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Archive for the ‘Genetic medicine’ Category

Callan Russell named a Knight-Hennessy Scholar – University of Georgia

Saturday, March 7th, 2020

University of Georgia senior Callan Russell, an Honors student from McDonough, has been selected for the third cohort of Knight-Hennessy Scholars, a global graduate-level program at Stanford University.

Established in 2016, the Knight-Hennessy Scholars program provides full funding for graduate students as they pursue studies ranging from medicine to law to doctoral programs as well as joint and dual degrees.

The program is designed to prepare students to take leadership roles in finding creative solutions to complex global issues.

Callan is a very active Honors student who has been selected for some of our most impressive scholarships and programs, including the Crane Leadership Scholarship, said David S. Williams, associate provost and director of the Honors Program. Callan has also been greatly engaged with undergraduate research through CURO, which has positioned her to enter a most exciting new field, genetic counseling. Given that Stanford has arguably the top program in this cutting-edge area, the Knight-Hennessy Scholarship is a perfect fit for her.

Callan Russell. (Photo by Stephanie Schupska)

Russell will graduate in May with a bachelors degree in genetics and a minor in music and will begin a masters degree in human genetics and genetic counseling at Stanford University this September. Her long-term goal is to be a prenatal genetic counselor in a hospital setting, educating potential parents about their family histories and the role genetics play in family planning.

Genetic counseling combines hard science with caring for people and the opportunity to directly interact with patients, Russell said. Stanford, the Knight-Hennessy Scholars program, and the niche they provide are a dream fit for my career goals.

For the past two years, Russell has conducted genetics research in the lab of Robert Schmitz, Lars G. Ljungdahl Distinguished Investigator in the Franklin College of Arts and Sciences. A CURO research assistant, she has been studying heat tolerance and photomorphogenesis in Arabidopsis thaliana, a small flowering plant widely used as a model organism in genetics and plant biology. She also spent six weeks last summer shadowing genetic counselors through the University of South Carolinas School of Medicine.

Russell is band captain and trombone section leader in both the UGA Redcoat Marching Band and various UGA ensembles and coordinates community and university events. She volunteers with Extra Special People, assisting children and adults with disabilities; co-founded UGA G.E.N.E.S., the first genetics club at UGA; and has presented her Arabidopsis research at the CURO Symposium. She also received the Vince Dooley Redcoat Band Scholarship.

UGAs major scholarships coordinator, housed in the Honors Program, provides students from across campus with assistance as they apply for national, high-level scholarships. For more information, contact Jessica Hunt at 706-542-6206 or jhunt@uga.edu.

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Alberta to cover another cystic fibrosis medication – Medicine Hat News

Saturday, March 7th, 2020

By Medicine Hat News on March 3, 2020.

The province will cover the cost of another drug for Albertans with cystic fibrosis.

Effective March 1 the drug kalydeco is part of the governments drug plan.

Since 2014 kalydeco has been available to patients more than six years old who had cystic fibrosis and one specific genetic mutation. The coverage is now expanded to include an additional eight genetic mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R.

Patients over 18 with an R117H mutation in the CFTR gene will also be covered for this medication.

Cystic fibrosis is a genetic disease affecting the digestive system and lungs primarily. The severity of the disease differs from person to person and it is often fatal.

The government said the pan-Canadian Pharmaceutical Alliance was able to negotiate a pricing agreement with the manufacturer of this prescription drug that made expanded coverage possible.

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Zebrafish are the tropical minnows advancing genetics and molecular biology – TMC News – Texas Medical Center News

Saturday, March 7th, 2020

Iridescent blue-striped zebrafish dart back and forth in tiny tanks stacked floor-to-ceiling in the basement of the Baylor College of Medicine. The freshwater minnowssome 13,000 strong in their watery studio apartmentsplay an integral role in innovative biomedical research.

They are part of the Gorelick Lab, one of more than 3,250 sites in 100 different countries using zebrafish to advance medicine and better understand human diseases. Led by Daniel Gorelick, Ph.D., assistant professor in the department of cellular and molecular biology at Baylor, the lab studies zebrafish to learn how certain hormones and chemicals affect the development and function of the human heart and brain, as well as other tissues.

Gorelick in the lab.

Although science and technology are constantly evolving, zebrafish have remained relevant research tools for almost 50 years. Today, scientists are harnessing the power of CRISPR-Cas9 technologywhich can edit segments of the genome by deleting, inserting or altering sections of the DNAto generate specific mutations in zebrafish.

This has been a huge advance because it allows us to create mutant strains of zebrafish that have the same mutations as are found in a human disease, said Gorelick, whose lab is housed in Baylors Center for Precision Environmental Health and is currently undergoing an expansion to accommodate as many as 30,000 fish.

In addition, scientists have long sought to map the cell-by-cell progression of animals, in pursuit of understanding how a single cell develops into trillions of cells that make up an intricate biological system of organs. With single-cell RNA sequencing, a technology named Science magazines 2018 Breakthrough of the Year, scientists are able to track the different, intricate stages of embryo development in unprecedented detail, allowing researchers like Gorelick to study the cascading effects at the cellular level.

Theres just so much evidence now that a lot of the drugs that are effective in humans are also effective in [zebrafish], so people are now starting to use fish to discover drugs, Gorelick said. You want to know, if youre taking a drug or youre exposed to some pollutant, does that cause birth defects? How does that affect the life of humans? We can use [zebrafish] as research tools to understand how the chemicals normally work in a normal embryo.

Regenerative heartZebrafish are named for the colorful horizontal stripes on their bodies, and can grow from 1.5 to 2 inches in length. The tropical fish are native to South Asia.

On the surface, zebrafish appear nothing like humans, but 70 percent of the genes in humans are found in zebrafish and 84 percent of human genes associated with human disease have a zebrafish counterpart, studies show.

George Streisinger, an American molecular biologist and aquarium enthusiast, pioneered the use of zebrafish in biomedicine at the University of Oregon in 1972. His breadth of knowledge about zebrafish laid the groundwork for research methodologies, including developing breeding and care standards and creating tools for genetic engineering and analysis. He performed one of the first genetic screens of zebrafish by using gamma rays to randomly mutate the DNA of certain zebrafish and identify offspring that had notable phenotypes, such as pigmentation defects.

That caused a big explosion in the field and then thats when things really took off, Gorelick said.

Zebrafish are now used as a genetic model for the development of human diseases, including cancer, cardiovascular diseases, infectious diseases and neurodegenerative diseasesto name a few. Housed down the street from Gorelicks lab, John Cooke, M.D., Ph.D., is using zebrafish to study atherosclerosis, the major cause of heart disease in the country. Although zebrafish have only one ventricle to pump blood to the heart, whereas humans have two (a left and a right ventricle), their vasculature is very similar to humans.

The zebrafish can help us in understanding the cardiovascular system, in achieving those basic insights, and in translating those basic insights towards something thats potentially useful for people, said Cooke, director of the Center for Cardiovascular Regeneration at Houston Methodist Research Institute.

Cooke hopes that studying the regenerative capabilities of the zebrafish heart will lead to new discoveries that help human patients.

You can remove 20 percent of their heart, and they can regenerate it, Cooke explained. Why is that? We want to know. There are groups that are studying that amazing regenerative capacity of the [zebrafish] heart, and those insights obtained from that work may lead us to new therapies for people to regenerate the human heart or, at least, improve the healing after a heart attack.

Watching cells migrateAlthough mice are genetically closer to humans than zebrafish, sharing 85 percent of the same genomes, zebrafish have a few key advantages for researchers.

On average, zebrafish produce between 50 to 300 eggs, all at once, every 10 days. Their rapid breeding allows scientists to quickly test the effects of genetic modifications (such as gene knockouts and gene knock-ins) on current fish, as well as ensuing generations.

In addition, zebrafish are fertilized and developed externally, meaning the sperm meets the egg in the water. This allows scientists to access the embryos more easily, as opposed to mouse embryos that develop inside the womb. In one of his research projects, Gorelick simply adds drugs to the water to see how the zebrafish are affected.

Most drugs in the water will get taken up by the embryo, Gorelick said. We add it into the water and it gets taken up the next day when theyre just one day old. All of that discovery happened in zebrafish because you can literally watch it live.

Not only do zebrafish embryos develop quickly, they are also transparent. Within two to four days, a zebrafish will develop all its major organsincluding eyes, heart, liver, stomach, skin and fins.

We can literally watch these cells migrate from different parts of the embryo, form the tube, constrict, form the hourglass, loop on itself, beat regularly and see blood flow all at the same time, Gorelick said. When theres a belly and a uterus, you dont have access. You can use things like ultrasound, like we do with humans, but you cant get down to single-cell resolution like we can with the fish.

Ultimately, zebrafish have proven to be a powerful resource for researchers. Although all zebrafish studies are confirmed in rats and mice, followed by human tissue, they constitute a significant stepping stone.

You wouldnt want to build a house only using a hammer and a screwdriver. I want a power drill and I want a band saw, Gorelick said. Fish are part of that. Theyre not a cure-all. Theyre not the only tool, but theyre an important tool.

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Washington University to break ground on major neuroscience research hub Washington University School of Medicine in St. Louis – Washington…

Saturday, March 7th, 2020

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New construction will inspire discovery, collaboration, faculty recruitment at School of Medicine

Washington University in St. Louis will begin construction in March on an 11-story, 609,000-square-foot neuroscience research building on the School of Medicine campus. The project initially will bring together more than 100 research teams focused on solving the many mysteries of the brain and the bodys nervous system.

Washington University in St. Louis will begin construction in March on what will be one of the largest neuroscience research buildings in the country. Located on the School of Medicine campus, the 11-story, state-of-the-art research facility will merge, cultivate and advance some of the worlds leading neuroscience research.

The 609,000-square-foot facility and interconnected projects initially will bring together over 100 research teams focused on solving the many mysteries of the brain and the bodys nervous system. Those teams, comprising some 875 researchers, will come from a wide array of disciplines, including the medical schools neurology, neuroscience, neurosurgery, psychiatry and anesthesiology departments.

Washington University is one of the premier institutions in the world in neuroscience research, with faculty known for their contributions to the understanding of normal brain development, how nerve cells communicate, neuroimaging, neurological diseases such as Alzheimers disease, and surgical treatments for cerebral palsy, among other contributions, said Chancellor Andrew D. Martin. With this new building, we are able to offer the neuroscience community a central home and a laboratory environment that can inspire entirely new concepts that allow us to grasp a much deeper understanding of the brain and have a global impact on health and science.

The School of Medicine has a long history as one of the worlds foremost centers for neuroscience research, including as a leading institution in the study of Alzheimers disease. Its scientists have identified key molecules involved in sculpting nervous system development and triggers of neurodegenerative diseases, mapped connections from brain region to brain region, and developed pioneering surgical treatments for nerve injuries, among other groundbreaking discoveries.

David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of the School of Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor, said the new facility will open the door to bold new research initiatives and partnerships.

