A data analytics firm has helped big health insurers cut payments to doctors, raising concerns about possible price fixing.Recent revelations about a data analytics firm’s role in determining medical payments have heightened concerns about possible price fixing in health care and led to a call for a federal investigation.In a letter this week, Senator Amy Klobuchar asked federal regulators to examine whether algorithms used by the firm, MultiPlan, have helped major health insurers conspire to cut payments to doctors and leave patients with large bills. She cited a New York Times investigation last month into MultiPlan’s dominance of the lucrative business of pricing out-of-network medical claims.“Algorithms should be used to make decisions more accurate, appropriate and efficient, not to allow competitors to collude to make health care more costly for patients,” Ms. Klobuchar wrote to the heads of the Justice Department’s antitrust division and the Federal Trade Commission.When patients see a medical provider outside their plan’s network, insurers often send their claims to MultiPlan, which uses proprietary algorithms to recommend how much to pay. By driving down payments to providers, MultiPlan and the insurers can collect higher fees for themselves, The Times reported, but this can lead to higher bills for patients, who may get charged the unpaid balance.UnitedHealthcare, Cigna, Aetna and other major insurers use MultiPlan’s pricing recommendations, and the firm has boasted to investors that it is “deeply embedded” in its clients’ claims-processing systems.In interviews, Ms. Klobuchar, a Democrat from Minnesota, and experts in antitrust law said this arrangement could amount to price fixing: Rather than competing to offer better coverage, insurers could use the low prices recommended by MultiPlan’s algorithms, knowing their competitors would likely do the same.“This should trigger an investigation by the agencies,” said Barak Orbach, a law professor at the University of Arizona. “There seems to be a really strong case.”The F.T.C. and Justice Department declined to comment, but both agencies have raised concerns in the past about similar arrangements in other industries.“Algorithms should be used to make decisions more accurate, appropriate and efficient, not to allow competitors to collude to make health care more costly for patients,” Senator Amy Klobuchar wrote in a letter to antitrust regulators.Valerie Plesch for The New York TimesMultiPlan did not have an immediate comment. But in legal filings, the firm has denied allegations of collusion and said that insurers are free to reject its pricing recommendations or negotiate higher payments with providers.The firm said in a previous statement to The Times that its work benefits patients and employers who pay for their workers’ coverage by “promoting affordability, efficiency and fairness across the U.S. health care system.”Insurers have said that MultiPlan’s tools help combat outrageous billing by some providers, including consolidated hospital systems and private-equity-backed staffing firms.Documents reviewed by The Times indicate that MultiPlan has sometimes told insurers how their unnamed competitors were using the firm’s pricing tools. In a 2017 presentation to UnitedHealthcare, MultiPlan shared “Recent Client Strategies to Improve Results,” which included techniques that could reduce payments to providers.After a 2019 meeting, a UnitedHealthcare senior vice president reported to her colleagues that a MultiPlan executive “did not specifically name competitors but from what he did say we were able to glean who was who.” She then described how Cigna, Aetna and some Blue Cross Blue Shield plans were apparently using the firm’s pricing tools.Three hospital systems have sued MultiPlan, accusing it of colluding with major insurers to set unreasonably low payments for medical care, and patients and providers have complained to the F.T.C. about MultiPlan, records obtained through a public records request show.One provider reported slashed payments from UnitedHealthcare, Cigna and an Aetna subsidiary after the insurers routed claims to MultiPlan’s most aggressive pricing tool. Another said the tool “has decimated my life” and caused “the closing of my business,” which has “left patients having to travel 2.5 hrs for surgery.”Patients complained to the agency of receiving large bills after insurers used MultiPlan-recommended prices. “This is now affecting my credit score,” wrote one patient, describing a bill that had been sent to a debt collector. Another reported being billed thousands of dollars “since they refuse to pay my providers the correct amount.”Pricing algorithms have driven MultiPlan’s growth over the past 15 years. The firm previously focused on controlling costs by negotiating with medical providers, but after being sold to private equity investors, it embraced automated, algorithm-based tools, which typically yield lower payment recommendations.Access to data from hundreds of clients has helped entrench the firm’s dominance, executives have told investors. “We build our algorithms on a much larger data lake,” one executive said in a 2020 presentation.The focus on MultiPlan’s automated pricing tools highlights growing concern among regulators and some in Congress that algorithms are supercharging price-fixing schemes and driving up costs for consumers.During the Biden administration, companies’ increasing embrace of technological advancements has collided with aggressive enforcement efforts by regulators. The results have been mixed, as the agencies seek to apply laws enacted to combat 19th-century oil and railroad robber barons to 21st-century technology firms.“Algorithms are the new frontier,” the Justice Department wrote in a brief in one case. “And, given the amount of information an algorithm can access and digest, this new frontier poses an even greater anticompetitive threat than the last.”Regulators and some antitrust scholars worry that algorithms can enable sophisticated collusion that is difficult to police. Competitors no longer need to meet in secret to hatch a conspiracy and communicate among themselves to perpetuate it. They can simply agree to use a common pricing algorithm.Weighing in on private lawsuits involving apartment rents and hotel room prices, the agencies have argued that such an arrangement is illegal, even if competitors agree with a wink and a nod rather than a formal pact.But in one case, a judge disagreed in a December ruling, allowing the lawsuit to go forward but requiring renters to offer more explicit evidence that landlords had conspired to raise prices using an algorithm.Ms. Klobuchar has introduced legislation that would effectively make the agencies’ position the default. Courts would presume it illegal for competitors to share nonpublic data with a middleman and use the pricing recommendations that the firm’s algorithms produced.“It is not clear whether current antitrust laws are sufficient to stop this practice,” Ms. Klobuchar said in an interview. “It is much better just to clarify this and to close the loophole.”The bill would also require companies to tell consumers if they are buying something that was priced using an algorithm, and it would give regulators greater authority to demand details about how an algorithm works.

