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Scientists map genetic networks that control the biology of regulatory T cells – News-Medical.Net

Reviewed by Emily Henderson, B.Sc.Oct 1 2020

Unlike most T cells, which launch immune responses against foreign molecules, regulatory T cells are the peacekeepers of the human immune system, damping down inflammatory reactions when they're not needed. Now, researchers at Gladstone Institutes, in collaboration with scientists at UC San Francisco (UCSF) and the Technical University of Munich (TUM), have mapped out the networks of genes that help differentiate regulatory T cells from other T cells. Their findings could lead to immune therapies that strengthen or weaken the function of regulatory T cells.

Piecing together the genetic networks that control the biology of regulatory T cells is a first step toward finding drug targets that change the function of these cells to treat cancer and autoimmune diseases."

Alex Marson, MD, PhD, senior author of the study, Director of the Gladstone-UCSF Institute of Genomic Immunology

All T cells, named because they develop in the thymus gland, have similar receptors on their surfaces and play a role in the immune responses that destroy viruses, bacteria, and some cancer cells. But regulatory T cells have a distinct function, acting as a brake to suppress other T cells so that immune reactions don't go overboard. Studies in mice have suggested that increasing the number of regulatory T cells--and therefore putting stronger "brakes" on the immune system--might help subdue symptoms of autoimmune diseases. On the other hand, blocking regulatory T cells, or lifting these molecular brakes, is suspected to help the immune system better fight cancer.

Therapies that boost populations of regulatory T cells--by removing the cells from patients' bodies, expanding them, and infusing them back in--are already being tested in people with autoimmune disease, including type 1 diabetes, and organ transplant recipients. So far, however, such treatments generally haven't involved actually altering the function of the immune cells.

"Most of our previous knowledge about regulatory T cells is from mouse models," says Kathrin Schumann, a co-first and co-corresponding author of the paper and former UCSF postdoctoral fellow, now an assistant professor at the Technical University of Munich. "We wanted to genetically dissect human regulatory T cells to better understand how they're wired and how we can manipulate them. Once we understand the functions of each gene, we can precisely edit cells to treat disease."

In the new study, published in the journal Nature Immunology, Marson, Schumann, and their collaborators used CRISPR-based gene-editing technology to alter regulatory T cells, selectively removing any of 40 different transcription factors. The 40 transcription factors--master genes that control the activation of many other genes--were chosen because previously published data had already hinted that they might perform specific functions in the regulatory cells compared to other T cells.

The researchers then focused on the 10 transcription factors that had the strongest effect in this initial screen, and looked across tens of thousands of genes to see which ones were turned on or off in the altered cells. In all, they performed this analysis on 54,424 individual regulatory T cells.

By analyzing the subsets of genes activated or silenced by these 10 original transcription factors, the team put together vast networks of genetic programs involved in the biology of regulatory T cells. Among the most surprising results, the study revealed that the little-studied transcription factor HIVEP2 has a strong effect on regulatory T cell function. In follow-up studies in mice, the scientists found that removing the HIVEP2 gene reduced the ability of the regulatory T cells to quell inflammation.

"This was a significant hit," said Sid Raju, a co-first author of the paper and former UCSF computational biologist who is now a graduate student at the Broad Institute of MIT and Harvard. "This gene had really never been implicated in regulatory T cell biology before."

The team also says their study acts as a proof-of-principle for how powerful the combination of CRISPR gene editing and the analysis of individually edited cells can be in studying the genetics of human biology and human disease.

"Now, we can theoretically take any specialized cell from the body and start removing individual genes and study the consequences on the cells in much finer detail than ever before," says Marson. "This really opens up human cells removed from the body as a tractable experimental system."

Source:

Journal reference:

Schumann, K., et al. (2020) Functional CRISPR dissection of gene networks controlling human regulatory T cell identity. Nature Immunology. doi.org/10.1038/s41590-020-0784-4.

