STAT+: Revolution Medicines touts ‘unprecedented’ data for pancreatic cancer pill

Metastatic pancreatic cancer patients who received a targeted pill from Revolution Medicines lived nearly twice as long as patients who received chemotherapy, a striking result in a notoriously deadly and intractable malignancy. 

Patients who took the daily pill, called daraxonrasib, lived a median of 13.2 months, compared to 6.7 months for patients who received chemotherapy.

It’s “very impressive,” said Benjamin Weinberg, an associate professor of medicine at Georgetown University who was not involved in the study, in an email.

Continue to STAT+ to read the full story…

STAT+: Spyre Therapeutics IBD drug shows promise in early trial

An inflammatory bowel disease treatment developed by Spyre Therapeutics succeeded in its first major test, setting the company up to compete with several large drugmakers developing new medicines for the chronic digestive condition. 

Spyre is currently running a Phase 2 trial testing three experimental ulcerative colitis drugs as standalone treatments and, eventually, as combination therapies. The company released the first batch of results Monday on one of the treatments, showing it was safe and met the primary goal of the study. 

The therapy, SPY001, targets the alpha 4 beta 7 inflammation pathway, one of the emerging avenues drugmakers are probing to reduce inflammation in the gut. In Spyre’s SKYLINE study, subjects taking SPY001 saw a 9.2 point decrease in a disease activity index. Approximately 40% of the trial subjects went into remission after 12 weeks of use. 

Continue to STAT+ to read the full story…

You have no choice in reading this article—maybe

Uri Maoz loved doing his human research, back when he was getting his PhD. He was studying a very specific topic in computational neuroscience: how the brain instructs our arms to move and how our gray matter in turn perceives that motion. 

Then his professor asked him to deliver an undergrad lecture. Maoz assumed his boss was going to tell him exactly what to do, or at least throw some PowerPoint slides his way. But no. Maoz had free rein to teach anything, as long as it was relevant to the students. “I could have gone to human brain augmentation,” he says. “Cyborgs or whatever.”

Yet that admittedly fun and borderline sci-fi topic wasn’t what popped, unbidden, into his mind. His idea, he recalls with excitement: “What neuroscience has to say about the question of free will!” 

How—or whether—humans make decisions (like, say, about what to discuss in an undergrad lecture) had been on his mind since he’d read an article in his early twenties suggesting that … maybe they didn’t. This question might naturally beget others: Had he even had a choice about whether to read that article in the first place? How would he ever know if he was responsible for making decisions in his life or if he just had the illusion of control?

“After that, there was no turning back,” says Maoz, now a professor at Chapman University, in California. He finished his PhD work in human movement, but afterward he scooted further up the neural chain to find out how desires and beliefs turn into actions—from raising an arm to choosing someone to ask out to dinner on a Friday night.

Today, Maoz is a central figure in the attempt to (sort of, maybe) answer how that neural chain functions. His research has since overturned and reinter­preted canonical neuroscience studies and united the straight-scientific and philosophical sides of the free-will question. More than anything, though, he’s succeeded in uncovering new wrinkles in the debate.

Machines and magic tricks

The concept of free will seems straightforward, but it doesn’t have a universally accepted definition. One intuitive notion is that it’s the ability to make our own decisions and take our own actions on purpose—that we control our lives. But physicists might ask if the universe is deterministic, following a preordained path, and if human choices can still happen in such a universe. 

That’s a question for them, Maoz says. What neuroscientists can do is figure out what’s going on in the brain when people make decisions. “And that’s what we’re trying to do: to understand how our wishes, desires, beliefs, turn into actions,” he says.

By the time Maoz had finished his PhD, in 2008, neuroscientific research into the question had been going on for decades. One foundational study from the 1960s showed that a hand movement—something a person seemingly decides to do—was preceded by the appearance in the brain of an electrical signal called the “readiness potential.” 

Building on that result, in the 1980s a neuroscientist named Benjamin Libet did the experiment that had first piqued Maoz’s interest in the topic—one that many, until recently, interpreted as a death knell for the concept of free will.

An electrical impulse in our brains can shed only so much light on whether we truly are the architects of our own fates.

“He just had people sit there, and whenever they feel like it, they would go like this,” says Maoz, wiggling his wrist. Libet would then ask where a rotating dot was on a screen when they first had the urge to flick. He found that the readiness potential appeared not only before they moved their hand but before they reported having the urge to move—or, in Libet’s interpretation, before they knew they were going to move. 

