Posts tagged with "University of Virginia School of Medicine"

Dentistry illustration by Kaelen Felix for 360 Magazine

Cold Sore Flareup Triggers

Virus Highjacks Important Immune Response, UVA Discovery Reveals

Researchers at the University of Virginia School of Medicine have shed light on what causes herpes simplex virus to flare up, explaining how stress, illness and even sunburn can trigger unwanted outbreaks.

The discovery could lead to new ways to prevent cold sores and recurrent herpes-related eye disease from reoccurring, the researchers report.

“Herpes simplex recurrence has long been associated with stress, fever and sunburn,” said researcher Anna R. Cliffe, PhD, of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This study sheds light on how all these triggers can lead to herpes simplex-associated disease.”

About Herpes Simplex Recurrence

Once you’re infected with herpes simplex virus (HSV) – and more half of Americans are – the virus never really goes away. Instead, it lurks inside neurons, waiting for the right moment to strike again, a process known as reactivation.

Cold sores, also known as fever blisters, are one of the most common symptoms of HSV reactivation. Recurrent reactivation in the eye leads to herpes keratitis, which, if left untreated, can result in blindness. HSV infection has also been linked to the progression of Alzheimer’s disease.

Recurrences of HSV are typically associated with stress, illness or sunburn, but doctors have been uncertain exactly what causes the virus to reactivate. Cliffe and her collaborators found that when neurons harboring the virus were exposed to stimuli that induce “neuronal hyperexcitation,” the virus senses this particular change and seizes its opportunity to reactivate.

Working in a model developed by the Cliffe lab using mouse neurons infected with HSV, the researchers determined that the virus highjacks an important immune response within the body. In response to prolonged periods of inflammation or stress, the immune system releases a particular cytokine, Interleukin 1 beta. This cytokine is also present in epithelial cells in the skin and eye and is released when these cells are damaged by ultraviolet light.

Interleukin 1 beta then increases the excitability in the affected neurons, setting the stage for HSV to flare up, the UVA researchers discovered.

“It is really remarkable that the virus has hijacked this pathway that is part of our body’s immune response,” Cliffe said. “it highlights how some viruses have evolved to take advantage of what should be part of our infection-fighting machinery.”

The scientists say that more research will need to be done to fully understand the potential factors which play into herpes simplex disease. It may vary depending on the virus strain or the type of neuron infected, even. And it is still unknown if the virus alters how neurons respond to cytokines such as Interleukin 1 beta. But the new insights help doctors better understand what is happening in neurons and the immune system, and that could lead to ways to prevent unwanted outbreaks, the researchers hope.

“A better understanding of what causes HSV to reactivate in response to a stimulus is needed to develop novel therapeutics,” Cliffe said. “Ultimately, what we hope to do is target the latent virus itself and make it unresponsive to stimuli such as Interleukin 1 beta.”

Findings Published

The researchers have published their findings in the scientific journal eLife. The research team consisted of Sean R. Cuddy, Austin R. Schinlever, Sara Dochnal, Philip V. Seegren, Jon Suzich, Parijat Kundu, Taylor K. Downs, Mina Farah, Bimal N. Desai, Chris Boutell and Cliffe.

The work was supported by the National Institutes of Health’s National Institute of Neurological Disorder and Stroke, grant R01NS105630; the National Institute of Allergy and Infectious Diseases, grant T32AI007046; the National Eye Institute, grant F30EY030397; the National Institute of General Medical Sciences, grants T32GM008136, T32GM007267, GM108989 and GM007055and Medical Research Council grant MC_UU_12014/5.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Woman at Computer by Mina Tocalini for 360 Magazine

UVA’s DNA Discovery

Scientists have identified a group of drugs that may help stop a leading cause of vision loss after making an unexpected discovery that overturns a fundamental belief about DNA.

The drugs, known as Nucleoside Reverse Transcriptase Inhibitors, or NRTIs, are commonly used to treat HIV. The new discovery suggests that they may be useful against dry macular degeneration as well, even though a virus does not cause that sight-stealing condition.

A review of four different health insurance databases suggests that people taking these drugs have a significantly reduced risk of developing dry macular degeneration, a condition that affects millions of Americans.

“We are extremely excited that the reduced risk was reproduced in all the databases, each with millions of patients,” said Jayakrishna Ambati, MD, a top macular degeneration researcher at the University of Virginia School of Medicine. “This finding provides real hope in developing the first treatment for this blinding disease.”

