Scientists at St. Jude Children’s Research Hospital have shown that improving metabolic health in obese mice before vaccination, but not after, protects against influenza virus.
Metabolic health (normal blood pressure, blood sugar and cholesterol levels, among other factors) influences the effectiveness of influenza vaccinations. Vaccination is known to be less effective in people with obesity compared to those with a healthier body mass index (BMI), but St. Jude Children’s Research Hospital scientists have found it is not obesity itself, but instead metabolic dysfunction, which makes the difference. In a study published today in Nature Microbiology, the researchers found switching obese mice to a healthy diet before flu vaccination, but not after, completely protected the models from a lethal dose of flu, despite BMI.
“We found that the vaccines worked effectively if at the time of vaccination an animal is metabolically healthy,” said corresponding author Stacey Schultz-Cherry, PhD, St. Jude Department of Host-Microbe Interactions and Center of Excellence for Influenza Research and Response co-director. “And the opposite was also true: Regardless of what the mice looked like on the outside, if they had metabolic dysfunction, the vaccines did not work as well.”
Prior research has shown that when exposed to influenza virus, even after vaccination, 100% of obese mice succumbed to disease. Contrary to the scientists’ original expectations, when mice who were vaccinated while obese returned to a healthy weight, outcomes did not improve. These now outwardly healthy mice still all succumbed to disease when exposed to the real virus. Only switching to a healthy diet four weeks before vaccination improved survival, with drastic effect, despite high BMI.
“We were excited to see this effect because mice with obesity are so susceptible to severe disease and succumbing to the infection,” Schultz-Cherry said. “Getting 100% survival with the vaccine where we had only seen 0% survival was impressive.” The improved survival suggests the researchers have discovered a greater underlying principle determining influenza vaccine efficacy.
Metabolic dysfunction hinders the immune system
While studying how metabolic function influences influenza vaccine responses, the scientists found that poor metabolic health causes immune system dysfunction. T cells, the primary immune cells involved in anti-viral responses, failed to act in animals that had been in an unhealthy metabolic state at the time of vaccination, even during later viral exposure. Even when the animals ate a healthy diet after vaccination and maintained a normal BMI, the anti-flu T cells were “frozen” in that dysfunctional state.

However, a healthy diet before vaccination improved T-cell function, which resulted in a robust anti-flu response during later exposure.
“The T cells were better able to do their job in the metabolically healthy mice at the time of vaccination,” Schultz-Cherry said. “It wasn’t a matter of the numbers of them or the types of them. It was their functional activity. There were plenty of them in the lungs, not working. The healthy diet switched them from not working to functioning properly, but only if the switch occurred before vaccination.”
The earlier healthy diet also improved inflammation. Pro-inflammatory cytokines are upregulated in obese animals. Schultz-Cherry’s team found that models also returned to a lower basal cytokine level when switched to a healthy diet before vaccination.
“A healthy diet lowered some of the systemic meta-inflammation in these animals, and they regained some of the epithelial innate immune responses,” said Schultz-Cherry. “We started seeing better signaling of things like interferons, which we know is problematic in obesity and in general saw the immune system starting to function the way that it should.”
Improving metabolic health may improve influenza vaccine effectiveness
“What we found and are emphasizing is that it’s not the phenotype of obesity that matters; it’s really about metabolic health,” Schultz-Cherry said. “It’s metabolic health at that moment of vaccination that really makes a difference.”
The study was restricted to mice, but it does open research opportunities to improve influenza vaccine efficacy in humans. The findings suggest methods of improving metabolic health may also improve subsequent influenza vaccinations. Given the recent introduction of metabolic improvement drugs, especially glucagon-like peptide 1 (GLP-1) agonists, there may be potential for a cooperative effect.