Studies since have confirmed the observation and shown that the readiness potential appears a second or two—and maybe, fMRI implies, up to 10 seconds—before participants report making a conscious decision. “It suggests we are essentially passengers in a self-driving car,” says Maoz. “The unconscious biological machine does all the steering, but our conscious mind sits in the driver’s seat and takes the credit.” 

Maoz initially approached his own research with variations on Libet’s experiments. He worked with epilepsy patients who already had electrodes in their brains, for clinical purposes, and was able to predict which hand they would raise before they raised it. 

Still, some of the Libet-inspired studies people were doing nagged at him. “All these results were about completely arbitrary decisions. Raise your hand whenever you feel like it,” he says. “Why? No reason.” A decision like that is quite different from, say, choosing to break up with your partner. Try telling someone they weren’t in the driver’s seat for that

The field wasn’t looking at meaningful decisions, he says—the ones that actually set the course of lives. 

Maoz began pulling in philosophers to help guide his approach. They would challenge him to confront the semantic differences between things like intention, desire, and urge. Neuroscientists have tended to lump those concepts together, but philosophers tease them apart: Desire is a want that doesn’t necessarily progress toward an action; urge carries implications of immediacy and compulsion; and intention involves committing to a plan. (Maoz has come to focus specifically on intention—including, recently, the potential intentions of AI.)

In 2017, he organized his first in a series of free-will conferences, drawing many autonomy-interested philosophers. “Thank you so much for coming,” he recalls saying at the opening of the meeting. “As if you had a choice.” One day, the crew took an excursion out on a lake. As the group munched on shrimp, someone joked that they hoped the boat didn’t sink, because everybody in the field would die. 

The comment didn’t make Maoz feel existential dread. Instead, he figured that if the whole field was already there, why not lasso them all into writing a research grant? “He just thinks what should be the next step and just has a very good ability to just make it happen,” says Liad Mudrik, a neuroscientist at Tel Aviv University and a frequent collaborator.

That ability is special among scientists, says Chapman colleague Aaron Schurger, with whom Maoz co-directs the Laboratory for Understanding Consciousness, Intentions, and Decision-Making (LUCID, appropriately). “I really think that Uri is kind of at the nexus of this field right now because he’s really, really good at bringing people together around these big ideas,” he says.

Donations and interruptions

Maoz has recently been making progress on one of the big ideas that have consistently occupied his working hours: how trivial and significant decisions play out differently in the brain. In collaborations with Mudrik, he’s parsed the neural difference between picking and choosing—their terms for arbitrary decisions and those that change your life and tug on your emotions. 

Readiness potential? Their measurements didn’t clock it ahead of choices. In 2019, Maoz and a crew published a paper measuring the electrical activity in people’s brains as they pressed a key to choose one of two nonprofits to donate $1,000 to—for real, with actual dollars. Then the researchers compared that activity with what they saw when the same group pressed a key at random to donate $500 each to two nonprofits. The team saw the readiness potential in the arbitrary decision, but not for the $1,000 question. 

Libet’s result, they concluded, doesn’t apply to the important stuff, which means readiness potential might not actually be a sign that your brain is making a choice before you’re aware of it. “If Libet would have chosen to focus on deliberate decisions, then maybe the entire debate about neuroscience proving free will to be an illusion would have been spared from us,” Mudrik says. 

Maoz’s research has spurred others to reinterpret Libet’s work. It’s “enriched my thought process a great deal,” says Bianca Ivanof, a psychologist whose dissertation scrutinized Libet’s methods. They turn out to identify readiness potential at different times depending on how the rotating-dot setup is designed, complicating the ability to compare and interpret results.

Maoz has also continued to gather data on the subject. Last year, for example, he used an EEG to measure electrical signals in people’s brains as they got ready to press a keyboard space bar. At random moments, he interrupted their preparations with an audible tone and asked them about their intentions. He saw no connection between the readiness potential and whether or not they were planning to tap the key—evidence that the potential doesn’t represent the buildup of either conscious or unconscious plans. The team did see a signal, though, in a different part of the brain when people said they were preparing to move.