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia’s Zuckerman Institute.
“The brain is the center of our thoughts, emotions, memories and feelings,” said Hao Jin, PhD, a co-first author of the study published online today in Nature. “Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body.”
Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.
“This new discovery could provide an exciting therapeutic venue to control inflammation and immunity,” said Charles S. Zuker, PhD, the study’s senior author, a principal investigator at Columbia’s Zuckerman Institute and a Howard Hughes Medical Institute investigator.
Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.
“We found all these ways in which the body is informing the brain about the body’s current state,” said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. “We wanted to understand how much farther the brain’s knowledge and control of the body’s biology went.”
The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve — a bundle of thousands of nerve fibers linking the brain and the body’s internal organs — could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain’s modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.
The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.
The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.
“Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner,” said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker’s lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. “In retrospect, it makes sense to have a master arbiter controlling this vital response.”
Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.
“A lot of psychosomatic effects could actually be linked to brain circuits telling your body something,” Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. “This opens up a new window into how the brain monitors and modulates body physiology,” said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia’s Vagelos College of Physicians and Surgeons.
Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn’s disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.
Autoimmune diseases may affect roughly one in 10 individuals, a 2023 Lancet study suggested. In the United States alone, autoimmune diseases may cost the economy $100 billion annually, a figure that may be a gross underestimate, according to the Autoimmune Association.
Harnessing the activity of this circuit may make a difference across a broad range of conditions affecting the immune system, and help treat dysregulated inflammatory states in people suffering from immune diseases and disorders, Drs. Jin and Li said.

Scientists have designed a new artificial intelligence model that emulates randomized clinical trials at determining the treatment options most effective at preventing stroke in people with heart disease.
The model was front-loaded with de-identified data on millions of patients gleaned from health care claims information submitted by employers, health plans and hospitals — a foundation model strategy similar to that of generative AI tools like ChatGPT.
By pre-training the model on a huge cache of general data, researchers could then fine-tune the model with information concerning specific health conditions and treatments — in this case, focusing on stroke risk — to estimate the causal effect of each therapy and determine which therapy would work best based on individual patient characteristics.
The team from The Ohio State University reported in the journal Patterns that their model outperformed seven existing models and came up with the same treatment recommendations as four randomized clinical trials.
“No existing algorithm can do this work,” said senior author Ping Zhang, associate professor of computer science and engineering and biomedical informatics at Ohio State. “Quantitatively, our method increased performance by 7% to 8% over other methods. And the comparison showed other methods could infer similar results, but they can’t produce a result exactly like a randomized clinical trial. Our method can.”
Replacing gold standard clinical research is not the point — but researchers hope machine learning could help save time and money by putting clinical trials on a faster track and support the personalization of patient care.
“Our model could be an acceleratory module that could help first identify a small group of candidate drugs that are effective to treat a disease, allowing clinicians to conduct randomized clinical trials on a limited scale with just a few drugs,” said first author Ruoqi Liu, a computer science and engineering PhD student in Zhang’s lab.