Understanding the brain is key to addressing some of the most devastating afflictions that affect mankind, Perlmutter said. So many of us have been touched by the inexorable decline of our loved ones due to diseases and conditions such as Alzheimers and Parkinsons, brain trauma, glioblastoma and severe mental illness, and we have learned that the development of effective therapies has proven formidable. As scientists, we believe that a deeper understanding of cognition and emotional regulation can help us address major public health problems such as obesity, substance abuse, depression and suicide.

The initiative will increase synergy and facilitate greater collaboration between scientists in the medical schools neuroscience-focused departments and researchers in related disciplines, especially those whose work requires close collaboration with neuroscientists.

This rendering shows a view from the west of the planned neuroscience research center.

Collaboration across disciplines will be key to advancing our understanding of this new frontier in medicine, Perlmutter said. For example, new studies have recognized the importance of the microbiome and its interaction with our immune system in shaping the development and function of the brain. Work on synaptic connections in the nervous system is also critical to the development of machine intelligence and socially interactive robots that could solve many of the most important challenges of modern society. This building will be dedicated to advancing our global leadership position in solving these very big problems with imagination and rigor.

The new research center also is expected to inspire health-minded entrepreneurial pursuits and synergy with visionary business developers situated within a stones throw of the new research center. The building and related construction, which will be built at an expected cost of $616 million, will sit at the eastern edge of the Medical Campus, in the 200-acre Cortex Innovation Community, one of the fastest growing business, innovation and technology hubs in the United States and home to numerous biotech startups founded by Washington University faculty, staff and students.

We are constructing the building at the intersection of Cortex and the Medical Campus to encourage efforts by Washington University neuroscientists to transform their research into innovations that can move rapidly to improve medical care and quality of life for people with neurological conditions, said Jennifer K. Lodge, PhD, the universitys vice chancellor for research.

Among Washington Universitys achievements in the field of neuroscience, two Nobel Prizes in Physiology or Medicine have been won by scientists at the university. In 1944, Joseph Erlanger and Herbert Gasser won the Nobel for their work studying nerve fibers. They showed that the conduction velocity of nerve impulses is faster in thick nerve fibers than in thin fibers, and identified numerous other properties of sensory and motor nerves. And in 1986, Stanley Cohen and Rita Levi-Montalcini won the Nobel for discovering chemical growth factors essential for cell growth and development in the body. In the 1950s, they discovered nerve growth factor, a protein crucial for building networks of nerves.

The School of Medicine has a longtime, deep commitment to understanding, treating and preventing Alzheimers in particular. In the U.S., 5.8 million people are living with the disease, with the number projected to rise to nearly 14 million by 2050. Alzheimers and other dementias cost the U.S. a staggering $290 billion in 2019, and the cost is predicted to climb as high as $1.1 trillion by 2050, according to the Alzheimers Association.

The new center is intended to complement and build on The Brain Research Advancing Innovative Neurotechnologies Initiative (The BRAIN Initiative), an extensive effort launched in 2013 by the National Institutes of Health (NIH) to revolutionize our understanding of the brain and brain disorders. Despite tremendous advances in neuroscience, the causes of numerous neurological and psychiatric conditions remain unknown. Like The BRAIN Initiative, Washington Universitys leadership understands how critical that information will be to figuring out how to effectively counter these diseases and help the many people suffering from them. In fact, several research projects led by Washington University investigators are funded by The BRAIN Initiative and will find a home in the new neuroscience building.

The medical schools faculty have long been lauded for the collaborations they develop across the university, and the new research facility is intended to boost and significantly drive such efforts. The building will feature research neighborhoods and a shared area on each floor to spur conversation and collaboration. The neighborhoods will be organized around research themes among them, addiction, neurodegeneration, sleep and circadian rhythm, synapse and circuits, and neurogenomics and neurogenetics that bring together people with common interests from multiple departments. The first researchers are slated to move into the building in 2023. While the initial construction will accommodate more than 100 research teams, additional shell space could be built out later for another 45 research teams.

This rendering shows a view from the southwest of the planned neuroscience research building.

The additional space created in this building represents the next step in the schools strategic plan to increase its research base by more than 30% over the next 10 years. The school is currently ranked fourth among U.S. medical schools in NIH funding and aims to leverage the breadth of its basic and clinical research assets, together with existing and new industry partnerships, to enhance its core mission in discovery and development of new treatments.

We have been very successful at attracting top-notch researchers and their teams to the School of Medicine, and this continues to be a chief goal, Perlmutter said. The focus on neuroscience in this building is also integral to our aspirations across the Medical Campus to utilize the paradigm of personalized medicine and to address the problems of aging and degenerative diseases.

Added David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology: A key goal for the neuroscience center is to take what we discover in our laboratories and get it out into the public sector so patients, and society as a whole, can benefit. This building and the collaborations it will grow will position us to achieve meaningful breakthroughs in science and medicine.

An internationally renowned expert on the causes of Alzheimers disease, Holtzman and his team helped develop antibodies aimed at preventing dementia by reducing deposits of the Alzheimers proteins amyloid beta and tau in the brain, and have advanced the understanding of how sleep and apolipoprotein E the most important genetic risk factor for Alzheimers contribute to brain injury. Holtzman also is involved in a project led byRandall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology, to develop a blood test that can measure levels of amyloid beta and other proteins in the blood with the goal of diagnosing Alzheimers before symptoms develop.

The new neuroscience facility to be located at 4370 Duncan Avenue extends the School of Medicines reach eastward. As part of the construction, the university will add to its network of elevated, connected walkways, known as the Link, to reach the neuroscience research hub, and also will build a utility plant. In addition to the facilitys labs and research-focused areas, the new building will have event space, a large seminar room and a food-service area, as well as an 1,860-space parking garage. The architectural firms Perkins and Will, and CannonDesign are the projects designers, and McCarthy Building Companies will oversee construction.

Neuroscience research is a synergetic enterprise that depends on the expertise of people in many fields, Holtzman said. By bringing together so much knowledge, talent and passion, this new facility will make it considerably more likely that people will have the kinds of water-cooler discussions that lead to interdisciplinary game-changing ideas and projects. Im very excited to see what we will do.

Neuroscience research highlights

Washington University researchers:

Through ongoing research, they are:

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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Molecular Signature of Young-Onset Parkinson’s Disease Is… : Neurology Today – LWW Journals

Saturday, March 7th, 2020

Article In Brief

A unique molecular structureevident in induced pluripotent stem cells taken from people with young-onset Parkinson's diseasesuggests that the defects may be present throughout patients' lives, and that they could therefore be used as diagnostic markers.

Induced pluripotent stem cells (iPSCs) taken from patients with young-onset Parkinson's disease (YOPD) and grown into dopamine-producing neurons displayed a molecular signature that was corrected in vitro, as well as in the mice striatum, by a drug already approved by the US Food and Drug Administration (FDA), a study published in the January 27 online edition of Nature Medicine found.

Although the patients had no known genetic mutations associated with PD, the neurons grown from their iPSCs nonetheless displayed abnormally high levels of soluble alpha-synucleina classic phenotype of the disease, but one never before seen in iPSCs from patients whose disease developed later in life. Surprisingly, for reasons not yet understood, the cells also had high levels of phosphorylated protein kinase C-alpha (PKC).

In addition, the cells also had another well-known hallmark of PD: abnormally low levels of lysosomal membrane proteins, such as LAMP1. Because lysosomes break down excess proteins like alpha-synuclein, their reduced levels in PD have long been regarded as a key pathogenic mechanism.

When the study team tested agents known to activate lysosomal function, they found that a drug previously approved by the FDA as an ointment for treating precancerous lesions, PEP005, corrected all the observed abnormalities in vitro: it reduced alpha-synuclein and PKC levels while increasing LAMP1 abundance. It also decreased alpha-synuclein production when delivered to the mouse striatum.

Unexpectedly, however, PEP005 did not work by activating lysosomal function; rather, it caused another key protein-clearing cellular structure, the proteasome, to break down alpha-synuclein more readily.

The findings suggest that the defects seen in the iPSCs are present throughout patients' lives, and that they could therefore be used as diagnostic markers. Moreover, the drug PEP005 should be considered a potentially promising therapeutic candidate for YOPD and perhaps even for the 90 percent of PD patients in whom the disease develops after the age of 50, according to the study's senior author, Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor of biomedical sciences and medicine at Cedars-Sinai.

These findings suggest that one day we may be able to detect and take early action to prevent this disease in at-risk individuals, said study coauthor Michele Tagliati, MD, FAAN, director of the movement disorders program and professor of neurology at Cedars-Sinai Medical Center.

But the study still raises questions regarding the biological mechanisms, and certainly does not warrant off-label prescribing of PEP005 at this time, said Marco Baptista, PhD, vice president of research programs at the Michael J. Fox Foundation, who was not involved with the study.

Repurposing PEP005 is a long way away, Dr. Baptista said. This is not something that neurologists should be thinking about prescribing or recommending to their patients.

Accumulation of alpha-synuclein has been seen in iPSC-derived dopaminergic cultures taken from patients with known genetic defects, but such defects account for only about 10 percent of the PD population. In those without known mutations, on the other hand, no defects in iPSC-derived dopamine-producing neurons have been seen. Until now, however, such studies had been conducted only in patients who had developed PD after age 50.

My idea was why to look in young-onset patients, said Dr. Svendsen.

The idea paid off more richly than he expected. We were shocked to find a very, very prominent phenotype, a buildup of alpha-synuclein, in the neurons of these patients who are genetically normal, Dr. Svendsen said. None of the controls had a buildup of synuclein, and all but one of the early PD patients had a twofold increase in it.

The signature is so consistent, he said, that it offers a natural model that can be interrogated to further understand its workings.

Because high levels of PKC were also seen, Dr. Svendsen said, We picked a bunch of drugs known to reduce PKC. We found one, PEP005, which is actually extracted from the milkweed plant, and it completely reduced synuclein levels almost to normal in dopaminergic neurons. And it also increased dopamine levels in those cells, so we got two for one.

After observing the effects of PEP005 in vitro, We put it into the mouse brain and found it reduced synuclein in vivo, Dr. Svendsen said. But we had to infuse it right into the brain. We're now trying to work out how to get it across the blood-brain barrier more efficiently.

To determine how PEP005 lowers cellular levels of alpha-synuclein, his group tested whether it was activating the lysosome, but found to their surprise that it did not do this until after the synuclein had already been degraded.

Then we asked whether it could be the proteosome, which also breaks down proteins but normally doesn't break down synuclein, Dr. Svendsen said. But when we applied PEP005, it did activate the proteasome. So we think that might be the mechanism.

Because the drug is currently applied externally, Dr. Svendsen said, the next step will be to see if it crosses the blood-brain barrier when applied to the skin of mice, and whether that results in a lowering of synuclein levels in dopaminergic neurons.

Justin Ichida, PhD, the Richard N. Merkin assistant professor of stem cell biology and regenerative medicine at the USC Keck School of Medicine, said the findings are quite important in the field. The potential diagnostic tools they made could be important in clinical care. And identifying a drug that may very effectively reverse the disease in neurons is a very important discovery.