So … that’s free will? Sadly, Maoz would be compelled to say Well, not exactly. An electrical impulse in our brains can shed only so much light on whether we truly are the architects of our own fates. And maybe the confusing data from neurons is actually the point. “I don’t think it is a yes-or-no question,” Maoz says. Maybe our less meaningful choices aren’t mindfully made but big ones are; maybe we have the conscious power to change an intended action, but only if our brains are in a particular state. 

Neuroscientists likely can’t figure out, on their own, if free will exists. But they can, Maoz says, parse how semantically distinct decision-making forces—desires, urges, intentions, wishes, beliefs—manifest in our brains and become actions. “That is something that we are making progress on,” he says, “and I think that that’s going to help us understand what we do control.” And perhaps also help us make peace with what we do not. 

Sarah Scoles is a freelance science journalist and author based in southern Colorado.

Opinion: STAT+: Landmines await Vinay Prasad’s successor at the FDA

Vinay Prasad’s short yet two-act tenure at the FDA was wild. How does anyone follow him as the new leader of biologics oversight at the agency?

Someone I know at the FDA joked to me recently that I should be the new director of the Center for Biologics Evaluation and Research (CBER) after Prasad. I literally laughed out loud at how comical that sounded, but it got me thinking: Who would be both willing to do it and could get picked? Further, what’s awaiting them?

Prasad became a favorite punching bag of many, including the Wall Street Journal editorial board and right-wing activists like Laura Loomer. They are teed up to clobber the next person, too.

Continue to STAT+ to read the full story…

Health Issues Linked to Obesity Differ Between Men and Women

A study of middle-aged adults carried out by researchers at Dokuz Eylul University in Turkey shows that health and metabolic profiles differ between men and women with obesity.

The results, which will be presented at the European Congress on Obesity in Istanbul in May, show men with obesity are more likely to develop abdominal fat and have high levels of liver enzymes and triglycerides in the blood than women.

In contrast, women with obesity had higher levels of total and low-density lipoprotein cholesterol and increased inflammatory markers such as C-reactive protein compared with men.

“Our findings reveal intriguing differences in the way men and women respond to obesity,” said presenting author Zeynep Pekel, from Dokuz Eylul University, Izmir, Turkey, in a press statement.

“They show just how important gender-specific research is. Not only are sex differences a powerful player in the pathology and course of obesity, but our results indicate that such differences could be a stepping stone toward finding targeted, sex-based therapies to help in the management of people living with obesity.”

Although it is known that men and women with obesity have different adipose tissue distribution and have differences in metabolism more generally, this knowledge is not widely applied in obesity care.

In this study, Pekel and colleagues carried out an analysis of 1134 adults living with obesity attending a tertiary obesity clinic, including 886 women and 248 men. They measured standard factors like age, body mass index (BMI), waist and hip circumference and blood pressure as well as blood-based biomarkers like lipids, liver enzymes and inflammatory markers such as C-reactive protein, erythrocyte sedimentation rate, and white blood cell count.

The results showed that women were slightly older at 45 years on average. Men had significantly greater waist circumference and systolic blood pressure than women, as well as higher levels of the liver enzymes alanine aminotransferase and gamma‑glutamyl transferase and the kidney health biomarker creatinine. Men also had higher levels of triglycerides than women in the study.

Women with obesity had significantly higher total and low-density lipoprotein cholesterol than men in the study. They also had greater erythrocyte sedimentation rate, C-reactive protein, and platelet count, than the men.

“It’s still early days and these findings need to be confirmed in other patient groups, but they offer important insight into how obesity may affect men and women differently,” said Pekel.

“These differences are likely influenced by biological factors such as hormones, immune responses, and fat distribution. Our next steps are to validate these findings in larger populations, better understand the biological processes behind these differences, and explore how these patterns relate to clinical risk.”

