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A drug used to treat certain advanced breast cancers may offer a new treatment option for a deadly blood cancer known as myelofibrosis, new research from UVA Cancer Center suggests.
The drug, palbociclib, may be able to prevent the scarring of bone marrow that existing treatments for myelofibrosis cannot. This scarring disrupts the marrow’s production of blood cells and causes severe anemia that leaves patients weak and fatigued. The scarring also reduces the number of platelets in the blood, making clotting difficult, and often causes an enlarged spleen.
“Current therapies only provide symptomatic relief without offering significant improvement of bone marrow fibrosis. So, there is a critical need to develop more effective therapy for myelofibrosis,” said senior researcher Golam Mohi, PhD, of the University of Virginia School of Medicine’s Department of Biochemistry and Molecular Genetics. “We have identified CDK6, a regulator of cell cycle, as a new therapeutic target in myelofibrosis. We demonstrate that CDK4/6 inhibitor palbociclib in combination with ruxolitinib markedly inhibits myelofibrosis, suggesting this drug combination could be an effective therapeutic strategy against this devastating blood disorder.”
Myelofibrosis: A Dangerous Cancer
Myelofibrosis is a form of leukemia. It occurs in approximately 1 to 1.5 of every 100,000 people, primarily those who are middle-aged or older. Patients with intermediate or high-risk cases typically survive only 16 to 35 months.
Existing treatments for myelofibrosis do not address the bone marrow scarring that is a hallmark of the disease. The drug ruxolitinib is used to relieve patients’ symptoms, but Mohi’s new research suggests that pairing the drug with palbociclib may make a far superior treatment.
Palbociclib, by itself, reduced bone marrow scarring in two different mouse models of myelofibrosis. It also decreased the abnormally high levels of white blood cells seen in myelofibrosis and shrank the mice’s enlarged spleens.
Combining the drug with ruxolitinib offered even more benefits, restoring the bone marrow and white blood cell counts to normal and dramatically reducing the size of the mice’s enlarged spleens.
Additional research is needed to determine if the findings will hold true in human patients. But Mohi and his team are hopeful. They note that palbociclib is known to quiet the activity of bone marrow in patients with metastatic breast cancer (cancer that has spread to other parts of the body), and they hope there will be beneficial effects in patients with myelofibrosis.
“A combinatorial therapeutic approach involving palbociclib and ruxolitinib will enable lowering the doses of each of the inhibitors and thus reducing toxicities while enhancing the therapeutic efficacy,” they write in a new scientific paper outlining their findings.
New treatments for myelofibrosis are particularly needed because ruxolitinib treatment does not offer significant reduction in bone marrow fibrosis and often loses its effectiveness with prolonged use, the researchers note.
“The findings from this study are very exciting, and they support the clinical investigation of palbociclib and ruxolitinib combination in patients with myelofibrosis,” Mohi said.
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Materials provided by University of Virginia Health System. Note: Content may be edited for style and length.

The research found that those with more severe COVID-19 symptoms scored lower on an online series of tests, with performance on reasoning and problem-solving tasks being most affected. Further analysis of the data indicated that those who received mechanical ventilation to help them breathe whilst in hospital had the greatest impairment on cognitive tasks.
Published in the journal EClinicalMedicine, the research was a collaboration between King’s College London, Imperial College London and Cambridge University. It was part-funded by the UK Dementia Research Institute Care Research & Technology Centre and the National Institute of Health Research (NIHR) Maudsley Biomedical Research Centre.
Online cognition tests
A series of online tests, developed by first author on the study and Reader in Restorative Neuroscience at Imperial College London Dr Adam Hampshire had been opened up to the general public just before the pandemic for the BBC2 Horizon’s Great British Intelligence test. In early 2020 the study team extended the questionnaires to gather information on SARS-CoV-2 infection, the symptoms experienced and the need for hospitalisation.
Out of the 81,337 who provided complete data, 12,689 people suspected they had COVID-19. Participants reported a range of severity of illness, with many experiencing respiratory symptoms whilst still being able to stay at home (3,559 participants). Nearly 200 were hospitalised (192 participants) and about a quarter of these (44 participants) required mechanical ventilation.
The time since illness onset was around 1-6 months, meaning the study could not draw any definitive conclusions about whether these effects on cognition were long-lasting.