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Scientists map genetic networks that control the biology of regulatory T cells - News-Medical.Net

Excerpt The Infinite Complexity of Cells – Discovery Institute

Image: Radiolarian shells, by Ernst Haeckel / Public domain.

Editors note: We are pleased to offer this excerpt from Dr. Dentons new book, The Miracle of the Cell.

In terms of compressed complexity, cells are without peer in the material world, actualized or imagined. And there is likely far more complexity still to uncover. Even as recently as 1913, when Lawrence Henderson composed his classic The Fitness of the Environment, the cell was a black box, its actual molecular complexity a mysterious unknown. Only as the veil began to lift with the mid-century molecular biological revolution did science begin to glimpse the sophistication of these extraordinary pieces of matter. Subsequently, every decade of research has revealed further depths of complexity. The discovery of ever more intricate structures and systems with each increase in knowledge including vastly complex DNA topologies and a vast and growing inventory of mini-RNA regulator molecules tells us there is probably much more to uncover. What we glimpse now may be only a tiny fraction of what remains to be discovered.

As Erica Hayden confessed in the journal Nature, As sequencing and other new technologies spew forth data, the complexity unearthed by cell biology has seemed to grow by orders of magnitude. Delving into it has been like zooming into a Mandelbrot set that reveals ever more intricate patterns as one peers closer at its boundary.

There is much more to discover about the cell, but even from our current limited knowledge of its depths it is clear that this tiny unit of compact, adaptive sophistication constitutes something like a third infinity. Where the cosmos feels infinitely large and the atomic realm infinitely small, the cell feels infinitely complex.

But cells are not just complex beyond any sensible measure and beyond any other conceivable material form. They appear in so many ways supremely fit to fulfill their role as the basic unit of biological life. One element of this fitness is manifest in their incomparable diversity of form. Contrast a neuron with a red blood cell, a skin cell with a liver cell, an amoeboid leucocyte with a muscle cell. Each of these different forms is found in the human body, and many more. Or consider the diversity of ciliate protozoans. From the trumpet-like Stentor to the dashing Paramecium, the universe of ciliate form is absurdly diverse. Or take the radiolarians. Even within this small related group of organisms, the diversity of cell forms is stunning. And yet every member of this fantastic zoo of radiolarian forms is built on exactly the same canonical design.

The unique fitness of the cell to serve as the fundamental unit of life is also manifest in its amazing abilities and the diversity of functions it performs. Even the tiny E. coli, a cylinder-shaped bacterium in the human gut, has spectacular capabilities. Howard Berg has marveled at the versatility and capacities of this minuscule organism, calling its talents legion. He notes that this tiny organism, less than one-millionth of a meter in diameter and two-millionths of a meter long, so small that 20 would fit end-to-end in a single rod cell of the human retina, is nevertheless adept at counting molecules of specific sugars, amino acids, or dipeptides; at integration of similar or dissimilar sensory inputs over space and time; at comparing counts taken over the recent and not so recent past; at triggering an all-or-nothing response; at swimming in a viscous medium even pattern formation.

Cells also move in many diverse ways. E. coli travel by the propeller- like action of the bacterial flagellum. Others do so via the beating action of cilia. Some creep and crawl. Some put out pseudopodia and grasp small objects in their immediate vicinity.

Some cells can survive desiccation for hundreds of years. Cells possess internal clocks and can measure the passage of time. They can sense electrical and magnetic fields, and communicate via chemical and electrical signals. Some can encase themselves in armor-like skins. Some may be able to see; one species of ciliate has a lens able to focus an image on another region of the cytoplasm in effect, an eye. All can replicate themselves with seeming ease, an act far beyond even the most complex human artifact. Some can even reconstruct themselves completely from tiny fractions cut surgically from the cell!

