Background: Unplanned hospital readmissions represent a critical operational and financial challenge for health care systems in the United States, with 3.8 million 30-day all-cause readmissions in 2018 at an average cost of US $15,200 each, totaling US $58 billion in costs. Many published prediction models rely on comprehensive information (eg, full billing abstractions, discharge summaries, laboratory tests, and vitals) that becomes available only late in the encounter, limiting usefulness for real-time, in-hospital intervention. This creates a timeliness-accuracy trade-off: models that are most accurate retrospectively may arrive too late to act upon. Objective: This study tests whether a clinically meaningful predictive signal for 30-day all-cause readmission is present within a limited set of structured clinical codes recorded during the patient’s hospital stay. This approach evaluates whether predictive signals are retained when using a restricted set of structured clinical codes. Methods: We conducted a retrospective comparative modeling study using a large, deidentified electronic health record dataset of 50,000 inpatient encounters from the 2019 New York State Emergency Department Database. Two feature sets were constructed: (1) a limited set consisting of the first 5 () diagnosis codes, the first 5 Current Procedural Terminology (CPT) codes, and Charlson Comorbidity Index (CCI; 11 input features); and (2) a rich set using all available and CPT codes plus CCI (up to 135 input features). We trained 4 models: random forest, CatBoost, multilayer perceptron, and DistilBERT (a distilled Bidirectional Encoder Representations from Transformers [BERT] model; structured codes mapped to text and tokenized with DistilBERT-base-uncased). Evaluation used an untouched hold-out set of 10,000 encounters, preserving the natural 21.1% readmission prevalence. Primary metrics were area under the receiver operating characteristic curve (AUROC), -score, and accuracy. To address class imbalance, the training split only was balanced via undersampling of the majority class and bootstrap oversampling of the minority class; validation/test distributions were left unchanged. Results: Models trained on the limited feature set achieved AUROC values ranging from 0.5369 to 0.5596 and -scores from 0.2555 to 0.3434. Across 3 of 4 architectures, models trained on the limited feature set matched or exceeded the discrimination of their rich counterparts. The best model (random forest, limited) achieved an area under the curve AUROC 0.5596 (95% CI 0.5440‐0.5739) compared to the best performing rich model (DistilBERT) at 0.5703 (95% CI 0.5565‐0.5842), an absolute difference of 0.0107. The highest -score (0.3434) was achieved by DistilBERT on the limited feature set. Differences across architectures were small in absolute terms, with threshold-dependent metrics (eg, -score) being comparable. Conclusions: The findings suggest that models using a limited set of structured clinical codes can achieve performance comparable to those using more comprehensive coding information.
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Neuromotor and Cognitive Outcomes of Preterm Infants at 3 Months of Corrected Age in a Northeastern Region of Brazil: Longitudinal Feasibility Study
<strong>Background:</strong> Preterm infants (PTIs) are at increased risk of neurodevelopmental impairment, particularly in socioeconomically vulnerable regions, where access to early intervention services is limited. However, little is known about the feasibility of longitudinal developmental monitoring in such contexts. <strong>Objective:</strong> This study aimed to evaluate the feasibility of recruiting, retaining, and assessing preterm infants in a resource-limited setting in Northeastern Brazil and to generate preliminary data on early neurodevelopmental outcomes. <strong>Methods:</strong> This longitudinal feasibility study was conducted at a referral maternity hospital in Northeastern Brazil between October 2023 and March 2024. PTIs born at ≤32 weeks of gestational age were recruited during hospitalization. Feasibility outcomes included recruitment rate, retention rate, and completeness of assessments. Development was assessed at three time points: (1) Neonatal Intensive Care Unit discharge, (2) Kangaroo Neonatal Intermediate Care Unit discharge, and (3) at 3 months of corrected age (CA), using the Motor Optimality Score (MOS), Test of Infant Motor Performance (TIMP), and Bayley Scales of Infant Development III (BAYLEY-III). Caregiver-infant interaction was assessed using the Recorded Interaction Task (RIT). <strong>Results:</strong> Of 45 eligible infants, 20 (44.4%) were enrolled, and 10 (50%) completed follow-up in 3 months CA. A total of 67 assessments were conducted. Attrition was due to death (n=5), loss of contact (n=2), withdrawal (n=2), and transfer to another service (n=1). Among infants assessed at 3 months CA, 60% (n=6) of infants had MOS <25, indicating increased risk of neurological impairment. At TIMP, 80% (n=8) showed motor performance below expected levels in 3 months. BAYLEY-III assessments (n=8) indicated below-average motor performance in 50% (n=4) of the infants and below-average cognitive performance in 50% (n=4). All caregiver-infant dyads assessed at follow-up (n=10) demonstrated adequate interaction on RIT (mean score 57.9, SD 12.3). <strong>Conclusions:</strong> Longitudinal developmental monitoring of PTIs in a resource-limited setting was feasible, although retention remained a major challenge. Preliminary findings indicated frequent motor and cognitive vulnerabilities after hospital discharge, underscoring the importance of structured follow-ups in early infancy. These findings support the need for larger studies to refine follow-up strategies and evaluate early intervention in similar contexts.
