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Could lead to universal flu vaccine, better flu therapies

A human antibody that protects mice against a wide range of lethal flu viruses could be the key to a universal vaccine and better treatments for severe flu disease, according to a new study from Washington University School of Medicine in St. Louis, Icahn School of Medicine at Mount Sinai in New York City, and Scripps Research in La Jolla, Calif.

Researchers have found an antibody that protects mice against a wide range of lethal influenza viruses, according to a study from Washington University School of Medicine in St. Louis, Icahn School of Medicine at Mount Sinai in New York City, and Scripps Research in La Jolla, Calif. The antibody could serve as a template to aid in design of a universal vaccine that protects against all strains of the virus, and a drug to treat and protect against severe cases of flu, including pandemics.

The research is published Oct. 25 in Science.

There are many strains of influenza virus that circulate, so every year we have to design and produce a new vaccine to match the most common strains of that year, said co-senior author Ali Ellebedy, PhD, an assistant professor of pathology and immunology at Washington University. Now imagine if we could have one vaccine that protected against all influenza strains, including human, swine and highly lethal avian influenza viruses. This antibody could be the key to the design of a truly universal vaccine.

Ellebedy discovered the antibody an immune protein that recognizes and attaches to a foreign molecule in blood taken from a patient hospitalized with flu at Barnes-Jewish Hospital in St. Louis in the winter of 2017. Ellebedy was working on a study analyzing the immune response to flu infection in humans, in collaboration with the Washington University Emergency Care and Research Core, which was sending him blood samples from consenting flu patients. He quickly noticed that this particular blood sample was unusual: In addition to containing antibodies against hemagglutinin, the major protein on the surface of the virus, it contained other antibodies that were clearly targeting something else.

At the time we were just starting, and I was setting up my lab so we didnt have the tools to look at what else the antibodies could be targeting, said Ellebedy, who is also an assistant professor of medicine and of molecular microbiology, and a scholar at Washington Universitys Bursky Center for Human Immunology & Immunotherapy Programs.

He sent three of the antibodies with unknown targets to co-senior author Florian Krammer, PhD, a microbiology professor at the Icahn School of Medicine at Mount Sinai. An expert on neuraminidase the other protein on the surface of the influenza virus Krammer tested the antibodies against his extensive library of neuraminidase proteins. At least one of the three antibodies blocked neuraminidase activity in all known types of neuraminidase in flu viruses, representing a variety of human and nonhuman strains.

The breadth of the antibodies really came as a surprise to us, Krammer said. Typically, anti-neuraminidase antibodies can be broad within a subtype, like H1N1, but an antibody with potent activity across subtypes was unheard of. At first, we did not believe our results. Especially the ability of the antibodies to cross between influenza A and influenza B viruses is just mind-boggling. It is amazing what the human immune system is capable of if presented with the right antigens.

Neuraminidase is essential to flu virus replication. The protein cuts newly formed viruses free of infected cells so they can move on and infect new cells. Tamiflu, the most widely used drug for severe flu infection, works by inactivating neuraminidase.

To find out whether the antibodies could be used to treat severe cases of flu, Krammer and colleagues tested them in mice given a lethal dose of influenza virus. All three were effective against many strains, and one antibody called 1G01 protected mice against all 12 strains tested, representing all three groups of human flu virus, as well as avian and other nonhuman strains.

All the mice survived, even if they were given the antibody 72 hours after infection, Ellebedy said. They definitely got sick and lost weight, but we still saved them. It was remarkable. It made us think that you might be able to use this antibody in an intensive care scenario when you have someone sick with flu and its too late to use Tamiflu.

Tamiflu should be administered within 48 hours of symptoms. A drug that could be used later would help many people diagnosed after the Tamiflu window has closed. But before the researchers could even think of designing such a drug based on the antibody, they needed to understand how it was interfering with neuraminidase.

They turned to co-senior author Ian Wilson, DPhil, a noted structural biologist at Scripps Research. Wilson and Xueyong Zhu, PhD, a staff scientist in his lab, mapped the structures of the antibodies while they were bound to neuraminidase. They found that the antibodies each had a loop that slid inside the active site of neuraminidase like a stick between gears. The loops prevented neuraminidase from releasing new virus particles from the surface of cells, thereby breaking the cycle of viral production in cells.

We were surprised how these antibodies managed to insert a single loop into the conserved active site without contacting the surrounding hypervariable regions, thereby achieving much greater breadth against the neuraminidase of different influenza viruses than we have seen before, Wilson said.

The structures showed that the antibodies provide such broad protection because they target parts of the active site of the neuraminidase protein that is much the same across distantly related flu strains. Even minor changes to that part of the protein could abolish its ability to do its job, thereby preventing the virus from replicating.

The researchers are working on developing new and improved treatments and vaccines for influenza based on antibody 1G01, which has been patented by Washington University.

Neuraminidase has been ignored as a vaccine candidate for a long time, Ellebedy said. These antibodies tell us that it should not have been overlooked. Now that we know what a broadly protective antibody to neuraminidase looks like, we now have an alternative approach to start designing novel vaccines that induce antibodies like this. And that could be really important if we are going to figure out how to design a truly universal vaccine.