He wondered, however, whether the increase in alpha-synuclein is truly specific to Parkinson's neurons or if it would also be seen in iPSC neurons from patients with Alzheimer's disease or amyotrophic lateral sclerosis.

I wonder if alpha-synuclein accumulating is a sign of PD in a dish or is a consequence of neurodegeneration or impaired protein degradation in general, Dr. Ichida said. That's a key question if you want to use this molecular signature as a diagnostic tool.

He also questioned if proteins other than alpha-synuclein, such as tau, would also be seen to accumulate in the iPSCs of YOPD patients.

If one of the protein-clearance mechanisms in the cell is working poorly, you would imagine that other things would also accumulate, Dr. Ichida said.

In response, Dr. Svendsen said that while some proteins other than alpha-synuclein were reported in the paper at increased levels, We did not look at tau specifically, but are in the process of looking right now. It could be that synuclein and some other proteins are somehow altered to evade them from being degraded by the lysosome, or that there is a general lysosomal problem.

Patrik Brundin, MD, PhD, director of the Center for Neurodegenerative Science and Jay Van Andel Endowed Chair at Van Andel Research Institute in Grand Rapids, MI, called the paper very interesting and thought-provoking. If these findings hold up, they could shift our understanding of young-onset PD. They imply that there is a strong genetic component that has not been picked up in prior genetic studies.

Dr. Brundin said he would like to see the results replicated in another lab using different sets of reagents. It is so intriguing and rather unexpected that one wonders if the observations really apply, as the study states, to 95 percent of all YOPD.

He also questioned whether all the young-onset PD patients are similar. Clearly the iPSCs studied here are not monogenetic PD, so they must be very diverse genetically and still all have the same alpha-synuclein change.

Dr. Brundin also asked why the abnormalities seen in YOPD neurons have not previously been seen in older cases of PD. Is there a specific cutoff regarding age-of-onset when these purposed genetic differences apply? he asked.

Dr. Svendsen responded: We don't know why the YO have this phenotype or exactly what the cut off is. We have, however, looked at one adult-onset case that did not show this phenotype. Also, one of our YO cases did not show this phenotype. Thus some patients even with early onset may not have it. We are currently testing many more cases from older-onset patients.

Dr. Brundin also wanted to know whether non-dopaminergic neurons have the same deficits described in the study.

We don't know which neurons specifically have the protein deficit as we cannot do single-cell proteomics, Dr. Svendsen answered. It could be a little in all cells or a lot in a small set. Immunocytochemistry is not quantitative but showed that it is more likely a general increase in synuclein and not specific to dopaminergic neurons.

While the findings in iPSCs suggest that the abnormal levels of alpha-synuclein must be present at birth, Dr. Brundin said, I do not know how to reconcile the present findings with genetic data.

The absence of previously described mutations in the YOPD patients means only that more work must be done to uncover the genetic underpinnings, Dr. Svendsen said.

We're just at the tip of the iceberg with understanding the genome, he said. It's such a bizarrely complex beast. Perhaps there are a thousand different proteins interacting to stop the synuclein from being degraded. In 10 years, we probably will be clever enough to see it. We know it must be there. Now the genome guys will go after it.

Dr. Baptista from the Michael J. Fox Foundation said he agreed with the view that there must be genetic alterations underpinning the defects seen in the iPSCs.

Just because we call something non-genetic could simply reflect the current ignorance of the field, he said. I think the discoveries are simply difficult to make.

He added that he wished that the main comparator in the study was not healthy controls, and that there were more older-onset iPSCs to compare against YOPD patients' samples.

Dr. Svendsen said it could be that the iPSCs from older-onset patients might yet be found with additional study to display abnormalities similar to those seen in YOPD.

Right now we only see it in young onset, he said. We may need to leave the cultures longer to see in the older-onset patients. We are doing those experiments now.

Drs. Tagliati and Svendsen disclosed that an intellectual patent is pending for diagnostic and drug screening for molecular signatures of early-onset Parkinson's disease. Dr. Ikeda is a co-founder of AcuraStem Inc. Dr. Brundin has received commercial support as a consultant from Renovo Neural, Inc., Lundbeck A/S, AbbVie, Fujifilm-Cellular Dynamics International, Axial Biotherapeutics, and Living Cell Technologies. He has also received commercial support for research from Lundbeck A/S and Roche and has ownership interests in Acousort AB and Axial Biotherapeutics. Dr. Baptista had no disclosures.

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Presence of Staph Bacteria in Skin Microbiome Promotes Netherton Syndrome Inflammation – UC San Diego Health

Saturday, March 7th, 2020

Netherton syndrome, a rare skin disease caused by a single genetic mutation, is exacerbated by the presence of two common Staphylococcal bacteria living on human skin, one of which was previously thought to only offer protective properties, report University of California San Diego School of Medicine researchers.

Our study shows how closely tied the human genome is to the genetic information in our skin microbiome. This rare disease is due to a mutation in a human gene. But, in adults, the symptoms of the disease are driven by the skin microbiome, said senior author Richard Gallo, MD, PhD, Irma Gigli Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine.

The two genomes work closely together. When one is off, even by a single gene, the other genome reacts.

In a multi-institutional study published online in Cell Reports on March 3, 2020, Gallo and collaborators identified how Staphylococcus aureus and Staphylococcus epidermidis can act as a catalyst for skin inflammation and barrier damage in mouse models.

S. aureus is a pathogenic bacteria known to aggravate skin conditions, such as atopic dermatitis. When it becomes resistant to antibiotics, it is known as methicillin-resistant Staphylococcus aureus or MRSA. It is a leading cause of death resulting from infection in the United States.

Conversely, S. epidermidis is common on healthy human skin and presumed benign. In a previous study, Gallo reported that a specific strain of this bacterium seemed to hold a protective property by secreting a chemical that kills several types of cancer cells but does not appear to be toxic to normal cells. S. epidermidis was also known to promote wound repair, skin immunity and limit pathogen infections. It was not known that, in some cases, S. epidermidis can have pathogenic effects.

Netherton syndrome is a result of a mutation in the SPINK5 gene, which normally provides instructions for making a protein called LEKT1. This protein is a type of protease inhibitor.

With the loss of LEKT1, excess proteases are stimulated by Staphylococcal bacteria on people with Netherton syndrome. This protease activity leads to a breakdown of proteins and skin inflammation.

This is a major breakthrough for these patients as it describes how we can treat a human genetic mutation by targeting the microbiome, said Gallo, who is also a faculty member in the Center for Microbiome Innovation at UC San Diego. Altering bacterial gene expression is much easier than trying to fix a mutation in humans.

Researchers swabbed the skin of 10 people with Netherton syndrome and found that their skin microbiome had an abundance of certain strains of S. aureus and S. epidermidis. However, unlike the skin of normal subjects, the excess bacteria produced genes that could not be controlled due to the gene mutation in Netherton syndrome.

According to the National Institutes of Health, most people with this recessive inherited genetic disorder have immune system-related problems, such as food allergies, hay fever, asthma, or an inflammatory skin disorder called eczema. It is estimated that 1 in 200,000 newborns are affected.

In addition to demonstrating how an abnormal skin microbiome promotes inflammation in Netherton syndrome, this study provides one of the most detailed genomic descriptions to date of the skin microbiome, said Gallo.

Co-authors include: Michael R. Williams, James A. Sanford, Livia S. Zaramela, Anna M. Butcher and Karsten Zengler of UC San Diego; Laura Cau, of UC San Diego and SILAB; Shadi Khalil, of UC San Diego and University of Virginia School of Medicine; Yichen Wang and Alain Hovnanian of Imagine Institute and Universit Paris Descartes-Sorbonne Paris Cit; Drishti Kaul and Christopher L. Dupont of J. Craig Venter Institute; and Alexander R. Horswill of Department of Veterans Affairs Denver Health Care System and University of Colorado Anschutz Medical Campus.

Funding for this research came, in part, from the National Institutes of Health (R37AI052453, R01AR076082, R01AR074302 and R01AR069653) and the Atopic Dermatitis Research Network (U19 AI117673).

Disclosure: Gallo is a co-founder, scientific advisor, consultant, and has equity in MatriSys Biosciences and is a consultant, receives income, and has equity in Sente. All other authors declare no competing interests.

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Stanford-developed coronavirus test to be used at Stanford Hospital – The Stanford Daily

Saturday, March 7th, 2020

The Stanford Medicine Clinical Virology Laboratory launched a new diagnostic test for detecting coronavirus on Wednesday. The new test, which can deliver results within 12 to 24 hours, will rapidly identify infected people and could help limit the spread of the virus.

The test is currently in use only on patients at Stanford Health Care and Stanford Childrens Health suspected of having the SARS-CoV-2 virus. The test was validated by the Food and Drug Administration (FDA) and Clinical Laboratory Improvement Amendments (CLIA) for testing involving human subjects.

The lab that developed the test is led by Benjamin Pinsky, associate professor of pathology and infectious diseases at the Stanford School of Medicine.

Testing is essential because it helps to identify both asymptomatic carriers and infected people, Pinsky told The Daily. These results then inform treatment, quarantine and the allocation of vital medical resources.

The sooner we know a patient is positive, the sooner we can take the right action to provide care and take steps to ensure the safety of people they came into contact with, whether thats health care providers or the patients loved ones, Pinsky wrote in an email to The Daily.

According to the Stanford Medicine News Center, it is not yet clear how long a patient needs to be infected before testing positive and whether someone not yet showing symptoms could test positive.

While the situation continues to evolve, rapid identification of infected people could help limit the spread of the virus, Pinsky wrote. Public health experts have indicated that prompt identification and quarantine of infected people is critical to limiting the spread of the virus.

Pinsky and his team began developing the test in late January, as they worked to optimize previous coronavirus tests for current U.S. testing guidelines.

The test uses a technique called real-time RT-PCR to detect the presence of genetic material in samples obtained from nasal swabs of potentially infected people, Pinsky wrote.

He added that the test screens for two viral genes.

The first encodes a protein called an envelope protein, which is found in the membrane that surrounds the virus, Pinsky wrote. It then confirms the positive result by testing for a gene encoding a second protein called RNA-dependent RNA polymerase.

The release of this test comes on the heels of an announcement from the Federal Drug Administration (FDA) that now allows in-house diagnostic testing without FDA approval. Previously, all nasal swabs had to be sent to public health agencies for further testing.

The release also came one day before Stanford President Marc Tessier-Lavigne confirmed that Stanford Medicine is currently caring for a few patients who have tested positive for COVID-19 in a statement to the University community on Thursday.

Our hospitals and clinics on campus provide essential health care for the people of our region, Tessier-Lavigne wrote.

This article has been corrected to reflect the correct technique used by the test to detect genetic material. The Daily regrets this error.

Contact Emma Talley at emmat332 at stanford.edu and Ujwal Srivastava at ujwal at stanford.edu.

