutes board and a nonprofit that advocates for privacy in genetic research. They contend that the proposition seeks too much money and does not sufficiently address the conflicts of interest that cropped up after Prop. 71 was passed. They also note that private funding, including venture capital, for stem cell research has grown in recent years. Opponents had raised only $250 by late September, from a single contribution by the California Pro Life Council.

The editorial boards of some of Californias biggest newspapers also have opposed the measure, including the Los Angeles Times, the Orange County Register, the San Francisco Chronicle and the San Jose Mercury News/East Bay Times. The Fresno Bee, Modesto Bee, and San Luis Obispo Tribune newspaper editorial boards support Prop 14.

Jeff Sheehy, the only institute board member not to support Proposition 14, told CalMatters that the research environment has changed since voters initially approved state funding for stem cell research in 2004 and that California should prioritize other needs like education, health care, and housing.

I think the agencys done good work, but this was never planned to be funded forever with debt, Sheehy said. At this point the state cant afford it; were looking at a huge deficit.

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Prop. 14: In the COVID age, can California still afford its stem cell research program? - CALmatters

Identification of a prognostic gene signature based on an immunogenomic landscape analysis of bladder cancer. – UroToday

Cancer immune plays a critical role in cancer progression. Tumour immunology and immunotherapy are one of the exciting areas in bladder cancer research. In this study, we aimed to develop an immune-related gene signature to improve the prognostic prediction of bladder cancer. Firstly, we identified 392 differentially expressed immune-related genes (IRGs) based on TCGA and ImmPort databases. Functional enrichment analysis revealed that these genes were enriched in inflammatory and immune-related pathways, including in 'regulation of signaling receptor activity', 'cytokine-cytokine receptor interaction' and 'GPCR ligand binding'. Then, we separated all samples in TCGA data set into the training cohort and the testing cohort in a ratio of 3:1 randomly. Data set GSE13507 was set as the validation cohort. We constructed a prognostic six-IRG signature with LASSO Cox regression in the training cohort, including AHNAK, OAS1, APOBEC3H, SCG2, CTSE and KIR2DS4. Six IRGs reflected the microenvironment of bladder cancer, especially immune cell infiltration. The prognostic value of six-IRG signature was further validated in the testing cohort and the validation cohort. The results of multivariable Cox regression and subgroup analysis revealed that six-IRG signature was a clinically independent prognostic factor for bladder cancer patients. Further, we constructed a nomogram based on six-IRG signature and other clinicopathological risk factors, and it performed well in predict patients' survival. Finally, we found six-IRG signature showed significant difference in different molecular subtypes of bladder cancer. In conclusions, our research provided a novel immune-related gene signature to estimate prognosis for patients' survival with bladder cancer.

Journal of cellular and molecular medicine. 2020 Oct 13 [Epub ahead of print]

Yongwen Luo, Liang Chen, Qiang Zhou, Yaoyi Xiong, Gang Wang, Xuefeng Liu, Yu Xiao, Lingao Ju, Xinghua Wang

Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC, USA.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33048468

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Identification of a prognostic gene signature based on an immunogenomic landscape analysis of bladder cancer. - UroToday

3 Covid-19 Trials Have Been Paused for Safety. Thats a Good Thing. – The New York Times

Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the F.D.A.s vaccine advisory panel, said that pausing a trial is a huge logistical challenge especially for one like Johnson & Johnsons, with plans for 60,000 volunteers in 10 countries.

Its this big warship that you just stop moving, Dr. Offit said.

Once a trial is paused, a safety board may ask for a volunteer who experienced an adverse event to be unblinded in other words, to find out if the volunteer got the placebo or the treatment. If the volunteer received a placebo, then the treatment cant be the cause of the event and the trial can continue.

If it turns out that the volunteer got the treatment, the board does a flurry of detective work. The members look over the medical records. They may ask for more information about volunteers health or even order new tests not just for the people who experienced adverse events, but for everyone in the trial.

The board uses this evidence to come to a conclusion about whether the treatment most likely had anything to do with the event. On very rare occasions, for example, some vaccines can cause a nerve disorder called Guillain-Barr syndrome. But the condition takes weeks to develop. If a volunteer shows signs of Guillain-Barr syndrome on the day of a vaccine injection, it cant be the cause.

Regulators then review the decision of these boards and may accept it or ask for more information. For trials that are running in several countries at once, this review can make pausing a trial even more of a challenge. After AstraZeneca paused its global trials on Sept. 6 for a review, regulators in Brazil, India, Japan, South Africa and the United Kingdom all gave the green light for the trial to resume. But American regulators are still keeping the U.S. trial on pause as they continue to look over the evidence.

If a safety board rules that an adverse event most likely was not a result of the vaccine or treatment, it may allow the trial to start up again. If, on the other hand, theres some urgent problem a contaminated batch of drugs, for example the trial may have to stop. When the evidence isnt so clear, the board may let the trial resume with extra tests or exams. A second case of the same event might be more common than you would expect from chance, forcing the trial to end.

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3 Covid-19 Trials Have Been Paused for Safety. Thats a Good Thing. - The New York Times

Role of Caspase-1 in the Pathogenesis of Inflammatory-Associated Chron | JIR – Dove Medical Press

Meseret Derbew Molla,1 Yonas Akalu,2 Zeleke Geto,3 Baye Dagnew,2 Birhanu Ayelign,4 Tewodros Shibabaw1

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Human Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of Biomedical Sciences, School of Medicine, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia; 4Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Correspondence: Meseret Derbew MollaDepartment of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, PO Box 196, Gondar, Ethiopia, Tel +251918331617Email messidrm19@gmail.com

Abstract: Caspase-1 is the first and extensively studied inflammatory caspase that is activated through inflammasome assembly. Inflammasome is a cytosolic formation of multiprotein complex that aimed to start inflammatory response against infections or cellular damages. The process leads to an auto-activation of caspase-1 and consequent maturation of caspase-1 target molecules such as interleukin (IL)-1 and IL-18. Recently, the role of caspase-1 and inflammasome in inflammatory-induced noncommunicable diseases (NCDs) like obesity, diabetes mellitus (DM), cardiovascular diseases (CVDs), cancers and chronic respiratory diseases have widely studied. However, their reports are distinct and even they have reported contrasting role of caspase-1 in the development and progression of NCDs. A few studies have reported that caspase-1/inflammasome assembley has a protective role in the initiation and progression of these diseases through the activation of the noncanonical caspase-1 target substrates like gasdermin-D and regulation of immune cells. Conversely, others have revealed that caspase-1 has a direct/indirect effect in the development and progression of several NCDs. Therefore, in this review, we systematically summarized the role of caspase-1 in the development and progression of NCDs, especially in obesity, DM, CVDs and cancers.

Keywords: caspase-1, inflammasome, IL-1, IL-18, noncommunicable diseases

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Role of Caspase-1 in the Pathogenesis of Inflammatory-Associated Chron | JIR - Dove Medical Press