Targeting Macular Degeneration

The new discovery comes from Ambati; Fred H. Gage, PhD, of the Salk Institute for Biological Studies; and collaborators around the world. The work rewrites our understanding of DNA, revealing for the first time that it can be manufactured in the cytoplasm of our cells, outside the cell nucleus that is home to our genetic material.

The buildup of a certain type of DNA in the cytoplasm, Alu, contributes to macular degeneration, the researchers found. This buildup appears to kill off an important layer of cells that nourishes the retina’s visual cells.

Based on this discovery, the researchers decided to look at drugs that block the production of this DNA, to see if they might help prevent vision loss. They analyzed multiple U.S. health insurance databases – encompassing more than 100 million patients over two decades – and found that people taking NRTIs were almost 40% less likely to develop dry macular degeneration.

The researchers are urging further study to determine if these drugs or safer derivatives known as Kamuvudines, both of which block a key inflammatory pathway, could help prevent vision loss from dry macular degeneration.

“A clinical trial of these inflammasome-inhibiting drugs is now warranted,” said Ambati, the founding director of UVA’s Center for Advanced Vision Science. “It’s also fascinating how uncovering the intricate biology of genetics and combining it with big data archeology can propel insights into new medicines.”

Ambati, of UVA’s Department of Ophthalmology, previously determined that NRTIs may help prevent diabetes as well.

Findings Published

The researchers have published their findings in the scientific journal PNAS. The research team consisted of Shinichi Fukuda, Akhil Varshney, Benjamin J. Fowler, Shao-bin Wang, Siddharth Narendran, Kameshwari Ambati, Tetsuhiro Yasuma, Joseph Magagnoli, Hannah Leung, Shuichiro Hirahara, Yosuke Nagasaka, Reo Yasuma, Ivana Apicella, Felipe Pereira, Ryan D. Makin, Eamonn Magner, Xinan Liu, Jian Sun, Mo Wang, Kirstie Baker, Kenneth M. Marion, Xiwen Huang, Elmira Baghdasaryan, Meenakshi Ambati, Vidya L. Ambati, Akshat Pandey, Lekha Pandya, Tammy Cummings, Daipayan Banerjee, Peirong Huang, Praveen Yerramothu, Genrich V. Tolstonog, Ulrike Held, Jennifer A. Erwin, Apua C.M. Paquola, Joseph R. Herdy, Yuichiro Ogura, Hiroko Terasaki, Tetsuro Oshika, Shaban Darwish, Ramendra K. Singh, Saghar Mozaffari, Deepak Bhattarai, Kyung Bo Kim, James W. Hardin, Charles L. Bennett, David R. Hinton, Timothy E. Hanson, Christian Röver, Keykavous Parang, Nagaraj Kerur, Jinze Liu, Brian C. Werner, S. Scott Sutton, Srinivas R. Sadda, Gerald G. Schumann, Bradley D. Gelfand, Fred H. Gage and Jayakrishna Ambati.

Jayakrishna Ambati is a co-founder of Inflammasome Therapeutics, iVeena Holdings, iVeena Delivery Systems and DiceRx; a full list of the authors’ disclosures is included in the paper.

The research was supported by UVA’s Strategic Investment Fund, the National Institutes of Health Director’s Pioneer Award, the National Institutes of Health’s National Eye Institute and many other generous contributors. A full list is included in the paper.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Science Tech Illustration by Gabrielle Archuleta

Blood Discovery Research x UVA

Blood Discoveries Advance Effort to Grow Organs, Battle Cancer 

New Research Reveals Important Insights Into How Our Bodies Make Blood 

CHARLOTTESVILLE, V.A.– Pioneering research into how our bodies manufacture the cells that make blood has moved us closer to regrowing tissues and organs. These findings also may let doctors grow the cells for transplantation into people to battle cancer, blood disorders and autoimmune diseases.

Researcher Karen K. Hirschi, PhD, of the Department of Cell Biology and Cardiovascular Research Center at the University of Virginia School of Medicine, has developed a simple and efficient way to generate “hemogenic endothelial cells.” These cells are the first step in the production line of blood cells, and Hirschi’s new findings provide a blueprint for creating them outside of the body.

“By studying how hemogenic endothelial cells develop normally, we gain the insight needed to generate them in the lab,” Hirschi said. “Now that we have established a method to produce human hemogenic endothelial cells outside of the body, we will continue to improve their production and function as we learn more about the mechanisms that promote their normal development.”

Building Blood-Making Factories

Hirschi’s latest work, published in a pair of scientific papers, offers important insights into how hemogenic endothelial cells form, and how they ultimately give rise to the cells that directly manufacture blood.

