Posts tagged with "University of Virginia School of Medicine"

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.

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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.

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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.

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Research Finds Exercise Prevents Vision Loss

Exercise can slow or prevent the development of macular degeneration and may benefit other common causes of vision loss, such as glaucoma and diabetic retinopathy, new research suggests.

A study from the University of Virginia School of Medicine found that exercise reduced the harmful overgrowth of blood vessels in the eyes of lab mice by up to 45%. This tangle of blood vessels is a key contributor to macular degeneration and several other eye diseases.

The study represents the first experimental evidence showing that exercise can reduce the severity of macular degeneration, a leading cause of vision loss, the scientists report. Ten million Americans are estimated to have the condition.

“There has long been a question about whether maintaining a healthy lifestyle can delay or prevent the development of macular degeneration. The way that question has historically been answered has been by taking surveys of people, asking them what they are eating and how much exercise they are performing,” said researcher Bradley Gelfand, PhD, of UVA’s Center for Advanced Vision Science. “That is basically the most sophisticated study that has been done. The problem with that is that people are notoriously bad self-reporters … and that can lead to conclusions that may or not be true. This [study] offers hard evidence from the lab for very first time.”

The Benefits of Exercise

Enticingly, the research found that the bar for receiving the benefits from exercise was relatively low – more exercise didn’t mean more benefit. “Mice are kind of like people in that they will do a spectrum of exercise. As long as they had a wheel and ran on it, there was a benefit,” Gelfand said. “The benefit that they obtained is saturated at low levels of exercise.”

An initial test comparing mice that voluntarily exercised versus those that did not found that exercise reduced the blood vessel overgrowth by 45%. A second test, to confirm the findings, found a reduction of 32%.

The scientists aren’t certain exactly how exercise is preventing the blood vessel overgrowth. There could be a variety of factors at play, they say, including increased blood flow to the eyes.

Gelfand, of UVA’s Department of Ophthalmology and Department of Biomedical Engineering, noted that the onset of vision loss is often associated with a decrease in exercise. “It is fairly well known that as people’s eyes and vision deteriorate, their tendency to engage in physical activity also goes down,” he said. “It can be a challenging thing to study in older people. … How much of that is one causing the other?”

The researchers already have submitted grant proposals in hopes of obtaining funding to pursue their findings further.

“The next step is to look at how and why this happens, and to see if we can develop a pill or method that will give you the benefits of exercise without having to exercise,” Gelfand said. “We’re talking about a fairly elderly population [of people with macular degeneration], many of whom may not be capable of conducting the type of exercise regimen that may be required to see some kind of benefit.” (He urged people to consult their doctors before beginning any
aggressive exercise program.)

Gelfand, a self-described couch potato, disclosed a secret motivation for the research: “One reason I wanted to do this study was sort of selfish. I was hoping to find some reason not to exercise,” he joked. “It turned out exercise really is good for you.”

Findings Published

The researchers have published their findings in the scientific journal IOVS. The research team consisted of Ryan D. Makin, Dionne Argyle, Shuichiro Hirahara, Yosuke Nagasaka, Mei Zhang, Zhen Yan, Nagaraj Kerur, Jayakrishna Ambati and Gelfand, who holds appointments in both UVA’s School of Medicine and School of Engineering. Ambati is a founder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics and has provided consulting services to Allergan, Immunovant, Olix Pharmaceuticals, Retinal Solutions and Saksin LifeSciences unrelated to the findings. Ambati, Gelfand and Kerur are named as inventors on macular degeneration patent applications filed by UVA and the University of Kentucky.

The research was supported by the National Institutes of Health, grants R01EY028027, DP1GM114862, R01EY022238, R01EY024068, R01EY028027, K99EY024336, R00EY024336, R01AI14874, R21EY030651, T32 HL007284, 5T32 GM008715 and R01GM114840; the American Heart Association, grant 13SDG16770008; the John Templeton Foundation, grant 60763; and the Beckman Initiative for Macular Research.

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