Radically different
Nature Medicine, Published online: 09 July 2026; doi:10.1038/s41591-026-04484-6
Once confined to post-market surveillance, real-world evidence is now being used to emulate trials, guide approvals and even run studies in real time, forcing a rethink of what constitutes a clinical trial.
Nature Medicine, Published online: 09 July 2026; doi:10.1038/s41591-026-04495-3
This review outlines the state of the art of biological clocks and how they could help understand pathobiology, reduce the burden of disease and extend healthspan.
Nature Medicine, Published online: 09 July 2026; doi:10.1038/s41591-026-04538-9
In phase 1b/2 trial, the treatment of patients with metastatic KRASG12D-mutant pancreatic cancer, the intravenously delivered KRAS-G12D inhibitor HRS-4642 plus nab-paclitaxel and gemcitabine led to encouraging clinical response rates that support investigation in larger trials.
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Good morning, everyone. Now that we’ve all narrowly survived a workday without the World Cup, we can at last return to our new normalcy this afternoon for France 3-1 Morocco.
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Northwest Biotherapeutics, a public biotech company developing a treatment for brain cancer, submitted a marketing application to U.K. regulators in late December 2023. The review was supposed to take 150 days, under an expedited regulatory pathway for drugs that address serious unmet medical needs.
As you’re reading this newsletter, two years, six months, and 18 days have elapsed without an approval decision. Why the extra-long delay? Regulators at the U.K’s Medicines and Healthcare products Regulatory Agency, or MHRA, won’t comment, telling anyone who inquires, including me, that it’s up to Northwest Bio to provide an update on its brain cancer treatment, called DCVax.
Researchers from the University of Pennsylvania and New York University have received a $4 million grant from the Wellcome Trust to develop an AI-driven platform to train mental health clinicians using simulations of real patients.
Within the next two years, the partners will work on the development of the STELLAR platform, which stands for Steering-Vector Enhanced LLM Agents for Realistic Digital Twins in Mental Health. The platform will create digital twins of patients that trainees can use to practice conducting clinical interviews and evaluating psychiatric symptoms.
“STELLAR brings together behavioral data, clinical expertise, and AI to ask a very practical question,” said Sharath Chandra Guntuku, PhD, associate professor of computer and information science at Penn Engineering. “Can we build training tools that better prepare clinicians for how varied and complex patients are?”
Preparing future mental health clinicians for clinical interviews can be challenging as patients will often report overlapping symptoms that shift over time and subjective experiences that can be expressed differently by each individual. STELLAR will give trainees an ethical option for trainees to simulate interviewing patients with a broad range of symptoms, backgrounds, and clinical scenarios.
“In psychiatry, the details of symptom experience matter: how someone describes distress, how symptoms overlap, how severity changes over time, and how context shapes the clinical interaction,” said Raquel E. Gur, MD, PhD, professor of psychiatry, neurology, and radiology at Penn’s Perelman School of Medicine.
Patient simulations will be created drawing from clinical data from the Philadelphia Neurodevelopmental Cohort, a repository including psychiatric assessments and clinical interviews from thousands of young people created by Penn Medicine and the Children’s Hospital of Philadelphia. Rather than copying individual patients, the simulations will create composites based on real-world data for clinicians to practice realistic conversations in the context of a clinical interview.
This will allow trainers to precisely control the symptoms students encounter, their intensity, and how they interact with each other. For instance, a trainee may practice interviewing a patient with mild anxiety and another whose anxiety overlaps with depression or psychosis to learn how to distinguish the differences in presentation between both.
Because many mental health symptoms manifest beyond formal clinical settings, the platform will also be trained using data from social media platforms, where people discuss mental health symptoms in everyday language.
“Patient simulations will only be useful for clinician training if they are grounded in real clinical speech and evaluated as clinical interactions, not just plausible AI dialogue,” said Neville Ryant, PhD, researcher at Penn’s Linguistic Data Consortium. “[Our] role is to bring speech and language science into the core of the project: adapting speech-recognition tools to clinical interviews, creating high-quality transcripts and annotations, and helping evaluate both what the simulations say and how they say it. That includes assessing the language generated by the models, the naturalness of synthetic voices, how well those voices reflect target speech patterns, and the behavior of the avatar during real trainee interactions.”