Stadlbauer D, Zhu X, McMahon M, Turner JS, Wohlbold TJ, Schmitz AJ, Strohmeier S, Yu W, Nachbagauer R, Mudd PA, Wilson IA, Ellebedy IA, Krammer F. Broadly protective human antibodies that target the active site of influenza virus neuraminidase. Science. Oct. 25, 2019. DOI: science.aay0678

The study was supported by the National Institute of Allergy and Infectious Diseases, contract number HHSN272201400008C and HHSN272201400006C and grant numbers R01 AI117287, R21 AI139813, and U01 AI141990; and the National Institutes of Health (NIH), grant number R56 AI117675.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Flu antibody protects against numerous and wide-ranging strains - Washington University School of Medicine in St. Louis

The flu virus (above) has frustrated scientists with its constant shapeshifting, eluding many vaccines and drugs.

By Kai KupferschmidtOct. 23, 2019 , 2:00 PM

Scientists often warn about the dangers of pandemic pathogens spreading quickly around the globe. But one virus already sweeps across the world every year, causing tens of millions of infections and hundreds of thousands of deaths: influenza. Now, a new drug that has shown promise in ferrets may help drive down that toll, researchers report today. The drug appears to be more effective than the most commonly used treatment, oseltamivir, and there are hints that it wont prompt easy resistance in the virus.

Scientists have long been frustrated by the constant shapeshifting of the flu virus, which necessitates an annual reformulation of flu vaccines to reflect commonly circulating strains. When that match is bad, vaccine protection can be low, especially for elderly people who are most at risk. Meanwhile, new influenza drugs have been slow to develop, and those that exist are often inadequate. Oseltamivir, for instance, provides a moderate benefit at best, and only when given early in the infection; whether it prevents hospitalizations and deaths is controversial.

Whats more, the flu virus has developed resistance to oseltamivir and to an older drug, amantadine. And there are already reports of flu strains resistant to baloxavir, a drug approved by the U.S. Food and Drug Administration just last year.

To come up with an alternative, scientists at Georgia State University and Emory University, both in Atlanta, investigated a compound named N-hydroxycytidine (NHC), which has been known for years to inhibit a broad range of RNA viruses like the flu. Previously, the researchers had shown that NHC is active against influenza; but in tests on macaques, they found the drug is not taken up well by the body, a potential deal breaker for human use, says Georgia State molecular virologist Richard Plemper, one of the researchers leading the new work.

The researchers tweaked NHCs structure to create a new compound named EIDD-2801, which converts back into NHC inside the body. They then tested it in ferrets, the most widely used animal model for influenza. If the ferrets received the compound 12 hours after infection, they did not develop disease at all. Those that received it after 24 hours, when fever had started, produced less virus than control animals that received oseltamivir or no treatment at all. The fever also ended faster in treated animals, the researchers write in Science Translational Medicine.

Its important that they showed a reduction in symptoms in ferrets, because it gets much closer to predicting what happens in people, says Andrew Pavia, an infectious disease expert at the University of Utah in Salt Lake City. Its a major step towards developing a drug for humans.

The scientists also investigated how NHC blocks influenza by sequencing the genomes of flu viruses exposed to the compound. They found that the virus incorporates the drug into its RNA when it replicates, instead of a molecule named cytosine, leading to a cascade of mistakes that virologists call error catastropheessentially overwhelming the virus with mutations.

To test how easily flu becomes resistant to EIDD-2801, the researchers also grew the virus while keeping it exposed to sublethal doses of NHC or slowly increasing the concentration of NHCmethods that typically dont kill the virus, but give it a chance to evolve resistance. Even though sequencing clearly shows the virus trying to resist the drug, no resistant strains developed. That bodes well, Pavia says, because oseltamivir and other older drugs all eventually fail the test.

Still, it doesnt mean resistance cannot develop, says Albert Osterhaus, a virologist at the University of Veterinary Medicine in Hanover, Germany. Favipiravir, a drug approved in 2014 in Japan for pandemic flu viruses resistant to all other drugs, was thought to have a similarly high barrier to resistance before resistant strains developed.

Plemper says additional toxicity tests in animals have not thrown up any red flags, and the first trials of EIDD-2801 in humans are likely to start next spring. Pavia says the new drug could eventually be used in combination with other drugs to stave off resistance, a strategy already in use for HIV and hepatitis B treatments.

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New drug forces flu virus into 'error catastrophe,' overwhelming it with mutations - Science Magazine

People with pancreatic cancer and a specific type of change or mutation in their DNA live longer when treated with platinum-based chemotherapy, compared to those who received the same treatment but didnt have the same mutation type. This study is out today in Journal of Clinical Oncology (JCO) Precision Oncology and draws on data from the Pancreatic Cancer Action Networks (PanCAN) Know Your Tumor precision medicine service.