“We don’t know for sure, but if the outcome of using GLP-1 drugs is weight loss and improved metabolic health, we would hypothesize that it will help,” Schultz-Cherry said. “But we do know that we can do better protecting our vulnerable populations, and this study is a start for understanding how.”
Authors and funding
The study’s co-first authors are Rebekah Honce, formerly of St. Jude, and Ana Vazquez-Pagan, formerly of the St. Jude Graduate School of Biomedical Sciences.
The study’s other authors are R. Chris Skinner, University of Vermont, Brandi Livingston, Alexandra Mandarano, Benjamin Wilander, Sean Cherry, Virginia Hargest, Bridgett Sharp, Pamela Brigleb, Ericka Kirkpatrick Roubidoux, Lee-Ann Van de Velde, Maureen McGargill and Paul Thomas, St. Jude.
The study was supported by grants and contracts from the National Institute of Allergy and Infectious Diseases (HHSN27220140006C, 75N93019C00052, 75N93021C00016, F31AI161986, R01 AI140766-03 and 32AI106700-07) and ALSAC, the fundraising and awareness organization of St. Jude.

The 2010 Gulf of Mexico Deepwater Horizon was the largest accidental oil spill in history. With almost 100 million gallons (379 million liters) of oil combined with dispersants suggested to remain in the Gulf, it is one of the worst pollution events ever. More than a decade later, its long-term effects are still not fully understood.
In a new study, researchers from Louisiana State University and Tulane University examined the endemic Gulf of Mexico fish species that may have been most impacted by the oil spill to see how their distribution has changed over the years. To get their data, they studied museum specimens from natural history collections, looked at relevant literature, and combed biodiversity databases.
With 1541 fish species known from the region, and 78 endemic fish species, the Gulf of Mexico is one of the most biologically rich and resilient marine environments in the world, but how much of this diversity is still left intact?
The study found that 29 out of the Gulf’s 78 endemic fish species haven’t been reported in museum collections since 2010. The Yucatan killifish, for example, which is considered endangered, was last reported pre-spill, in 2005, off the Yucatán Peninsula.
Six of the non-reported species are considered of greatest concern, because their areas of distribution largely overlap with the affected area — although the authors note that their absence in the Gulf in recent years cannot automatically be attributed to the oil spill.
“Understanding the impacts of catastrophic environmental events such as the 2010 Gulf of Mexico Oil Spill does not end when the wellhead is capped or when the last drops of oil cease to flow. The disaster only begins to end when the data no longer show impacts of the event. We are far from the beginning of the end for the Deepwater Horizon Oil Spill. Lingering chemicals, lost generations of wildlife and a continued ecosystem imbalance may all be factors that prevent an environment from rebounding from such cataclysmic events,” the authors note in their resear article.
However, they also point out that nature’s ability to recover should not be overlooked.
“The Gulf of Mexico continues to face many challenges, from the Dead Zone, to climate change, loss of coast habitats and continued oil spills. Efforts like this report aim to bring attention to vulnerable species that continue to be impacted by human activities and to the unique endemic fauna of the region,” the researchers write in conclusion.

The change followed a sweeping review by England’s National Health Service that found “remarkably weak” evidence for youth gender treatments.Scotland’s National Health Service has stopped all new prescriptions of puberty-blocking drugs and other hormone treatments for minors, citing a sweeping review of youth gender services released in England last week. It is the sixth country in Europe to limit such treatments, and its changes are among the most restrictive.The review, commissioned by N.H.S. England and carried out by Dr. Hilary Cass, an independent pediatrician, over the course of four years, concluded that the evidence for benefits of youth gender treatments was “remarkably weak” and that pressing questions remained about potential long-term risks.This month, following recommendations by Dr. Cass, N.H.S. England halted puberty blockers for children outside of clinical trials. Hormone therapies, including estrogen and testosterone, are still available to teenagers in England aged 16 and up.Scotland’s new changes go further, pausing prescriptions of puberty blockers while also restricting hormone therapies until teenagers turn 18. The changes will not affect patients already getting these medications from the country’s Young People Gender Service.“We will continue to give anyone who is referred into the Young People Gender Service the psychological support that they require while we review the pathways in line with the findings,” said Dr. Emilia Crighton, director of public health for N.H.S. Greater Glasgow and Clyde, which houses Scotland’s sole youth gender clinic, Sandyford Sexual Health Services.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