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Thinking Outside the Box to Elevate, Increase Access to Cancer Care – AJMC.com Managed Markets Network

Saturday, March 7th, 2020

Maggie L. Shaw

Evolution. Disruption. Innovation. Telemedicine. A virtual exchange of information. Healthcare has lagged behind in these aspects, but its necessary to transcend time and distance, according to Susan Dentzer, senior policy fellow at the Duke-Margolis Center for Health Policy.

Dentzer spoke passionately about elevating the quality of cancer care delivery by changing the system and asking these questions:

Her biggest question of all: for healthcare that mainly involves exchanges of information, not the laying of hands, why isnt more of it done virtually today? Especially when study results show high levels of patient satisfaction, higher quality of life, less depression, and less stress with telehealth and tele-oncology.

According to Dentzer, its time to think outside the box, incorporating data and technology to elevate cancer care delivery. And she provided a telling question from her friend A. Mark Fendrick, MD, co-editor in chief of The American Journal of Managed Care, that illustrates how despite advancements in cancer care, obstacles to optimizing its delivery remain: Why do we have Star Wars medicine on a Flintstones delivery platform. Shouldnt we at least advance to The Jetsons?

What many dont realize is that telemedicine, at least the idea of it, has been around for decades. Since the late 1960s. During her presentation, Dentzer told of how Kenneth D. Bird, MD, a former internist and pulmonary specialist at Massachusetts General Hospital, developed the first telemedicine system between Logan Airport and Mass General in 1968, with a second link in 1970. However, the system was abandoned in the 1970s.

A common theme that ran throughout her presentation was that its time for healthcare and cancer care to move outside the conventional walls of practices. To not be afraid of innovation. To move closer to patients where they are in their homes and communities. To elevate the quality of cancer care to such a level that it minimizes the amount of time people have to be in the hospital. But doing so first means addressing several important challenges:

So, what can we do? What are some examples of where opportunities to innovate in medicine lie?

Tele-oncology. This has already been shown to improve access to care and decrease costs, Dentzer noted. And with oral cancer drugs and immunotherapies being delivered on an outpatient basis in some instance, tele-oncology can help in this space by providing remote supervision of chemotherapy, thereby preventing unnecessary trips to the hospital or doctors office.

For example, Boston Universitys Biomedical Optical Technologies Lab (BOTLab) has developed a wearable probe, now in clinical trials, that uses near-infrared spectroscopy to measure hemoglobin, metabolism, water, and fat levels in tumors. The University of Arizona created its telemedicine program in 1996 and introduced tele-mammography between rural locations and the university in the early 2000s; womens images from a remote location are analyzed within 45 minutes at the university. Lastly, in 1995, Kansas University Medical Center instituted its first tele-oncology program with a multidisciplinary team that is 250 miles from a rural medical center, which itself has nurses.

Tele-genetics. Abramson Cancer Center in Philadelphia, Pennsylvania, offers genetic counseling in real-time, which can be accessed over the phone or through video conference. As this is a service that is not easy to always access, especially when patients are hundreds of miles away, making the counseling more portable can only serve to increase access to care.

Symptom management. Because not all patients need to be seen in the clinic, Seattle Cancer Care Alliance provides a web portal through which they can enter symptoms, and this will send an alert to their care team. And that alert leads to a phone call.

Provider education in immuno-oncology. This is especially needed foremergency medicine physicians. Telemedicine can increase engagement and communication between experienced oncologists and emergency medicine physicians who may have limited knowledge of immunotherapies and their adverse effects. It also provides opportunities for online learning and 24/7 access to critical care information.

Access to clinical trials. Denzler pointed out that almost 8 of 10 clinical trials can be delayed, even closed, because recruitment takes too long. Telemedicine can remedy this by expediting patients access to clinical trials through automated platforms.

I would argue that the status quo is not an option. You need to take advantage of these capabilities really fast, Dentzer noted.

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World’s First Cloned Cat Dies – Texas A&M University Today

Saturday, March 7th, 2020

Copy Cat was born Dec. 22, 2001.

Texas A&M College of Veterinary Medicine & Biological Sciences

CC, the worlds first cloned cat, has passed away at the age of 18 after being diagnosed with kidney failure.

CC, short for Copy Cat, passed away on March 3 in College Station, the same place where her life began as a result of groundbreaking cloning work done by Texas A&M University College of Veterinary Medicine & Biomedical Sciences (CVM) researchers.

CC was born Dec. 22, 2001, and was adopted by Dr. Duane Kraemer, a senior professor in the colleges Reproduction Sciences Laboratory, and his wife, Shirley, six months after her birth.

We in the CVM are saddened by the passing of CC. As the first cloned cat, CC advanced science by helping all in the scientific community understand that cloning can be effective in producing a healthy animal, said Dr. Eleanor M. Green, the Carl B. King dean of veterinary medicine at Texas A&M.

While she lived a long, normal, and happy life, CC was extraordinary in what she represented to the Kraemers, the CVM, and science as a whole, Green said. The entire CVM community mourns her loss, as all at Texas A&M cared deeply about her as a member of the Aggie family, and especially for the Kraemers, for whom CC was a beloved pet for 18 years.

CCs story began with Dr. Mark Westhusin, a CVM professor and the principal investigator of the Missyplicity Project, a $3.7 million effort to clone a mixed-breed dog named Missy that was owned by John Sperling, founder of the University of Phoenix.

When the news of the project spread, people around the country became interested in saving pets tissues that could possibly be used for cloning in the future. This demand resulted in the establishment of Genetic Savings and Clone (GSC), Inc., led by Sperlings colleagues Lou Hawthorne and Dr. Charles Long.

While GSC became a bank for these tissues, Westhusin and his team at Texas A&M began to explore the cloning of other pet species, specifically cats.

CC was produced using nuclear transfer of DNA from cells that were derived from a female domestic shorthair named Rainbow.

Copy Cat was adopted at six months old by Dr. Duane Kraemer, a senior professor in Reproduction Sciences Laboratory, and his wife, Shirley, six months after her birth.

Texas A&M College of Veterinary Medicine & Biological Sciences

Once it was clear the nuclear transfer was successful, Kraemer and other scientists transferred the embryos into a surrogate mother, who gave birth to a healthy kitten about two months later.

Though the cats were identical on a genetic level, developmental factors led them to have slightly different coat patterns and color distributions.

CCs passing makes me reflect on my own life as much as hers, Westhusin said. Cloning now is becoming so common, but it was incredible when it was beginning. Our work with CC was an important seed to plant to keep the science and the ideas and imagination moving forward.

CC also became one of the first cloned cats to become a mother. When CC was five years old, she gave birth to three kittens that lived with her for the rest of her life in a custom, two-story cat house in the Kraemers backyard.

CC was the biggest story out of A&M ever and still is, as far as international reach is concerned, Kraemer said. Every paper and magazine had pictures of her in it. She was one of the biggest accomplishments of my career.

While CC represented a great advancement in genetic research, to the Kraemers, she was also a beloved pet. She will be missed by them especially, but also by those at the CVM, Texas A&M and beyond who have followed her story since birth.

CC was a great cat and a real joy, Kraemer said. She was part of the family and very special to us. We will miss her every day.

Throughout her lifetime, CC regularly made news for her birth, pregnancy and each birthday. She proved to the world that cloned animals can live the same full, healthy lives as non-cloned animals, including being able to produce healthy offspring.

Before CC, no pet had ever been successfully cloned with 100 percent genetic identity.

The research that led to CCs birth kickstarted a global pet cloning industry led by ViaGen Pets, which today clones cats for $35,000 and dogs for $50,000.

Though CC was the first successfully cloned pet, Texas A&M has gone on to clone more species than any other institution in the world, including horses, pigs, goats, cattle and deer.

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Too Lazy to Exercise? Is It Genetic? – Science Times

Saturday, February 29th, 2020

(Photo : Piqsels)A recent study suggests that laziness can be blamed on one's genes.

Do you ever wonder why you find it hard to exercise everyday, while others don't? It must be your genes. A recent study found that a certain genetic mutation reduces one's ability to exercise.

For quite some time now, it has been thought that some people consider exercising much easier than others. While some find joy in jogging off to the gym, others find it terrifying to even do anything that may possibly lead to shortness of breath or perspiration. Now this is no longer just some random situation. In fact, scientists have already discovered the link between one's ability to efficiently exercise and certain genes.

The study, published in the New England Journal of Medicine, reported that a genetic mutation in some individuals are making it more difficult for them to exercise. The mutation can impact the "cellular oxygen sensing" that is linked to ahuman's ability to effectively work out.

The research team also found that those with the gene had reduced growth rate, constantly low blood sugar, limited capacity for exercise and an extremely high red blood cell number. With these findings, it can then be said that laziness is indeed, hereditary.

ALSO READ:Wearable Medical Devices: The Next Most Popular Gadgets for Health and Fitness Enthusiasts

(Photo : Photo by bruce mars on Unsplash)

In an attempt to figure out why individuals with a limited capacity to exercise behave the way they do, the team of researchers thoroughly evaluated one case study.

After several tests, including genetic analysis, the scientists found that themutated genebeing examined was thevon Hippel-Lindau, or the VHL gene. It is a type of gene playing a vital role in one's genetic makeup, mainly contributing to the survival of human cells when the ability to take in oxygen is reduced.

Additionally, the researchers also found that the VHL gene was damaged in some individuals struggling to exercise. The main reason for this is that this gene is associated with the mitochondria. When the mitochondria fail to fire on all cylinders, which is the usual case in those with mutated VHL, exercising is certainly quite a hard thing to do.

Dr. Federico Formenti, one of the study's lead authors said that they find this discovery of mutation, as well as the linked phenotype, exciting as it allows for a deeper understanding of human physiology, particularly when it comes how the human body senses and responds to the reduced availability of the oxygen.

The researchers experimented on mice, which were bred to have a mutation ingenesclose to that of humans in order to interrupt its function. In relation to this, researchers characterized the mice in terms of obesity, physical activity, as well as the cellular biology to understand how this gene was associated with obesity.

The saidstudyshowed the levels of physical activity, body weight and how much the mice ate. The study also showed othercellular level measurements that are obesity-related, such as the expression of the protein on the brain cells' surface.

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They Recovered From the Coronavirus. Were They Infected Again? – The New York Times

Saturday, February 29th, 2020

Can people who recover from a bout with the new coronavirus become infected again and again?

The Japanese government reported this week that a woman in Osaka had tested positive for the coronavirus for a second time, weeks after recovering from the infection and being discharged from a hospital.

Combined with reports from China of similar cases, the case in Japan has raised some uncomfortable questions. Reinfections are common among people who have recovered from coronaviruses that cause the common cold.

But those pathogens are very different from the new coronavirus, and experts said its unlikely that these are cases of people getting infected a second time.

Im not saying that reinfection cant occur, will never occur, but in that short time its unlikely, said Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York.

Even the mildest of infections should leave at least short-term immunity against the virus in the recovering patient, he said.

