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A drug used to target IDH1 mutations in select cancers also appears to inhibit the wild-type form of the enzyme, under certain conditions. This feature explains why a large group of different cancers are vulnerable to the drug. This discovery opens up the possibility that the drug, Ivosidenib or AG-120, could become more broadly applicable against a variety of cancers, given that mutant IDH1 is present in just 1% of cancers. The findings were recently published in Nature Cancer.
“Historically, only a few groups have cared about wild-type IDH1,” said Jordan Winter, MD, Division Chief of Surgical Oncology at University Hospitals (UH) Seidman Cancer Center and senior author on the study. Dr. Winter is also John and Peggy Garson Family Endowed Chair in Pancreatic Cancer Research and Jerome A. and Joy Weinberger Family Master Clinician in Surgical Oncology. “IDH1 therapeutic investigations have principally focused on the development of mutant IDH1 inhibitors. Less than a handful of reports have focused on wild-type IDH1 inhibition. We showed, along with a few others, that wild-type IDH1 is an important target. We think that Ivosidenib, previously called AG-120, may be applicable to the large majority of cancers-the one percent with mutant IDH1 and the remaining 99% with wild-type IDH1.”
Fundamental to this discovery is the observation that cancer cells rely on IDH1 metabolism to thrive in a harsh and nutrient-deprived tumor microenvironment. Nutrient limitation universally present in pancreatic tumors could open a new therapeutic window, explains the study’s first author Ali Vaziri-Gohar, PhD, Postdoctoral Fellow in the Department of Surgery at Case Western Reserve University School of Medicine.
“Wild-type IDH1 activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu,” he said. “We found that IDH1 is very important for cancer cells’ survival in a stressful microenvironment. When the cancer cells have less oxygen and less glucose or glutamine, anything that hurts them, they need a defense mechanism to protect them, which is this important molecule IDH1.”
In laboratory experiments, Dr. Winter, Dr. Vaziri-Gohar, and colleagues demonstrated that genetically suppressing IDH1 reduced growth of pancreatic cancer cells in cell culture under low nutrient conditions and in mouse models of pancreatic cancer. They found, too, that the FDA-approved inhibitor of mutant IDH1, Ivosidenib, was surprisingly potent against the wild-type form of the protein-especially when paired with the important condition of low magnesium. This latter point had been overlooked in prior studies.
Dr. Vaziri-Gohar said that this finding was a bit of scientific serendipity.

In your home, storing books on a bookshelf, tools in a tool box, and a broom in a broom cupboard makes it easy to access these items whenever you need them. Within the body, hematopoietic stem cells (HSCs) reside in their own specialized “spots” in the bone marrow known as HSC niches. Recently, researchers in Japan have identified genes that play a key role within these niches.
In a new study published in Nature Communications, researchers led by Osaka University have shed new light on the role of transcription factors Runx1 and Runx2 in the bone marrow microenvironments known as HSC niches. HSC niches are essential for the maintenance of HSCs, which give rise to blood cells.
A major component of HSC niches is a cell type known as CXC chemokine ligand 12-abundant reticular (CAR) cells. CAR cells express signaling molecules known as cytokines that are important for the maintenance of hematopoietic stem and progenitor cells (HSPCs). The team previously found that CAR cells express a transcription factor called Runx2, which is known to play a role in the development of the skeleton. In this study, they newly found that CAR cells also express Runx1, which is known to be essential for development of hematopoietic stem cells. However, it is completely unknown how Runx transcription factors function in the maintenance of HSC niches, which prompted the research team to investigate this role.
“To evaluate the impact of Runx transcription factors on the bone marrow, we used mouse models in which Runx1 and/or Runx2 was deleted specifically within CAR cells,” says lead author Yoshiki Omatsu.
The researchers found that mice lacking Runx1 in mesenchymal cells including CAR cells showed normal bone and bone marrow development, while mice lacking Runx2 exhibited normal CAR cells and bone marrow but short and immature bone. However, mice lacking both Runx1 and Runx2 in CAR cells showed a significant reduction of HSPCs and immune cells, along with an increase in fibrosis (the abnormal build-up of connective tissue) in the bone marrow, a hallmark of a condition known as myelofibrosis.
“Our results strongly indicate the essential role of Runx1 and/or Runx2 in the inhibition of fibrosis and maintenance of the HSC niche,” says senior author Takashi Nagasawa.