A sensitive perception of the environment is crucial for guiding our behavior. However, an overly sensitive response of the brain’s neural circuits to stimuli can lead to neurodevelopmental disorders such as epilepsy. University of Basel researchers report in the journal Nature how neuronal networks in the mouse brain are fine-tuned.
We are constantly exposed to a wide range of sensory stimuli, from loud noises to whispers. In order to efficiently process these diverse stimulus intensities, the brain needs to strike a balance in its responsiveness. An excessive sensitivity triggers an over-activation of nerve cells in response to a stimulus, leading to epileptic seizures. Conversely, insufficient sensitivity results in a reduced ability to perceive and discriminate stimuli.
But how does the brain manage to be highly sensitive without becoming over-activated? “The key lies in maintaining a balance between neural excitation and inhibition,” explains Professor Peter Scheiffele from the Biozentrum, University of Basel. “In mouse models, we have now discovered how this balance is maintained to ensure stable brain function.” The study particularly focused on the neocortex, a brain area responsible for perception and a range of complex functions such learning.
Our brain consists of billions of interconnected nerve cells that interact through so-called synapses and process sensory stimuli such as sounds, touch, and sights. While excitatory neurons pass on the input signal, inhibitory neurons control the timing and intensity of the information flow. This internal control system ensures that the nervous system responds appropriately to stimuli.
Network over-activation and its link to epilepsy
Neurons are able to detect an elevated neuronal network activity and subsequently reduce the system’s sensitivity to stimuli. But how the cells are instructed at the molecular level was poorly understood. “We have now revealed that highly activated excitatory neurons release a protein called BMP2,” says lead author Dr. Zeynep Okur. “BMP2 signals to the inhibitory neurons, initiating a genetic program that leads to the formation of new synapses.” These additional synapses increase the impact of inhibitory neurons and dampen network activity.
This feedback mechanism is critical for tuning the sensitivity of neuronal networks, preventing over-activation and thus excessive responses to stimuli. “Switching-off the BMP2-induced genetic program in inhibitory neurons triggers epileptic seizures in mice, but only when they are older,” explains Okur. Thus, this process is involved in long-term adaptations of cortical networks.
New approaches to treat neurodevelopmental disorders
The BMP2 signaling pathway has been known for its role in early brain developmental, particularly in nerve cell differentiation. “We have been able to show that this pathway is re-purposed to stabilize neuronal circuits in the adult brain ” emphasizes Scheiffele. This plays an important role for brain plasticity in adulthood — the basis for learning and memory.
“We now understand at the molecular level how neural networks balance excitation and inhibition,” summarizes Scheiffele. “With our work, we are expanding the repertoire of options to treat epilepsy and other neurodevelopmental disorders.” Targeted interventions in the BMP2 signaling pathway could help to fine-tune and re-adjust brain sensitivity.

In posttraumatic stress disorder (PTSD), intrusive thoughts, changes in mood, and other symptoms after exposure to trauma can greatly impact a person’s quality of life. About 6 percent of people who experience trauma develop the disorder, but scientists don’t yet understand the neurobiology underlying PTSD.
Now, a new genetic study of more than 1.2 million people has pinpointed 95 loci, or locations in the genome, that are associated with risk of developing PTSD, including 80 that had not been previously identified. The study, from the PTSD working group within the Psychiatric Genomics Consortium (PGC — PTSD) together with Cohen Veterans Bioscience, is the largest and most diverse of its kind, and also identified 43 genes that appear to have a role in causing PTSD. The work appears in Nature Genetics.
“This discovery firmly validates that heritability is a central feature of PTSD based on the largest PTSD genetics study conducted to date and reinforces there is a genetic component that contributes to the complexity of PTSD,” said Caroline Nievergelt, co-first and corresponding author on the study and a professor in the Department of Psychiatry at the University of California, San Diego. Adam Maihofer, a genetic epidemiologist in Nievergelt’s lab, was a co-first author as well.
The findings both confirm previously discovered genetic underpinnings of PTSD and provide many novel targets for future investigation that could lead to new prevention and treatment strategies.
“It’s exciting that we see the exponential increase in loci with increases in sample size we see for other disorders,” said Karestan Koenen, senior author on the study, an institute member of the Broad Institute of MIT and Harvard, and an investigator with the Stanley Center for Psychiatric Research at Broad. Koenen leads the Stanley Center’s Biology of Trauma Initiative and the Global Neuropsychiatric Genomics Initiative, and is a professor of psychiatric epidemiology at the Harvard T. H. Chan School of Public Health. “This is a milestone for PTSD genetics.”
Genetic roots
Previous twin and genetic studies, including an investigation by the same team in 2017 and an expanded study in 2019, showed that PTSD has a genetic component, and that many genes contribute to the condition.