To ensure the conversations are realistic, respectful, and useful to trainees, the team will involve people with lived experience of mental health conditions as well as family members and caregivers to provide their perspective into the evaluation process. Their feedback will help researchers assess the accuracy of simulations, avoid stereotyping patients, and prepare trainees for complex and nuanced clinical conversations with real patients.
“The promise of this approach is that we can move beyond stylized and potentially biased simulations,” said João Sedoc, PhD, assistant professor of technology, operations and statistics at NYU’s Stern School of Business. “If we can create digital patients that simulate controllable plausible symptom expression and responsibly evaluate, we can augment current clinician training practices with the kinds of conversations that are essential to better mental health care.”
The post Virtual Patients Will Train Future Mental Health Clinicians appeared first on Inside Precision Medicine.
Cancer cachexia has long been viewed as a systemic inflammatory syndrome driven primarily by tumor-secreted molecules circulating through the bloodstream. Now, a study published in Science suggests that at least one subset of lung cancers may instead exploit the nervous system to trigger appetite loss and rapid weight loss, revealing a potential new avenue for therapeutic intervention.
Using mouse models and supporting clinical observations, researchers found that certain lung tumors produce prostaglandin E2 (PGE2), a lipid signaling molecule that activates sensory neurons in the lung. Those neurons transmit signals through the vagus nerve to appetite-regulating centers in the brainstem, ultimately driving anorexia and cachexia.
The findings challenge the prevailing view that circulating inflammatory cytokines are the primary drivers of cancer-associated wasting and instead point to direct neural communication between tumors and the brain.
“We found that there’s some subsets of lung cancer that are at high risk of developing cachexia,” said senior author Thales Papagiannakopoulos, PhD, from the Salk Institute. “We wanted to understand how the cachexia is actually mediated, and in particular the neurological symptoms related to anorexia—the lack of appetite.”
Cachexia affects up to 80% of patients with advanced cancer and contributes substantially to treatment intolerance, reduced quality of life, and mortality. Despite decades of research, effective therapies remain limited because the biological mechanisms underlying the syndrome have been incompletely understood.
One of the study’s most unexpected findings involved diet.
Clinicians have often recommended calorie-dense, high-fat foods to help patients maintain weight during cancer treatment. Instead, the investigators found that high-fat diets—particularly those rich in animal fats—accelerated cachexia in their lung cancer models.
“We found that high-energy, high-calorie, high-fat diets, particularly animal-containing fat, instead of delaying the weight loss and the cachexia, made it worse,” Papagiannakopoulos said. “That’s quite surprising, but important to know.”
The researchers traced this effect to prostaglandin E2, a bioactive lipid involved in inflammation and known to be regulated by drugs such as aspirin and ibuprofen. Tumors produced higher levels of PGE2 when animals consumed diets rich in animal fat, intensifying appetite loss.
Importantly, the investigators found little evidence that well-known cachexia-associated cytokines, including IL-6 and GDF15, were responsible for the anorexia observed in this model. Instead, the biology appeared to mirror mechanisms previously described during respiratory infections.
Studies of influenza and bacterial lung infections have shown that sensory neurons detect inflammatory signals in the lung and relay information directly to the brainstem, producing sickness behaviors such as reduced appetite, decreased activity, and diminished water intake.
Papagiannakopoulos and colleagues suspected lung tumors were co-opting this same pathway. “The tumors are sort of co-opting these infection-like scenarios,” he said. “They’re signaling to the neurons and, by doing so, directly connecting to the brain and not requiring factors in circulation.”
To test that hypothesis, the researchers disrupted communication between the lung and the brain in two different ways.
In one experiment, they surgically severed one branch of the vagus nerve, reducing neural signaling from the lung by approximately half. The intervention significantly improved anorexia. The team then used chemogenetics—a neuroscience technique that selectively turns specific neurons on or off—to inhibit only lung sensory neurons projecting to the brain. “When we did that, we could rescue the mice,” Papagiannakopoulos said. “They were able to eat and drink and move as if they didn’t have cachexia.”
While surgically interrupting the vagus nerve is unlikely to become a treatment for cancer cachexia, the experiments identified an actionable biological pathway that could be targeted pharmacologically.
One possibility is developing therapies that block the specific prostaglandin receptors on sensory neurons rather than broadly suppressing prostaglandin production with nonsteroidal anti-inflammatory drugs.
“We want to identify what receptors on the neurons prostaglandin E2 is signaling through,” Papagiannakopoulos said. “Then we could potentially use inhibitors against the specific receptors, which would be much more focused than using ibuprofen or aspirin.”