Writing in the prestigious journal, Science, she and her team reveal a key trigger that causes the endothelial cells to “transdifferentiate,” or turn into blood-making factories, during embryonic development. These blood-making (i.e. hemogenic) endothelial cells generate hematopoietic stem and progenitor cells (HSPCs) that have long been used for the treatment of cancer and other diseases. Typically, they are taken from sources such as an individual’s bone marrow, but doctors would like to be able to manufacture them quickly and easily for patients on demand. “Generating human hemogenic endothelial cells in the lab from each patient that needs HSPC is the first step toward patient therapies for blood disorders,” Hirschi said.

In a paper published nearly simultaneously in Cell Reports, Hirschi unveils a blueprint for creating the hemogenic endothelial cells, the source of HSPCs, outside of the body. The secret is a substance called retinoic acid. You may have heard of retinoic acid in association with beauty products, but in this case its responsibilities include triggering genes to cause “hematopoietic transition”–to put more vascular endothelial cells in the business of making blood by producing HSPCs.

The new insights provided by the work “will improve our ability to apply developmental insights to the generation of distinct endothelial cell subtypes for tissue engineering and regenerative medicine,” the researchers write in their new paper. “In addition, our system could likely be developed further to optimize the generation of transplantable HSPCs from human hemogenic endothelial cells for clinical therapies.”

The approach offers several advances over existing means, including being quicker and less expensive, the researchers note.

“We hope our continued efforts will move us closer to treating both vascular and blood disorders,” Hirschi said. “These studies highlight the importance of basic cell and developmental biology research as a foundation for devising strategies for patient-specific clinical therapies.”

Hirschi was recruited from Yale in 2019 to join the faculty in the Department of Cell Biology, which has long been interested in addressing how embryos develop and applying this basic knowledge to the repair and regeneration of damaged tissues and organs.

Findings Published

The Science paper was authored by Dionna M. Kasper, Jared Hintzen, Yinyu Wu, Joey J. Ghersi, Hanna K. Mandl, Kevin E. Salinas, William Armero, Zhiheng He, Ying Sheng, Yixuan Xie, Daniel W. Heindel, Eon Joo Park, William C. Sessa, Lara K. Mahal, Carlito Lebrilla, Hirschi and Stefania Nicoli. The work was supported by the National Institutes of Health (grants F32HL132475, U54DK106857, 1K99HL141687, R01HL130246, R56DK118728, R01HL146056. R01HL128064, R01DK118728 and R01GM049077) and the American Heart Association (grants 19PRE34380749 and19TPA34890046).

The research team responsible for the Cell Reports paper consisted of Jingyao Qiu, Sofia Nordling, Hema H. Vasavada, Eugene C. Butcher and Hirschi. That work was supported by NIH grants HL128064, U2EB017103, R01-AI130471 and R01-CA228019; CT Innovations grant 15-RMB-YALE-04; Department of Veterans Affairs Merit Review award I01BX002919; the Swedish Society for Medical Research; and a Stanford Dean’s Fellowship.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

COVID-19 Trial Tests if Common Drug Can Keep Patients Out of Hospital

At-risk people diagnosed with COVID-19 across the United States and Canada can participate in a clinical trial testing whether a common drug can keep them from getting sicker and keep them out of the hospital.­­

The trial, conducted by Washington University School of Medicine in St. Louis, is based on a discovery by the University of Virginia School of Medicine’s Alban Gaultier, PhD, and a former graduate student, Dorian A Rosen, PhD.

Gaultier and Rosen found last year that the antidepressant fluvoxamine may stop the deadly inflammation known as sepsis, in which the immune response spirals out of control. The drug’s apparent benefit for dampening dangerous inflammation prompted the Washington University researchers to begin investigating its potential benefit for COVID-19, which can also cause dangerous overreactions of the immune system.

“If this clinical trial is proven successful, fluvoxamine could become a standard treatment for patients newly diagnosed with COVID-19, especially patients at risk,” Gaultier said. “Even the best vaccines do not protect 100% of the population, and discovery of safe and affordable treatments to prevent COVID-19-associated complications is critical.”

Fluvoxamine and COVID-19

Earlier this year, the Washington University researchers launched their first clinical trial of the drug in patients with COVID-19. That trial compared fluvoxamine with a harmless placebo in 152 adult outpatients. None of the 80 participants who received fluvoxamine became seriously ill after 15 days, while six patients who received placebo did. Of those six, four were hospitalized, for periods ranging from four to 21 days. One was on a ventilator for 10 days.