These remarkable specks of organized matter have constructed every multicellular organism on Earth, including the human body, itself a vast collective of as many as 100 million million cells. Cells compose the human brain, making a million connections a minute for nine months during gestation. Cells build blue whales, butterflies, birds, and the giant sequoias of Yosemite. Cells constituted the dinosaurs and all past life ever born on Earth. And through the activities of some of the simplest of their kind, cells gradually terraformed the planet over the past 3,000 million years, generating oxygen via photosynthesis and releasing its energizing powers for all the higher life forms. They are the universal constructor set of life on Earth. In short, they can do almost anything, adopt almost any shape, and obey any order. They appear, in every sense, perfectly adapted to their assigned task of creating a biosphere replete with multicellular organisms like ourselves.

When we observe the goings-on of protozoans in a drop of pond water or the antics of an amoeboid leucocyte in the human blood stream chasing a bacterium, it is hard to resist the feeling that these microscopic life forms are sentient, autonomous beings. This was the case when we had relatively primitive microscopic technology more than one hundred years ago, and it is all the more so today.

It is not just their hunting strategies (seen in a video of a leucocyte chasing its prey, below) that resemble the behaviors of higher organisms.

Another striking example is the courtship rituals of ciliates, rituals that include pre-conjugal mating dances, reciprocal learning, repeated touching of prospective mates, and even deceit and cheating when communicating reproductive fitness to potential mates. One of the founders of behaviorism, Herbert Spencer Jennings, strongly suspected that protozoa were sentient. As he confessed, If Amoeba were a large animal, so as to come within the everyday experience of human beings, its behavior would at once call forth the attribution to it of states of pleasure and pain, of hunger, desire, and the like, on precisely the same basis as we attribute these things to the dog.

Jenningss thoughts were recently echoed by biologist Brian Ford: The microscopic world of the single, living cell mirrors our own in so many ways: cells are essentially autonomous, sentient and ingenious. In the lives of single cells we can perceive the roots of our own intelligence. And as Ford continues, We regard amoebas as simple and crude. Yet many types of amoeba construct glassy shells by picking up sand grains from the mud in which they live. The typical Difflugia shell, for example, is shaped like a vase, and has a remarkable symmetry We just dont know how this single-celled organism builds its shell.

Even if cells are not sentient beings, their accomplishments, their complexity, their diversity of structure and function, remain to astound us. The unique powers of cellswhat Jacques Monod called their demonic catalytic powers and their extraordinary fitness to play their unique role as the building blocks of all life on Earth are a wonder apparent to anyone who gives them even a cursory consideration.

An even greater wonder is the stunning prior fitness in nature that enables the material actualization of the canonical carbon-based cell. This prior fitness is manifest in the unique utility of the properties of a significant number of the atoms in the first half of the periodic table to serve highly specific ends essential for the assembly of the core macromolecular constituents and the physiological functioning of the cell. I call this the unique fitness paradigm.

This prior fitness is manifest also in the extraordinary utility of water to serve as the matrix of the cell, and by chemical processes in the dark vastness of interstellar space that result in the abiotic synthesis of many of the molecular monomers used by the first cells to build their macromolecular constituents. In other words, the demonic fitness of the cell depends on a deeper fitness prefigured into the very fabric of reality. This deeper fitness is inscribed in the laws of nature from the beginning of time, a fitness that reveals the cosmos to be, as Henderson proclaimed, a profoundly biocentric whole.

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Excerpt The Infinite Complexity of Cells - Discovery Institute

Cytovia Therapeutics to present at Jefferies Cell Therapy Virtual Summit, BIO Investor Forum and New York Stem Cell Foundation Conference in October…

NEW YORK, Sept. 29, 2020 (GLOBE NEWSWIRE) -- Cytovia Therapeutics an emerging biopharmaceutical company developing Natural Killer Cell Therapeutics, today announced that it will participate in three key conferences in October 2020.

The Jefferies Cell Therapy Virtual Summit will take place on October 5-6, 2020.Cytovia CEO Dr. Daniel Teper will present on October 6th at 5.30 PM EDT. Webcast link

The BIO Investor Forum will take place on October 13-15, 2020.Cytovia will have an on-demand company presentation during the Bio Investor Forum Digital.