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Evaluating an Incentive-Based mHealth App for Physical Activity Promotion Using the Obesity-Related Behavioral Intervention Trial Model: Small Cohort Study

Background: Physical inactivity remains a public health concern, with 42% (around 1 in 2) of women and 34% (around 1 in 3) of men in the United Kingdom, for example, failing to meet moderate-to-vigorous physical activity guidelines. To promote physical activity (PA) at scale, smartphone-based mHealth (mobile health) software apps offer a promising solution. Objective: This study aims to evaluate the feasibility of implementing an mHealth app offering very small (“micro”) financial incentives for PA in Leeds, United Kingdom. Methods: A 5-week single-arm proof-of-concept study was conducted with rolling recruitment among Caterpillar Health app users between September 12 and December 12, 2022 (Obesity-Related Behavioral Intervention Trial model, phase IIa). Users earned microincentives in the form of “points,” redeemable for consumer rewards (eg, movie tickets and gym passes), for meeting personalized daily step goals (US $0.13 per goal achieved; set using data from a 5-day baseline) and completing educational quizzes (US $0.33 per quiz). Descriptive statistics assessed feasibility outcomes (ie, reach, recruitment, retention, engagement, and acceptability) and preliminary effectiveness. Paired-samples tests (<.05) examined changes in weekly mean daily step count (from baseline) and step goal achievement over 5 weeks. Results: Of 285 app downloads, 46 users consented to participate (recruitment rate: 16.1%). Participants (mean age: 39.9, SD 11.1 y; 71.1%, 33/46 woman) had a baseline step count of 5598 (SD 2664) steps/day. A total of 25 participants remained engaged (ie, completed at least 1 quiz) at study week 5 (retention rate: 54.3%). Acceptability was high, with 75% of respondents (12/16) indicating they would recommend the app. Weekly mean daily step count did not significantly increase from baseline (mean difference 317, SD 2273, =.53). Weekly daily step goal achievement rate (%) decreased from study week 1 to 5 (−23.23, SD 22.85, =.02). Conclusions: Despite lower-than-expected recruitment and no statistically significant PA increase, relatively high engagement and acceptability suggest future pilot testing (Obesity-Related Behavioral Intervention Trial model, phase IIb) of a refined intervention (eg, wider selection of loyalty reward partners) and modified study protocol (eg, simplified consent process) is warranted. Trial Registration: ClinicalTrials.gov NCT05294692; https://clinicaltrials.gov/study/NCT05294692

Epigenetics at Birth Links Microbiome to Neurodevelopment, Potentially ASD and ADHD

The results of a study headed by researchers at Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, indicate that the gut microbiome and epigenetics are intertwined, and that both contribute to neurodevelopment.

The researchers showed that epigenetic changes present at birth can impact how an infant’s gut microbiome develops during their first year. They also identified specific epigenetic changes and gut microbes that were associated with signs of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) when the children were three years old.

“Certain bacteria seem to offer protection, which is exciting because it suggests there could be ways to support a child’s development through diet or probiotics in the future,” said research lead and gastroenterologist Francis Ka Leung Chan, MD. Chan is co-senior author of the team’s published paper in Cell Press Blue, titled “Epigenome-microbiome interplay in early life associates with infants’ neurodevelopmental outcomes,” in which they stated, “We showed that epigenetic alterations at birth were associated with early-life microbiome development and that they determine the risks of neurodevelopmental consequences in children.”

The first years of life are critical for brain development and immune system maturation. Though previous studies have shown that both early epigenetic changes and gut microbiome development can impact health in later life, little is known about how these two systems interact. “Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and can impact health outcomes in children,” the authors wrote. “One environmental cue known to trigger host epigenetic modifications is the genes of bacteria, fungi, and viruses inside the human body, collectively known as the microbiome.”

Co-senior author and public health researcher Hein Min Tun, PhD, of The Chinese University of Hong Kong, commented, “We wanted to see how the epigenome and microbiome interact in early life and if their interaction could influence a child’s risk of developing neurodevelopmental conditions like ASD and ADHD.” The authors added, “New understanding of host-microbe-epigenome interactions and mechanisms of epigenetic changes in early life can be leveraged for the prevention, early detection, and novel interventions of common childhood diseases.”

For their study the researchers characterized DNA methylation patterns from the umbilical cord blood of 571 infants. They paired this information with gut microbiome data collected from 969 infants at two, six, and 12 months of age, and from their parents during the third trimester of pregnancy. When the children reached 36 months of age, the researchers used a behavioral questionnaire to assess their neurodevelopment and investigate links between the microbiome, epigenome, and early signs of ASD and ADHD.

“This, to our knowledge, represents the first longitudinal study with multiple sample types to depict the intimate interplay between perinatal exposures, epigenetic hallmarks, and gut microbiome development and neurodevelopmental outcomes within the first three years of life,” the authors stated.