Based on those initial results, Washington University is now launching a much larger trial open to residents across the United States and Canada. The trial is seeking approximately 880 at-risk participants, age 18 and older, who have tested positive for COVID-19 and are experiencing mild symptoms.

Participants will be provided with either fluvoxamine or a placebo for approximately 15 days. No face-to-face contact is required; everything necessary will be sent to the participants’ doorsteps.

Contactless Check-Ins

The researchers will track the patients by videochat, email or telephone to determine if fluvoxamine provides a benefit and helps keep participants out of the hospital. During brief daily check-ins, trial participants will report their oxygen levels, blood pressure and temperature, along with whether they are feeling shortness of breath or have had any other problems.

The study team will continue to follow the participants for approximately 90 days after they have finished taking fluvoxamine or the placebo.

The trial is open to people who have at least one risk factor for severe COVID-19, such as being 40 or older, being part of a high-risk racial/ethnic group (such as African-American, Hispanic, Native American or biracial), or having one or more medical conditions such as obesity, diabetes, high blood pressure, heart disease, a lung disease or an immune disorder such as rheumatoid arthritis.

For more information about the trial, visit this website.

health

UVA Tests Different Approach to Managing Type 2 Diabetes

A researcher at the University of Virginia School of Medicine is testing what he calls a “radically different” approach to managing type 2 diabetes for those who can’t or don’t want to lose weight.

Daniel Cox, PhD, professor of psychiatry and internal medicine, said his program “flies in the face of conventionality” in that it doesn’t insist on weight loss as a key component of controlling blood sugar. Instead, it combines continuous glucose monitoring with well-informed eating choices, to understand the effect of different foods on blood-sugar levels, and well-timed exercise, to reduce those levels as needed.

“The convention is ‘lose weight.’ And if you lose weight, you lose belly fat, and if you lose belly fat, you lose adipose tissue in the liver. And that, in turn, reduces insulin resistance,” Cox said. “That’s all fine and good. And if you can, in fact, lose a significant amount of weight and keep it off for a long time – a lifetime – you’re golden. You can even put diabetes in remission. There’s nothing wrong with that approach, and it’s a very effective approach. But some people don’t need to lose weight, and some people don’t want to lose weight, and other people want to lose weight but they can’t, or they can’t keep it off for a lifetime.”

A Different Take on Diabetes Management

Cox’s approach relies on continuous glucose monitoring to help people understand how their food choices affect their blood sugar. Different foods may affect people differently, he notes.medicine

Continuous glucose monitoring involves wearing a sensor on the back of the arm that continually sends a signal to a receiver that shows the person’s blood glucose level, without the need for fingersticks. Continuous glucose monitoring lets people see how a particular food affects their blood-glucose levels, whether it’s a sugary slice of cake or a seemingly healthy bowl of oatmeal, Cox said. Understanding that lets them make smart choices to keep their blood sugar under control.

If they do choose to indulge in a sugar-spiking food, the program encourages them to use light exercise, such as walking, to help bring their blood sugar back into check.

“This is the innovation: One, you dampen how much [blood sugar] goes up by minimizing the amount of carbohydrate you eat, and, two, you hasten its recovery by becoming more physically active,” Cox said. “Physical activity does two things: One, the skeletal muscle burns blood glucose as fuel, and, two, physical activity reduces your insulin resistance for a short period of time, about 24 hours.”

“Instead of fixing supper and having a great dinner and then plopping in front of the TV for the rest of the night, the alternative is becoming more physically active,” Cox said. “Do your shopping after you eat, walk the dog after you eat, clean your house after you eat.”

About the Diabetes Clinical Trial

Cox, of UVA’s Department of Psychiatry and Neurobehavioral Sciences, is testing his approach in small clinical trials at UVA, West Virginia University and the University of Colorado. Each site is recruiting four people newly diagnosed with type 2 diabetes who have not yet begun taking medication. The participants will be provided with a treatment manual, continuous glucose monitors and activity/sleep trackers. Trial organizers will then check in with them virtually over several weeks to see how well the approach keeps their blood sugar under control.

The study is the latest in a series evaluating the approach. Cox said he has been encouraged by previous results but notes that “there’s no one approach that works for everybody.”

“In our 12-month follow-up study, slightly over half of participants – 52 percent of people – we would still classify as responders, meaning they’re having a significant benefit,” he said.

For the right people, he said, the approach may offer a way to control blood sugar without medication or with less medication, while still allowing flexibility in dietary choices. “We’re not asking for radical changes in lifestyle,” he said. “We’re asking for modest changes in lifestyle that directly impact blood sugar.”