The team dubbed the proposed framework CURE: CaUsal tReatment Effect estimation.
The beauty of a treatment effect estimation model pre-trained with massive amounts of unlabeled real-world data is its applicability to a multitude of diseases and drugs, Liu said.
“We can pre-train the model on large-scale datasets without limiting it to any treatments. Then we fine-tune the pre-trained model on task-specific small-scale datasets so that the model can adapt quickly to different downstream tasks,” she said.
Unlabeled data used to pre-train the model came from MarketScan Commercial Claims and Encounters from 2012-2017, providing 3 million patient cases, 9,435 medical codes (including 282 diagnosis codes) and 9,153 medication codes.
Two of Liu’s model-constructing techniques added to CURE’s power: filling in gaps in patient records by pairing patient information with biomedical knowledge graphs that represent biomedical concepts and relationships, and pre-training a deep synergized patient data-knowledge foundation model using medical claims and knowledge graphs at scale.
“We also proposed KG-TREAT, a knowledge-enhanced foundation model, to synergize the patient data with the knowledge graphs to have the model better understand the patient data,” said Liu, who was the first author of a March Proceedings of the AAAI Conference on Artificial Intelligence paper describing the knowledge graph work.

To come up with treatment effect estimates, the model considers pre-trained data overlapped with more specific information on medical conditions and therapies, and after further fine-tuning, predicts which patient outcomes would correspond to different treatments.
As part of comparing the model to other machine learning tools and validating it against clinical trial results, the study showed that the broad pre-training is the backbone of CURE’s effectiveness — and incorporation of knowledge graphs improved its performance further.
Zhang envisions a day — pending Food and Drug Administration approval of AI as a decision-support tool — when clinicians could use this type of algorithm, loaded with electronic health record data from tens of millions of people, to access an actual patient’s “digital twin” and let the model function as a treatment guide.
“This model is better than a crystal ball: Based on big data and foundation model AI, we can have reasonable confidence to be able to say what treatment strategy is better,” said Zhang, who leads the Artificial Intelligence in Medicine Lab and is a core faculty member in the Translational Data Analytics Institute at Ohio State. “We want to put physicians in the driver’s seat to see whether this is something that can be helpful for them when they’re making critical decisions.”

Early detection has the potential to transform treatment and outcomes in cancer care, especially for cancers like liver cancer, which is typically diagnosed at a late stage with limited options for cure. A new study led by investigators from Mass General Brigham and Beth Israel Deaconess Medical Center suggests that proteins detectable in the blood could improve predictions about risk of liver cancer years before typical diagnosis. Results are published in JNCI.
“Liver cancer rates are rapidly increasing, and liver cancer has a high mortality rate, but if we can diagnose it early, therapeutic interventions can be potentially curative,” said lead author Xinyuan (Cindy) Zhang, PhD, of the Channing Division of Network Medicine at Brigham and Women’s Hospital. “We need to have a way to detect this form of cancer early enough to intervene with surgery or liver transplantation to treat the disease before it becomes metastatic.”
Liver cancer, or hepatocellular carcinoma (HCC), ranks as the third leading cause of cancer worldwide and the second leading cause of cancer-related deaths globally, with its incidence rate nearly tripled since 1980s in the US. Detection of liver cancers often occurs at advanced stages, where life expectancy typically spans less than 12 months. Certain high-risk populations, such as individuals with cirrhosis and hepatitis, stand to significantly benefit from early detection tests. Currently, there is a notable deficiency in accurate, sensitive, and specific tools for the early detection of liver cancer. Many existing methods are relatively expensive, invasive, or limited in accessibility, primarily confined to major hospitals.
The research team included investigators from Mass General Brigham’s founding members, Brigham and Women’s Hospital and Massachusetts General Hospital, Harvard T.H. Chan School of Public Health, Beth Israel Deaconess Medical Center and Yale University. The team utilized proteomics (profiling of proteins) to develop a prediction model aimed at diagnosing or screening for liver cancer at an earlier stage. They used the SomaScan Assay Kit, a high-throughput proteomics platform that measures protein levels in biological samples, available through the Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center. The SomaScan platform allowed them to detect minute levels of circulating proteins that may be present at early stage of disease, measuring 1,305 proteins simultaneously in the blood.
“It’s always been challenging to identify highly specific disease biomarkers in the blood using traditional tools, but this new technology allows us to detect a broad and dynamic range of both high and low abundant proteins,” said co-senior author Towia A. Libermann, PhD, of the Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center. “New insights into the biological mechanisms underlying liver cancer development emerge from our data that may lead to identification of novel therapeutic targets. Most importantly, we were able to validate these early detection biomarkers using alternative protein analysis techniques and in an independent population cohort from the UK.”
The study team used SomaScan to analyze plasma samples from participants in both the Nurses’ Health Study and the Health Professional Follow-Up Study, two longitudinal, ongoing, prospective cohorts in the U.S. Notably, they examined blood samples obtained from individuals an average of 12 years before their liver cancer diagnosis to pinpoint protein biomarker signals. After examination, the researchers cross-referenced medical records to confirm whether these patients ultimately developed liver cancer.
From the blood samples, the researchers identified 56 plasma proteins that showed significantly elevated levels in individuals with liver cancer compared to matched control individuals without hepatocellular cancer. The team selected four of these proteins to create a predictive model, which they tested on the UK Biobank Pharma Proteomics dataset, comprised of 50,000 individuals, 45 of whom were diagnosed with liver cancer. Their model had greater accuracy in predicting liver cancer compared to traditional risk factors.
The authors caution that their study included a limited number of liver cancer cases and further validation in larger, more diverse patient populations and in high-risk populations is needed.
“Even though further investigation in additional populations is absolutely needed, our results reveal a robust circulating protein profile associated with liver cancer years before diagnosis, which is remarkable,” said co-senior author Xuehong Zhang, MBBS, ScD, who conducted work on this study while at the Channing Division of Network Medicine at the Brigham. Zhang is now at Yale.
The study team also aims to extend their methodology to uncover additional plasma protein biomarkers utilizing the more expanded SomaScan assay measuring 11,000 proteins, explore biomarkers linked with different cancer types, and gain deeper insights into the role of hepatocellular cancer risk factors across specific patient populations. With further progress, the protein biomarkers investigated in the study could potentially hold clinical significance as a non-invasive test for assessing liver cancer risk.