More likely, the reinfected patients still harbored low levels of the virus when they were discharged from the hospital, and testing failed to pick it up.

Even if there were occasional cases of reinfection, they do not seem to be occurring in numbers large enough to be a priority at this point in the outbreak.

Updated Feb. 26, 2020

A report published Thursday in JAMA supports the idea that people may test positive for the virus long after they seem to have recovered.

In four medical professionals exposed to the virus in Wuhan, China, the epicenter of the epidemic, a test that detects the viral genetic material remained positive five to 13 days after they were asymptomatic.

This does not necessarily mean that they were still able to infect others, however.

The PCR diagnostic test is highly sensitive and can amplify genetic material from even a single viral molecule. As such, the test could merely be picking up fragments of the virus.

PCR tests may detect remnants of the measles virus months after people who had the disease stop shedding infectious virus, Dr. Krammer said.

The other possibility is that the negative test was done poorly, or the samples were stored at a temperature at which the virus deteriorates. The throat swab may also simply miss the virus that is hiding elsewhere in the body.

A virus test is positive if the virus was there on the swab in sufficient quantities at the time you swabbed the person, said Marc Lipsitch, an epidemiologist at the Harvard T.H. Chan School of Public Health.

A negative test is not a definitive that there is no more virus in that person.

Dr. Lipsitch offered an analogy: a jam jar with mold on top. Scraping off the surface might give the impression that the jam is now mold-free, but in fact the jar may still contain mold that continues to grow.

The Japanese woman initially had mild symptoms of coronavirus infection and tested positive in late January. She was released from the hospital on Feb. 1. She tested positive again on Wednesday after coming in for a sore throat and chest pain.

That certainly sounds like it could be an actual resurgence of the virus in infectious form, Dr. Lipsitch said. But, he added, Single anecdotes are really hard to interpret.

One worrisome possibility is that the coronavirus follows what is known as a biphasic infection: the virus persists and causes a different set of symptoms than observed in the initial bout.

In patients infected with Ebola, the virus may persist for months in the testes or eyes even after recovery and can infect others and keep the epidemic going.

The recovered person, too, can develop other symptoms, including insomnia and neurological problems, said Angela Rasmussen, a virologist at Columbia University.

We dont know if thats the case with this coronavirus, Dr. Rasmussen said. We dont know anything about this virus.

Coronaviruses are on the whole poorly understood, she said. Before the SARS epidemic, coronaviruses were not known to cause serious illnesses.

Some scientists have said that people infected with the new coronavirus produce antibodies that will protect them in the future. And a single-patient report suggests that the immunity may last at least seven days.

But this finding is neither surprising nor reassuring, said Dr. Stanley Perlman, a coronavirus expert at the University of Iowa. The issue is whether youll see it in seven months or in a year, he said. Thats what you care about.

The new coronavirus closely resembles the ones that cause SARS and, to a lesser extent, MERS. There are no reports of reinfections with the SARS virus, Dr. Perlman said, and only one that he has heard of in a patient recovering from MERS.

Dr. Perlmans research with MERS has shown that the strength of the immune response depends on the severity of the infection, but that even in those with severe disease which should produce the strongest immune responses the immunity seemed to wane within a year.

How long immunity lasts will also be a key question to resolve when designing a vaccine for the new coronavirus, particularly if the virus becomes a seasonal threat like influenza.

What is the nature of immunity to this virus after infection? Dr. Lipsitch said. Thats a research question thats urgent.

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Working on ‘the human side’ of heritable cancers – Penn: Office of University Communications

Saturday, February 29th, 2020

I love working with people, says Allison Werner-Lin of the School of Social Policy & Practice (SP2). Werner-Lins office overlooking Locust Walk is homey and lamp-lit, with student gifts sharing space with scholarly tomes. This is just one of her workspaces, however. Recently returned from sabbatical, Werner-Lin has been working with the National Cancer Institute (NCI), as well as out of her home in upstate New York, which doubles as a private practice for families seeking bereavement therapy. The divide between academia and clinical practice suits her. I feel like I have one foot in each world and in a very positive way, Werner-Lin says.

Werner-Lin has extensive clinical and research experience and uses both to inform her work, which centers on heritable cancers. She began her academic work studying young adults with mutations in genes associated with breast and ovarian cancer, BRCA1 and BRCA2. Recently, her work with the NCI has branched out to the study of Li-Fraumeni syndrome (LFS). Patients with LFS have a mutation in a tumor-suppression gene, resulting in a high incidence of cancer starting in childhood, and 50% of LFS patients develop cancer by age 40. Both patient populations make life-altering decisions based upon their family histories and medical diagnoses.

Dr. Werner-Lins groundbreaking research merges science with social work at the intersection of qualitative health research, the structure and evolution of genes, hereditary cancer, and how it impacts individuals and families at various stages of life, says SP2 Dean Sara Sally Bachman. Each day, Allison is pushing the frontiers of genomic study and oncological social work while also mentoring other social change agents who will undoubtedly make a difference locally, nationally, and internationally.

For more than a decade, Werner-Lin has worked in the Clinical Genetics Branch of the Division of Cancer Epidemiology and Genetics of the NCI organizing the human side of research. Patients come annually to the NCI to receive full-body MRI cancer screenings and participate in data collection that covers everything from cancer history to family communication to risk management. Werner-Lin mentors an interdisciplinary team of predoctoral and postdoctoral fellows to explore how these families understand and cope with genetic information. Her work is used to train providers in delivering holistic medical and psychological care.

We talk with families about their experiences communicating cancer-risk information with loved ones, making reproductive decisions, and managing the endless cycle of screening, Werner-Lin says. She has seen patterns in how families share cancer-risk information and seek support, noting that information travels based on relationship patterns and emotional closeness, not necessarily degree of risk.

People with LFS have limited options for cancer prevention, and expectations for a cancer diagnosis and early death are common. Were seeing a lot of physical loss, where amputations and other changes in physical function are common consequences of treatment.

Many of the people Werner-Lin speaks with are looking at different pathways to parenthood or are choosing not to have children at all, she says. Grief becomes a chronic part of their lives, and those kinds of sustained of losses can connect individuals in and across families.

Former SP2 graduate student Catherine Wilsnack is a Cancer Research Training Award Fellow at the NCI, doing qualitative research as part of Werner-Lins team. Wilsnack first met Werner-Lin while in her second year at SP2 and calls the encounter transformative. Werner-Lin is a phenomenal mentor in every way, says Wilsnack, who earned her masters in social work (MSW) in 2019. She always goes above and beyond for her students. I would not be where I am today if it were not for her and her guidance, so I just feel extremely lucky.

Now in midcareer, Werner-Lin is taking the time to mentor younger generations. There are so many opportunities to focus on other peoples career development without such a bounded focus on my own professional needs, she says, crediting her own mentors with the ability to achieve professional success.

At Penn, Werner-Lin is involved in the Cancer Moonshot initiative led by Katherine Nathanson and Steve Joffe, an effort designed to accelerate cancer research aimed at prevention, detection, and treatment. Werner-Lins aspect of the project, based at the Abramson Cancer Center at Penn Medicine, involves issues surrounding genetic testing in people aged 18 through 40. Susan Domchek, executive director of the Basser Center for BRCA, says, Allisons work in terms of the psychosocial implications of having a BRCA mutationhow an individual can come to terms with that and how that information gets disseminated between familieshas been extremely helpful. She has a deep expertise on helping families navigate these situations.

Approximately 1 in 400 people carry mutated breast cancer genes, though mutations are more common in certain groups of people. The gene mutations are passed in an autosomal dominant pattern, meaning each parent with a mutation has a 50% chance of passing it on. Children of a BRCA-positive parent can pursue genetic testing to learn if they carry the mutation, adding pressure to family planning.

Werner-Lin was one of these children. Her mother has a BRCA1 mutation. She recovered from colon cancer when Werner-Lin was in college and is currently in remission from a rare ovarian cancer. When I was 23 and was thinking about having kids, I couldnt figure out how to do it, Werner-Lin says. I started talking to people, talking to other women, and that became my dissertation.

This curiosity and compassion led Werner-Lin to operate a private therapy practice out of her home, where she exclusively sees children and young adults with a deceased parent. People often dont see how therapy is connected to the genetics part of my work, but for me they are inseparable, Werner-Lin says. In my cancer work, parents often die young, leaving small children. Frequently, the children of cancer patients conflate their parents lives with their own, not seeing options, degrees of freedom, or technological innovation.

Working together with an MSW student, Werner-Lin does whole family-therapy, from diagnosis to end-of-life, through the grieving process. She helps to facilitate goodbyes, talks about legacy building, and makes the concept of death more concrete for young people.

The language adults use to talk about death is often confusing and shrouded in existential concepts, Werner-Lin says, citing references to angels or going to a better place. Young kids dont necessarily understand time or geography, she says. If were in New York, and Mommy went to the other side, is that a better place?

Instead, she says, we talk about the brain being a light switch, and once you turn it off you cant turn it on again. We talk about how the heart stops beating and the eyes stop seeing. These practical realities are important, Werner-Lin says. Kids need to understand the way the world is predictable, especially when people they love and need can fall off the earth at any moment.

Now back on campus, Werner-Lin is focusing on teaching and engaging with her graduate students. Acting in service to her patients, her students, and her colleagues is a core part of Werner-Lins brand of academia. If you tell her that you want to do something, Wilsnack says, she will go out of her way to help.

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Learning In The Lab – Texas A&M University

Saturday, February 29th, 2020

Texas A&M veterinary student Marshal Covin.

Texas A&M College of Veterinary Medicine & Biomedical Sciences

Marshal Covin, a second-year veterinary student at theTexas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), never expected a simple howdy to lead to countless opportunities for advancing his veterinary career.

But after introducing himself and striking up a conversation with an unfamiliar staff member who turned out to be veterinary technician Chanel Reinertsen, Covin was encouraged to apply for jobs at the CVM and was soon employed at the Gastrointestinal Laboratory (GI Lab)as a junior biomedical sciences major.

For about a year or so, I was a student worker there helping with service, Covin said. Veterinary clinics from around the world send fecal, serum, and other samples to the GI Lab, and Id help them process it, put it where its supposed to be, answer phones, and things like that.

Soon,Dr. Jorg Steiner, GI Lab director and distinguished professor, and Dr. Mark Morris. chair in small animal gastroenterology and nutrition, noticed Covins potential and requested his help on a research project. They began to develop a real-time polymerase chain reaction test to detect an especially elusive liver fluke called O. viverrini, a zoonotic parasite that can cause serious illness in animals and people.

We extracted DNA from adult specimens ofO. viverriniand chose a primer to target the gene we wanted, but we were unsuccessful in getting sufficient amplification of the DNA in our test, Covin said. Thus, more work is needed on the project.

After that project was put on hold, Covin was moved to the research sector of the GI Lab and given his next project, for which he used analytical validation to prove that two new protein tests were as effective as the older version that took a far greater amount of time to run. These new tests detect C-reactive protein in dogs, a common marker for inflammation from various causes, including pancreatitis, parvovirus infection and surgical trauma.