But these analyses pointed to different genetic loci across datasets, and many studies struggled to distinguish loci that were specific to PTSD risk from those that were also linked to conditions such as depression and cardiovascular disease. Genetic datasets have also historically focused on people of European ancestry, even though there is a disproportionately high burden of trauma and PTSD among people of African, Native American, and Latin American ancestry in the United States and globally.
In the new study, Nievergelt, Koenen, and other researchers from the PGC compiled data from 88 different genome-wide association studies, which use genetic data from large groups of people to look for associations between regions of the genome and the chance of developing a condition or trait. In all, the dataset contained information about the risk of developing PTSD from more than 1.2 million individuals of European ancestry (including about 140,000 with PTSD), about 50,000 with African ancestry (including about 12,000 with PTSD), and about 7,000 with Native American ancestry (about 2,000 with PTSD).
Meta-analysis of the data revealed 95 loci strongly associated with PTSD, including 80 that had not been identified previously. Forty three genes appeared to play a role in causing PTSD, including some that affect brain cells called neurons, brain chemicals called neurotransmitters, ion channels (which allow ions to pass in and out of cells), connections between neurons called synapses, and the endocrine and immune systems. The researchers found that PTSD shared many genetic features with depression, as well as several PTSD-specific loci.
Although previous studies found a higher prevalence of PTSD in females than males, the researchers did not find evidence for this in their data. They examined the X chromosome, which earlier studies did not do, and found five loci linked with PTSD. But they add that these changes on the X chromosome would have similar effects in males and females.
To more deeply probe how PTSD genetics affect the brain, the team studied gene expression data and found that the cerebellum, the brain region that controls movement and balance, may be involved in the disorder in addition to regions scientists have previously connected with PTSD, such as the cortex and amygdala. In particular, the research team found that interneurons, which connect motor and sensory neurons, were involved in PTSD risk. Future studies could help determine how key genes in these tissues and cells affect PTSD symptoms and behaviors.
“For the first time, we are approaching a genetic architecture for PTSD, which both validates prior understanding of some of the critical biology underlying trauma-related disorders, while also pointing towards exciting and novel new targets and mechanisms,” said Kerry Ressler, a co-leader of the PGC — PTSD working group, chief scientific officer at McLean Hospital, and Professor of Psychiatry at Harvard Medical School. “These data are an important first step in next generation approaches to novel interventions for PTSD.”
In line with previous findings, Nievergelt, Koenen, and their colleagues also found that polygenic scores — a calculation of a person’s genetic chance of developing a certain condition based on millions of single-letter changes in their DNA — for PTSD risk are not readily translatable across populations. The researchers say this disparity highlights the importance of continuing to expand the depth and diversity of populations included in future studies of PTSD.

“We know that trauma and PTSD disproportionately affects under-resourced populations globally, particularly African ancestry populations,” said Koenen. “Our next steps will focus on addressing that inequity through partnerships with African scientists to make sure research in PTSD genetics benefits everyone equally.”
Funding:
This work was supported by the National Institute of Mental Health, Cohen Veterans Bioscience, and the Stanley Center for Psychiatric Research at the Broad Institute.