For More Information

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

Gym Illustration by Rita Azar for 360 Magazine

UVA on Battling Diseases by Exercise

A top exercise researcher and colleagues at the University of Virginia School of Medicine have launched an ambitious effort to understand the whole-body benefits of exercise so that doctors can use that information to prevent and treat disease.

Zhen Yan, PhD, and his collaborators aim to identify the sources, functions and targets of the molecules that provide exercise’s well-documented health benefits. By understanding this, doctors will better understand how exercise helps fend off disease, and they may be able to design drugs to mimic those benefits for people who cannot exercise, such as those with limited mobility. The cutting-edge research could open new doors both for preventing and treating many common illnesses, the researchers hope.

“No one would dispute that physical activity or regular exercise is the best measures for health promotion and disease prevention,” said Yan, director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center. “In fact, the health benefits of exercise are way beyond our imagination. The underlying reasons for the superb health benefits of exercise are being uncovered by many talented and passionate scientists around the world.”

Understanding How Exercise Improves Health

The UVA researchers have recently joined a national consortium seeking to create a “molecular map” of exercise benefits. Known as the Molecular Transducers of Physical Activity Consortium, or MoTrPAC, the group includes researchers at top institutions across the country, including Harvard, Duke, Stanford and Mayo Clinic.

The consortium came about after the National Institutes of Health invited Yan and a dozen other prominent scientists to a roundtable discussion in 2010 about the future of exercise research and the obstacles that stood in its way. The NIH then set aside almost $170 million for MoTrPAC’s research – believed to be the agency’s largest-ever investment into the mechanisms of how physical activity improves health and prevents disease.

“The program’s goal,” Yan explained, “is to study the molecular changes that occur during and after exercise and ultimately to advance the understanding of how physical activity improves and preserves health.”

The consortium is looking at exercise benefits in both humans and animal models. Initial animal research was conducted at Harvard, the University of Iowa and the University of Florida. In the latest round, UVA is joined by the University of Missouri, the University of Kansas Medical Center and the University of California, Los Angeles.

The vast amount of information collected as part of the project so far has poised the UVA team to make “unprecedented” advances, Yan reports. He and his multi-disciplinary team will employ advanced computer algorithms to sift through the heaps of data to identify specific molecules to study. They will then conduct state-of-the-art research in lab mice using gene editing, combined with a wide range of functional assessment, including muscle, cardiac, metabolic and cognitive/mental functions. This will let them determine the effects the molecules have and lay a foundation for doctors to harness the molecules to benefit human health in the future.

Yan’s team will work closely with colleagues at Stanford, who will conduct advanced “multiomics” analyses, meaning they will bring together data on genes, cellular proteins and much more to obtain a more holistic understanding of exercise’s benefits to the body.

UVA’s research team includes Yan, of the Robert M. Berne Cardiovascular Research Center and the Departments of Medicine, Pharmacology and Molecular Physiology and Biological Physics; Wenhao Xu, PhD, of the Department of Microbiology, Immunology and Cancer Biology; Chongzhi Zang, PhD, of UVA’s Center for Public Health Genomics, the Department of Public Health Sciences and the Department of Biochemistry and Molecular Genetics; Matthew Wolf, MD, PhD, of the Department of Medicine’s Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center; Thurl Harris, PhD, of the Department of Pharmacology; and Alban Gaultier, PhD, and John Lukens, PhD, both part of UVA’s Department of Neuroscience and the Center for Brain Immunology and Glia (BIG).

“It is well known that exercise is one of the best treatments for mood disorders,” Gaultier said. “We are excited to test the group discoveries using animal models of anxiety and depression.”

“This is an exciting opportunity for team science,” Zang said. “I am happy to work with colleagues at UVA and across the country and use data-science approaches to unravel the complex molecular effects of exercise.”

UVA’s effort has received almost a half-million dollars in backing from the NIH’s fund for MoTrPAC’s research.

“Our research team encompasses exceptional talents. The collective wisdom and expertise of the team at UVA and MoTrPAC will allow us to reach a level that we would not be able to reach by an individual,” Yan said. “It is an unprecedented opportunity in our lifetime to tackle this incredibly important question to mankind.”

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

MORE: Exercise may help prevent deadly COVID-19 complication.

Kaelen Felix Illustrates a COVID-19 Article for 360 MAGAZINE

Antidepressant x COVID-19

Based on a trial from the University of Virginia School of Medicine, the antidepressant fluvoxamine appears to prevent COVID-19 infections from worsening, even keeping patients out of the hospital.