Being able to define subsets of patients who should be treated a certain way, based on their tumors biology, underscores the value of molecular profiling to improve patient outcomes in this challenging disease, said Lynn Matrisian, PhD, MBA, chief science officer at PanCAN and a co-author of the study. These are the types of results we hoped to see when we launched Know Your Tumor in 2014.

Looking at Know Your Tumor reports and follow-up patient outcomes, the study authors, led by researchers at Perthera, Inc., examined data on 820 pancreatic cancer patients who either had advanced disease or who had their tumors partially or completely removed by surgery. They then looked at whether the study participants had a specific type of mutation that impaired a DNA repair process known as homologous recombination (HR).

A persons DNA gets damaged daily, which is why the cell is designed to repair errors in DNA through many ways, including HR. But when some genes, like the BRCA genes (BRCA1 and BRCA2), become mutated, they can no longer repair DNA by HR. Mutations in other genes can impair HR also, including PALB2, ATM, ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2 and several others.

When HR is not functioning, certain conditions may develop, like cancer.

The patients evaluated in the study could have been born with mutations in HR genes (germline mutations) or could have mutations present only in their tumor tissue (somatic mutations). PanCANs Know Your Tumor is able to test patients tumor tissue and saliva to identify both types of mutations.

For patients with metastatic disease, those with HR-related mutations lived an average of 11 months longer when treated with platinum-based chemotherapy, as compared to patients who underwent the same treatment but didnt have HR-related mutations.

The new study supports other research suggesting that cancers with HR-related mutations are especially vulnerable to platinum-based chemotherapy. Further, this study follows promising phase III clinical trial results showing that pancreatic cancer patients who responded to this chemotherapy type also responded well to a PARP inhibitor called Lynparza (olaparib).

Lynparza is an FDA-approved treatment for ovarian cancer, but not yet for pancreatic cancer. Published phase III clinical trial results suggest it may have the potential to extend the good results seen by some patients undergoing platinum-based chemotherapy.

While platinum-based chemotherapy is shown to be effective for certain patients, many patients may not have the chance to benefit from this treatment type. The study authors noted that while its estimated that 17 to 25 percent of pancreatic cancers have HR-related mutations, about half of all patients do not receive platinum-based therapy as their first line of treatment. This highlights the importance of patients undergoing molecular profiling to identify mutations, such as those disrupting the HR pathway, or other alterations that may impact their treatment options.

One theory in the field was that pancreatic cancer patients with HR-related mutations naturally ended up living longer than patients without such mutations, Matrisian said. But our study shows thats not true. Unless they underwent platinum-based treatment, these patients did not see any survival benefit.

Every pancreatic tumor is different. Patients who receive treatment based on their tumors biological characteristics have better outcomes. PanCAN strongly recommends molecular profiling to help determine best treatment options.

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Matched Therapy Increases Pancreatic Cancer Survival - Pancreatic Cancer News & Stories

CAMBRIDGE, Mass.--(BUSINESS WIRE)--CAMP4 Therapeutics, a biotechnology company unraveling transcriptional machinery and the network of signaling pathways to accelerate drug discovery and development across therapeutic areas, announced that Richard Young, Ph.D., one of the companys founders, has been elected to the National Academy of Medicine (NAM). Dr. Young, a Member of the Whitehead Institute and Professor of Biology at the Massachusetts Institute of Technology (MIT), was one of 90 regular members and 10 international members elected to NAM earlier this week. Election to NAM is considered one of the highest honors in the fields of health and medicine, recognizing individuals who have made major contributions to the advancement of the medical sciences, health care and public health. Dr. Young was elected to the National Academy of Sciences in 2012 as well.

Dr. Youngs research focuses on mapping the regulatory circuitry that controls cell state and differentiationusing experimental and computational technologies to determine how signaling pathways, transcription factors, chromatin regulators, and small RNAs control gene expression.

CAMP4 was founded based on the seminal discoveries made by Dr. Young, along with Leonard Zon, M.D., Grousbeck Professor of Pediatric Medicine at Harvard Medical School, Investigator at Howard Hughes Medical Institute, and Director of the Stem Cell Program at Boston Childrens Hospital.

Based on Drs. Young and Zons discoveries, CAMP4 has built its proprietary Gene Circuitry Platform, with which it is pioneering a systematic and scalable approach to discover new, druggable targets to control gene expression to treat diseases across all therapeutic areas.

On behalf of the entire CAMP4 team, I want to congratulate Rick on this tremendous and well-deserved honor, said Josh Mandel-Brehm, President and Chief Executive Officer of CAMP4. In addition to all of his remarkable scientific accomplishments that have the potential to impact peoples lives around the world, and the numerous resulting accolades bestowed on him, I am continually struck by Ricks incredible humility and humanity. We are grateful to have the opportunity to work with and advance Ricks science and vision.