These projects may help improve patient care for any clinic or lab that is looking to use either of these two tests to measure canine C-reactive protein, Covin said. I got two abstracts out of it, which is really awesome. I was fortunate enough to go to Seattle and present the first one at the Annual Forum of the American College of Veterinary Internal Medicine, and then Dr. Jonathan Lidbury presented the second at the European College of Veterinary Internal Medicine Congress in Rotterdam, the Netherlands, in Europe.

Covins current project with Steiner involves studying blood serum to develop a new medication for Wilsons Disease, a genetic disorder in people and dogs.

Its a copper-storage disease wherein people cant excrete copper, so their liver ends up failing, Covin said. The current medication for it takes a year to work. This new one that were trying to work on takes potentially a week.

Though Covin and Steiner have only worked on a few projects together, Covin said it has been fantastic having the opportunity to work in the GI Lab with CVM faculty members who enjoy mentoring students.

I think were really fortunate here, because we have such wonderful faculty who are willing to take us under their wings, he said. Dr. Steiner has helped me in so many ways.

Covin even had the opportunity to travel to Germany this summer with Steiner and two other CVM veterinary students. There, they studied pigs in an effort to develop a new pancreatitis treatment for humans.

Besides the world-class mentorship I get from Dr. Steiner and Dr. Lidbury, I also get a ton of help from other GI Lab staff, Covin said. Our technicians, Ph.D. students, and supervisors are always eager to lend a helping hand, which is one of the things I love the most about the GI Lab.

We definitely have a team-player mentality, he said. I can confidently say that none of my research would have been possible without their support and guidance.

With three years left at the CVM, Covin has plenty of time to work on many more research projects with GI Lab faculty and staff members. As for now, he finds his past and present research projects have been an interesting part of his time at the CVM.

Theyre all really cool, he said. I cant even pick a favorite. Each one has its own unique challenges.

Even though Covin doesnt plan to go into research after graduation, his experiences in the GI Lab will be beneficial when he is working as a mixed-practice veterinarian.

As a general practitioner, having a background in research is really helpful because you can help enroll clients in clinical trials and keep up to date with the latest and greatest innovations, Covin said. But, at some point in the future, I might absolutely go back to academics or research.

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Trends that will shape the 2020s: Psychedelics as medicine, diagnostic cell phone apps and AI prediction of disease outbreaks – Genetic Literacy…

Saturday, February 29th, 2020

Clearly, a lot can happen in a decadebut innovation has to start somewhere. Based on whats breaking through now, here are some trends that have the potential to shape the 2020s.

The 2010s saw18 statesapprove the use of marijuana for medical purposes, bringingthe total to 33 states. In the 2020s, research into the potential medicinal uses of psychedelics could increase dramatically.

In another recent example, one researcher found that MDMA, or ecstasy, can make thecharacteristically shy octopus act friendlier. Though cephalopod brains are more similar to snails than to humans, scientists gleaned insights about how neurons and neurotransmitters behave on the drug that could inform future studies in humans. Other researchers doing experiments with mice hope MDMA ability to manipulate oxytocin could benefit people suffering PTSD.

At the University of California, Berkeley, scientists have developedcell phone appsthat can spot pathogens in biologic samples. The World Health Organization hasincreased fundingto initiatives working to scale up vaccine production in disease-afflicted countries.Artificial intelligenceis also starting to make a big splash in the infectious disease arena as computer scientists deploy the technology to predictand hopefully temperoutbreaks that originate in animals.

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How personal will nutritional advice become in the future? Medicine made for you part 2 – The Conversation UK

Saturday, February 29th, 2020

In the second episode of Medicine made for you, a series from The Anthill podcast that takes a deep dive into the future of healthcare, were looking at the food we eat and how dietary advice could soon get a lot more personalised.

We start with muffins. Our producer Gemma Ware tells the story of a two-week nutritional study run by Kings College London that she took part in with her identical twin sister, aimed at trying to better understand which factors influence how we react to particular foods.

A core part of the study, called PREDICT, involves eating muffins, prepared by the research team with different levels of fat, sugar and fibre, and doing multiple blood tests afterwards to measure the reaction.

Tim Spector, professor of genetic epidemiology at Kings College London, and who is leading the study, explains:

Up to recently, say, the last ten years, weve been thinking that the difference between people and how they respond to food is primarily down to their genes. And this has led some people to have a rather fatalistic view of dieting and health and everything else and say, well, Id blame my parents.

Spector explains that through the researchers ongoing analysis of more than 2 million data points from the PREDICT study which includes data from sets of identical twins who share 100% of the same DNA scientists are now able to separate how many of the differences between peoples bodily responses to certain foods are down to their genes. And everybody reacts differently, even identical twins.

When it comes to a persons reaction to sugar, for example, the researchers found that about 30% could be explained by genes, but for a persons reaction to fat it was only around 5%.

The more we find out about the human body the more complex it is. And its definitely not all explained by genes and its definitely not all explained by microbes. And were finding other things we didnt think were important do have a role.

Now the results are available to participants in a new app, which gives personalised recommendations on how healthy certain foods or meals are for your body, based on the study results. We put it to the test.

Part of the analysis is based on the diversity of a persons gut microbiome, and the influence this has on metabolising the food they eat. To find out more about the importance of these gut microbes we visited the (pretty smelly) lab of Glenn Gibson, professor of food microbiology at the University of Reading, to see the models of the gut his team have created.

Gibson says hes not convinced that well ever get to a point where its possible to personalise dietary advice based on a persons individual microbiome:

Because it would suggest that every single person has a rather different diet to propel their gut microbiota in terms of their own health. And I dont think that is necessary. We kind of know which microbes in the gut are positive for health and which ones are negative. And so I dont think that individually, there are going to be massive differences in those bugs.

Gibson explains that he thinks the factors that influence the health of the gut microbiome are more environmental than genetic.

When it comes to genes, theres still a lot researchers dont know for certain about the way our genes and diets interact, and this means that personalising dietary advice based on someones DNA is so far, quite limited.

But even if people do have more personalised dietary advice available at their fingertips in the future, will they use it? Julie Lovegrove, Hugh Sinclair chair in human nutrition at the University of Reading, explains the results of a study, called Food4Me, that looked at how people responded to different types of personalised advice. Some people in the study received advice based simply on their diet, some based on their phenotype risk, such as whether they have risk of high cholestoral or diabetes, and some based on their genes.

While Lovegrove says that the overall personalisation did have a beneficial effect on how much red meat or saturated fats people ate the type of personalisation didnt have much impact.

I think we have to understand with our colleagues in psychology, for example, what motivates people to change. And I think we are all motivated by different things. And I think we also must frame it in a way that people can not only take on board, but understand the importance of that.

In our third episode of Medicine made for you, out on March 3, well look at how choices about treatment could become more personalised, including the growth of social prescribing. You can listen here to part 1, focusing on genes, clinical trials and precision medicine.

The music in this episode is Is That You or Are You You? by Chris Zabriskie and Hallon by Christian Bjoerklund. Medicine made for you is produced and reported by Holly Squire and Gemma Ware, and hosted by Annabel Bligh for The Anthill podcast. A big thanks to City, University of London, for letting us use their studios.

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Her parents taught her grit, caring for others. She’s using those traits to fight heart disease. – Thrive Global

Saturday, February 29th, 2020

On stage at the Miss America 2020 pageant, Svati Shah looked into the camera and delivered her important message.

It wasnt merely that heart disease and stroke kill more women than all forms of cancer combined. Or that cardiovascular diseases are largely preventable.

It was telling the television audience of over 3.6 million people there are clear ways to change that ways that go far beyond the usual advice of diet and exercise.

By urging more women to take up careers in science and medicine, she said. By ensuring women are included in medical research. By empowering women to change the fact that women living 20 miles apart can have a 20-year difference in lifespan.

When women come together to demand change, change happens.

Dr. Svati Shah is an associate dean in the Duke University School of Medicine and, Im proud to say, a volunteer for my organization, the American Heart Association. I asked her to speak on our behalf at the Miss America pageant because of the passion and spirit she brings to this fight, and to emphasize that women are helping lead the way.

I hope girls who watched were as inspired by Svati as they were by any of the women on that stage. Whats really inspiring is everything that led Svati to that moment.

Her parents fled India in the early 1970s to escape poverty and disease, and so their children could lead happier, healthier lives. Her dad arrived in the United States with $8 and no job. The grit and dedication she saw from her parents especially her mom has turned her into the person she is today: doctor, scientist, wife, mother and so much more.

***

Her story begins in Ahmedabad, India, where her father was born into a home without running water or electricity. As the oldest child, he upheld the custom of helping raise his five siblings.

Her mother also was an oldest child. She had seven siblings; five died before age 5. Sadly, that was somewhat common. Even more sadly, they died of conditions that couldve been treated with antibiotics and fluid hydration.

In his 20s, her dad plunked his life savings into a plane ticket to London and, thus, to a new, more prosperous life. Upon landing at Heathrow Airport, rules required him to take a tuberculosis test. He tested positive. A false positive. Regardless, he was sent back to India, penniless.

Once he earned enough for another ticket, although this time to New York. During the flight, he stepped out of the bathroom and saw a gun pointed at his head. Hijackers. His emigration was rerouted through Cuba, eventually, safely delivering passengers to their intended destination.

Working as an engineer, he was able to bring over his wife a year later. In another year and a half, they had their first child. Svati.

***

The first home Svati remembers was a very small, very nasty apartment across from Montefiore Medical Center in the Bronx.

Her dad worked days as a civil engineer. Her mom worked nights as a punch-card operator for a bank. In the middle of every night, dad woke up and went to the subway stop to escort mom home.

Between her parents opposite schedules and their challenge of raising another younger daughter, Svati began walking to school alone at an early age. She encountered things no child should see. Like someone getting shot on the subway.

She was 9 when her dad got a job in Richland, Washington, the town where the atomic bomb that was dropped on Nagasaki was built. He became an engineer at the nuclear plant and her mom became a secretary there. The family bought a small house.

Then, when Svati was in seventh grade, her parents divorced. Her dad moved away, leaving her mom to raise two teen girls on $19,000 a year.

Although their community included many Indian families, the stigma of divorce made this family outcasts in that community. Food and staples were sometimes bought with food stamps. The thermostat was kept at 55 to save money.

***

Halfway through her senior year of high school, Svati wondered whether she could get into an elite college.

Problem was, shed missed the application deadline. Except for one: Johns Hopkins University.

All she knew was that it was a good school. She got in and, most importantly, earned enough scholarships to make it affordable.

Once on campus, she made a powerful discovery. Hopkins was the perfect school for someone who aimed to wipe out preventable diseases.

That had become Svatis goal because of the horror stories shed heard just from her family.

In addition to the deaths of her moms siblings decades before, both of her fathers parents had gone blind because of cataracts and one of her uncles died from a fever, leaving behind four young children.

I knew from a very young age that I wanted to be in health care, she said. And I just loved science.