The clinical trial was conducted by the Washington University School of Medicine in St. Louis. Fluvoxamine was compared with a placebo in 152 adult patients who were infected with the coronavirus.

80 participants received the fluvoxamine, and not one of the 80 became seriously ill after 15 days. Six patients receiving the placebo became seriously ill with four being hospitalized for between four and 21 days. One of the four in the hospital was on a ventilator for 10 days.

Though the sample size was relatively small, the data is believed to be statistically significant. The plan is to launch a larger trial in coming weeks.

Eric J. Lenze, MD, of the Washington University School of Medicine, said patients who took fluvoxamine did not require hospitalization because of issues in lung function.

“Most investigational treatments for COVID-19 have been aimed at the very sickest patients, but it’s also important to find therapies that prevent patients from getting sick enough to require supplemental oxygen or to have to go to the hospital,” Lenze said. “Our study suggests fluvoxamine may help fill that niche.”

UVA’s Alban Gaultier, PhD, and former graduate student Dorian A. Rosen, PhD, found in 2019 that fluvoxamine may stop sepsis, a deadly inflammation causing the immune system to spiral out of control. The findings of Gaultier and Rosen inspired the tests at the Washington University School of Medicine.

Gaultier and Rosen determined that fluvoxamine reduces the production of cytokines, which have been linked to deadly cytokine storms, which are thought to occur in severe cases of COVID-19

“Because elevated cytokines levels have been associated with COVID-19 severity, testing fluvoxamine in a clinical trial made a lot of sense to us,” said Gaultier. “We are still unclear about the mode of action of fluvoxamine against SARS-CoV-2, but research is under way to find the answer.”

Washington University’s Angela M. Reiersen, MD, said the drug works by interacting with the sigma-1 receptor to reduce the production of inflammatory molecules.

“Past research has demonstrated that fluvoxamine can reduce inflammation in animal models of sepsis, and it may be doing something similar in our patients,” Reiersen said.

The limitations of the research were emphasized. The small sample size was noted along with the fact that 20% of participants stopped answering surveys during the trial. Though the researchers could rule out hospital visits for those who stopped answering, they did believe it possible that the participants sought treatment elsewhere.

Because of the limitations, the findings should be considered encouraging and worthy of further research rather than iron clad truth.

Gaultier said, “If a larger clinical trial (phase III) confirms the results, fluvoxamine would be a perfect treatment for COVID patients newly diagnosed. Fluvoxamine is not an experimental drug, it is cheap and safe and could be available as a first line of defense to unburden the hospitals that are overwhelmed by the COVID health crisis.”

For more medical research news from UVA, you can click right here.

Brain Cancer illustrated by Mina Tocalini for 360 MAGAZINE.

Cancer Discovery Reveals Key Process in Tumor Formation

A discovery from the University of Virginia School of Medicine may open the door to an entirely new approach to treating cancer: by disrupting a vital condensation process inside cancer cells.

Researchers led by Hao Jiang, PhD, of UVA’s Department of Biochemistry and Molecular Genetics, discovered that cancer cells are exceptionally dependent on the proper condensation of a particular protein, AKAP95, during tumor formation. Blocking this process halted the cancer cells in their tracks.

“It is now clear that biomolecular condensation is a fundamental mechanism that underlies numerous biological processes in normal physiology and also in human disease including cancer,” said Jiang, of UVA’s Department of Biochemistry and Molecular Genetics and the UVA Cancer Center. “Our work reveals a new level of regulation – how liquid-like the condensates are can affect their activity in cancer control.”

Cancer and Condensation

The process of “biomolecular condensation” inside our cells is an area of great interest for scientists. In essence, our cells use condensation to create little compartments for important biological processes. You might think of these compartments as virtual mixing bowls that cells manufacture as needed.

It has been largely unclear if this condensation process is important in cancer. Jiang and his team showed that both the formation of the condensates and their material properties are important for cancer, and their work suggests that disrupting condensation or changing the condensate properties may offer a new treatment strategy.

The researchers’ lab experiments show that the AKAP95 protein gets condensed in cells, and cancer cells become heavily reliant on it. For that to happen, the condensed proteins, which are liquid-like, must be just the right consistency. Hardening them, for example, significantly impaired tumor formation, Jiang and his team discovered. Disrupting the condensation process halted cancer formation entirely.

A treatment based on the discovery might take a similar approach. Disrupting the condensation of AKAP95, the research suggests, could prevent cancer from hijacking our cells.