Reliability and Safety of Smartwatch Blood Pressure and Oxygen Saturation Measurements in Older Adults: Instrument Validation Study
Background: Hypertension is a significant risk factor for cardiovascular diseases and premature mortality, with its prevalence increasing due to population aging and lifestyle factors. Accurate measurement of blood pressure (BP) and arterial oxygen saturation is crucial for disease prevention and monitoring, and wearable devices have emerged as a promising alternative. However, their clinical reliability requires validation, particularly in older populations. Objective: The aim of this research was to evaluate and compare the measurement of BP and arterial oxygen saturation in older people using a smartwatch in comparison with reference devices. Methods: We recruited 50 participants aged between 50 and 89 years (mean 70.60, SD 12.03 y), including 34 female participants and 16 male participants. A total of 3 BP measurements were taken simultaneously using the smartwatch and an ambulatory BP monitoring device (reference device). Arterial oxygen saturation was measured simultaneously using the smartwatch and the oximeter. The paired-sample test (2-tailed) was used to compare variables, and the intraclass correlation coefficient (ICC) was used to verify the correlation. Results: When averaged values were considered, no significant differences were observed between the Samsung Galaxy Watch 6 and the reference device for systolic BP (=.31) or diastolic BP (=.88), with good agreement for both parameters (systolic BP ICC=0.88; diastolic BP ICC=0.88). Arterial oxygen saturation showed no significant difference between devices (=.10), with moderate agreement (ICC=0.68). Heart rate measurements also showed no significant differences between devices (=.54), demonstrating good agreement. Conclusions: The Samsung Galaxy Watch 6 demonstrated acceptable agreement with reference devices for BP and arterial oxygen saturation measurements in older adults without decompensated clinical conditions, evaluated under controlled resting conditions. These findings indicate that the device provides reliable measurements within this specific population and context when measurements are obtained under standardized and physiologically stable conditions.
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Older Adults’ Motivators and Barriers to Using Mindfulness Apps for Stress Management in Brain Health Interventions: Interview Study
<strong>Background:</strong> Population aging is driving a rapid rise in dementia cases worldwide, posing a major challenge for health care systems around the globe, including in the Netherlands. Digital multidomain lifestyle interventions, which target multiple lifestyle domains simultaneously, can protect against cognitive decline in at-risk older adults but struggle to sustain engagement. Addressing stress in these interventions is crucial, as it can directly increase dementia risk and may promote unhealthy behaviors in other domains targeted in these interventions, including physical activity, diet, and sleep. <strong>Objective:</strong> This study explores the motivators and barriers for Dutch adults aged 60 years and older to use mindfulness apps for stress management within digital multidomain lifestyle interventions. Despite their potential, it remains unclear which stress-related needs would motivate older adults to use mindfulness apps in these interventions and whether these apps effectively address those needs. Moreover, little is known about how older adults practice mindfulness independently in everyday settings alongside other lifestyle priorities. <strong>Methods:</strong> We conducted 15 semistructured interviews with former participants of a 26-week multidomain lifestyle intervention study (the “HELI” [Hersenfuncties na Leefstijlinterventie] study) that included a mindfulness app for stress management. Participants (8 females; age range 61-73 years) were first invited to describe their practices to improve brain health to see whether stress and mindfulness emerged spontaneously. Follow-up questions and scenarios explored experiences with stress and mindfulness before these concepts were explicitly introduced midway through the interview, providing insight into their roles in participants’ lives free from associations with the terms. Data were analyzed using template analysis. <strong>Results:</strong> Older adults reported experiencing fewer minor daily stressors than earlier in life and having developed effective coping strategies with age. These strategies often included elements associated with mindfulness, such as acceptance and deliberate attention to the present moment. However, many frequently worried at night about major concerns, including personal health, the well-being of loved ones, and global issues. These findings suggest that older adults may be more motivated to use mindfulness apps to cope with nighttime worry than with minor daily stressors. At the same time, older adults reported barriers to using mindfulness apps, including negative associations with the term “mindfulness” (eg, perceived as too spiritual) and challenges in maintaining focus during exercises. <strong>Conclusions:</strong> We discuss how older adults develop mindfulness skills with age and how these skills help older adults cope with daily stressors but not with nighttime rumination. Specifically, we argue that diminished cognitive resources at night, fewer distractions, and metacognitive patterns may sustain worry before sleep. This study highlights the importance of tailoring multidomain lifestyle interventions to the unique challenges of older adults. We also offer recommendations to present mindfulness in ways that help older adults stay focused during practice.