Dr. Young received his Ph.D. in Molecular Biophysics and Biochemistry at Yale University, conducted postdoctoral research at Stanford University and joined Whitehead Institute and MIT in 1984. He has served as an advisor to the National Institutes of Health, the World Health Organization, the Vatican and numerous scientific societies and journals. Dr. Young has founded and advised companies in the biotechnology and pharmaceutical industry and is currently a member of the Board of Directors of CAMP4, Syros Pharmaceuticals and Omega Therapeutics. His honors include Membership in the National Academy of Sciences, the Chiron Corporation Biotechnology Research Award, Yales Wilbur Cross Medal, and in 2006 Scientific American recognized him as one of the top 50 leaders in science, technology and business.

The National Academy of Medicine, established in 1970 as the Institute of Medicine, is an independent organization of eminent professionals from diverse fields including health and medicine; the natural, social, and behavioral sciences; and beyond. It serves alongside the National Academy of Sciences and the National Academy of Engineering as an adviser to the nation and the international community. Through its domestic and global initiatives, the NAM works to address critical issues in health, medicine, and related policy and inspire positive action across sectors. The NAM collaborates closely with its peer academies and other divisions within the National Academies of Sciences, Engineering, and Medicine.

View the Whitehead Institutes statement on Dr. Youngs election to NAM.

About CAMP4 Therapeutics

At CAMP4 Therapeutics, we are revolutionizing drug discovery and development to be faster, smarter and better. With our Gene Circuitry Platform, we have discovered how to dial up or dial down the expression of any gene. Using the foundational insights enabled by our platform, we are pioneering a systematic and scalable approach to discover new, druggable targets to control gene expression to treat diseases across all therapeutic areas. This approach involves creating tissue-specific Gene Circuitry Maps that comprehensively reveal the transcriptional machinery and its connected network of signaling pathways governing gene expression. Each map serves as its own therapeutic area discovery engine, revealing dozens, sometimes even hundreds of disease-solving opportunities. Our goal is to decipher the transcriptional machinery and signaling networks controlling gene expression for all cell types central to disease, ultimately delivering druggable targets for a multitude of undruggable diseases. Our vision is to create a world where a treatment for every disease is possible. Learn more about us at http://www.camp4tx.com.

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Richard Young, Ph.D., Founder of CAMP4 Therapeutics, Elected to National Academy of Medicine - Business Wire

New cellular and molecular processes underlying communication between gut microbes and brain cells have been described for the first time by scientists at Weill Cornell Medicine and Cornells Ithaca campus.

Over the last two decades, scientists have observed a clear link between autoimmune disorders and a variety of psychiatric conditions. For example, people with autoimmune disorders such as inflammatory bowel disease (IBD), psoriasis and multiple sclerosis may also have depleted gut microbiota and experience anxiety, depression and mood disorders. Genetic risks for autoimmune disorders and psychiatric disorders also appear to be closely related. But precisely how gut health affects brain health has been unknown.

Our study provides new insight into the mechanisms of how the gut and brain communicate at the molecular level, said co-senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine. No one yet has understood how IBD and other chronic gastrointestinal conditions influence behavior and mental health. Our study is the beginning of a new way to understand the whole picture.

For the study, published in Nature, the researchers used mouse models to learn about the changes that occur in brain cells when gut microbiota are depleted. First author Dr. Coco Chu, a postdoctoral associate in the Jill Roberts Institute for Research in Inflammatory Bowel Disease, led a multidisciplinary team of investigators from several departments across Weill Cornell Medicine, Cornells Ithaca campus, the Boyce Thompson Institute, Broad Institute at MIT and Harvard, and Northwell Health with specialized expertise in behavior, advanced gene sequencing techniques and the analysis of small molecules within cells.

Mice treated with antibiotics to reduce their microbial populations, or that were bred to be germ-free, showed a significantly reduced ability to learn that a threatening danger was no longer present. To understand the molecular basis of this result, the scientists sequenced RNA in immune cells called microglia that reside in the brain and discovered that altered gene expression in these cells plays a role in remodeling how brain cells connect during learning processes. These changes were not found in microglia of healthy mice.

Changes in gene expression in microglia could disrupt the pruning of synapses, the connections between brain cells, interfering with the normal formation of new connections that should occur through learning, said co-principal investigator Dr. Conor Liston, an associate professor of neuroscience in the Feil Family Brain & Mind Research Institute and an associate professor of psychiatry at Weill Cornell Medicine.

The team also looked into chemical changes in the brains of germ-free mice and found that concentrations of several metabolites associated with human neuropsychiatric disorders such as schizophrenia and autism were changed. Brain chemistry essentially determines how we feel and respond to our environment, and evidence is building that chemicals derived from gut microbes play a major role, said Dr. Frank Schroeder, a professor of chemistry and chemical biology at Cornell and at the Boyce Thompson Institute.

Next, the researchers tried to reverse the learning problems in the mice by restoring their gut microbiota at various ages from birth. We were surprised that we could rescue learning deficits in germ-free mice, but only if we intervened right after birth, suggesting that gut microbiota signals are required very early in life, said Dr. Liston. This was an interesting finding, given that many psychiatric conditions that are associated with autoimmune disease are associated with problems during early brain development.