While much more work needs to be done to determine the possibility of developing a treatment based on the discovery, Jiang is happy to have shed light on tumor formation and to have provided cancer researchers a new avenue to explore.

“I was completely enthralled by this mechanism, as I had never learned or thought of such a seemingly simple principle of molecular organization in textbooks, previous classes or training, but it actually makes great sense and has such a profound impact on almost all basic cellular activities. My lab is thus very interested in how biomolecular condensation regulates gene expression on various levels, especially in the context of cancer,” Jiang said. “Further studies in this field will likely provide us unconventional strategies in cancer treatment.”

Findings Published

The researchers have published their findings in the scientific journal Nature Cell Biology. The research team consisted of Wei Li, Jing Hu, Bi Shi, Francesco Palomba, Michelle A. Digman, Enrico Gratton and Jiang.

The research was supported by startup funds from UVA and the University of Alabama at Birmingham, along with Department of Defense Breast Cancer Research Program Breakthrough Award BC190343. The work used the confocal microscopy system at UVA’s Keck Center that was supported by National Institutes of Health grant OD016446.

Jiang was supported by the American Society of Hematology Scholar Award, the American Cancer Society Research Scholar Award (RSG-15-166-01-DMC) and the Leukemia & Lymphoma Society Scholar Award (1354-19). Palomba and Digman were supported in part by National Science Foundation grant MCB-1615701. Digman and Gratton were supported by NIH grant P41-GM103540.

To keep up with the latest medical research news from UVA:

Subscribe to the Making of Medicine blog HERE.

 

Covid Mental Health illustration by Mina Tocalini

The Coma Plan – New Treatment for Comatose Patients

Leading coma experts have created an ambitious plan to help doctors better care for comatose patients and answer that most awful question: “Will my loved one wake up?”

To clarify, the three-part plan outlines key steps physicians and researchers should take in the coming years to improve patient care and deepen our understanding of coma and other conditions that reduce consciousness. The plan was developed by a blue-ribbon scientific advisory council as part of the Neurocritical Care Society’s Curing Coma Campaign, a major effort launched in 2019.

“We now have the tools to understand comatose patients in a way we haven’t in the past. This opens the door to ask the question, ‘Can we improve consciousness in patients in a coma?’” said advisory council member and lead author J. Javier Provencio, MD, director of UVA Health’s Nerancy Neuroscience Intensive Care Unit. “This research endeavor aims to help patients and families dealing with the consequences of brain damage gain clarity about the current chances for improvement and maintain hope that, in the future, there will be treatments to help recover consciousness.”

The Coma Plan’s Three Pillars

The plan’s first recommendation is to better classify and understand different types of coma and their causes. Currently, treatments are limited in part because it is difficult for physicians to distinguish between different underlying mechanisms of impaired consciousness, the researchers say. This makes it challenging to predict whether patients will recover.

Therefore, they suggest several different classifications. For example, coma without underlying physical damage, such as those caused by drug overdoses or seizures, are often reversible using available treatments. Another category is particularly tricky – coma with hidden physical causes. Better categorization of common coma “endotypes” will help physicians with their diagnoses and treatment decisions, the council says.

The council also urges the development of better indicators of patient prognosis. These indicators, known as biomarkers, already play important roles in guiding treatment. But more sophisticated ones are needed to understand the complex interactions occurring inside the brain. This will help doctors guide patients to better outcomes and advise families on how well their loved one will recover.

Finally, the council urges clinical trials of new therapies to promote recovery of consciousness for intensive-care patients who are in comas or suffering from other forms of reduced consciousness.

“We envision that a principled, mechanistic approach to predicting and measuring responses to new therapies in the ICU could allow clinicians to provide targeted treatments that are personalized to each patient, ensuring that each patient is given the best possible chance to recover consciousness in the ICU and beyond,” the council members write in a new paper outlining their recommendations.

“Coma is the most severe manifestation of brain injury,” Provencio said. “With this initiative, we hope to be able to treat patients in a coma the way we treat patients with strokes and heart attacks. In the future, having impaired consciousness from brain injury won’t be the lifelong medical condition it is now.”