With more than 200 types of cancer and every cancer individually unique, ongoing efforts to develop precision oncology treatments remain daunting. Most of the focus has been on developing genetic sequencing assays or analyses to identify mutations in cancer driver genes, then trying to match treatments that may work against those mutations.
But many, if not most, cancer patients do not benefit from these early targeted therapies. In a new study published on April 18, 2024, in the journal Nature Cancer, first author Sanju Sinha, Ph.D., assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys, with senior authors Eytan Ruppin, M.D., Ph.D., and Alejandro Schaffer, Ph.D., at the National Cancer Institute, part of the National Institutes of Health (NIH) — and colleagues — describe a first-of-its-kind computational pipeline to systematically predict patient response to cancer drugs at single-cell resolution.
Dubbed PERsonalized Single-Cell Expression-Based Planning for Treatments in Oncology, or PERCEPTION, the new artificial intelligence-based approach dives deeper into the utility of transcriptomics — the study of transcription factors, the messenger RNA molecules expressed by genes that carry and convert DNA information into action.
“A tumor is a complex and evolving beast. Using single-cell resolution can allow us to tackle both of these challenges,” says Sinha. “PERCEPTION allows for the use of rich information within single-cell omics to understand the clonal architecture of the tumor and monitor the emergence of resistance.” (In biology, omics refers to the sum of constituents within a cell.)
Sinha says, “The ability to monitor the emergence of resistance is the most exciting part for me. It has the potential to allow us to adapt to the evolution of cancer cells and even modify our treatment strategy.”
Sinha and colleagues used transfer learning — a branch of AI — to build PERCEPTION.
“Limited single-cell data from clinics was our biggest challenge. An AI model needs large amounts of data to understand a disease, not unlike how ChatGPT needs huge amounts of text data scraped from the internet.”
PERCEPTION uses published bulk-gene expression from tumors to pre-train its models. Then, single-cell data from cell lines and patients, even though limited, was used to tune the models.

PERCEPTION was successfully validated by predicting the response to monotherapy and combination treatment in three independent, recently published clinical trials for multiple myeloma, breast and lung cancer.
In each case, PERCEPTION correctly stratified patients into responder and non-responder categories. In lung cancer, it even captured the development of drug resistance as the disease progressed, a notable discovery with great potential.
Sinha says that PERCEPTION is not ready for clinics, but the approach shows that single-cell information can be used to guide treatment. He hopes to encourage the adoption of this technology in clinics to generate more data, which can be used to further develop and refine the technology for clinical use.
“The quality of the prediction rises with the quality and quantity of the data serving as its foundation,” says Sinha. “Our goal is to create a clinical tool that can predict the treatment response of individual cancer patients in a systematic, data-driven manner. We hope these findings spur more data and more such studies, sooner rather than later.”
Additional authors on the study include Rahulsimham Vegesna, Sumit Mukherjee, Ashwin V. Kammula, Saugato Rahman Dhruba, Nishanth Ulhas Nair, Peng Jiang, Alejandro Schäffer, Kenneth D. Aldape and Eytan Ruppin, National Cancer Institute (NCI); Wei Wu, Lucas Kerr, Collin M. Blakely and Trever G. Biovona, University of California, San Francisco; Mathew G. Jones and Nir Yosef, University of California, Berkeley; Oleg Stroganov and Ivan Grishagin, Rancho BioSciences; Craig J. Thomas, National Institutes of Health; and Cyril H. Benes, Harvard University.
This research was supported in part by the Intramural Research Program of the NIH; NCI; and NIH grants R01CA231300, R01CA204302, R01CA211052, R01CA169338 and U54CA224081.

Multiple sclerosis (MS) is an insidious disease. Patients suffer because their immune system is attacking their own nerve fibres, which inhibits the transmission of nerve signals. People with MS experience mild to severe impairment of their motor function and sensory perception in a variety of ways. These impairments disrupt their daily activities and reduce their overall quality of life. As individual as the symptoms and progression of the disease are, so too is the way it is managed. To monitor the disease progression and be able to recommend effective treatments, physicians ask their patients on a regular basis to describe their symptoms, such as fatigue.
Going off memory
Patients are thus faced with the tricky task of having to provide information about their state of health and what they have been capable of over the past few weeks and even months from memory. The data gathered in this way can be inaccurate and incomplete because patients might misremember details or tailor their responses to social expectations. And since these responses have a significant impact on how the progression of the disease is recorded, it could be mismanaged.
“Physicians would benefit from having access to reliable, frequent and long-term measurements of patients’ health parameters that give an accurate and comprehensive view of their state of health,” explains Shkurta Gashi. She is lead author of a new study and postdoc in the groups led by ETH Professors Christian Holz and Gunnar Rätsch at the Department of Computer Science as well as a fellow of the ETH AI Center.
Together with colleagues from ETH Zurich, the University Hospital Zurich, and the University of Zurich, Gashi has now shown that fitness trackers and smartphones can provide this kind of reliable long-term data with a high temporal resolution. Their study was published in the journal NPJ Digital Medicine.
Digital markers for MS
The researchers recruited a group of volunteers — 55 with MS and a further 24 serving as control subjects — and provided each person with a fitness tracking armband. Over the course of two weeks, the researchers collected data from these wearable devices as well as from participants’ smartphones. They then performed statistical tests and a machine learning analysis of this data to identify reliable and clinically useful information.