The gut-brain axis impacts every single human being, every day of their lives, said Dr. Artis. We are beginning to understand more about how the gut influences diseases as diverse as autism, Parkinsons disease, post-traumatic stress disorder and depression. Our study provides a new piece of understanding of how the mechanisms operate.

We dont know yet, but down the road, there is a potential for identifying promising targets that might be used as treatments for humans in the future, Dr. Liston said. Thats something we will need to test going forward.

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

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Researchers Discover First Clues on How Gut Health Influences Brain Health - Technology Networks

Im a Badger, says Mark Green (left), walking toward the Stock Pavilion, and when I look at everything this fantastic university is doing, I say, the sky is the limit. Photo by Rodee Schneider

As a Wisconsin native and UW alumnus, USAID Administrator Mark Green understands better than most the breadth of expertise that exists on the University of WisconsinMadison campus. He saw it as a law student, as a state representative and later as a member of congress representing Wisconsins 8th district.

Green visits the lab of Tony Goldberg, an epidemiology professor in the School of Veterinary Medicine whose research focuses on global health and infectious disease. Photo by Rodee Schneider

On Oct. 18, Greens knowledge of UWMadisons academic range brought him to campus for a discussion about potential partnership opportunities between USAID and the university. Green has held the top post at USAID the United States foreign aid and development since 2017.

I cant think of any USAID interests where UW doesnt have a subject matter expert, said Green. The issues where we have questions, you have answers.

The agency frequently works with top U.S. universities on issues related to hunger and agriculture, economic development, education, global health and more.

Green, who also served as the U.S. ambassador to Tanzania from 2007 to 2009, spent the day on campus meeting with faculty, university administrators and researchers. His morning included a discussion with a group of campus leaders working on international issues, a visit with Chancellor Rebecca Blank, and a trip to the laboratory of TonyGoldbergin the School ofVeterinary Medicine to learn about global health and international studies in infectious disease.

PhD student Leah Owens, who is doing research in Goldbergs lab on molecular diagnostics of wildlife disease, shows Green components of their lab in a box, which is designed as a mobile field lab. Photo by Rodee Schneider

For USAID, the visit represents a broader effort to expand its partner base and tap into universities regional and technical knowledge and research expertise.

For UWMadison, the meeting offered a chance to explore new opportunities for mutually beneficial collaborations with USAID, potentially extending the reach and impact of work already occurring on campus.

We have a long history of research related to USAID interests, said Nancy Kendall, an associate professor of educational policy studies, who was part of a committee exploring opportunities for partnership with USAID. We want to see the Wisconsin Idea shared with the world.

Greens visit included a discussion with a group of campus leaders working on international issues. Photo by Rodee Schneider

While Greens global work exposes him to some of the planets biggest challenges, including hunger, natural disaster and political turmoil, given what hes seen from university partners, hes hopeful for the future.

One of the reasons Im really optimistic is your students. Theyre coming up with designs and innovation we never considered, said Green.

Im a Badger, and when I look at everything this fantastic university is doing, I say, the sky is the limit.

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Foreign aid leader's visit focuses on UW partnership opportunities - University of Wisconsin-Madison

25 Oct 2019

Too much salty food wreaks havoc on the cardiovascular system, raising blood pressure, damaging small blood vessels, and limiting perfusion into the brain. But is this why salt increases the chances of cognitive impairment? Not so fast. At this years Society for Neuroscience meeting, held October 1923 in Chicago, Giuseppe Faraco from Costantino Iadecolas lab at Feil Family Brain and Mind Research Institute of Weill Cornell Medicine, New York, reported that learning and memory deficits in mice chowing on a high-salt diet correlated with phosphorylation of tau, not with damage to the brains blood vessels. The study, published October 23 in Nature, links reduced nitric oxide in blood vessel walls to activation of kinases that modify tau. The findings present a new twist in the well-known link between cardiovascular disease and risk for cognitive decline.

Admittedly, at eight to16 times the norm, the amount of salt the mice consumed exceeds all but the very highest equivalents in which people might indulge. Still, researchers found the results thought-provoking. However artificial the diet, this highlights that salt has effects independent of high blood pressure and that salt is a risk factor in its own right, said Joanna Wardlaw, University of Edinburgh. Wardlaw thinks the mechanism may explain some clinical observations. Weve seen in studies of small stroke that despite treating high blood pressure, people continue to get worse clinically and on their brain scans, she told Alzforum. We need to think about the role of other common risk factors, including dietary salt.

Li-Huei Tsai and Joel Blanchard, Massachusetts Institute of Technology, found the Columbia groups work fascinating. They illustrate that neuronal cells and the cerebrovasculature have dynamic molecular and biochemical interactions that clearly influence neurodegenerative pathologies, they wrote to Alzforum (full comment below). Faraco found the salt-induced reduction in nitric oxide (NO) boosted levels of p25, which activates the kinase Cdk5. Tsai has linked p25/Cdk5 to neurodegeneration (Dec 1999 news).