A simple addition to injected COVID-19 vaccines could enhance their effectiveness and provide “border protection” immunity in areas like the nose and mouth to supplement antibodies in the bloodstream, new research suggests.
The strategy involves dampening the activity of an enzyme produced by some white blood cells when they’re responding to the vaccine challenge. When highly active, this enzyme breaks down not just the pathogen — its job — but also degrades pieces of cells that participate in the immune response.
Research in mice showed that an experimental COVID-19 vaccine containing a compound to inhibit the enzyme stimulated a robust antibody response that included immunity in the nose and mouth, ultimately providing extra protection for airways and the gastrointestinal tract.
“Our approach is to improve ‘border control.’ The benefits are broad because in addition to providing protection in the bloodstream like most vaccines do, we also have excellent protection in the doors and windows of the body that communicate with the outside,” said senior study author Prosper Boyaka, professor and chair of the Department of Veterinary Biosciences at The Ohio State University.
“If we protect the mucosal area where the pathogen enters, then even if you don’t reach total immunity there, you limit the amount of pathogen that enters the body so the antibodies inside are more efficient at clearing the infection.”
The experimental vaccine was produced by packaging a segment of the SARS-CoV-2 (the virus that causes COVID-19) spike protein as an antigen with the common vaccine ingredient aluminum salts and an enzyme inhibitor. The findings suggest this affordable design could be particularly helpful in developing countries, where cold storage needed for existing vaccines is a challenge, said Boyaka, also an investigator and program director in Ohio State’s Infectious Diseases Institute.

One of the reasons pancreatic cancer remains the most deadly of the major cancers is that it craftily rewires normal cell survival mechanisms to keep itself supplied with nutrients to fuel its expansion.
A new study led by the University of Michigan Rogel Cancer Center demonstrates how inhibiting a key enzyme known as GOT1 can flip a switch in the cancer cells — causing them to shift from using nutrients to fuel growth toward conserving them to maintain energy levels.
In this state, the cancer cells release their iron stores and become vulnerable to a form of programmed, iron-dependent cell death known as ferroptosis, according to findings in cell cultures that appear in Nature Communications.
“If pancreatic cancer’s success comes from approaching nutrient metabolism differently than other cancers, our goal is to target aspects of that metabolism for therapeutic benefit,” said study senior author Costas Lyssiotis, Ph.D., an associate professor of molecular and integrative physiology and of internal medicine at U-M.
The study was led by first author Daniel Kremer, Ph.D., a recent graduate of U-M Program in Chemical Biology and former member of the Lyssiotis lab.
The GOT1 pathway helps the cancer cells maintain their energy balance, Kremer explained.
“When we inhibit the enzyme, it doesn’t kill the cell, but it puts it into a state of energetic stress, so it has to use those nutrients to maintain the cell rather than for growth,” he said. “This study describes the mechanisms of that process and how we might be able to exploit it to trigger cell death through ferroptosis.”
Key collaborators on the project include Yatrik Shah, Ph.D., of the Rogel Cancer Center and Kenneth Olive, Ph.D., of Columbia University and the Herbert Irving Comprehensive Cancer Center.
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Materials provided by Michigan Medicine – University of Michigan. Original written by Ian Demsky. Note: Content may be edited for style and length.

Steroid-based inhalers deliver life-saving medication for millions of asthma sufferers, providing relief and the ability to simply breathe. Unfortunately, inhalers do not work for all patients, and with rates on the rise for a disease that leads to hundreds of thousands of deaths world-wide each year, new asthma treatments and strategies are needed.
A team of UConn researchers — including Assistant Professor of Chemistry in the College of Liberal Arts and Sciences Jessica Rouge and Associate Professor of Pathobiology in the College of Agriculture, Health, and Natural Resources Steven Szczepanek — are collaborating to develop novel asthma therapeutics using gene-silencing nanocapsules in a bid to help patients who aren’t benefiting from existing treatments. Their research was published in ACS Nano.
“When treating asthma, many people think of small molecule anti-inflammatory medications as the way to go, but there are plenty of patients who have asthma who do not respond to corticosteroids,” says Rouge. “There’s an unmet need for creating different therapeutics that can suppress asthma for this group of people.”
Rouge’s research group, including co-authors Ph.D. student Shraddha Sawant and Alyssa Hartmann ’20 Ph.D., designs nanomaterials and targeted therapeutics that deliver gene silencing messages to cells. This paper details a nucleic acid nanocapsule (NAN) designed to selectively deliver an enzyme, called a DNAzyme, to silence a component of the immune response, called GATA-3, that leads to the over-expression of immune components that play a significant role in allergic asthma attacks.
Szczepanek explains there are different types of asthma, and this technology is designed to treat allergic asthma specifically, which constitutes about 50% of cases in adults and 90% in children. GATA-3-based treatments are already showing promise in clinical trials, and Rouge says that by pairing the sequence with nanotechnology, they hope to provide more efficient means of delivery and treatment straight to the source of inflammation.
“When using nanomaterials, we try to administer the therapy in a way that could allow us to use less materials to get a bigger effect,” Rouge says.