Using multiple nicotine products can be associated with higher levels of nicotine dependence among youth and increased mortality in adults, compared with the use of one product alone. Yale researchers have now uncovered factors that contribute to adolescents using multiple nicotine products.
These findings, they say, will help inform efforts to prevent escalation from single to multiple product use.
Their findings were reported April 24 in the journal Preventative Medicine.
While public health campaigns have spread awareness on the harms of smoking and, more recently, vaping, an increasingly diverse landscape of nicotine products, widespread adoption of e-cigarettes, and a growing use of multiple products among young people may require updated strategies, says Patricia Simon, an assistant professor adjunct of psychiatry at Yale School of Medicine (YSM) and lead author of the study.
“Using nicotine products has numerous health impacts and multiple product use can have additional negative consequences, including increased nicotine dependence, reduced intent to quit, and increased mortality,” said Simon. “One challenge now is to find ways to prevent young people from progressing from single to multiple product use, but we need to know what contributes to that progression in order to develop effective interventions.”
For the study, Simon and her colleagues used data from the Population Assessment of Tobacco and Health (PATH) Study, a long-term evaluation of tobacco use in the United States that began in 2013 and is administered and funded by the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA). The researchers analyzed data from over 10,000 individuals who joined the PATH study when they were between the ages 12 and 17. The participants completed the PATH Study assessments in 2013 and 2014 (Wave 1 of the PATH Study) and again in 2017 and 2018 (Wave 4).
Among the study group during Wave 4, nearly 11% reported having used multiple nicotine products, over 13% reported using one product, and just over 76% said they had not used any nicotine products during the previous 30 days, the researchers found. Cigarettes were the product most reportedly used followed by e-cigarettes, cigars, hookah, and smokeless tobacco.

“We also found several personal, familial, and environmental factors that contributed to nicotine product use and multiple product use,” said Ralitza Gueorguieva, a senior research scientist in the Department of Biostatistics at Yale School of Public Health (YSPH) and coauthor of the study.
Those who reported using nicotine products in Wave 4 of the study reported more problems with sleep, anxiety, or feelings of hopelessness, were less likely to have talked with parents or guardians about not using tobacco products, and more likely to have seen advertisements for tobacco products in Wave 1, compared with those not reporting nicotine use.
The researchers then compared individuals who used multiple products with those who reported using just one in Wave 4, finding they were more likely to be male, in the older 15- to 17-year-old age group, and to have reported ever using a nicotine product at the start of the study (Wave 1). When asked to rate how much harm they thought came from using various nicotine products, those who used multiple products assigned less harmful ratings than those who used just one product.
“This more nuanced understanding of nicotine use in adolescents allows us to better differentiate those who use single products versus multiple products, which is an important new perspective,” said Elina Stefanovics, a research scientist in the Department of Psychiatry at YSM and coauthor of the study.
These findings should be considered by regulators aiming to align policies with modern usage patterns, clinicians advising parents on risk and protective factors, and prevention scientists developing targeted programs based on specific risk factors for youth, said the researchers.
“This study provides crucial evidence that will help shape interventions aimed at preventing both the initiation and escalation of nicotine product use among adolescents,” said Eugenia Buta, a research scientist with the Yale Center for Analytical Sciences at YSPH and coauthor of the study. “By understanding these factors, we can develop more effective public health strategies and regulatory policies to reduce the prevalence of multiple nicotine product use among our youth.”
Shiyao Ying at YSPH and Suchitra Krishnan-Sarin at YSM were also coauthors of the study.
Research reported in this publication was supported by grant number U54DA036151 from the National Institute on Drug Abuse (NIDA), part of the NIH, and the Center for Tobacco Products, part of the FDA. Partial support is also provided by National Cancer Institute, NIH grant R03 CA245991 and NIDA grant L40 DA042454. The content is solely the responsibility of the authors, and it does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.