What proved particularly meaningful was the data on physical activity and heart rate, which was collected from participants’ wearable devices. The higher the participants’ disease severity and fatigue levels, the lower their physical activity and heart rate variability proved to be. Compared to the controls, MS patients took fewer steps per day, engaged in an overall lower level of physical activity and registered more consistent intervals between heartbeats.
How often people used their smartphone also delivered important information about their disease severity and fatigue levels: the less often a study participant used their phone, the greater their level of disability and the more severe their level of fatigue. The researchers gained insights into motor function through a game-like smartphone test. Developed at ETH a few years ago, this test requires the user to tap the screen as quickly as possible to make a virtual person move as fast as possible. Monitoring how fast a person taps and how their tapping frequency changes over time allows the researchers to draw conclusions about their motor skills and physical fatigue.
“Altogether, the combination of data from the fitness tracker and smartphone lets us distinguish between healthy participants and those with MS with a high degree of accuracy,” Gashi says. “Combining information related to several aspects of the disease, including physiological, behavioural, motor performance and sleep information, is crucial for more effective and accurate monitoring of the disease.”
Reliable approach
This new approach gives MS sufferers a straightforward way of collecting reliable and clinically useful long-term data as they go about their day-to-day lives. The researchers expect that this type of data can lead to better treatments and more effective disease management techniques: more comprehensive, precise and reliable data helps experts make better decisions and possibly even propose effective treatments sooner than before. What’s more, evaluating this patient data lets the experts verify the effectiveness of different treatments.
The researchers have now made their data set available to other scientists. They also point out the need for a larger study and more data to develop reliable and generalizable models for automatic evaluation. In the future, such models could enable MS patients to experience a significant improvement in their lives thanks to data from fitness trackers and smartphones.

Two siblings who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could help progress the search for new treatments in type 1 diabetes.
Type 1 diabetes (also known as autoimmune diabetes) is a devastating and life-long disease, in which the patient’s immune cells wrongly destroy the insulin producing beta cells in the pancreas. People living with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugars and prevent complications.
Autoimmune diabetes with clinical onset in very early childhood is rare and can result from a variety of genetic variants. However, there are many cases of early onset diabetes without known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors — which target the same pathway that the mutation was found in — are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy — there is currently no cure.
The new research, published in the Journal of Experimental Medicine, began when researchers studied two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old. For most of these babies, this service provides a genetic diagnosis and in around half of these babies, it allows for a change in treatment.
When researchers tested the two siblings in the study, no mutation in any of the known causes was identified. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realised it could be responsible for their very-early-onset autoimmune diabetes.
Study authorDr Matthew Johnson, from the University of Exeter, UK, said: “PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the globe, looking at all the large-scale datasets that we know of, and we haven’t been able to find another family. These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”
The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins bind together it provides a stop signal to the immune system, preventing collateral damage to the bodies tissues and organs.

Researchers from the Rockefeller Institute in New York and King’s College London joined forces with Exeter to study the siblings, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. After contacting the family’s clinician in Morocco, the Exeter team visited the siblings where they were living to collect samples and return them to King’s College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The London and New York teams then performed extensive analysis on the siblings’ cells.
Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes. As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings. To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”
Study co-author Professor Timothy Tree, from King’s College London, said: “Through studying this one set of siblings — unique in the world to our knowledge — we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function. This leads us to the grand question; ‘what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?’ We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the “communication” between different cell types that is critical for preventing autoimmune diabetes.
“This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future. Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment — our findings will help accelerate the search for new and better drugs.”
Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.
“By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes.”
Helmsley Program Officer Ben Williams said: “New drugs often fail in development because scientific discoveries made in animal models don’t translate into humans. As such, drug developers strongly prefer to pursue new drugs where human genetic evidence supports the drug’s target. This study provides such compelling evidence that PD-L1 is a high-priority target to treat T1D, and should be pursued with the ambition of eventually reducing the burden of this difficult to manage disease.”
The paper is entitled ‘Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency’ and is published in the Journal of Experimental Medicine. The research was supported by the National Institute of Health and Care Research (NIHR) Exeter Biomedical Research Centre and The NIHR Exeter Clinical Research Facility.