Parabilis Files for IPO, a Day After Signing Up-to-$2.3B Regeneron Collaboration
Parabilis Medicines, the developer of drugs and antibody-drug conjugates targeting historically undruggable protein targets and based on stabilized helical peptides or Helicons
, has filed for an initial public offering (IPO), joining a growing parade of companies seeking to raise capital by tapping into the improving market for first time biotech stocks.
The company’s IPO filing came a day after Parabilis inked an up-to-$2.3 billion-plus strategic research collaboration with Regeneron Pharmaceuticals to discover and develop an initial five candidates encompassing “antibody-Helicon conjugates,” a new form of antibody-drug conjugates aimed at challenging and historically undruggable targets.
Regeneron has agreed to purchase approximately $75 million of Parabilis common stock in a concurrent private placement, at 90% of the IPO price per share.
It’s too soon to know how much money Parabilis plans to raise through the IPO. The company’s Form S-1 registration statement, filed Tuesday with the U.S. Securities and Exchange Commission (SEC), includes a placeholder “$100 million” figure that will inevitably be revised, and doesn’t say how many shares will be sold. Parabilis has applied to list its shares on The Nasdaq Global Market under the ticker symbol “PBLS.”
It’s also too early to know how much of the proceeds will go toward the four priorities it highlighted in its registration statement. Two of the four priorities relate to Parabilis’ lead Helicon peptide candidate zolucatetide (formerly FOG-001), a first and only direct inhibitor of the elusive β-catenin:TCF interaction, according to the company. Parabilis stated that it plans to continue ongoing clinical development of zolucatetide in desmoid tumors, including continuation of dose expansion and the launch of a Phase III registrational trial to topline data.
Parabilis also plans to continue ongoing clinical development of zolucatetide across several additional indications, including dose escalation and expansion in familial adenomatous polyposis (FAP); hepatocellular carcinoma, the most common type of primary liver cancer; and other rare tumors, with the aim of collecting data to support a registrational trial.
‘Expansive opportunity’
“We believe zolucatetide provides clinical validation of our first-in-industry Helicon approach and represents an expansive opportunity for medical and commercial impact,” Parabilis stated.
In addition, Parabilis plans to use IPO proceeds toward advancing its pipeline of additional programs—including its ERG protein degrader, an allosteric androgen receptor in its active state (ARON), and beta-catenin degraders—to Phase I clinical data; toward continued evolution of the Helicon platform for discovering and developing drug candidates; as well as toward general corporate purposes that include additional development efforts, working capital, and operating expenses.
According to Parabilis, zolucatetide has been evaluated in more than 150 patients to date and has generated positive clinical data in solid tumors characterized by alterations in the Wnt/beta-catenin pathway. In the drug’s lead indication of desmoid tumors, researchers have seen tumor reductions in 100% of patients with a 74% objective response rate (ORR) in patients who have had at least two post-baseline scans.
In March, Parabilis presented preliminary clinical data at the 11th Biennial Meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) showing significant improvement in duodenal polyposis at 60 weeks in a patient with familial adenomatous polyposis (FAP) treated with zolucatetide in the company’s ongoing Phase I/II trial (NCT05919264).
The patient showed a 52.2% reduction in desmoid tumor diameter, as well as “substantial” reductions in polyp number and size compared with a pre-treatment evaluation nearly two years prior, consistent with downstaging from Spigelman stage II to stage I.
Parabilis says its Helicon discovery platform allows it to precisely tune potency, selectivity, and pharmacologic properties by integrating ligands and additional functionalities at multiple positions. The platform integrates artificial intelligence (AI)- and physics-based computational modeling with high-throughput peptide synthesis and experimental screening.
“While our initial programs are focused on disrupting protein-protein interactions and inducing targeted protein degradation, we believe our platform can incorporate other advances in small molecule drug design and extend them to targets that are likely to remain out of reach for other modalities,” Parabilis stated.
Parabilis was founded in 2015 as FogPharma to commercialize technology developed in and inlicensed from the lab of Harvard University researcher and serial entrepreneur Gregory Verdine, PhD. The company, which rebranded itself into Parabilis in 2024, says it has generated proprietary datasets, comprising millions of data points for hundreds of thousands of Helicons across dozens of drug-like properties, following a decade of Helicon drug discovery.