A set of brain signals known to help memories form may also influence blood sugar levels, finds a new study in rats.
Researchers at NYU Grossman School of Medicine discovered that a peculiar signaling pattern in the brain region called the hippocampus, linked by past studies to memory formation, also influences metabolism, the process by which dietary nutrients are converted into blood sugar (glucose) and supplied to cells as an energy source.
The study revolves around brain cells called neurons that “fire” (generate electrical pulses) to pass on messages. Researchers in recent years discovered that populations of hippocampal neurons fire within milliseconds of each other in cycles, with the firing pattern is called a “sharp wave ripple” for the shape it takes when captured graphically by EEG, a technology that records brain activity with electrodes.
Published online in Nature on August 11, a new study found that clusters of hippocampal sharp wave ripples were reliably followed within minutes by decreases in blood sugar levels in the bodies of rats. While the details need to be confirmed, the findings suggest that the ripples may regulate the timing of the release of hormones, possibly including insulin, by the pancreas and liver, as well of other hormones by the pituitary gland.
“Our study is the first to show how clusters of brain cell firing in the hippocampus may directly regulate metabolism,” says senior study author György Buzsáki, MD, PhD, the Biggs Professor in the Department of Neuroscience and Physiology at NYU Langone Health
“We are not saying that the hippocampus is the only player in this process, but that the brain may have a say in it through sharp wave ripples,” says Buzsáki, also a faculty member in the Neuroscience Institute at NYU Langone.

The World Health Organization is testing three additional drugs as part of an enormous global trial to find effective treatments for Covid-19, the agency announced on Wednesday.The trial, which involves researchers at more than 600 hospitals in 52 countries, will evaluate whether the drugs that have already been approved for other uses — one for malaria, one for cancer and one for autoimmune diseases — can reduce the risk of death in patients who are hospitalized with Covid.Dr. Tedros Adhanom Ghebreyesus, the director general of the W.H.O., said Wednesday that he hoped that “one or more of the drugs” would prove effective in treating the virus.Although there are already some treatments available for people with Covid-19, including steroids and monoclonal antibodies, Dr. Tedros said, “We need more for patients at all ends of the clinical spectrum.”The first phase of the W.H.O.’s trials for new drugs, which it called Solidarity, yielded disappointing results. Researchers found that four different drugs, including hydroxychloroquine and the antiviral drug remdesivir, had few or no benefits for hospitalized Covid patients.The three drugs in the new trial, called Solidarity Plus were selected by an independent panel of experts and are being donated by their manufacturers, Ipca, Novartis and Johnson & Johnson. The drugs are artesunate, an antimalarial drug that may have an anti-inflammatory effect; imatinib, an anticancer drug that might help reverse lung damage; and infliximab, a drug for autoimmune disorders that might help tamp down an overly aggressive immune response to the virus.

In a new study, U.S. and Danish researchers report that patients hospitalized with Lyme disease had a 28 percent higher rate of mental disorders and were twice as likely to have attempted suicide post-infection, compared to individuals without the diagnosis.
The study, a collaboration of Columbia University and the Copenhagen Research Centre for Mental Health, is believed to be the first large, population-based study examining the relationship between Lyme disease and psychiatric outcomes.
The research appears in the July 28 online edition of the American Journal of Psychiatry.
“It is time to move beyond thinking of Lyme disease as a simple illness that only causes a rash,” said Brian Fallon, MD, MPH, a psychiatrist with the New York State Psychiatric Institute and Columbia University who is the lead author of the paper. “In addition to the risk of severe cardiac, rheumatologic, and neurologic problems, Lyme disease can cause severe mental health problems as well.”
Dr. Fallon, one of the foremost researchers of the neuropsychiatric effects of Lyme disease, is director of the Lyme and Tick-borne Diseases Research Center at Columbia. The team of investigators on the study includes Michael Benros MD, PhD, principal investigator; Trine Madsen, PhD, co-first author; and Annette Erlangsen, PhD, all psychiatric epidemiologists at the Research Centre for Mental Health.
Higher Rate of Death by Suicide
To conduct their study, the researchers analyzed the medical record diagnoses of nearly 7 million people living in Denmark over a 22-year period, comparing the mental health data of individuals after a hospital-based diagnosis of Lyme disease to the rest of the Danish population who had never had a Lyme diagnosis recorded in the national medical register.