***

Svati trained in biostatistics, coding, epidemiology and clinical research on her way to earning a masters degree at the Johns Hopkins School of Public Health.

The plan was to go into public health. Instead, she opted for medical school. Affordability lured her back toward her mom and sister: the University of Washington.

Her ability to code and work with statistics made her in high demand among researchers. Between her desire to do everything and a work ethic forged by her parents and her own hardscrabble youth, she dove into every project she could.

I wasnt the smartest medical school student, but I worked really, really hard, she said. Taking care of patients was fun. It was a constant academic assault: reading about them, figuring out whats wrong and then trying to solve that puzzle.

She did so well that she landed her top choice for an internal medicine residency. Harvard.

***

While in Boston, she decided to focus on cardiology because of the variety. She could interact with patients, perform procedures in the catheterization lab and do research.

Then cardiologist Pat OGara asked what specific area of cardiology she wanted to study.

Stumped, she said, Dr. OGara, if you were me, what would you do?

Genetic epidemiology, he said.

Genetics was emerging as the future of research. Learning how a persons hardwiring could put them at risk for a disease seemed exciting, especially when paired with heart disease, the deadliest of them all. Plus, improving risk prevention seemed like a straight shot to the family history that lured her into medicine.

Svati had never considered it.

Until now.

That sounds great, she told him.

***

Her next stop was a fellowship at Duke, where she aimed to do clinical research through the schools renowned institute.

Then she learned that Duke recently started a Center for Human Genetics. And that one of its main studies involved seeking the genes that cause early onset heart disease in 1,000 families. She gladly joined that team.

The human genome has 3 billion letters and we were looking at 420, she said. It was like searching for a needle in a haystack.

They found several needles.

Soon after, in April 2003, a consortium of scientists completed the Human Genome Project, which then led to major technology advances.

That rocked my world and exploded it, she said. Now we could measure 500,000 letters across the genome.

Out of 3 billion, thats still a tiny amount: 1/6,000.

Again, Svati and her Duke colleagues picked the right haystack.

We found the first gene that causes heart disease, she said. Its actually not in a gene its on the outside of a gene on chromosome 9p21. Its the most consistent risk factor for heart disease, and its held true decades later.

***

Because she continues to have a variety of interests, the focus of her work has shifted many times. One thing shes dug into is the Undiagnosed Diseases Network, a federally funded program that seeks to solve rare, mysterious conditions that afflict families, and she started a genetics clinic at Duke to take care of patients and their families who have genetic heart disorders.

Meanwhile, Svati started her own family. She married another Duke cardiologist, Patrick Hranitzky, and had two sons.

Four years ago, when their oldest son, Kieran, was 5, he was hospitalized because of a severe gastrointestinal bleed. Months later, doctors found the source. One of those rare diseases.

Its called Factor VII deficiency. Its caused by a lack of a protein needed for blood to clot. Screening showed that her younger son, Kellan, has it, too.

We think of different conditions as rare diseases, but in aggregate, they actually affect a lot of people about 1 in 40, she said.

Among the ways to fight it? Genomics.

Last summer, Svati was named director of the Duke Precision Genomics Collaboratory and associate dean of genomics.

Because theres a convergence of data science, electronic health records, population health and a deeper understanding of the genome, we can actually screen people for diseases and identify who is at risk, she said. Theres a long way to go, but this is an exciting time.

***

Its also an exciting time for women in science.

Thats why the American Heart Association partnered with the Miss America pageant.

Thats why Svati stood on stage delivering our message.

Thats why shes sharing her story here.

Many of us were told we cant do everything. We can, she said. Were capable of being great mothers, great scientists, great doctors. You can do it all.

I want women to hear that message, but I also want all people considering this career to know: You can do it all.

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Her parents taught her grit, caring for others. She's using those traits to fight heart disease. - Thrive Global

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Why COVID-19 is more insidious than other coronaviruses – Salon

Saturday, February 29th, 2020

Scientists around the world are racing to understandCOVID-19, the novel coronavirus that has infected more than 82,000 people worldwide and killed 2,817 people as of Thursday. While there are many known viruses in the same class of coronavirus as COVID-19, some of its peculiarities including its infectivity are perplexing researchers. Now, a recent research paper viewableon the Chinese research siteChinaxiv.organd previously reported on by theSouth China Morning Postnotes that the new coronavirus has an "HIV-like mutation" that gives it novel properties.

"Because of this mutation, the packing mechanism of the 2019-nCoV may be changed to being more similar to those of MHV, HIV, Ebola virus (EBoV) and some avian influenza viruses," the English abstract of the paper states.

Though the paper is yet to be peer-reviewed, the scientists involved hail from Nankai Unviersity in Tianjin, one of the top universities in the world's most populousnation.

The paper adds to the crucial body of research around COVID-19, which still includes more unknowns than knowns. Currently,scientists still do notknow COVID-19's origin, though suspect it is zoonotic, meaning it likely started in an animal before spreading to humans. As the U.S. Centers for Disease Control and Prevention (CDC)note on theirwebsite, COVID-19 is an "emerging disease," and much of what we do know is "based on what is known about similar coronaviruses." More recently,news surfaced today that there are new cases in Germany and California inwhich the patient had no known risk factors.

TheNankai University researchers suggestthat COVID-19's ability to bind tocells is as much as1,000 times greaterthan SARS' ability. Like COVID-19, SARSis also a coronavirus. As explained by the South China Morning Post, SARSand the novel coronavirus share about 80 percent of their genetic structure. However, COVID-19 attacksa proteincalled furin the same proteinthat is attacked byEbola andHIV, which are not coronaviruses. A 2014 research paper suggested that the key to finding a cure for Ebola lay in understanding the protein furin.

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According tothe World Health Organization, SARS is more deadly than COVID-19, but the novel coronavirus is more infectious.

This echoes a separate finding from researchers at the University of Washington (UW) School of Medicine who analyzed the virus's spike architecture.

"The spike is the business part as far as viral entry is concerned," David Veesler, senior author of the report and assistant professor of biochemistry at the UW School of Medicine, said in a media statement."It is in charge not only of attachment at the host cell surface, but also of fusing the viral and host cell membranes to allow the infection to start. The spike is also the main target of neutralizing antibodies, so it's very important for vaccine and therapeutic design."

In their analysis, the researchers found "a furin cleavage site at a boundary between two subunits of the spike protein in the newly emerged coronavirus," according to the media release.

Considering what we do know about the novel coronavirus' genetic makeup, researchers are repurposing drugs used to treat other viral infections in various clinical trials to treat COVID-19.

"The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] viruses are very similar, so testing drugs which target relatively generic parts of these coronaviruses is a logical step," Vincent Munster, chief of theViral Ecology Unit at the U.S. National Institute of Health, told Nature.

Americans are bracing for a potential outbreak or even pandemic. In the United States, the CDC said it wasn't a matter of if there will be a disruptive outbreak, but when. Markets in the United States dropped precipitously this week over fears of global economic disruption stemming from COVID-19.

Despite the widespread fear over COVID-19,the seasonal fluremains a greater public health threatin the United States.

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Rejected from five clinical trials, a cancer patient waits for one to say yes – STAT

Saturday, February 29th, 2020

Its hard enough for any cancer patient to get into clinical trials. Its even harder for a patient with a rare cancer like Todd Mercer.

Mercer, a 52-year-old defense industry professional, lives in Michigan with his wife and their two teenagers. At age 50, Mercer got a colonoscopy, as is recommended for people his age, and received a clean bill of health. Six weeks later, his appendix burst.

The diagnosis, which came in December 2017, was cancer of the appendix. It was the tumor that had ruptured his appendix just beyond the reach of the endoscopic exam meaning his cancer was effectively stage 4 at diagnosis. Mercers cancer has since spread to his liver and lungs.

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Mercer first started looking for clinical trials in November 2018, after his cancer recurred for the first time. Since then, hes been turned down from five studies, and is now trying to get into a sixth.

Mercer recently called in to STATs podcast The Readout LOUD to talk about his experience hunting for a trial that will be willing to take him. Its an experience thats frustratingly familiar in a system in which only about one-seventh of adult cancer patients who are eligible to enroll in clinical trials actually sign up.

What kinds of trials are you looking at?

Originally, I looked at clinical trials that were new and exciting and seemed to have some science behind them that might be promising. Lately, though, Ive done some genetic testing thats revealed some genetic information that is leading me towards trials that are designed for the particular blockades or the phenotypes that my genetic testing has introduced. So, now, Im actually being more strategic about my trial hunt.

Ill be lucky to see five years, and I almost wont see 10 years. There are only a few things that I can do directly to affect the outcome.

Why is it important to you to enroll in a clinical trial?

For me, its hope. And its a little bit of hope for others as well.

If I look online, if I look at the data, I can see the trajectory of where my disease is headed with standard of care. Ill be lucky to see five years, and I almost wont see 10 years. There are only a few things that I can do directly to affect the outcome thats understanding my diagnosis, understanding my cancer, becoming an advocate for myself, for my treatments, for my care.

I can also look out at whats on the horizon: What other new drugs and new treatments are out there that are helping people? And some of those are in trials, or at least thats my hope. New drugs are being created all the time. There has been promise in other cancers, and so Im looking for that promise in my cancer.

Youve tried to get into five clinical trials and were turned away. Tell us some of the reasons why you were unable to participate in those studies.

For me, the tumor origination in my appendix was my number one obstacle. A lot of trials are designed to enroll only people whose cancer originated in a particular organ. Thats because drug makers are often seeking FDA approval only for cancer with that particular site of origin. And so trials are very careful about which patients they let into the trial because it wont do them any good to collect data on someone with an orphan disease like mine. Not all trials are prohibitive of appendiceal cancer, but many of them are.

Number two for me and so this probably affects more people is something called measurable disease. When you have measurable disease, that means your cancer has formed in such a way that doctors can do a particular measurement. For example, a radiologist can do a measurement to say how large your cancer is to begin with and then how much the treatment affects it in terms of percentage. Is it growing by 10%? Is it shrinking by 20% or 30%? If you dont have measurable disease, many trials wont take you because then they cant get those data.

But theres another factor called evaluable disease, which means the cancer may not be technically measurable but it can still be evaluated. Some clinical trials will use that characteristic. And so I have to find an evaluable trial because, so far, my cancer hasnt been measurable. Now, it could develop that way, but for now, I have to look at other things.

And then Id say the third biggest obstacle for me is exposure. If youve already been exposed to a drug thats in the trial, many trials will exclude you from being in that study. They want virgin candidates who have never been exposed to those particular drugs before, so they know that its the way the drug is administered in the study thats affecting the outcome.

Which kinds of drugs have you been exposed to so far?

Because of my particular situation with an orphan disease, my oncologist has been open to trying some drugs off-label, meaning well do a trial of one for just me. Hell request the drugs, and then we will design a trial that mimics a trial that might be out there at an institution. So he has a pretty good idea of its safety profile and that the drugs arent going to interact inappropriately.