The New York Stem Cell Foundation Conference will take place on October 20-21, 2020.Dr. Wei Li, Cytovia Executive Vice President, R&D and Chief Scientific Officer, will present during the Stem Cell Application in Therapeutics session, on October 21st at 11.15 AM EDT.

The webcast links will be available on the company website and social media pages.

On-demand interview opportunities with Cytovia Therapeutics spokespersons:Daniel Teper, CEO Wei Li, Chief Scientific Officer

ABOUT CYTOVIA THERAPEUTICS:Cytovia Therapeutics Inc is an emerging biotechnology company that aims to accelerate patient access to transformational immunotherapies, addressing several of the most challenging unmet medical needs in cancer and severe acute infectious diseases. Cytovia focuses on Natural Killer (NK) cell biology and is leveraging multiple advanced patented technologies, including an induced pluripotent stem cell (iPSC) platform for CAR (Chimeric Antigen Receptors) NK cell therapy, next-generation precision gene-editing to enhance targeting of NK cells, and NK engager multi-functional antibodies. Our initial product portfolio focuses on both hematological malignancies such as multiple myeloma and solid tumors including hepatocellular carcinoma and glioblastoma. The company partners with the University of California San Francisco (UCSF), the New York Stem Cell Foundation (NYSCF), the Hebrew University of Jerusalem, and CytoImmune Therapeutics. Learn more at http://www.cytoviatx.com and Follow Cytovia on Social Media Facebook, LinkedIn, Twitter.

For more information please contact:Cytovia Therapeutics, IncSophie Badr, Vice President, Corporate Affairs1 (929) 317 1565 sophie.badre@cytoviatx.com

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Cytovia Therapeutics to present at Jefferies Cell Therapy Virtual Summit, BIO Investor Forum and New York Stem Cell Foundation Conference in October...

Open Rank Principal Investigator at Life Sciences Institute job with ZHEJIANG UNIVERSITY | 227718 – Times Higher Education (THE)

Would you like to learn more about moving your academic career to Zhejiang University (ZJU)? If so,registerfor our Careers in China webinar mini-series for a chance to meet representatives fromZJUand discuss the latest opportunities there.

Applications are invited for open rank principal investigator (PI) position at Life Sciences Institute (LSI), Zhejiang University.

Founded in October 2009, LSI is the first special academic zone of Zhejiang University. As a key construction project of Zhejiang University, LSI enjoys autonomy in scientific research, human resources, and budgeting as well as an independent graduate training program. Led by Director Dr. Xin-Hua Feng and Co-Director Dr. Kun-Liang Guan, LSI aims for an internationally recognized institute of biomedical research. We are currently recruiting scientists at all ranks, from Investigator to Senior and Distinguished Investigators, regardless of specific areas of research. Candidates with strong track record in cancer biology, stem cell biology, inflammation biology, chemical biology, structural biology (Cryo EM) and other major areas related to human diseases are particularly encouraged.

LSI has established an interdisciplinary research program, state-of-the-art core facilities, and efficient administrative support, all aiming to support cutting edge biomedical research. LSI also offers generous and internationally competitive packages for incoming PIs, including salary/benefit (400,000 RMB), housing (or housing subsidies), and start-up research support (5,000,000 RMB).

Zhejiang University New Hundred Talents Program

The newly launched New Hundred Talents Program is aimed at attracting outstanding scholars both at home and abroad. To those recruited via this program, the university is to adopt an international academic standard and procedure --- the tenure track system.

The university plans to recruit distinguished scholars from both China and abroad by the Hundred Talents Program. Ample funds are available for this program to ensure that scholars have a favorable academic environment and optimum working and living conditions so that they can be dedicated to academic research and the advancement of their fields.