Pickled. AT8 immunostaining detects phosphorylated tau in the brains of mice fed a high-salt diet (right), but not in brains of mice on normal chow (left). [Courtesy of Giuseppe Faraco et al., Nature.]

The NO link most intrigued Zvonimir Katusic, Mayo Clinic, Rochester, Minnesota, as well. Susan Austin in Katusics lab found that knocking out endothelial nitric oxide synthase (eNOS) increases processing of A precursor protein and impairs learning and memory, and most recently that it boosts p25 and phosphorylation of tau (Austin et al., 2010; Austin et al., 2013; Katusic and Austin et al., 2016). In Chicago, Austin reported that microglia from eNOS knockouts ramp up production of ADAM17, the primary sheddase for TREM2, and tone down production of the anti-inflammatory cytokine IL-10. It appears release of NO by the endothelium is an important control mechanism for the brain, said Katusic.

The plot gets thicker. The effect of high salt may not start in the endothelial cells of the brain, but in immune cells of the gut. Last year Faraco reported that a high-salt diet elicits a flood of interleukin-17 from T helper cells in the intestine. That IL-17 lead to a dearth of endothelial NO and impaired memory (Jan 2018 news). The IL-17 reduced cerebral blood flow by about 25 percent, but Faraco considers this insufficient to cause the memory impairment. Since tau pathology has been linked to cerebrovascular disease, he decided to see if a high-salt diet affected the microtubule binding protein.

Faraco put normal C56/Bl6 mice on a diet comprising 8 percent NaCl. This is 16 times the normal amount of salt in mouse chow; seawater is about 3.5 percent NaCl. The mice ate as much food as usual, but over the next 36 weeks, levels of phosphorylated tau rose. AT8 immunoreactivity peaked after 24 weeks, RZ3 immunoreactivity after 36 weeks. These antibodies recognize tau phosphorylation at serine 202/threonine 205 and threonine 231, respectively. Hyperphosphorylation of tau was detected in both male and female mice, and in mice on a 4 percent NaCl diet, albeit only AT8 staining in that case. Faraco found similar tau changes when he fed 8 percent salt to Tg2576 mice, which model amyloidosis. Levels of A were unaffected.

What about neurofibrillary tangles? Faraco found none in any of the mice, but levels of insoluble tau released by formic acid did increase slightly in the cortices and hippocampi of mice on the high-salt diet.

In parallel with the tau phosphorylation, C57/Bl6 mice began having learning and memory problems. They struggled to recognize novel objects in their cages and had trouble finding the escape route in the Barnes maze. The deficits modestly correlated with AT8 binding in the cortex and hippocampus.

Was hyperphosphorylation of tau to blame? The authors tested this in two ways. They administered anti-tau antibodies to wild-type mice on high salt, and they fed high salt to tau knockouts. In both cases the animals performed as well as mice on normal chow, despite hypoperfusion of the brain, suggesting that indeed it was the tau that drove the cognitive decline due to the salt and not reduced blood flow.

Given Katusics prior data suggesting links between endothelial NO and tau phosphorylation, Faraco tested if he could stop the protein modification with L-arginine, a precursor in NO production. This suppressed both tau phosphorylation and the learning and memory deficits. In addition, elevated p-tau in eNOS knockouts could not be boosted further by high salt, supporting the idea that suppression of endothelial NO was behind the tau modification.

Delving more deeply into the mechanism, Faraco found that the salty food elevated calpain activity in the brain. Calpain cleaves p35 to p25; in keeping with this, the levels of the smaller peptide rose, as did activity of Cdk5, the tau kinase. All told, the data suggest that by triggering IL-17 production in the gut, high salt triggers loss of endothelial NO, which in turn leads to phosphorylation of tau and cognitive impairment.

Precisely how NO is suppressed remains to be seen. Katusic emphasized that the gas easily diffuses. Since cells in the brain are rarely more than 15 micrometers away from a blood vessel, NO could be an important signaling molecule. Faraco found no gross changes in astrocytes, microglia, or neurons in mice on high salt, as judged by GFAP, Iba1, and NeuN staining, but agreed it would be important to study downstream effects on these cells.

In her SfN talk, Austin reported that NO affected on microglia more profoundly. In cultures of the cells from eNOS knockout mice, she found not only an increase in ADAM17, but also decrease in cell surface TREM2. Mutations in this microglial receptor increase risk for Alzheimers and frontotemporal dementia. The sensor plays a central role in microglial homeostasis (Nov 2012 news; Oct 2012 news; Aug 2019 news). Austin also found that eNOS-/- microglia, either cultured or isolated from brain by cell sorting, make less TNF and IL-10, pro- and anti-inflammatory cytokines, respectively, while at the same time ramping up phospholipase A2, which mobilizes arachidonic acid, a precursor for inflammatory molecules.

We are slowly developing this concept that vascular mechanisms independent of perfusion affect cognitive impairment, said Katusic. Tsai and Blanchard agreed. Further unraveling these mechanisms will undoubtedly be a promising endeavor that will strengthen our understanding of how dietary habits influence susceptibility to age-related cognitive decline, they wrote.