Contrary to the popular song, the neck bone is actually connected to one of 22 separate head bones that make up the human skull. These plate-like bones intersect at specialized joints called sutures, which normally allow the skull to expand as the brain grows but are absent in children with a birth defect called craniosynostosis. A new study in Nature Communications presents a detailed cellular atlas of the developing coronal suture, the one most commonly fused as a consequence of single gene mutations. The study brought together scientists from the laboratories of Gage Crump, Robert Maxson, and Amy Merrill at USC, and the laboratories of Andrew Wilkie and Stephen Twigg at the University of Oxford.
“Named for its location at the crown of the head, the coronal suture is affected in a number of birth defects,” said lead author D’Juan Farmer, a postdoctoral fellow in the Crump Lab. “These infants and children have to undergo a series of invasive and dangerous surgeries to expand their skulls, and we wanted to understand why the coronal suture is particularly sensitive to gene disruptions. So with an aim toward advancing new interventions for patients, we created the first detailed cell-by-cell description of how this suture develops.”
To achieve this, Farmer and his collaborators isolated cells from the developing coronal sutures of mice. The team then used sophisticated new DNA sequencing techniques to catalog the activities of all the protein-coding genes in thousands of individual cells.
Based on unique fingerprints of gene activity, they were able to identify 14 distinct types of cells in and around the developing suture. In so doing, they also identified new genes that may be involved in generating and maintaining the stem cells that grow the skull bones on either side of the suture.
In the tissue connecting the skull bones to the underlying brain, the scientists identified many interesting cell types that may communicate to the suture stem cells to regulate their activity. The scientists also found overlying ligament-like cells that connect the skull plates and persist into adulthood. When stretched by the growing brain, these ligament-like cells could potentially serve as an indicator to nearby bone precursors that it’s time to enlarge the skull.
The scientists also looked at a mouse model for a particular form of craniosynostosis, Saethre-Chotzen Syndrome, to understand how the different cell types may be affected. In healthy mice, the suture stem cells were distributed asymmetrically. This likely contributes to a unique feature of the coronal suture: an overlap of the skull plates. In contrast, mice with craniosynostosis had far fewer suture stem cells, arranged in a more symmetrical distribution. This may cause the edges of the skull plates to grow directly into each other and contribute to suture fusions.
“By examining the very earliest stages of coronal suture development at cellular resolution, our study provides key insights into why this suture is particularly vulnerable to defects in newborns with craniosynostosis,” said Farmer. “We hope that these findings can inform less invasive or even preventative treatments for infants and children with this devastating birth defect.”
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Materials provided by Keck School of Medicine of USC. Original written by Cristy Lytal. Note: Content may be edited for style and length.

A team of researchers at Washington University School of Medicine have developed a deep learning model that is capable of classifying a brain tumor as one of six common types using a single 3D MRI scan, according to a study published in Radiology: Artificial Intelligence.
“This is the first study to address the most common intracranial tumors and to directly determine the tumor class or the absence of tumor from a 3D MRI volume,” said Satrajit Chakrabarty, M.S., a doctoral student under the direction of Aristeidis Sotiras, Ph.D., and Daniel Marcus, Ph.D., in Mallinckrodt Institute of Radiology’s Computational Imaging Lab at Washington University School of Medicine in St. Louis, Missouri.
The six most common intracranial tumor types are high-grade glioma, low-grade glioma, brain metastases, meningioma, pituitary adenoma and acoustic neuroma. Each was documented through histopathology, which requires surgically removing tissue from the site of a suspected cancer and examining it under a microscope.
According to Chakrabarty, machine and deep learning approaches using MRI data could potentially automate the detection and classification of brain tumors.
“Non-invasive MRI may be used as a complement, or in some cases, as an alternative to histopathologic examination,” he said.
To build their machine learning model, called a convolutional neural network, Chakrabarty and researchers from Mallinckrodt Institute of Radiology developed a large, multi-institutional dataset of intracranial 3D MRI scans from four publicly available sources. In addition to the institution’s own internal data, the team obtained pre-operative, post-contrast T1-weighted MRI scans from the Brain Tumor Image Segmentation, The Cancer Genome Atlas Glioblastoma Multiforme, and The Cancer Genome Atlas Low Grade Glioma.