LSI adopts a tenure-track system and is seeking applications for an open rank position:

To apply, please submit the following materials to:

Contact:Ms. GengTel: +86-0571-88206016E-mail:lsi@zju.edu.cn

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Open Rank Principal Investigator at Life Sciences Institute job with ZHEJIANG UNIVERSITY | 227718 - Times Higher Education (THE)

Aqua-Spark Announces an Investment in Singapore-based Shiok Meats, the First Cell-Based Company to Produce Clean, Sustainable, Cruelty-Free Shrimp and…

New York, NY Aqua-Spark(the Fund), the first investment fund focused on sustainable aquaculture, announced an investment inShiok Meats(Shiok), the worlds first cell-based crustacean meat company based in Singapore. Shiok is the first cell-based meat company in South East Asia, and the first and only cell-based meat company working on shrimp. Their flagship product is a highly-anticipated cell-based shrimp, which offers clean, traceable alternatives to the shrimp farming industry.

Aqua-Spark is the lead investor in Shiok Meats $12.6M Series A round, which also includes investments from SEEDS Capital (the investment arm of Enterprise Singapore), Real Tech Fund (Japan), Irongrey (a Global tech investing family office based in Korea), Yellowdog Empowers Fund (South Korea), Ilshin Holdings Pte. Ltd (Singapore), Toyo Seikan Group Holdings, Ltd (Japan),Veg Invest Trust (USA), Makana Ventures (Singapore), AiiM Partners LP (USA), Beyond Impact (Europe), Kelvin Chan Siang Lin (Singapore), and Alex Payne and Nicole Brodeur (USA). The funds will contribute towards building the first-of-its-kind commercial pilot plant from which Shiok plans to launch its minced shrimp product in 2022. This puts Shiok on schedule to become the first company in the world to have a fully functioning commercial pilot plant for cell-based crustacean production.

Mike Velings and Amy Novogratz, co-founders of Aqua-Spark:

The cell-based animal protein industry has been on our radar for some time as once it is at scale it will have an enormous influence on food production efficiency, food safety, and the environment. As our first investment in cell-based seafood, Shiok Meats immediately stood out to us with their strong, female-led team and impressive milestones to-date. While weve invested in a number of technologies working to make shrimp farming more efficient, healthier, and less polluting, Shiok is the first company in our portfolio to focus on shrimp production. We are excited to help shape this novel and innovative industry, which we expect to have a huge impact on the future of seafood, while continuing to support sustainable aquaculture operations, inputs, and innovations across the value chain.

The shrimp market is a $50 billion market globally with Vietnam, Thailand, Indonesia, and India being the major producers of shrimp. While there are many farms and technologies improving shrimp farming, there is still work to be done. Much of what is currently on the market is raised in crowded factories/farms and treated with antibiotics, chemicals, and hormones. Conventional production processes often contribute to overfishing, excessive bycatch, misrepresentation, and mislabeling as well as contamination with effluents, heavy metals, and microplastics. This form of production is unsustainable and the sector strain will only increase as the population grows. Shiok is addressing this need and disrupting crustacean production to ensure people can eat clean shrimp, crab and lobster from a safe source. Clean meat production could reduce the industrys greenhouse gas emissions by 96 percent, energy consumption by 45 percent, land use by 99 percent, and water consumption by 96 percent.

Shiok Meats was founded in August 2018 by two stem cell scientists, Dr. Sandhya Sriram and Dr. Ka Yi Ling, with over 20 years of combined experience in the muscle, fat, and stem cell biology fields. Shioks mission is to produce clean, healthy, cruelty-free seafood. Their cell-based production process is non-GMO and chemical and antibiotic-free.

Dr. Sandhya Sriram, CEO and co-founder of Shiok Meats:

We are extremely excited to work in partnership with Aqua-Spark as we develop cell-based seafood and meats that are contributing towards a cleaner and healthier seafood industry and solving for the inefficiencies around global protein production. Aqua-Spark was the perfect partner to lead our Series A because they care deeply about funding companies that address planetary health and food security. With their help, we hope to become the global leader in cell-based crustaceans and seafood. We are pleased that Aqua-Spark supports our global impact vision and will be with us for the long haul.