Researchers at the University of Michigan Rogel Cancer Center have developed a new urine-based test that addresses a major problem in prostate cancer: how to separate the slow-growing form of the disease unlikely to cause harm from more aggressive cancer that needs immediate treatment.
The test, called MyProstateScore2.0, or MPS2, looks at 18 different genes linked to high-grade prostate cancer. In multiple tests using urine and tissue samples from men with prostate cancer, it successfully identified cancers classified as Gleason 3+4=7 or Grade Group 2 (GG2), or higher. These cancers are more likely to grow and spread compared to Gleason 6 or Grade Group 1 prostate cancers, which are unlikely to spread or cause other impact. More than one-third of prostate cancer diagnoses are this low-grade form. Gleason and Grade Group are both used to classify how aggressive prostate cancer is.
Results are published in JAMA Oncology.
“Our standard test is lacking in terms of its ability to clearly pick out those who have significant cancer. Twenty years ago, we were looking for any kind of cancer. Now we realize that slow-growing cancer doesn’t need to be treated. All of a sudden, the game changed. We went from having to find any cancer to finding only significant cancer,” said co-senior study author John T. Wei, M.D., David A. Bloom Professor of Urology at Michigan Medicine.
Prostate-specific antigen, or PSA, remains the linchpin of prostate cancer detection. MPS2 improves upon a urine-based test developed by the same U-M team nearly a decade ago, following a landmark discovery of two genes that fuse to cause prostate cancer. The original MPS test, which is used today, looked at PSA, the gene fusion TMPRSS2::ERG, and another marker called PCA3.
“There was still an unmet need with the MyProstateScore test and other commercial tests currently available. They were detecting prostate cancer, but in general they were not doing as good a job in detecting high-grade or clinically significant prostate cancer. The impetus for this new test is to address this unmet need,” said co-senior author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology. Chinnaiyan’s lab discovered the T2::ERG gene fusion and developed the initial MPS test.
To make MyProstateScore even stronger at identifying high-grade cancers, researchers used RNA sequencing of more than 58,000 genes and narrowed it to 54 candidates uniquely overexpressed specifically in higher-grade cancers. They tested the biomarkers against urine samples collected and stored at U-M through another major study, the National Cancer Institute’s Early Detection Research Network. This included about 700 patients from 2008-2020 who came for a prostate biopsy due to an elevated PSA level.

This first step narrowed the field to 18 markers that consistently correlated with higher grade disease. The test still includes the original MPS markers, plus 16 additional biomarkers to complement them.
From there, the team reached out to the larger Early Detection Research Network (EDRN), a consortium of more than 30 labs across the country that are similarly collecting samples. This ensured a diverse, national sampling. Knowing no specific details about the samples, the U-M team performed MPS2 testing on more than 800 urine samples and sent results back to collaborators at the NCI-EDRN. The NCI-EDRN team assessed MPS2 results against the patient records.
MPS2 was shown to be better at identifying GG2 or higher cancers. More importantly, it was nearly 100% correct at ruling out GG1 cancer.
“If you’re negative on this test, it’s almost certain that you don’t have aggressive prostate cancer,” said Chinnaiyan, S. P. Hicks Endowed Professor of Pathology and professor of urology at Michigan Medicine.
Moreover, MPS2 was more effective at helping patients avoid unnecessary biopsies. While 11% of unnecessary biopsies were avoided with PSA testing alone, MPS2 testing would avoid up to 41% of unnecessary biopsies.
“Four of 10 men who would have a negative biopsy will have a low risk MPS2 result and can confidently skip a biopsy. If a man has had a biopsy before, the test works even better,” Wei explained.