Another approach could involve neuromodulation. Devices that electrically stimulate the vagus nerve are already FDA-approved for certain inflammatory diseases, and early studies are exploring similar technologies in cancer patients.
The researchers ultimately hope to identify the precise population of vagal sensory neurons responsible for transmitting cachexia signals and determine where those neurons communicate within the brain.
Beyond cachexia, the work raises broader questions about how tumors communicate with the nervous system. Rather than acting solely through hormones and inflammatory proteins circulating in blood, cancers may directly manipulate neural circuits to produce many of the systemic symptoms experienced by patients.
“The brain acts as a central integrator of all these signals coming from the body,” Papagiannakopoulos said. “We actually think that a lot of the effects seen in cancer patients—some of them grouped under cachexia or other paraneoplastic syndromes—are mediated through the brain through these neural networks.”
If confirmed in patients, those neural pathways could represent an entirely new class of precision medicine targets aimed not at shrinking tumors themselves, but at preventing one of cancer’s most devastating complications.
The post Lung Tumors Hijack Nerve Signals to Drive Cachexia, Opening New Therapeutic Target appeared first on Inside Precision Medicine.
A study carried out in Estonia on healthy relatives of breast and ovarian cancer patients shows around 20% of those tested carried some form of genetic variant that increased their risk of developing cancer.
The study showed that BRCA1/2 cancer-associated variants, currently the most widely recognized and tested cancer predisposition genes overall, accounted for 58.4% of all pathogenic variants uncovered by the investigators, but 41.6% were in non-BRCA genes.
“A carrier rate of 19.7% is remarkably high compared with the general population and strongly supports broader and more systematic genetic testing of relatives in families affected by breast and ovarian cancer,” lead investigator Mikk Tooming, PhD, a researcher at the Institute of Clinical Medicine in Tartu, Estonia, told Inside Precision Medicine.
“The highest yield was observed when a pathogenic variant was already known in the family… However, even among relatives without a previously identified familial variant, 8% carried a pathogenic variant. This is a clinically meaningful detection rate and suggests that genetic testing should not be restricted only to families in which a specific variant has already been identified.”
The current study, published in Frontiers in Genetics, included 3,472 healthy family members of people with breast and ovarian cancer. Of these individuals, 88% were female and 12% male. Most of those tested (79%) were younger than 51 years, which is when cancer screening often starts.
The researchers retrospectively analyzed genetic results from the family members, tested at four hospitals between 2007 and 2023. Testing evolved from targeted Sanger sequencing and microarrays in the early years to broad multigene next generation screening panels covering up to 6,700 genes by 2023.
Overall, around 20% of the tested family members carried a pathogenic or likely pathogenic variant. This went up to 41.8% when a familial variant was already known, versus 8.0% when it was not. BRCA1/2 variants accounted for most variants, but 23 genes were implicated in total, with CHEK2, ATM, BRIP1, and PALB2 also prominent.
Notably, the youngest group tested, those who were 30 years or younger, were more likely to have a cancer risk variant than older groups with a rate of 28%. “Age is highly relevant because many hereditary cancer syndromes begin to confer increased cancer risk well before routine screening starts,” says Tooming. “Identifying carriers early allows surveillance and prevention plans to be implemented at the most appropriate time.”
Despite being under tested, the carrier rate of risk variants in the men tested was high at 34%. Breast and ovarian cancers are thought of as predominantly female conditions. While women may be more impacted by these cancers than men, men can also carry relevant risk variants and these can increase their risk of developing other cancers.
“Both healthcare providers and families may focus testing efforts on women, unintentionally overlooking men,” emphasizes Tooming. “This highlights a significant gap in current practice. Male carriers, particularly those with BRCA2 variants, have elevated risks of prostate cancer, male breast cancer, pancreatic cancer, and several other malignancies. Health systems should actively promote genetic counselling and testing for male relatives when hereditary cancer risk is suspected.”
The researchers support expanded testing but believe that earlier and more personalized genetic risk assessment, for example, in families known to be impacted by cancer, would produce better results than simply lowering the age of cancer screening.
“The data suggest that individuals from families affected by breast and ovarian cancer should undergo earlier evaluation for hereditary cancer risk. When a pathogenic variant is identified, surveillance should be tailored according to the specific gene and associated cancer risk,” says Tooming.