Shiok stands out from other cell-based meat production companies because of their proprietary technology that isolates stem cells from shrimp, lobster, and crabthey are the first company to be able to do this for cell-based production at the moment. Once the stem cells are harvested, the shrimp, lobster, and crab meats are grown in nutrient-rich conditions, similar to that of a greenhouse. After four-to-six weeks, the cell-based seafood is exactly the same as its conventional counterpart but more sustainable, clean, and nutritious. Shioks patent-pending technology can grow crustaceans four times faster than conventional production.

The output of Shioks pilot plant will be frozen cell-based shrimp meat for dumplings and other shrimp-based dishes. Beyond cell-based shrimp, Shiok plans to launch shrimp flavouring paste and powder, fully-formed 3D shrimp, and cell-based lobster and crab products in the coming years.

To date, Aqua-Spark has now invested in 20 complementary companies, technologies, and inputs that are working toward the sustainable production of aquatic life.

About Aqua-Spark

Launched in 2011, Aqua-Spark is an investment fund with a mission to transform the global aquaculture industry into one that is healthier, more sustainable, and more accessible. They invest in aquaculture companies across the value chainspanning farming operations, alternative feed ingredients, disease-battling technology, and consumer-facing aquaculture products. These companies are solving some of the industrys big challenges while bringing returns that are comparable to todays traditional industry. The portfolio works as an ecosystem, with the companies agreeing to collaborate on optimal solutions, and working together toward this shared vision of a more efficient global aquaculture industry.

Since 2015, the fund has invested in 20 complementary SMEs. Thus far, Aqua-Spark has EUR 152 million in assets under management, dedicated to investments in elements of the aquaculture industry that will make fish farming sustainable. The goal of the fund is to ultimately make sustainability widespread and profitable enough that it becomes the only way to farm fish.

About Shiok Meats

Shiok Meats is a cell-based, clean meat company. It is the first of its kind in Singapore and South-East Asia with a mission to deliver delicious, clean, and healthy seafood by harvesting from cells instead of animals. Shiok Meats is working to bring cell-based crustacean meats (shrimp, crab, lobster) to the kitchen. Their meats are cruelty-free, healthy, and better for the environment with the same taste and texture and more nutrients than their traditional counterparts.

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Aqua-Spark Announces an Investment in Singapore-based Shiok Meats, the First Cell-Based Company to Produce Clean, Sustainable, Cruelty-Free Shrimp and...

Global Single Cell Multi-Omics Market 2020 One the most booming industry in forthcoming years due to worldwide demand in Coronavirus (COVID-19)…

Global Single Cell Multi-Omics Market Analysis Providing Latest Market Trends And Developments

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Global Single Cell Multi-Omics Market 2020 One the most booming industry in forthcoming years due to worldwide demand in Coronavirus (COVID-19)...

President Trump Is Taking an Experimental COVID Treatment Not Approved by the FDA – VICE

U.S. President Donald Trump walks on the South Lawn of the White House after arriving on Marine One in Washington, D.C., U.S., Thursday, Oct. 1, 2020. (Photo: Yuri Gripas/Abaca/Bloomberg via Getty Images)

President Trump has taken a significant dose of an experimental treatment for COVID-19 that hasnt yet been approved by the Food & Drug Administration.

Trump will be moved to Walter Reed National Military Medical Center and plans to remain there for a few days, the White House said Friday.

Taken together, Friday evening presented the astonishing spectacle of a sitting American president being rushed to the hospital hours after announcing he tested positive for the novel coronavirus, while taking a drug so new that its not generally available for public use.

Hes been given an experimental drug that shows promise, said Dr. Jeanne Marrazzo, Director of infectious diseases at University of Alabama, Birmingham.