In humans, embryonic cell compaction is a crucial step in the normal development of an embryo. Four days after fertilisation, cells move closer together to give the embryo its initial shape. Defective compaction prevents the formation of the structure that ensures the embryo can implant in the uterus. In assisted reproductive technology (ART), this stage is carefully monitored before an embryo is implanted.
An interdisciplinary research team1 led by scientists at the Genetics and Developmental Biology Unit at the Institut Curie (CNRS/Inserm/Institut Curie) studying the mechanisms at play in this still little-known phenomenon has made a surprising discovery: human embryo compaction is driven by the contraction of embryonic cells. Compaction problems are therefore due to faulty contractility in these cells, and not a lack of adhesion between them, as was previously assumed. This mechanism had already been identified in flies, zebrafish and mice, but is a first in humans.
By improving our understanding of the early stages of human embryonic development, the research team hopes to contribute to the refinement of ART as nearly one third of inseminations are unsuccessful today.2
The results were obtained by mapping cell surface tensions in human embryonic cells. The scientists also tested the effects of inhibiting contractility and cell adhesion and analysed the mechanical signature of embryonic cells with defective contractility.
Notes : 1 — Scientists from the following entities also took part in the study: the Centre interdisciplinaire de recherche en biologie (CNRS/Collège de France/Inserm), the Reproductive Biology Department — CECOS (AP-HP) and the Institut Cochin (CNRS/Inserm/Université Paris Cité).
2 — Source: Agence de la biomédecine

In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine developed at the University of Florida quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumor.
The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumors whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. The breakthrough now will be tested in a Phase 1 pediatric clinical trial for brain cancer.
Reported May 1 in the journal Cell, the discovery represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient’s own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.
“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions,” said senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist who pioneered the new vaccine, which like other immunotherapies attempts to “educate” the immune system that a tumor is foreign. “And the reason we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”
Among the most impressive findings was how quickly the new method, delivered intravenously, spurred a vigorous immune-system response to reject the tumor, said Sayour, principal investigator of the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy and a UF Health Cancer Center and McKnight Brain Institute investigator who led the multi-institution research team.
“In less than 48 hours, we could see these tumors shifting from what we refer to as ‘cold’ — immune cold, very few immune cells, very silenced immune response — to ‘hot,’ very active immune response,” he said. “That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response.”
Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. Current standard of care involves surgery, radiation and some combination of chemotherapy.

The new publication is the culmination of promising translational results over seven years of studies, starting in preclinical mouse models and then in a clinical trial of 10 pet dogs that had spontaneously developed terminal brain cancer and had no other treatment options. That trial was conducted with owners’ consent in collaboration with the UF College of Veterinary Medicine. Dogs offer a naturally occurring model for malignant glioma because they are the only other species that develops spontaneous brain tumors with some frequency, said Sheila Carrera-Justiz, D.V.M., a veterinary neurologist at the UF College of Veterinary Medicine who is partnering with Sayour on the clinical trials. Gliomas in dogs are universally terminal, she said.
After treating pet dogs that had spontaneously developed brain cancer with personalized mRNA vaccines, Sayour’s team advanced the research to a small Food and Drug Administration-approved clinical trial designed to ensure safety and test feasibility before expanding to a larger trial.
In a cohort of four patients, genetic material called RNA was extracted from each patient’s own surgically removed tumor, and then messenger RNA, or mRNA — the blueprint of what is inside every cell, including tumor cells — was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream and prompt an immune-system response. The vaccine was personalized to each patient with a goal of getting the most out of their unique immune system.
“The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, pet dogs that have developed cancer spontaneously and human patients with brain cancer is a really important finding, because oftentimes we don’t know how well the preclinical studies in animals are going to translate into similar responses in patients,” said Duane Mitchell, M.D., Ph.D., director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program and a co-author of the paper. “And while mRNA vaccines and therapeutics are certainly a hot topic since the COVID pandemic, this is a novel and unique way of delivering the mRNA to generate these really significant and rapid immune responses that we’re seeing across animals and humans.”
While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected.
The 10 pet dogs lived a median of 139 days, compared with a median survival of 30 to 60 days typical for dogs with the condition.