They found that an infant’s epigenome at birth was associated with birth mode, length of gestation, having older siblings, and maternal allergies, but it was not affected by their parents’ gut microbiomes. Microbiome development, on the other hand, was associated with birth mode, antibiotics, having older siblings, and breastfeeding. Infants who were born by Caesarean section (CS) showed different patterns of DNA methylation for several genes involved in immune responses and brain development. “Some of the changes in methylations of immune- and nervous-system-related genes, associated with CS delivery, are linked to neurodevelopmental outcomes,” they noted.

Their reported findings, the team suggested, “… resonate with studies linking CS to increased risks of immune-mediated and neurodevelopmental disorders, providing mechanistic plausibility through epigenomic and microbial dysbiosis.” The team also showed that an infant’s epigenome at birth impacted how their microbiome developed during their first year. Specifically, infants developed less diverse gut microbiomes at 12 months of age when they showed higher rates of DNA methylation in immune genes involved in recognizing pathogens. “We found that methylation rates in the major histocompatibility complex (MHC) region of infants at birth were linked to differences in the diversity of the infant gut microbiome at 12 months,” they commented.

The behavioral survey revealed that signs of ASD and ADHD in three-year-olds were associated with specific epigenetic patterns and the presence of certain gut microbes. “Importantly, we reported that epigenetic modifications were associated with an increased susceptibility to neurodevelopmental conditions in children, and these effects were in part mediated by microbial colonization.”

However, other microbial species seemed to mitigate these effects: infants with epigenetic patterns associated with ASD or ADHD were less likely to show signs of the disorders if they acquired Lachnospira pectinoschiza and Parabacteroides distasonis, respectively, during their first year. “We discovered a kind of conversation happening: a baby’s epigenetic setting at birth can influence their risk for neurodevelopmental disorders, but the presence of certain ‘good’ bacteria in their gut can step in and modify the risk,” Tun reported. “The foundations for brain health are laid very early, even before birth. However, we don’t want people to think this means a child’s developmental path is fixed at birth. These are complex conditions with many causes, and we’ve only uncovered a small piece of a very large puzzle.”

The researchers are continuing to follow the children who participated in the study to see how these early-life factors relate to their health as they grow. They note that laboratory experiments are needed to confirm the associations between gut microbes and neurodevelopment. In their discussion, the team wrote, “In conclusion, our findings revealed dual alterations to the neonatal epigenome and gut microbiome by perinatal factors and highlight the role of the ‘holo-epigenome’—the integrated host epigenome and microbiome—as a key mediator of neuro-immune outcomes. Interventions targeting microbial restoration or epigenetic modulation during critical developmental windows may mitigate risks of neurodevelopmental disorders.”

First author and gastroenterologist Siew Chien Ng, MD, PhD, added, “The ultimate goal is to develop safe, non-intrusive early interventions such as specific probiotics or live biotherapeutics, that could help nurture a healthy gut microbiome and potentially reduce the risk of neurodevelopmental challenges.”

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First Detailed Insight into Bornavirus Nucleoprotein–RNA Complex Reveals Unique Assembly

Borna disease virus 1 (BoDV-1) is a neurologic disease of horses and sheep that causes rare human infections. The outcome in those who develop disease almost always results in inflammation in the brain or fatal encephalitis.

The nucleoprotein–RNA complex in viruses protects the RNA genome and supports viral RNA synthesis. Increasing our understanding of the structure of this complex is essential to targeting viral replication. Structural characterization has been completed for several viruses in the same order as BoDV-1 (Mononegavirus) that more commonly infect humans, but detailed information for the family Bornaviridae has not been sufficiently explored.

“Bornaviruses are less well known than many other human RNA viruses, yet they represent the last major unresolved case for nucleoprotein–RNA structural analysis among human-infecting mononegaviruses,” says Yukihiko Sugita, PhD, associate professor at Kyoto University. “Closing this long-standing gap and connecting structural biology with virological function were major motivations for our team.”

Using cryo-electron microscopy, researchers from Kyoto University, Osaka Dental University, and Osaka Metropolitan University obtained high-resolution images of BoDV-1 nucleoprotein–RNA complexes and performed computational classification to separate and reconstruct the distinct assembly states of each complex in the sample. They also used mutational and functional assays to test nucleoprotein–RNA residues and evaluate their roles in viral RNA synthesis and assembly.