The drug hasnt even received emergency use authorization from the FDA, which is normally how an early drug would be accessible to a patient.

It hasnt got any kind of FDA authorization, Marrazzo said. The only way people would normally be able to get this is by participating in a clinical trial.

The drug ranks as one of the most promising treatments available for COVID-19, medical experts say, although it hasnt yet received extensive testing. Marrazzo said shes only aware of a single, public, randomized trial involving some 275 participants. But she cautioned that the company, and the federal government, may have more data that hasnt yet been made public.

Trump has been given a single eight-gram dose of an antibody cocktail made by the drugmaker Regeneron, the White House said in a statement Friday.

Trump got the drug through whats known as a compassionate use exception, Regeneron said, in which a sick patient can be granted access to a drug thats not yet approved by the FDA outside of a clinical trial.

The companys CEO, Leonar Schleifer, told The New York Times in an interview that Trumps medical staff reached out to the company for permission to use the drug, and that the FDA cleared the request.

All we can say is that they asked to be able to use it, and we were happy to oblige, Schleifer told the Times. When its the president of the United States, of course, that gets obviously gets our attention.

Giving Trump the drug at this stage is probably safe, said Jonathan D. Dinman, chair of the Department of Cell Biology and Molecular Genetics at the University of Maryland. But monoclonal antibodies could, in theory, trigger an autoimmune response, in which the body begins to attack itself.

I think its a pretty low-risk approach, Dinman told VICE News. Were pretty good at making monoclonal antibodies that have a minimal side effect.

The point of dosing the president with a cocktail of antibodies would be to try and reduce the amount of virus in Trumps body before they replicate too far, Dinman said.

Its like throwing a bucket of water on a fire thats just begun. Youre hoping you knock it out. though it might not, Dinman said. Hes already tested positive, so the virus is already established. That means we dont know if the bucket of water is big enough.

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President Trump Is Taking an Experimental COVID Treatment Not Approved by the FDA - VICE

Genetics may contribute to weight gain after switching from efavirenz to an integrase inhibitor – aidsmap

Genetic variations in a liver enzyme could explain why some people put on unwanted weight after switching from efavirenz to an integrase inhibitor, Dr Michael Leonard of Vanderbilt University Medical Center in Nashville and colleagues report in Clinical Infectious Diseases. Slow metabolism of efavirenz due to the CYP2B6 gene leading to higher blood concentrations of the drug was associated with greater weight gain after switching from efavirenz to some integrase inhibitors.

The second part of the study showed that among people starting HIV treatment for the first time, taking efavirenz with tenofovir (TDF) rather than abacavir was associated with less weight gain, even in the context of CYP2B6 and efavirenz concentrations.

Our findings suggest that TDF exposure in the presence of higher efavirenz concentrations interferes with expected weight gain, write the authors. A known TDF side effect is loss of appetite. The association with efavirenz may only be apparent with concomitant TDF-related appetite suppression.

A class of antiretroviraldrugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

Statistical tests are used to judge whether the results of a study could be due to chance and would not be confirmed if the study was repeated. If result is probably not due to chance, the results are statistically significant.

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

A protein which speeds up a chemical reaction.

People often experience weight gain due to a return to health effect when beginning HIV treatment. Specific anti-HIV medications, including integrase inhibitors, are associated with greater weight gain than other regimens. There is more research on weight gain after starting treatment than after switching to a different regimen.

Treatment guidelines recommend integrase inhibitors for first-line antiretroviral therapy. They include bictegravir, dolutegravir, elvitegravir and raltegravir. Their potency and side-effect profile also make them a good choice for people who need to change their HIV treatment because of virological failure or side effects. For many years, efavirenz was a mainstay of HIV therapy. But the drug can cause neuropsychological side effects. Large numbers of individuals have therefore switched from efavirenz to an integrase inhibitor. Unwanted weight gain has been observed among some people making this switch.