The next step, through support from the Food and Drug Administration and the CureSearch for Children’s Cancer foundation, will be an expanded Phase I clinical trial to include up to 24 adult and pediatric patients to validate the findings. Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2, said Sayour, an associate professor in the Lillian S. Wells Department of Neurosurgery and the department of pediatrics in the UF College of Medicine, part of UF Health.
For the new clinical trial, Sayour’s lab will partner with a multi-institution consortium, the Pediatric Neuro-Oncology Consortium, to send the immunotherapy treatment to children’s hospitals across the country. They will do this by receiving an individual patient’s tumor, manufacturing the personalized vaccine at UF and sending it back to the patient’s medical team, said Sayour, co-leader of the Immuno-Oncology and Microbiome research program at the UF Health Cancer Center.
Despite the promising results, the authors said one limitation is continued uncertainty about how best to harness the immune system while minimizing the potential for adverse side effects.
“I am hopeful that this could be a new paradigm for how we treat patients, a new platform technology for how we can modulate the immune system,” Sayour said. “I am hopeful for how this could now synergize with other immunotherapies and perhaps unlock those immunotherapies. We showed in this paper that you actually can have synergy with other types of immunotherapies, so maybe now we can have a combination approach of immunotherapy.”
Sayour and Mitchell hold patents related to the vaccine which are under option to license by iOncologi Inc., a biotech company born as a “spin out” from UF in which Mitchell holds interest.

The gut microbiota is the microbial community that occupies the gastrointestinal tract. It is responsible for producing enzymes, metabolites, and other molecules crucial for host metabolism and in response to the environment.
Consequently, a balanced gut microbiota is important for mammalian health in many ways, such as helping to regulate the immune and endocrine systems. This in turn, impacts the physiology of tissues throughout the body. However, little was known about the impact of the gut microbiota on host reproduction, and whether an altered microbiota in a father could influence the fitness of his offspring.
The Hackett group at EMBL Rome, in collaboration with the Bork and the Zimmermann groups at EMBL Heidelberg, set out to answer this question, with their results now published in the journal Nature. The scientists showed that disrupting the gut microbiota in male mice increases the probability that their offspring are born with low weight, and are more likely to die prematurely. 
What is passed on to the next generation
To study the effects of the gut microbiota on male reproduction and their offspring, the researchers altered the composition of gut microbes in male mice by treating them with common antibiotics that do not enter the bloodstream. This induces a condition called dysbiosis, whereby the microbial ecosystem in the gut becomes unbalanced.
The scientists then analysed changes in the composition of important testicular metabolites. They found that in male mice dysbiosis affects the physiology of the testes, as well as metabolite composition and hormonal signalling. At least part of this effect was mediated by changes in the levels of the key hormone leptin in blood and testes of males with induced dysbiosis. These observations suggest that in mammals, a ‘gut-germline axis’ exists as an important connection between the gut, its microbiota, and the germline.
To understand the relevance of this ‘gut-germline’ axis to traits inherited by offspring, the scientists mated either untreated or dysbiotic males with untreated females. Mouse pups sired by dysbiotic fathers showed significantly lower birth weights and an increased rate of postnatal mortality. Different combinations of antibiotics as well as treatments with dysbiosis-inducing-laxatives (which also disrupt microbiota) affected offspring similarly.

Importantly, this effect is reversible. Once antibiotics are withdrawn, paternal microbiota recover. When mice with recovered microbiota were mated with untreated females, their offspring were born with normal birthweight and developed normally as well.
“We have observed that intergenerational effects disappear once a normal microbiota is restored. That means that any alteration to the gut microbiota able to cause intergenerational effects could be prevented in prospective fathers” said Peer Bork, EMBL Heidelberg Director, who participated in the study. “The next step will be to understand in detail how different environmental factors such as medicinal drugs including antibiotics can affect the paternal germline and, therefore, embryonic development.” Ayele Denboba, first author of the publication and former postdoc in the Hackett Group, now Group Leader at the Max Planck Institute of Immunology and Epigenetics in Freiburg, Germany added “The study originated to understand environmental impacts on fathers by considering the gut microbiota as a nexus of host-environment interactions, thus creating a sufficient-cause model to assess intergenerational health risks in complex ecological systems.”
Paternal impact on pregnancy disease risk
In their work, Hackett and his colleagues also discovered that placental defects, including poor vascularisation and reduced growth, occurred more frequently in pregnancies involving dysbiotic males. The defective placentas exhibited hallmarks of a common pregnancy complication in humans called pre-eclampsia, which leads to impaired offspring growth and is a risk factor for developing a wide range of common diseases later in life.
“Our study demonstrates the existence of a channel of communication between the gut microbiota and the reproductive system in mammals. What’s more, environmental factors that disrupt these signals in prospective fathers increase the risk of adverse health in offspring, through altering placental development” said Jamie Hackett, coordinator of the research project and an EMBL Rome Group Leader. “This implies that in mice, the environment of a father just prior to conception can influence offspring traits independently of genetic inheritance.”
“At the same time, we find the effect is for one generation only, and I should be clear that further studies are needed to investigate how pervasive these effects are and whether they have relevance in humans. There are intrinsic differences to be considered when translating results from mouse models to humans.” Hackett continued: “But given the widespread prevalence of dietary and antibiotic practices in Western culture that are known to disrupt the gut microbiota, it is important to consider paternal intergenerational effects more carefully — and how they may be affecting pregnancy outcomes and population disease risk.”