The research team also found that in a mouse model of primary myelofibrosis, expression of Runx1 and Runx2 was reduced while expression of fibrotic genes was increased, further highlighting the role of Runx1 and Runx2 in the inhibition of fibrosis in the bone marrow. Although more work is needed on the topic, these findings suggest that Runx1 and Runx2 may be potential targets for the diagnosis and treatment of myelofibrosis.
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Intestinal flora plays an important role in health — including mental health. Researchers from the University of Basel and the University Psychiatric Clinics Basel (UPK) have shown that probiotics can support the effect of antidepressants and help to alleviate depression.
When he was visited by what he called “the black dog,” Winston Churchill could barely get out of bed. He had no energy, no interests and no appetite. Although the British prime minister didn’t invent this metaphor for depression, he was the one who popularized it.
Experts use medication and psychotherapy to try to help patients escape from the “black dog,” but it persists in some individuals. Researchers are therefore searching for ways to improve existing therapies and develop new ones.
One promising approach is the microbiome-gut-brain axis. The microbiome is generally understood to mean all the microorganisms that live in or on the human body, such as the intestinal flora. Intestinal bacteria can influence the nervous system for instance via metabolic products.
In a recent study, a research team from the University of Basel and the University Psychiatric Clinics Basel (UPK) has shown that probiotics can support treatment with antidepressants. They have reported their findings in the journal Translational Psychiatry.
Intestinal flora influences the psyche
It is known from previous studies that patients with depression show an above-average prevalence of intestinal and digestive problems. If the intestinal flora of people with depression is implanted in mice raised in sterile conditions — that is, with no intestinal flora — then the animals also develop depressive-like behavior. For example, they are less energetic and show decreased interest in their surroundings than their peers. Researchers therefore suspect that the composition of the bacterial community in the gut plays an important role in depressive symptoms.

A new study published in today’s issue of PLoS Pathogens is the first to link SARS-CoV-2 specific T cells to lung function and those who suffer from long-term COVID symptoms (PASC). The study found that patients suffering from long COVID had virus-specific T cell levels more than 100 times higher than those who recovered from the disease.
“The persistence of high numbers of virus-specific T cells in individuals with long COVID suggests that there may be hidden viral reservoirs that are maintaining and leading to long-term symptoms. Current treatments for long COVID, out of necessity, are focused on addressing specific symptoms and not the root cause of the illness. This evidence points toward the reservoirs as a significant factor causing long COVID, which can guide future treatments,” said the paper’s senior author Brent Palmer, PhD, associate professor of allergy and clinical immunology at the University of Colorado School of Medicine on the University of Colorado Anschutz Medical Campus.
The findings could shift treatment recommendations to focus on vaccines and antiviral medications that could reduce long COVID symptoms and help clear the virus from people’s system.
The study addressed the cause of long COVID by better understanding the adaptive immune response to the SARS-CoV-2. The research team’s findings linked systemic inflammation, persistent pulmonary symptoms and reduced lung function to the presence of high numbers of SARS-CoV-2 specific T cells. During the primary infection, these virus-specific T cells are important for controlling infection but in the context of long COVID, they are associated with ongoing symptoms, shortness of breath and lung damage.
Brookings Institution estimates more than one million Americans are out of work due to long COVID. In addition, with over 500 million people infected during the pandemic so far, and 20-30 percent of them developing long COVID, that leaves upwards of 15 million people suffering from long COVID worldwide. This represents a serious burden to the population and healthcare system.
“Our findings hope to help change treatment focus to therapies that improve viral clearance. For example, antiviral medications like Paxlovid could help reduce symptoms in those burdened by long COVID, helping to clear the virus out of their system and get them back to a more normal life,” said Palmer.
The study also looked at two key biomarkers that are used to measure inflammation in the body. Researchers found that the higher the levels of SARS-CoV-2 T cells the higher the measure of inflammation, indicating that these T cells could also play a role in driving chronic inflammation and other long COVID symptoms.
Without continued studies that focus on the origin of long COVID, Palmer said people, the workforce and the healthcare system will continue to suffer.
“It’s clear that kitchen sink symptomatic treatments have not solved this problem. We need to continue this research in order to develop specific treatments for those whose lives have been completely uprooted because of a virus we are still working to understand,” Palmer adds.
Palmer and his team have applied for a National Institutes for Health (NIH) grant to further this research. If approved, they would be able to wash cells out of the lungs using a noninvasive procedure that would allow them to compare the cells of patients with long COVID to the cells of people without the virus.
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Materials provided by University of Colorado Anschutz Medical Campus. Original written by Laura Kelley. Note: Content may be edited for style and length.