The investigators wanted to find out why. They hypothesised that it could be down to genetics, especially the role of specific genetic mutations or polymorphisms in the metabolising of efavirenz and integrase inhibitors.

The CYP2B6 polymorphism is associated with the processing of efavirenz, and slow metabolising of the drug can lead to high blood concentrations, leading to neuropsychological side effects. A polymorphism called UGT1A1 can affect the speed with which the body processes integrase inhibitors but its effect on weight gain is unknown.

To test if their theory was correct they studied two different groups of people living with HIV. Group 1 included 61 individuals with an undetectable viral load, who had been taking efavirenz for two years and switched to an integrase inhibitor. They had blood tests to determine how the CYP2B6 polymorphism affected blood concentrations of efavirenz. Weight gain 48 weeks after switching to an integrase inhibitor was examined.

Group 2 comprised 462 HIV-positive individuals who were starting antiretroviral therapy for the first time. They were treated with efavirenz in combination with either TDF/emtricitabine or abacavir/lamivudine. Genetic characteristics, drug metabolism and weight gain 48 weeks after treatment initiation were assessed.

In the first group, weight increased by an average of 2kg after switching from efavirenz to an integrase inhibitor. The extent of this increase differed according to race. The median weight gain was higher among Black individuals (3kg) than White individuals (2kg).

After taking into account factors such as age and sex, the investigators found a statistically significant relationship between slow metabolising of efavirenz (and therefore higher concentrations) related to CYP2B6 and weight gain (p = 0.001). This finding was weakened when the investigators excluded from their analysis an individual who gained 27kg in the year after making the treatment change.

Weight gain after the treatment switch differed between specific integrase inhibitors and was present for elvitegravir and raltegravir but not dolutegravir. But even for elvitegravir and raltegravir, the association was weakened and was no longer statistically significant when the person with extreme weight gain was excluded from analysis.

There was no evidence that the UGT1A1 polymorphism was associated with weight gain.

The above findings suggested that events that preceded switching affected weight gain after switching, as CYP2B6 does not metabolize integrase inhibitors, comment the authors.

The relationship between CYP2B6, processing of efavirenz and weight gain was further suggested by analysis of the individuals who were starting HIV therapy for the first time. But the extent of weight gain after 48 weeks of treatment differed according to the treatment backbone and individuals taking TDF/emtricitabine had significantly less weight gain (p = 0.001) than people treated with abacavir/lamivudine.

Among patients who switched from efavirenz- to integrase-inhibitor-based therapy, CYP2B6 genotype was associated with change in weight at week 48, likely because greater efavirenz exposure causes less weight gain during the pre-switch regimen, conclude Dr Leonard and his co-authors. They were unable to explain why the risk of weight gain among people starting treatment differed between TDF and abacavir.

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Genetics may contribute to weight gain after switching from efavirenz to an integrase inhibitor - aidsmap

Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics…

This article was originally published here

JCO Oncol Pract. 2020 Sep 28:OP2000431. doi: 10.1200/OP.20.00431. Online ahead of print.

ABSTRACT

Germline genetic testing is now routinely recommended for patients with prostate cancer (PCa) because of expanded guidelines and options for targeted treatments. However, integrating genetic testing into oncology and urology clinical workflows remains a challenge because of the increased number of patients with PCa requiring testing and the limited access to genetics providers. This suggests a critical unmet need for genetic services outside of historical models. This review addresses current guidelines, considerations, and challenges for PCa genetic testing and offers a practical guide for genetic counseling and testing delivery, with solutions to help address potential barriers and challenges for both providers and patients. As genetic and genomic testing become integral to PCa care, developing standardized systems for implementation in the clinic is essential for delivering precision oncology to patients with PCa and realizing the full scope and impact of genetic testing.

PMID:32986533 | DOI:10.1200/OP.20.00431

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Practical Considerations and Challenges for Germline Genetic Testing in Patients With Prostate Cancer: Recommendations From the Germline Genetics...