Researchers from Children’s Hospital of Philadelphia (CHOP) have identified a causal genetic variant strongly associated with childhood obesity. The study provides new insight into the importance of the hypothalamus of the brain and its role in common childhood obesity and the target gene may serve as a druggable target for future therapeutic interventions. The findings were published today in the journal Cell Genomics.
Both environmental and genetic factors play critical roles in the increasing incidence of childhood obesity. While the exact role of genetics in childhood obesity is still not fully understood, prior studies show that neuronal pathways in the hypothalamus control food intake and are key regulators for the disease.
Prior international genome-wide association studies (GWAS) led by CHOP investigators found specific genetic markers, or loci, linked with obesity. Most of these studies revealed loci associated with childhood and adult obesity in equal measure, and most of these loci have been in non-coding regions of the genome, which means they do not code for specific proteins, making their mechanisms much more difficult to study. This latest research focused on chr12q13, a locus harboring the nearby gene FAIM2 that generated a strikingly stronger signal with childhood obesity when compared to adult obesity.
“By focusing specifically on this locus, we were able to pinpoint a causal variant associated with one of the strongest genetic signals we have implicated in childhood obesity,” said first study author Sheridan H. Littleton, PhD, a postdoctoral research associate who conducted this work as a member of the Center for Spatial and Functional Genomics team at CHOP. “With more research, there’s potential to learn how the target of this variant’s action may be a target for new therapies specifically designed to treat childhood obesity.”
In addition to childhood obesity, the locus in question has been found to be connected to a variety of related health issues, including elevated type 2 diabetes susceptibility, increased body fat percentage in children and adults, and earlier age of menstruation. Using a variety of techniques, the researchers narrowed their focus on rs7132908, a single nucleotide polymorphism (SNP), or variant, at the locus.
Prior related CHOP research implicated the hypothalamus in appetite, a trait that could be linked to childhood obesity. Since the hypothalamus is deep inside the brain, it is particularly challenging to study. To further study the effects of the rs7132908 variant, the researchers used stem cells that evolve into hypothalamic neurons, a key cell type associated with eating behavior, to study the variant’s alleles. The allele associated with obesity risk influenced how the FAIM2 gene was expressed and decreased the proportion of neurons produced when the stem cells differentiated, suggesting that the variant is also associated with neurodevelopment.
“In spite of a series of challenges, a study like this demonstrates how extra effort can reveal important information about hitherto uncharacterized genetic variants and the role they play in a variety of childhood and adult illnesses,” said Struan F.A. Grant, PhD, Director of the Center for Spatial and Functional Genomics and the Daniel B. Burke Endowed Chair for Diabetes Research at CHOP. “This work further underscores how the brain is central to the genetics of obesity and provides us with a strategy for further study.”
This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants F31 HD105404 and R01 HD056465, the National Institute of Diabetes and Digestive and Kidney Diseases grant UM1 DK126194, and the Daniel B. Burke Endowed Chair for Diabetes Research.