Researchers at Massachusetts General Hospital (MGH) have discovered that the interferon gamma receptor (IFNgR) signaling pathway is critical for susceptibility of glioblastoma tumors to killing by CAR T-cell immunotherapy. The same phenomenon was observed in other solid tumors. This discovery may partly explain why liquid and solid tumors respond very differently to CAR T-cell treatment. The research is published in a paper in the Nature.
A chimeric antigen receptor (CAR) is any synthetic molecule that specifically commands the T cells of the immune system to identify and stick onto a target, or antigen. CARs recognize targets that are on the surface of tumor cells. While CAR therapy has had a transformative impact on the treatment of hematologic cancers like leukemia and lymphoma, it has not this translated into similar success in solid tumors.
To identify the resistance pathways in solid tumors, researchers led by Marcela Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Mass General Hospital Cancer Center developed a genome-wide CRISPR knockout screen in glioblastoma.
“With a CRISPR screen we were able to interrogate the entire genome in a pooled format in a completely unbiased manner, instead of looking for one or two genes of interest at a time,” explains first author Rebecca Larson, PhD. This allowed the researchers to see which genes are lost and determine the mechanisms of resistance that solid tumors use to evade CAR T-cell therapy. In this study, they applied selective pressure with a CAR to each barcoded cell in the screen. “We then sequenced the cells and could see which tumor cells were alive afterwards telling us which genes were knocked out.”
When Larson and colleagues applied the screen in multiple glioblastoma cell lines, including several cell lines derived from patients, they unexpectedly found that loss of genes in the interferon gamma signaling pathway rendered them resistant to CAR T-cell killing. “That means those interferon gamma-related genes are necessary for the tumor to die in the face of a CAR, something we had not known before and that we did not expect,” adds Larson.
This same resistance pattern was also found in vivo in knock-out mice models. Further study in other solid tumor types, including pancreatic, ovarian, and lung cell lines, showed the same: resistance to CAR T-cell therapy resulted from loss of interferon gamma pathway genes.
“We found that CAR T-cells did not bind to glioblastoma cells lacking interferon gamma signaling,” Larson explained, adding that while interferon gamma does not kill the cancer directly, it makes tumor cells stickier. “That way, the CAR T-cell can bind to it better and eliminate the cancer cell.”
Conversely, the researchers observed that the interferon gamma pathway did not have a role on the sensitivity of leukemia, lymphoma, or multiple myeloma to CAR T-cell therapy. “The fact that we can see how solid and liquid tumors are responding to CAR T-cell therapy in different ways is very informative for how we design a future therapy.”
Moving forward, this discovery gives researchers an opportunity clinically on two fronts, according to Maus. First, enhancing T-cell/tumor cell-binding interactions by targeting the interferon gamma pathway may yield improved responses with CAR T-cell therapy in solid tumors. Second, blocking this pathway in liquid tumors may help reduce the well-known toxicities of CAR T-cell therapies, known as cytokine release syndrome. “Even though CAR T-cell treatment can in some cases be amazingly effective with more than 40% cure rates in some liquid tumors, toxicity is a real concern,” she adds. “Tamping down the interferon gamma in these cancers might keep the efficacy but reduce the rollercoaster of toxicity.”
Funding was provided by grants from the National Institutes of Health, the Richard N. Cross Fund; the Damon Runyon Cancer Research Foundation, and Stand Up to Cancer,
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Those who are among the heaviest drinkers in England are four times more likely to smoke than the general population, according to a new study led by UCL researchers.
The study, published in The Lancet Regional Health – Europe, looked at survey responses from a nationally representative sample of 144,583 people in England, completed over the course of seven years, from 2014 to 2021.
They found that 58% of people at risk of becoming alcohol dependent (assessed through a survey designed to detect harmful drinking habits) were current smokers, compared to 15% among the general population.
They also found that smoking prevalence and dependency increased in line with alcohol consumption – that is, the more a person drank, the more likely it was that they smoked, and the more cigarettes they were likely to smoke in a day.
The researchers said that the government needed to prioritise people at risk of alcohol dependency who smoked in its plans to achieve “smoke-free” status in England by 2030, defined to mean an adult smoking prevalence of 5% or less.
Lead author Dr Claire Garnett (UCL Institute of Epidemiology & Health Care) said: “To get close to a ‘smoke-free’ England in 2030, the government needs to target groups where smoking is highly prevalent. Our study strongly suggests that those who are among the heaviest drinkers in England, who are risk of becoming dependent on alcohol, should receive targeted smoking cessation support.