I tried an immunotherapy drug in that situation. And then once I did that, it didnt work. That now prevents me from most trials that have that particular drug in it. I wanted to try it because I wanted to try immunotherapy. Thats a big hope out there for a lot of cancer patients, that can not only bring you into remission, but possibly a cure. So I wanted to expose myself to that, but the tradeoff is that I cant apply to some other trials.

This is not a unique situation in terms of patients getting access to clinical trials. What are you hearing from fellow patients about why theyre getting rejected and how they feel about it?

I havent run into this, butsome people get turned down as they get sicker and sicker ,and their blood work comes back with higher enzymes or is deemed out of tolerance. So, theyre not allowed into the trials as theyre too sick. So we try to advocate to people with cancer: Dont wait until the very end to try trials. Try them while youre still healthy enough to test the medicine, when theyll take you.

People can also be shut out of trials even they meet a trials inclusion criteria. Cost is a big obstacle. The trial will usually pay for the drugs, but a lot of the time it wont pay for the travel to get there, or the doctor exams and the radiology exams, and things like that. So if you dont have good insurance, those costs would become out-of-pocket costs.

Location is another obstacle. Im lucky Im healthy enough to travel right now, so I can get to a trial anywhere. But a lot of people arent either financially or health-wise able to travel to some of these trial locations.

There can, of course, be sound medical and scientific reasons why certain patients arent allowed to enroll in a trial; the goal of scientific research, after all, is to evaluate an experimental treatment as rigorously as possible. But at the same time, theres a growing line of thought that certain exclusion criteria are overly restrictive, especially when so many clinical trials go unfilled. From your vantage point as a patient, how do you think these concerns should be balanced?

Things are restrictive. I mean, cost, location, the exclusion criteria. I try to look at it a little bit differently.

There are a lot of trials out there and a lot of patients. But the trials dont necessarily always publish what their target is. What is the science behind the trial? Are they attacking a particular mutation, a typical blockade, a phenotype? What science directed them to try that combination of drugs or develop that new drug? What are they trying to determine? That needs to be a required piece of information about trials.

And then correspondingly, the patients and the doctors need to be educated on the value of genetic testing.

No patient should ever be diagnosed with cancer without getting genetic testing. That way, you learn what the particular characteristics of your cancer, of your tumor are, what mutations you have, what your blockades are? And if you have that information about your cancer, and the trial is making that information available about what theyre targeting, then youre going to be more desirous of getting into that trial.

So itll incentivize the patients and the doctors to seek out those trials. And then if those trials know that there is a population of patients out there with those particular characteristics that theyre looking for, then theyre incentivized to reach out to those doctors and those patients to find them, to make those matches. Youve got to match the two.

And really, there just needs to be a platform that matches the patients to the trials, and the trials to the patients. Right now, there are for-profit companies out there working on this. Its a large endeavor to gather patient information. Theres all kinds of privacy ramifications. But the problem is theyre selling that information to institutions. So the institution has to buy the information to understand the patient population, the trial population. It becomes problematic very quickly for that information to get into the hands of the doctor, into the hands of the patients, or the hands of the trials where those patients are. Its not being done right now.

Youre now trying to get into a sixth trial. Tell us where things stand there.

So far, its encouraging. It has been delayed, though.

My genetic mapping indicates that there are two drugs that are my highest blockades. And this particular trial has those two drugs in it.

Dont wait until the very end to try trials.

The problem is its a first-in-humans Phase 1 trial. Theyre doing a dose escalation meaning they start by enrolling three people and start them out at a minimal dose. And then when those three people dont have any adverse reactions, then they incorporate three more people and they increase the dose. And then if they dont have any adverse reactions, then three more and then three more until they find out what the maximal tolerating dose is.

The way they they recruit for it, they dont really open slots until theyre ready for the next three people. So Ive located the trial. It happens to be 30 minutes from where I live. So its very fortuitous.

I attended the ASCO-GI conference in San Francisco last month. I just so happened to be flying back from San Francisco to Michigan, and I sat down next to the trial director for the trial that I wanted to get into. So I was able to strike up a conversation and find out where it was with his particular institution, if there were openings or not. And the problem is: no slots have been opened because theyre still waiting for the dose escalation process to work its way out.

I was progressing on my previous treatment, so I was getting sicker and couldnt wait for the slot to open. Im now recycling the previous treatment that I was on last year to see if it will have some effectiveness, just to get me through until potentially a slot opens up. And then I will go through a 28-day detox period where they want no chemo or medicines in your system so that when you do get to the trial, they can better gauge the results. The idea is to show its not residue medicine in my system, its the actual trial drugs, that are making an effect.

Please keep us updated when you get word on that trial. Were rooting for you.

I absolutely will.

This is a lightly edited transcript from a recent episode of STATs biotech podcast, The Readout LOUD. Like it? Consider subscribing to hear every episode.

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Rejected from five clinical trials, a cancer patient waits for one to say yes - STAT

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Sequencing the Human Genome Was Supposed to Revolutionize Treatment of Disease Heres Why It Failed – SciTechDaily

Saturday, February 29th, 2020

Early proponents of genome sequencing made misleading predictions about its potential in medicine.

An emergency room physician, initially unable to diagnose a disoriented patient, finds on the patient a wallet-sized card providing access to his genome, or all his DNA. The physician quickly searches the genome, diagnoses the problem and sends the patient off for a gene-therapy cure. Thats what a Pulitzer prize-winning journalist imagined 2020 would look like when she reported on the Human Genome Project back in 1996.

The Human Genome Project was an international scientific collaboration that successfully mapped, sequenced and made publicly available the genetic content of human chromosomes or all human DNA. Taking place between 1990 and 2003, the project caused many to speculate about the future of medicine. In 1996, Walter Gilbert, a Nobel laureate, said, The results of the Human Genome Project will produce a tremendous shift in the way we can do medicine and attack problems of human disease. In 2000, Francis Collins, then head of the HGP at the National Institutes of Health, predicted, Perhaps in another 15 or 20 years, you will see a complete transformation in therapeutic medicine. The same year, President Bill Clinton stated the Human Genome Project would revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.

It is now 2020 and no one carries a genome card. Physicians typically do not examine your DNA to diagnose or treat you. Why not? As I explain in a recent article in the Journal of Neurogenetics, the causes of common debilitating diseases are complex, so they typically are not amenable to simple genetic treatments, despite the hope and hype to the contrary.

The idea that a single gene can cause common diseases has been around for several decades. In the late 1980s and early 1990s, high-profile scientific journals, including Nature and JAMA, announced single-gene causation of bipolar disorder, schizophrenia, and alcoholism, among other conditions and behaviors. These articles drew massive attention in the popular media, but were soon retracted or failed attempts at replication. These reevaluations completely undermined the initial conclusions, which often had relied on misguided statistical tests. Biologists were generally aware of these developments, though the follow-up studies received little attention in popular media.

There are indeed individual gene mutations that cause devastating disorders, such as Huntingtons disease. But most common debilitating diseases are not caused by a mutation of a single gene. This is because people who have a debilitating genetic disease, on average, do not survive long enough to have numerous healthy children. In other words, there is strong evolutionary pressure against such mutations. Huntingtons disease is an exception that endures because it typically does not produce symptoms until a patient is beyond their reproductive years. Although new mutations for many other disabling conditions occur by chance, they dont become frequent in the population.

Instead, most common debilitating diseases are caused by combinations of mutations in many genes, each having a very small effect. They interact with one another and with environmental factors, modifying the production of proteins from genes. The many kinds of microbes that live within the human body can play a role, too.

A silver bullet genetic fix is still elusive for most diseases.

Since common serious diseases are rarely caused by single-gene mutations, they cannot be cured by replacing the mutated gene with a normal copy, the premise for gene therapy. Gene therapy has gradually progressed in research along a very bumpy path, which has included accidentally causing leukemia and at least one death, but doctors recently have been successful treating some rare diseases in which a single-gene mutation has had a large effect. Gene therapy for rare single-gene disorders is likely to succeed, but must be tailored to each individual condition. The enormous cost and the relatively small number of patients who can be helped by such a treatment may create insurmountable financial barriers in these cases. For many diseases, gene therapy may never be useful.

The Human Genome Project has had an enormous impact on almost every field of biological research, by spurring technical advances that facilitate fast, precise and relatively inexpensive sequencing and manipulation of DNA. But these advances in research methods have not led to dramatic improvements in treatment of common debilitating diseases.

Although you cannot bring your genome card to your next doctors appointment, perhaps you can bring a more nuanced understanding of the relationship between genes and disease. A more accurate understanding of disease causation may insulate patients against unrealistic stories and false promises.

Written by Ari Berkowitz, Presidential Professor of Biology; Director, Cellular & Behavioral Neurobiology Graduate Program, at the University of Oklahoma.

Originally published on The Conversation.

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Cancers That Survive Chemotherapy Acquire Resistance Genes in Different Ways – MedicalResearch.com

Saturday, February 29th, 2020

MedicalResearch.com Interview with:

Lajos Pusztai, M.D, D.Phil.Professor of MedicineDirector, Breast Cancer Translational ResearchCo-Director, Yale Cancer Center Genetics and Genomics ProgramYale Cancer CenterYale School of MedicineNew Haven, CT 05620

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

Response: We analyzed breast cancer tissues obtained before any therapy and the same cancers after 20 weeks of chemotherapy. This setting is ideal to find out what genomic changes have occurred in cancers that survived therapy. Due to the paucity of such specimens few other studies exist in this space.

MedicalResearch.com: What are the main findings?

Response: All patients received very similar chemotherapy but we found no evidence that a single gene or mutation mediate response to therapy.

Each cancer that survived chemo harbored a different combination of mutations. However, mutations were significantly more common in genes that regulated cell proliferation. We also found that at baseline those cancers that showed genomic signs of DNA repair deficiency had high sensitivity to chemotherapy and these cancers rarely survived the chemo (we call this pathologic complete response).

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

Response: Breast cancers with genomic scars are more sensitive to chemotherapy. Cancers that have survived chemotherapy tend to have more dysregulated proliferation after treatment due to acquired mutations in many different genes compared to pretreatment cancer.

MedicalResearch.com: What recommendations do you have for future research as a result of this work?

Response: Studying drug resistance is very challenging because each cancer develops resistance through its own way.

Any disclosures? This study was funded by the Breast Cancer Research Foundation, the Susan Komen Foundation and the HOPE foundation.

Citation:

Analysis of pre- and post-treatment tissues from the SWOG S0800 trial reveals an effect of neoadjuvant chemotherapy on the breast cancer genome

Ryan L.Powles,Vikram B.Wali,XiaotongLi,William E.Barlow,ZeinaNahleh,Alastair MThompson,Andrew K.Godwin,ChristosHatzisandLajosPusztaiClin Cancer ResJanuary 9 2020DOI:10.1158/1078-0432.CCR-19-2405

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Cancers That Survive Chemotherapy Acquire Resistance Genes in Different Ways - MedicalResearch.com

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