The health benefits of exercise are well known but new research shows that the body’s response to exercise is more complex and far-reaching than previously thought. In a study on rats, a team of scientists from across the United States has found that physical activity causes many cellular and molecular changes in all 19 of the organs they studied in the animals.
Exercise lowers the risk of many diseases, but scientists still don’t fully understand how exercise changes the body on a molecular level. Most studies have focused on a single organ, sex, or time point, and only include one or two data types.
To take a more comprehensive look at the biology of exercise, scientists with the Molecular Transducers of Physical Activity Consortium (MoTrPAC) used an array of techniques in the lab to analyze molecular changes in rats as they were put through the paces of weeks of intense exercise. Their findings appear in Nature.
The team studied a range of tissues from the animals, such as the heart, brain, and lungs. They found that each of the organs they looked at changed with exercise, helping the body to regulate the immune system, respond to stress, and control pathways connected to inflammatory liver disease, heart disease, and tissue injury.
The data provide potential clues into many different human health conditions; for example, the researchers found a possible explanation for why the liver becomes less fatty during exercise, which could help in the development of new treatments for non-alcoholic fatty liver disease.
The team hopes that their findings could one day be used to tailor exercise to an individual’s health status or to develop treatments that mimic the effects of physical activity for people who are unable to exercise. They have already started studies on people to track the molecular effects of exercise.
Launched in 2016, MoTrPAC draws together scientists from the Broad Institute of MIT and Harvard, Stanford University, the National Institutes of Health, and other institutions to shed light on the biological processes that underlie the health benefits of exercise. The Broad project was originally conceived of by Steve Carr, senior director of Broad’s Proteomics Platform; Clary Clish, senior director of Broad’s Metabolomics Platform; Robert Gerszten, a senior associate member at the Broad and chief of cardiovascular medicine at Beth Israel Deaconess Medical Center; and Christopher Newgard, a professor of nutrition at Duke University.

Co-first authors on the study include Pierre Jean-Beltran, a postdoctoral researcher in Carr’s group at Broad when the study began, as well as David Amar and Nicole Gay of Stanford. Courtney Dennis and Julian Avila, both researchers in Clish’s group, were also co-authors on the manuscript.
“It took a village of scientists with distinct scientific backgrounds to generate and integrate the massive amount of high quality data produced,” said Carr, a co-senior author of the study. “This is the first whole-organism map looking at the effects of training in multiple different organs. The resource produced will be enormously valuable, and has already produced many potentially novel biological insights for further exploration.”
The team has made all of the animal data available in an online public repository. Other scientists can use this site to download, for example, information about the proteins changing in abundance in the lungs of female rats after eight weeks of regular exercise on a treadmill, or the RNA response to exercise in all organs of male and female rats over time.
Whole-body analysis
Conducting such a large and detailed study required a lot of planning. “The amount of coordination that all of the labs involved in this study had to do was phenomenal,” said Clish.
In partnership with Sue Bodine at the Carver College of Medicine at the University of Iowa, whose group collected tissue samples from animals after up to eight weeks of training, other members of the MoTrPAC team divided the samples up so that each lab — Carr’s team analyzing proteins, Clish’s studying metabolites, and others — would examine virtually identical samples.

“A lot of large-scale studies only focus on one or two data types,” said Natalie Clark, a computational scientist in Carr’s group. “But here we have a breadth of many different experiments on the same tissues, and that’s given us a global overview of how all of these different molecular layers contribute to exercise response.”
In all, the teams performed nearly 10,000 assays to make about 15 million measurements on blood and 18 solid tissues. They found that exercise impacted thousands of molecules, with the most extreme changes in the adrenal gland, which produces hormones that regulate many important processes such as immunity, metabolism, and blood pressure. The researchers uncovered sex differences in several organs, particularly related to the immune response over time. Most immune-signaling molecules unique to females showed changes in levels between one and two weeks of training, whereas those in males showed differences between four and eight weeks.
Some responses were consistent across sexes and organs. For example, the researchers found that heat-shock proteins, which are produced by cells in response to stress, were regulated in the same ways across different tissues. But other insights were tissue-specific. To their surprise, Carr’s team found an increase in acetylation of mitochondrial proteins involved in energy production, and in a phosphorylation signal that regulates energy storage, both in the liver that changed during exercise. These changes could help the liver become less fatty and less prone to disease with exercise, and could give researchers a target for future treatments of non-alcoholic fatty liver disease.
“Even though the liver is not directly involved in exercise, it still undergoes changes that could improve health. No one speculated that we’d see these acetylation and phosphorylation changes in the liver after exercise training,” said Jean-Beltran. “This highlights why we deploy all of these different molecular modalities — exercise is a very complex process, and this is just the tip of the iceberg.”
“Two or three generations of research associates matured on this consortium project and learned what it means to carefully design a study and process samples,” added Hasmik Keshishian, a senior group leader in Carr’s group and co-author of the study. “Now we are seeing the results of our work: biologically insightful findings that are yielding from the high quality data we and others have generated.That’s really fulfilling.”
Other MoTrPAC papers published today include deeper dives into the response of fat and mitochondria in different tissues to exercise. Additional MoTrPAC studies are underway to study the effects of exercise on young adult and older rats, and the short-term effects of 30-minute bouts of physical activity. The consortium has also begun human studies, and are recruiting about 1,500 individuals of diverse ages, sexes, ancestries, and activity levels for a clinical trial to study the effects of both endurance and resistance exercise in children and adults.