For example, a patient may get a prostate biopsy due to an elevated PSA, but no cancer is detected. The patient is followed over time and if his PSA inches up, he would typically need another biopsy.
“In those men who have had a biopsy before and are being considered for another biopsy, MPS2 will identify half of those whose repeat biopsy would be negative. Those are practical applications for patients out there. Nobody wants to say sign me up for another biopsy. We are always looking for alternatives and this is it,” Wei said.
MPS2 is currently available through LynxDx, which is University of Michigan spin-off company that has an exclusive license from the university to commercialize MPS2. Patients interested in learning more can call the Michigan Medicine Cancer AnswerLine at 800-865-1125.
The paper’s first authors are Jeffrey J. Tosoian, M.D., M.P.H., who is now at Vanderbilt University, and Yuping Zhang, Ph.D., and Lanbo Xiao, Ph.D., at U-M. Additional authors are Cassie Xie; Nathan L. Samora, M.D.; Yashar S. Niknafs, Ph.D.; Zoey Chopra; Javed Siddiqui; Heng Zheng, M.D.; Grace Herron; Neil Vaishampayan; Hunter S. Robinson, M.D.; Kumaran Arivoli; Bruce J. Trock, Ph.D.; Ashley E. Ross, M.D., Ph.D.; Todd M. Morgan, M.D.; Ganesh S. Palapattu, M.D.; Simpa S. Salami, M.D., M.P.H.; Lakshmi P. Kunju, M.D.; Scott A. Tomlins, M.D., Ph.D.; Lori J. Sokoll, Ph.D.; Daniel W. Chan, Ph.D.; Sudhir Srivastava, Ph.D.; Ziding Feng, Ph.D.; Martin G. Sanda, M.D.; Yingye Zheng, Ph.D.
Funding for this work is from the Michigan-Vanderbilt Early Detection Research Network Biomarker Characterization Center and Data Management and Coordinating Center, which are through the National Cancer Institute grants U2C CA271854 and U24 CA086368. Additional funding is from NCI grants P50 CA186786, R35 CA231996, U24 CA115102, U01 CA113913; Prostate Cancer Foundation; Howard Hughes Medical Institute; and the American Cancer Society.
Disclosures: Chinnaiyan serves on the advisory boards of Tempus, LynxDx, Ascentage Pharmaceuticals, Medsyn therapeutics, Esanik and RAAPTA therapeutics. Tomlins is an equity holder and chief medical officer of Strata Oncology. LynxDx has obtained an exclusive license from the University of Michigan to commercialize MPS2 and the TMPRSS2-ERG gene fusion. Tosoian and Chinnaiyan are equity holders and scientific advisers to LynxDx. Siddiqui, Zhang, Xiao and Niknafs have served as scientific advisers to LynxDx.

The company has told countries that it can supply only 18.8 million of the 29.6 million doses it was contracted to deliver this year.Nearly 1.5 million teenage girls in some of the world’s poorest countries will miss the chance to be protected from cervical cancer because the drugmaker Merck has said it will not be able to deliver millions of promised doses of the HPV vaccine this year.Merck has notified Gavi, the international organization that helps low- and middle-income countries deliver lifesaving immunizations, and UNICEF, which procures the vaccines, that it will deliver only 18.8 million of the 29.6 million doses it was contracted to deliver in 2024, Gavi said.That means that more than 10 million girls will not receive their expected HPV shots this year — and 1.5 million of them most likely will never get them because they will be too old to qualify for the vaccine in subsequent years.Patrick Ryan, a spokesman for Merck, said the company “experienced a manufacturing disruption” that required it to hold and reinspect many doses by hand. He declined to give further details about the cause of the delay.“We are acting with urgency and rigor to deploy additional personnel and resources to resolve this matter as soon as possible,” he said.Mr. Ryan said that Merck would deliver the delayed doses in 2025. He also said the company would ship 30 million doses of the vaccine to Gavi-supported countries this year. However about a third of these are doses that were supposed to have been sent in 2023, leaving Gavi with the 10.7 million dose shortfall.We are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.