This work is published in Science Advances in the paper, “Structure and assembly of Borna disease virus 1 nucleoprotein-RNA complexes.”

These findings are the first detailed structural description of the nucleoprotein–RNA complex in the family Bornaviridae and revealed the three-dimensional structure of this nucleoprotein-RNA complex, showing ring-like assemblies and viral RNA binds in the inner groove. The researchers also found that each nucleoprotein subunit accommodates eight RNA nucleotides, suggesting a binding mode distinct from those reported for other related viruses.

The work also reveals that mutations impairing RNA binding disrupt viral RNA synthesis, but that nucleoprotein assemblies can form even without RNA. Together, these findings suggest an incremental model in which nucleoprotein assembly and RNA engagement are separate but coordinated processes.

This study provides a molecular framework for a systematic comparison of Bornaviridae nucleoprotein–RNA architecture alongside that of other mononegaviruses, and supports broader questions about the principles governing nucleoprotein–RNA interactions. It also lays the groundwork for future antiviral studies targeting viral replication through nucleoprotein–RNA interactions.

Next, the team would like to analyze complexes derived from infected cells as well as those with longer RNA segments. They also plan to integrate structural analysis and biochemical approaches in order to observe intermediate complex formation states and compare them with those of related viruses.

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FDA Clears First AI Algorithm to Diagnose Cardiac Amyloidosis

Anumana has received FDA approval for its ECG-AI algorithm designed to support the diagnosis of cardiac amyloidosis at the point of care. This makes it the first and only AI algorithm cleared by the FDA for this severe heart condition, which is often missed by the human eye when looking at electrocardiogram (ECG) data.  

“Cardiac amyloidosis can be challenging to detect early, especially when its signs overlap with more common heart conditions,” said Martha Grogan, MD, consultant in cardiovascular medicine at Mayo Clinic and co-principal investigator of the clinical study that supported the approval. “A tool that helps clinicians recognize suspicion of amyloidosis from a routine ECG could support earlier diagnosis and more timely next steps in care.”

Caused by abnormal protein deposits in the heart, cardiac amyloidosis is a life-threatening condition that can lead to heart failure if missed. Early diagnosis is critical to ensure a timely intervention, which can significantly improve patient outcomes, but the condition is often underdiagnosed due to unspecific symptoms that can be easily mistaken for other, more common heart conditions. 

Symptoms of cardiac amyloidosis are evaluated using a routine ECG. However, diagnosis requires identifying a combination of subtle features found in ECG data, meaning human interpretation can often miss the condition. 

Anumana’s ECG-AI algorithm can analyze ECG waveform to detect these subtle patterns in the data and support the diagnosis process. In a validation study involving more than 15,000 adults presenting signs, symptoms, or comorbidities of cardiac amyloidosis, the AI model detected the condition with 78.9% sensitivity and 91.2% specificity. 

“What makes this work especially meaningful is the rigor of the validation,” said Angela Dispenzieri, MD, hematologist at Mayo Clinic and co-principal investigator of the clinical study. “This ECG-AI algorithm was validated in a large multicenter study that included both ATTR and AL cardiac amyloidosis at major referral centers with deep expertise in amyloidosis diagnosis, supporting its potential to help identify patients earlier.”

Because the algorithm leverages ECGs obtained in routine clinical practice, it can be directly integrated into existing workflows without requiring clinicians to conduct any additional testing, helping them identify patients at risk and informing treatment decisions. 

Anumana previously received FDA clearance for two other ECG-AI algorithms, one for the diagnosis of low ejection fraction and another for pulmonary hypertension. All of these heart conditions are characterized by complex diagnoses that are often delayed or missed; for these patients, early diagnosis and treatment can significantly increase their outcomes and life expectancy.

“Each of our FDA-cleared algorithms addresses a specific and frequently missed cardiovascular condition, and cardiac amyloidosis represents an important addition to that portfolio,” said Maulik Nanavaty, CEO of Anumana. “The more conditions we can identify from a single ECG, the more valuable the test becomes in clinical practice. That’s what Anumana is working toward with each new clearance as we continue to advance our rigorous clinical evidence approach.”

The post FDA Clears First AI Algorithm to Diagnose Cardiac Amyloidosis appeared first on Inside Precision Medicine.