About the Coma Plan

The advisory council has published its recommendations in the scientific journal Neurocritical Care. The council consisted of Provencio, J. Claude Hemphill, Jan Claassen, Brian L. Edlow, Raimund Helbok, Paul M. Vespa, Michael N. Diringer, Len Polizzotto, Lori Shutter, Jose I. Suarez, Robert D. Stevens, Daniel F. Hanley, Yama Akbari, Thomas P. Bleck, Melanie Boly, Brandon Foreman, Joseph T. Giacino, Jed A. Hartings, Theresa Human, Daniel Kondziella, Geoffrey S.F. Ling, Stephan A. Mayer, Molly McNett, David K. Menon, Geert Meyfroidt, Martin M. Monti, Soojin Park, Nader Pouratian, Louis Puybasset, Benjamin Rohaut, Eric S. Rosenthal, Nicholas D. Schiff, Tarek Sharshar, Amy Wagner, John Whyte and DaiWai M. Olson writing on behalf of the Neurocritical Care Society Curing Coma Campaign.

Provencio disclosed that he has received grants and personal fees from Minnetronix Inc., a medical technology company. A full list of the other authors’ disclosures is included in the paper.

Keep up with the latest medical research news from UVA

Subscribe to the Making of Medicine blog HERE

 

Brain Cancer illustrated by Mina Tocalini for 360 MAGAZINE.

Brain Cancer Gene Identified

Scientists have identified an oncogene (a cancer-causing gene) responsible for glioblastoma, the deadliest brain tumor. The discovery offers a promising new treatment target for a cancer that is always fatal.

The researchers say the oncogene is essential to the survival of the cancer cells. Without it, the cancer cells die. Scientists have already developed many targeted therapies for other cancers with a similar “oncogene addiction.”

“Glioblastoma is one of the most deadly cancers. Unfortunately, there is no effective treatment option for the disease. The current standard option, radiation plus temozolomide, which displayed a 2.5-month better survival rate, was hailed as a great success. Clearly, better understanding and new therapeutic targets are urgently needed,” said researcher Hui Li, PhD, of the University of Virginia School of Medicine. “The novel oncogene we discovered promises to be an Achilles’ heel of glioblastoma, with its specific targeting potentially an effective approach for the treatment of the disease.”

Targeting Glioblastoma

Oncogenes are naturally occurring genes that spiral out of control and cause cancer. The oncogene Li and his colleagues identified, AVIL, normally helps cells maintain their size and shape. But the gene can be shifted into overdrive by a variety of factors, the researchers found. This causes cancer cells to form and spread.

Blocking the gene’s activity completely destroyed glioblastoma cells in lab mice but had no effect on healthy cells. This suggests targeting the gene could be an effective treatment option.

“AVIL is overexpressed in 100% of glioblastoma cells and clinical samples, and is expressed at even higher level in so-called glioblastoma stem cells, but hardly expressed in normal cells and tissues,” said Li, of UVA’s Department of Pathology. “Silencing the gene wiped out glioblastoma cells in culture and prevented animal xenografts, while having no effect on normal control cells. Clinically, high AVIL expression correlates with worse patient outcome. These findings and classic transformation assays proved AVIL being a bona fide oncogene.”

Identifying Oncogenes

Identifying an oncogene, as Li and his colleagues have done, is an important step toward developing a treatment. But identifying oncogenes is very difficult. The environment inside cells is so complex that it’s hard to determine cause-and-effect.

Li and his team weren’t even working on glioblastoma when they first caught the scent that led to the discovery. Instead, they were studying a rare childhood cancer called rhabdomyosarcoma. (Childhood cancers typically are easier to understand and involve fewer mutations than adult cancers.)

During their research, the scientists discovered an abnormality in the AVIL gene. That prompted them to examine adult cancers to see if the gene could be contributing there. And it was. The researchers concluded the gene plays a “critical role” in glioblastoma, they report in a new scientific paper outlining their findings.

Li and his team believe their approach can be used to discover other oncogenes – hopefully leading to new treatments for a variety of cancers.

“In this day and age, many people thought that all the significant oncogenes have been discovered, Here we uncovered a novel, powerful oncogene and elucidated its signaling pathways, all starting from studying a structure variant in pediatric cancer. In the past, numerous significant discoveries in cancer also stemmed from studying pediatric tumors,” Li said. “We believe this is a strategy that can be applied to find novel players in other adult cancers.”

Glioblastoma Findings Published

The researchers have published their findings in the scientific journal Nature Communications. The research team consisted of Zhongqiu Xie, Pawel Ł. Janczyk, Ying Zhang, Aiqun Liu, Xinrui Shi, Sandeep Singh, Loryn Facemire, Kristopher Kubow, Zi Li, Yuemeng Jia, Dorothy Schafer, James W. Mandell, Roger Abounader and Li.

The research was supported by the National Institutes of Health’s National Cancer Institute, grant CA240601, and Stand Up To Cancer, grant SU2C-AACR-IRG0409.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Follow UVA School of Medicine: Facebook | Twitter | YouTube