“While our study did not include longitudinal follow-up and therefore cannot directly measure reductions in cancer incidence or mortality, the high proportion of carriers identified before standard screening age strongly suggests that expanded testing has the potential to deliver substantial public health benefits in Estonia and elsewhere.”
The post <i>BRCA</i> Tests Alone Miss 42% of Hereditary Cancer Risk appeared first on Inside Precision Medicine.
A comprehensive multi-omics analysis published in Nature Medicine provides new mechanistic insights into extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts, advancing understanding of the molecular and cellular interactions that will shape the clinical translation of xenogeneic liver support.
The study builds on a previously reported first-in-human decedent model in which blood from four brain-dead human recipients was circulated through ten-gene-edited porcine livers for up to 84 hours. While the initial work demonstrated that ELC could provide meaningful metabolic support, significant thrombocytopenia and evidence of host immune activation remained major barriers. The new study applies longitudinal, species-resolved multi-omics to dissect these biological responses at unprecedented resolution.
Researchers from NYU Langone Health, NYU Grossman School of Medicine, and the Perelman School of Medicine at the University of Pennsylvania profiled 64 serial blood samples using proteomics, metabolomics, and lipidomics alongside spatial transcriptomic analysis of 25 porcine liver biopsies and three native human liver samples. This integrated approach enabled simultaneous tracking of human and porcine molecular signatures throughout the xenoperfusion procedures.
Spatial transcriptomics revealed progressive infiltration of human innate immune cells into the porcine xenografts, dominated by inflammatory macrophages and neutrophils. These infiltrating cells expressed pro-inflammatory cytokines including IL1B, TNF, and IL6, while resident porcine Kupffer-like macrophages and T cells declined over time. Adaptive immune cell infiltration remained comparatively limited, suggesting that the extensive genetic engineering of the donor pigs may mitigate early adaptive rejection during short-term support.
One of the study’s most important findings was the distinct behavior of the human and porcine complement systems. While human complement proteins declined during ELC, the pig liver continued producing high levels of complement components C3 and C5 alongside acute-phase proteins and coagulation factors. The findings suggest that the xenograft actively drives innate immune and inflammatory responses rather than simply replacing liver function. Because currently available complement inhibitors are designed to target human proteins, they may not adequately suppress pig-derived complement activity, highlighting a potential need for species-specific therapeutics and additional genetic engineering to improve xenograft compatibility.
The investigators also identified candidate mechanisms underlying the profound thrombocytopenia consistently observed during ELC. Human platelets rapidly accumulated within the porcine liver, where they colocalized with activated sinusoidal endothelial cells expressing increasing levels of porcine von Willebrand factor (vWF), as well as infiltrating macrophages, neutrophils, and hepatocytes. Elevated expression of platelet adhesion receptors and evidence of platelet activation, aggregation, and phagocytosis point to a multifactorial process involving endothelial activation, innate immune responses, and platelet clearance pathways. These findings nominate multiple potential therapeutic targets, including porcine-specific vWF interactions and complement-mediated inflammatory signaling.
Beyond immune compatibility, the multi-omics analyses demonstrated sustained hepatic metabolic activity throughout the procedures. The xenografts supported bilirubin clearance, amino acid metabolism, detoxification, and synthesis of albumin, transferrin, apolipoproteins, and coagulation factors. In one recipient who underwent hepatectomy, the extracorporeal pig liver maintained critical metabolic functions for more than 48 hours in the absence of a native liver, although circulating lipid levels remained reduced during exclusive xenograft support.
The study also illustrates the growing value of systems biology approaches in transplantation research. By integrating longitudinal proteomic, metabolomic, lipidomic, and spatial transcriptomic datasets, investigators were able to distinguish donor- and recipient-derived biological processes while identifying dynamic molecular networks that would likely remain undetected using conventional analyses.
Although the cohort comprised only five ELC procedures in four decedents, it represents the most comprehensive molecular characterization of pig-to-human liver xenoperfusion reported to date. The findings provide a roadmap for improving xenograft biocompatibility through both genetic engineering and targeted therapeutics, while establishing species-resolved multi-omics as a powerful platform for biomarker discovery and mechanism-driven optimization of xenotransplantation strategies.
The post Human-Pig Interactions in Liver Xenotransplant Recipients: A Multi-Omics Study appeared first on Inside Precision Medicine.