A genetic variant that is present in nearly 30% of Greenlanders is linked to high cholesterol and an increased risk of cardiovascular disease, according to a study published on June 9th in the journal Human Genetics and Genomics Advances.As noted by the authors, this is the first report of an association between this Arctic-specific variant, known as p.G137S, and cardiovascular disease.
“Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of high cholesterol and cardiovascular disease for up to 30% of the Greenlandic population,” says co-first study author Emil Jorsboe of the University of Copenhagen. “The variant is therefore a potential marker for early intervention in Arctic populations.”
Cardiovascular disease is the number-one cause of death in many populations worldwide. It is tightly linked to elevated levels of low-density lipoprotein (LDL) cholesterol. The uptake of LDL-cholesterol particles from the blood into tissues such as the liver is mediated by the LDL receptor (LDLR). Mutations in the LDLR gene, which encodes this receptor, is a common cause of high cholesterol levels in the bloodstream.
Among Greenlanders, the prevalence of cardiovascular disease is likely to increase in the future due to increasing life expectancy and changing lifestyle. The common Arctic-specific LDLR variant, known as p.G137S, was recently shown to be associated with elevated cholesterol levels. But until now, it was not clear whether this variant is also associated with an increased risk of cardiovascular disease.
In the new study, Jorsboe and his collaborators examined this possibility in a group of 5,063 Greenlanders. Roughly 30% of the individuals carried at least one copy of the p.G137S risk allele. Approximately 25% of the heterozygous and 55% of the homozygous carriers had high blood levels of LDL cholesterol.
Moreover, p.G137S was associated with an increased risk of ischemic heart disease, peripheral artery disease, and coronary operations. Yet only a low proportion of individuals with very high levels of LDL cholesterol were receiving cholesterol-lowering therapy. In addition, elevated levels of LDL cholesterol for p.G137S carriers were independent of age, indicating that these individuals would benefit from early intervention and treatment.
“Our results showed that the p.G137S variant had an even larger impact on the lipid profile of Greenlanders than previously reported,” Jorsboe says. “This variant further highlights the importance of carrying out genetic studies in smaller populations like the Greenlandic.”
According to the authors, the results suggest that a screening program for the p.G137S variant could be highly useful for the early identification of individuals at increased risk for cardiovascular disease, potentially improving preventive care and public health.
“We think an intervention study would be of great importance, where one could investigate how cholesterol-lowering medicine improves the lipid profile in carriers of this genetic variant,” Jorsboe says. “Defining the optimal treatment and prevention strategies for carriers of this variant is crucial, especially because one-third of the Greenlandic population are at risk.”
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A new study led by the global Cancer Grand Challenges PRECISION team, including researchers from The University of Texas MD Anderson Cancer Center, shifts the long-held belief that all invasive breast cancers following ductal carcinoma in situ (DCIS) arise from the original DCIS lesion. The results, published today in Nature Genetics, demonstrate that roughly one in five invasive cancers were genetically unrelated to the original DCIS.
The findings provide a deeper understanding of the biology of DCIS, serving as a foundation for future studies to better identify cases of DCIS most likely to progress and to determine appropriate intervention strategies for women with DCIS.
“By analyzing the largest DCIS cohort of its kind in the world, we discovered that a subset of invasive breast cancers following an initial DCIS are not related to the primary DCIS,” said co-lead author Tapsi Kumar, Ph.D., graduate student in Genetics. “This data challenges our prior understanding of DCIS progression and gives us a starting point to identify better predictive biomarkers to determine which DCIS lesions are most likely to progress to invasive cancer.”
DCIS, which indicates the presence of abnormal cells inside the breast milk duct, is the most common form of pre-invasive breast cancer. The condition is harmless in most; less than 10% of women with DCIS will later develop an invasive cancer.
Because it’s currently hard to predict which cases of DCIS will progress, treatment is recommended for most cases to prevent the development of invasive cancer. Therefore, most patients diagnosed with DCIS are treated with some combination of surgery, radiation and hormone therapy that will ultimately provide little benefit.
The Cancer Grand Challenges PRECISION team was established to develop better tools to distinguish between high- and low-risk DCIS and thus avoid overtreatment for many women. Together with Kumar, the work at MD Anderson was led by Nicholas Navin, Ph.D., professor of Genetics and Bioinformatics & Computational Biology, and Andy Futreal, Ph.D., chair of Genomic Medicine. Kumar is a member of both the Navin laboratory and Futreal laboratory.
This study was designed to determine whether subsequent invasive breast cancers are, in fact, connected to the original DCIS. Because there are relatively few women with DCIS who later develop invasive cancer, obtaining samples for this study was a challenge. Through the global collaboration, the team was able to pool and analyze 95 pairs of samples from women who had DCIS, were treated and later developed invasive cancer in the same breast.