Metabolic Driver of Radiation Resistance in Lung Cancer Identified

Radiation therapy remains a cornerstone of lung cancer treatment, yet its long-term effectiveness is often undermined by a persistent challenge: tumors adapt and become resistant. Understanding, and overcoming, this resistance is a major priority in oncology.

A new study from researchers at The University of Texas MD Anderson Cancer Center, published in Cancer Research, identifies a metabolic mechanism that allows lung cancer cells to evade radiation-induced death and proposes a clinically actionable strategy to counter it.

A hidden driver of resistance

Radiotherapy works by damaging cancer cells in multiple ways, including triggering ferroptosis—an iron-dependent form of cell death driven by oxidative stress. However, many tumors develop the ability to suppress this process, allowing them to survive treatment.

The new study pinpoints a key player in this resistance: the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Researchers found that radiation exposure increases DHODH activity in lung cancer cells, enabling them to withstand ferroptosis and continue growing.

“This is an important finding because of the immediate translational opportunity,” said Boyi Gan, PhD, senior author of the study. “By understanding how DHODH is preventing cell death in radioresistant cancer cells, we were able to develop a strategy to overcome radiation therapy resistance in tumor models.”

A metabolic shield against cell death

DHODH is best known for its role in nucleotide synthesis, helping cells produce the building blocks needed for DNA repair and replication. But the study highlights an additional function that is particularly relevant in cancer.

The enzyme also supports the production of ubiquinol, a molecule that protects cells from oxidative damage. In the context of radiation therapy, this acts as a shield, preventing the lipid damage required to trigger ferroptosis.

By simultaneously promoting DNA repair and suppressing ferroptosis, DHODH enables cancer cells to survive what would otherwise be lethal radiation-induced stress.

Repurposing an existing drug

Rather than developing a new inhibitor from scratch, the researchers turned to leflunomide—an FDA-approved drug currently used to treat rheumatoid arthritis, which is known to inhibit DHODH.

In preclinical models, blocking DHODH alone modestly increased sensitivity to radiation. However, the most striking results emerged when the team combined three treatment modalities: radiation therapy, immune checkpoint blockade, and DHODH inhibition.

Radiation plus immunotherapy alone was insufficient to control tumor growth. But when leflunomide was added, the combination restored ferroptosis and led to a marked reduction in tumor progression.

“DHODH inhibition alone had some effect on sensitization to radiation therapy, but it was really this triple combination that had a marked effect,” Gan said.

Leveraging the immune response

A key aspect of the strategy lies in its interaction with the immune system. Immunotherapy, specifically anti–PD-1 checkpoint blockade, stimulates the production of interferon-gamma (IFN-γ), a signaling molecule that can enhance ferroptosis.

However, in resistant tumors, this signal alone is not enough to overcome the protective effects of DHODH. By inhibiting the enzyme, the researchers effectively remove this metabolic barrier, allowing IFN-γ–driven ferroptosis to proceed.

The result is a coordinated therapeutic effect in which radiation induces stress, immunotherapy amplifies cell death signals, and DHODH inhibition prevents tumor cells from escaping.

Toward clinical translation

One of the most compelling aspects of the study is its translational potential. Leflunomide is already widely used in clinical practice, with a well-characterized safety profile, potentially accelerating its evaluation in oncology settings.

“These findings provide a good rationale for testing this combination in clinical studies,” Gan said in a press release.

If validated in patients, this approach could offer a new strategy for overcoming resistance not only in lung cancer but potentially in other solid tumors treated with radiotherapy.

A broader shift in cancer therapy

The findings also reflect a broader trend in cancer research: targeting metabolic pathways that enable tumor survival under stress. While traditional therapies focus on directly damaging cancer cells, emerging approaches aim to disrupt the adaptive mechanisms that allow tumors to recover.

By linking metabolism, immune signaling, and cell death pathways, the study provides a more integrated view of how resistance develops—and how it can be reversed.

Although the results are based on preclinical models, they offer a clear path forward. Future clinical trials will be needed to determine whether the triple combination strategy can improve outcomes in patients with radioresistant lung cancer.

More broadly, the work highlights the importance of identifying “druggable” vulnerabilities within resistance pathways, especially those that can be targeted with existing therapies.

In this case, a drug originally developed for autoimmune disease may help solve one of the most persistent challenges in cancer treatment: restoring the effectiveness of radiation therapy when it begins to fail.

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