For his part, Faraco is using RNA-Seq to study what happens in the endothelial cells to reduce NO. It will be interesting to examine interactions with other genetic and dietary risk factors, such as high-fructose or high-fat diets, he said. He thinks it will be important to identify the tau species responsible for the effects on cognition. We need to go much more deeply into the mechanism of neuronal dysfunction.Tom Fagan

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Not Just Blood PressureDietary Salt Linked to Tau Phosphorylation | ALZFORUM - Alzforum

Minister Harsh Vardhan claims project will help in cost-effective, precision medicine

Research laboratories working under the Council of Scientific and Industrial Research (CSIR) on Friday announced completion of whole genome sequencing of 1008 Indian individuals representing diverse ethnic groups in the country. The data will act as baseline information for developing various applications in predictive and preventive medicine.

The genomic data will help scientists understand genetic diversity of the Indian population and make available genetic variant frequencies for clinical applications. The data and knowhow are expected to produce evidence and help in development of technologies for clinical and biomedical applications, scientists explained.

The project called IndiGen was implemented by Delhi-based Institute of Genomics and Integrative Biology (IGIB) and Hyderabad-based Centre for Cellular and Molecular Biology (CCMB). The whole genome sequencing of individuals drawn from across the country has been completed, enabling benchmarking the scalability of genome sequencing and computational analysis at population scale, Union Minster for Science and Technology Harsh Vardhan said.

The genome data will be important for building the knowhow, baseline data and indigenous capacity in the emerging area of precision medicine, he said. The outcomes of the IndiGen will find applications in a number of areas, including faster and efficient diagnosis of rare genetic diseases, he added.

It will further lead to cost-effective genetic tests, carrier screening applications for expectant couples, enabling efficient diagnosis of heritable cancers and pharmacogenetic tests to prevent adverse drug reactions are some of the other benefits of this initiative.

Scientists have also developed IndiGenome card and mobile application for researchers and clinicians to access clinically actionable information. The minister said it would ensure privacy and data security, which is vital for personal genomics to be implemented at large scale.

CSIR has been engaged in genomic studies in India and its Indian Genome Variation has made major contributions in understanding genetic makeup of Indian population. It has also pioneered the application of genomics in clinical settings in the area of rare genetic diseases by means of DNA and genome based diagnostics and interaction with large number of clinical collaborators. (India Science Wire)

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Genome sequencing data to help in predictive and preventive medicine - Down To Earth Magazine

Summary

Doctors and scientists from Memorial Sloan Kettering report on an innovative technique for noninvasively watching where a targeted therapy is going in the body. It also allows them to see how much of the drugreaches the tumor.

Targeted therapy has become an important player in the collection of treatments for cancer. But sometimes its difficult for doctors to determine whether a persons tumor has the right target or how much of a drug is actually reaching it.

A multidisciplinary team of doctors and scientists from Memorial Sloan Kettering has discovered an innovative technique for noninvasively visualizing where a targeted therapy is going in the body. This method can also measure how much of it reaches the tumor. What makes this development even more exciting is that the drug they are studying employs an entirely new approach for stopping cancer growth. The work was published on October 24 in Cancer Cell.

This paper reports on the culmination of almost 15 years of research, says first author Naga Vara Kishore Pillarsetty, a radiochemist in the Department of Radiology. Everything about this drug from the concept to the clinical trials was developed completely in-house at MSK.

Our research represents a new role for the field of radiology in drug development, adds senior author Mark Dunphy, a nuclear medicine doctor. Its also a new way to provide precision oncology.

Our research represents a new role for the field of radiology in drug development.

The drug being studied, called PU-H71, was developed by the studys co-senior author Gabriela Chiosis. Dr. Chiosis is a member of the Chemical Biology Program in the Sloan Kettering Institute. PU-H71 is being evaluated in clinical trials for breast cancer and lymphoma, and the early results are promising.

We always hear about how DNA and RNA control a cells fate, Dr. Pillarsetty says. But ultimately it is proteins that carry out the functions that lead to cancer. Our drug is targeting a unique network of proteins that allow cancer cells to thrive.

Most targeted therapies affect individual proteins. In contrast, PU-H71 targets something called the epichaperome. Discovered and named by Dr. Chiosis, the epichaperome is a communal network of proteins called chaperones.

Chaperone proteins help direct and coordinate activities in cells that are crucial to life, such as protein folding and assembly. The epichaperome, on the other hand, does not fold. It reorganizes the function of protein networks in cancer, which enables cancer cells to survive under stress.

Previous research from Dr. Chiosis and Monica Guzman of Weill Cornell Medicine provided details on how PU-H71 works. The drug targets a protein called the heat shock protein 90 (HSP90). When PU-H71 binds to HSP90 in normal cells, it rapidly exits. But when HSP90 is incorporated into the epichaperome, the PU-H71 molecule becomes lodged and exits more slowly. This phenomenon is called kinetic selectivity. It helps explain why the drug affects the epichaperome. It also explains why PU-H71 appears to have fewer side effects than other drugs aimed at HSP90.