The researchers performed genomic sequencing on all samples, including single-cell DNA sequencing on a subset, to compare mutations and copy number changes between the DCIS and invasive cancer.
The combined results of these analyses revealed that 75% of paired samples were indeed related, meaning they shared the same genetic abnormalities and the invasive cancer developed from the DCIS lesion.
However, the researchers also discovered that 18% of the paired samples were unrelated, suggesting the invasive cancer later developed independently of the original DCIS lesion. A final 7% of samples had ambiguous results, and researchers were not able to clarify a relationship.
These findings demonstrate that around one in five cases of invasive cancer following DCIS are not true recurrences, but instead represent new cancers. These results may explain why it has remained difficult for researchers to identify biomarkers that accurately predict the risk of DCIS recurrence. Future studies will build upon these findings to discover risk factors for women with DCIS likely to develop either a recurrence or a new cancer.
“Our study indicates we can no longer consider DCIS solely as a precursor but rather also a risk factor for the development of invasive breast cancer later on in life,” says joint senior author Elinor Sawyer, M.B.B.S., Ph.D., of King’s College London in the United Kingdom. “This important new information about DCIS biology and behaviour, together with other findings, could change the way we manage and treat the condition in clinics in the future.”

Researchers have discovered that infiltrating gliomas, a common brain and spinal cord tumor, are shaped by their genetic evolution and microenvironment, a finding that could lead to more targeted treatments.
“We have identified epigenetic alterations at recurrence that are not only prognostic in some cases, but may lead to different treatment options for the various subtypes that can improve long-term survival,” said study co-author D. Ryan Ormond, MD, PhD, a University of Colorado Cancer Center member and associate professor of neurosurgery at the University of Colorado School of Medicine on the CU Anschutz Medical Campus.
The study was published May 31 in the journal Cell.
The researchers looked at how gliomas interact with the brain, change over time, develop treatment resistance and become more invasive.
They identified three distinct phenotypes or observable traits at glioma recurrence — neuronal, mesenchymal and proliferative. Each of them converge with cellular, genetic and histological features that reveal themselves at recurrence. Some of these are associated with less favorable outcomes.
In this study, scientists used participant samples from the Glioma Longitudinal Analysis Consortium or GLASS cohort, a consortium created to identify the drivers of treatment resistance in glioma.

Of the three groups of rotavirus that cause gastroenteritis in people, called groups A, B and C, groups A and C affect mostly children and are the best characterized. On the other hand, of group B, which causes severe diarrhea predominantly in adults, little is known about the tip of the virus’s spike protein, called VP8* domain, which mediates the infection of cells in the gut.
“Determining the structure of VP8* in group B rotavirus is important because it will help us understand how the virus infects gastrointestinal cells and design strategies to prevent and treat this infection that causes severe diarrheal outbreaks,” said corresponding author Dr B. V. Venkataram Prasad, professor of biochemistry and molecular biology at Baylor College of Medicine.
The team’s first step was to determine the 3D structure of VP8* B using X-Ray crystallography, a laborious and time-consuming process. However, this traditional approach was unsuccessful in this case. The researchers then turned to a recently developed artificial intelligence-based computational program called AlphaFold2.
“AlphaFold2 predicts the 3D structure of proteins according to their genetic sequence,” said first author and co-corresponding author Dr. Liya Hu, assistant professor of biochemistry and molecular biology at Baylor. “We knew that the protein sequence of VP8* of rotavirus group B was about 10% similar to the sequences of VP8* of rotavirus A and C, so we expected differences in the 3D structure as well. But we were surprised when AlphaFold2 predicted a 3D structure for the VP8* B that was not just totally different from that of the VP8* domain in rotavirus A and C, but also that no other protein before had been reported to have this structure.”
With this information in hand, the researchers went back to the lab bench and experimentally confirmed that the structure of VP8* B predicted by ALphaFold2 indeed coincided with the actual structure of the protein using X-ray crystallography.
How rotavirus infects cells
Previous research has shown that rotavirus A and C infect cells by using the VP8* domain to bind to specific sugar components on histo-blood group antigens, including the A, B, AB and O blood groups, present in many cells in the body. It has been proposed that the ability of different rotavirus to bind to different sugars on the histo-group antigens might explain why some of these viruses specifically infect young children while others affect other populations. Unlike the VP8* A and VP8* C, the sugar specificity of VP8* B had not been characterized until now.