At the same time, this means that PU-H71 works only in tumors where an epichaperome has formed. This circumstanceled to the need for a diagnostic method to determine which tumors carry the epichaperome and, ultimately, who might benefit from PU-H71.

Communal Behavior within Cells Makes Cancers Easier to Target

Findings about proteins called molecular chaperones are shedding new light on possible approaches to cancer treatment.

In the Cancer Cell paper, the investigators report the development of a precision medicine tactic that uses a PET tracer with radioactive iodine. It is called [124I]-PU-H71 or PU-PET. PU-PET is the same molecule as PU-H71 except that it carries radioactive iodine instead of nonradioactive iodine. The radioactive version binds selectively to HSP90 within the epichaperome in the same way that the regular drug does. Ona PET scan, PU-PET displays the location of the tumor or tumors that carry the epichaperome and therefore are likely to respond to the drug. Additionally, when its given along with PU-H71, PU-PET can confirm that the drug is reaching the tumor.

This research fits into an area that is sometimes called theranostics or pharmacometrics, Dr. Dunphy says. We have found a very different way of selecting patients for targeted therapy.

He explains that with traditional targeted therapies, a portion of a tumor is removed with a biopsy and then analyzed. Biopsies can be difficult to perform if the tumor is located deep in the body. Additionally, people with advanced disease that has spread to other parts of the body may have many tumors, and not all of them may be driven by the same proteins. By using this imaging tool, we can noninvasively identify all the tumors that are likely to respond to the drug, and we can do it in a way that is much easier for patients, Dr. Dunphy says.

The researchers explain that this type of imaging also allows them to determine the best dose for each person. For other targeted therapies, doctors look at how long a drug stays in the blood. But that doesnt tell you how much is getting to the tumor, Dr. Pillarsetty says. By using this imaging agent, we can actually quantify how much of the drug will reach the tumor and how long it will stay there.

Plans for further clinical trials of PU-H71 are in the works. In addition, the technology reported in this paper may be applicable for similar drugs that also target the epichaperome.

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Bulls-Eye: Imaging Technology Could Confirm When a Drug Is Going to the Right Place - On Cancer - Memorial Sloan Kettering

Theres a new frontier in medicine that seeks to cure not just treat symptoms by regenerating healthy tissue destroyed by disease.

In the firing line are currently incurable diseases that impose enormous suffering, debilitation and costs. This includes the muscle wasting inflicted by muscular dystrophy, for example, or the loss of brain neural cells in the case of Parkinsons disease.

Its the latter that the startup Convalesce Inc is primarily targeting, based on the development of a self-assembling and self-repairing material called AmGel. It contains nanofibres capable of nurturing stem cells to replace damaged nerves a function that can make or break the use of stem cells therapeutically.

To get all the interacting factors right meant drawing on nanotechnology, bioengineering, cell biology, developmental biology and material science super-advanced stuff.

AmGels development and commercialisation, however, owes a great deal to a new model for producing the next generation of innovators in this case, Convalesces co-founder, Dr Subhadeep Das.

He graduated with a PhD in 2017 from an academy specifically established to use advanced multidisciplinary research techniques to address critical global challenges, including in energy, infrastructure and manufacturing. Called the IITB-Monash Research Academy, its a joint venture between the Indian Institute of Technology Bombay (IITB) and Monash University.

Speaking from the prestigious IndieBio accelerator program in San Francisco, Das explains that stem cell technology perfectly fits the academys mission. These are cells that are potentially game-changing for medicine, yet their use is held back by the cells complex relationship to its molecular, cellular and extra-cellular environment.

You cant just inject stem cells into inflamed and damaged tissue. They dont survive in that micro environment, Das says. The solution requires drawing on multiple disciplines like having smaller pieces for a jigsaw puzzle.

For Parkinsons disease, that involves understanding the biophysicality of the brain and the dimensions and topography of its subcellular structures. This has led to the designing of nanofibres that form a scaffold for stem cells to attach and grow into. This matrix also cues stem cell growth and development into functioning nerve cells.

To get all the interacting factors right meant drawing on nanotechnology, bioengineering, cell biology, developmental biology and material science super-advanced stuff, Das says.

The science, however, is just the first step towards a cure. Convalesce constitutes the second phase meeting the testing, regulatory and commercialisation hurdles needed to get a viable therapy to patients.

Das admits the learning curve has been steep in the segue from research to commercialisation. Working alone, he might not have succeeded.

Instead, he took advantage of ongoing support provided by the IITB-Monash Research Academy, including the provision of exclusive rights to the intellectual property for AmGel, and mentoring from across both universities, especially from the academys CEO, Professor Murali Sastry.

He discovered that while starting a company is tough, there are people who are willing to help if you reach out. Its making the connections in the first place that matters.

On that score, the Monash alumni office do a great job. They provided us with introductions to alumni that included highly successful entrepreneurs and heads of venture firms. These are people who are willing to help because of the connection with Monash University.

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Repairing the brain through stem cell therapy - Monash Lens