‘Continuous learning loop’
“These data power a continuous learning loop that refines our models from target selection through lead optimization, enhancing our speed, precision, and ability to generate high quality molecules against difficult targets,” Parabilis explained. “As a result, our platform produces unique complex synthetic molecules at scale and a compounding advantage that we believe is difficult to replicate.”
If it carries out the planned IPO, Parabilis would be the 12th biotech to go public this year. The 11 IPO companies to date have raised a combined $3.491 billion, compared to the $1.556 billion raised by 11 companies this time last year. Six of the 11 companies have seen their shares rise since their initial offerings, led by the 520% share price increase of Veradermics, a developer of treatments for dermatology and aesthetic conditions that closed Wednesday at $105.32 a share.
This year’s largest IPO—and the largest of any biotech—was the $625 million offering of Kailera Therapeutics, a developer of therapies for obesity and weight management based on glucagon-like peptide receptor 1 (GLP-1) agonists, alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists.
Kailera last month completed what grew into a $718.75 million IPO last month that generated an estimated $662.1 million in net proceeds through the sale of 44,921,875 shares of common stock—including the exercise in full by underwriters of their option to purchase 5,859,375 additional shares—at the IPO price of $16 per share.
Should Parabilis’ planned IPO raise the placeholder $100 million amount, it would increase by 30% the $329.039 million in cash and cash equivalents that the company reported as of March 31.
Parabilis disclosed in its IPO filing that it ended the first quarter with a $45.316 million net loss, up 18% from its $38.342 million net loss of Q1 2025—as well as a net loss of $145.9 million for last year, up nearly 24% from its $117.9 million net loss for 2024. The company has no reported revenue.
Parabilis’ accumulated deficit rose 8% during Q1, to $586.82 million from $541.504 million at the end of 2025.
To fund its operations, Parabilis reported, it has raised a total $876.8 million as of March 31. That total consisted of $811.8 million from sales of its convertible preferred stock, $15 million in borrowings under a term loan and a $50 million Simple Agreement for Future Equity (SAFE).
The IPO comes just four months after Parabilis completed its last financing, an oversubscribed $305 million Series F round completed in January and co-led by investment firms RA Capital Management, Fidelity Management & Research Co., and Janus Henderson Investors.
Five investment firms were listed in the Form S-1 as underwriters for the IPO: Leerink Partners, BofA Securities, Evercore ISI, Guggenheim Securities, and LifeSci Capital.
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Human Gut Organoids with Functional Nerves Developed that Can Be Mass Produced
Researchers at Cincinnati Children’s Hospital Medical Center and Nantes Université in France have designed 3D-printed scaffolding trays that will reportedly allow scientists to produce larger versions of functional human gut organoids twice as fast as previous methods—and these organoids grow their own nerve cells.
This improved technology could help accelerate production of human mini-organ tissues that are large enough to be useful in patching damage or restoring diminished functions of a person’s small intestine, stomach, or colon. Such tissues also would be valuable for future disease studies and to more accurately evaluate organ damage risks linked to oral medications, according to the investigators.
Details of the study “Large-scale and innervated functional human gut tissues for transplantation via transient spheroid confinement” appear in Nature Biomedical Engineering.
Using a confined culture system (CCS), the team grew small intestine, colon, and stomach organoids from tiny spherical forms into centimeter-scale tubular forms nearly 10 times larger than previous methods. Also, unlike methods that require a complex effort to introduce nerve cells, these organoids develop a nervous system on their own.
“By reaching transplantation maturity twice as fast and developing their own functional nerves, these organoids demonstrate how engineering principles can drive biological innovation,” said staff investigator Holly Poling, PhD. “Our confined culture system is more than a production method; it’s a scalable, flexible platform for building complex human tissues.”
New production system prompts faster growth
Experts at Cincinnati Children’s Center for Stem Cell & Organoid Medicine (CuSTOM) have been making miniature versions of digestive system organs for more than 15 years, working on improving the sophistication of the lab-grown tissues. More recently, the team has been developing methods to make enough customized tissue to transplant into patients to help patch organ damage or restore diminished specialized functions.
The new technique uses 3D printing technology to make tray-like scaffolding molds from surgical resin, then filling the molds with degassed polydimethylsiloxane—a flexible rubber-like type of silicone.
The new trays contain grooves designed to confine a collection of sphere-shaped organoids into a row, which encourages the spheroids to fuse together and mature. The fusions occur within a special mix of nutrients and other ingredients that support initial growth from induced pluripotent stem cells (iPSCs) into more complex organoids.
By day six, the discrete spheroids develop into unified constructs along the grooves of the trays. These are moved into another hydrogel medium for continued growth for another eight days.
By day 14, the organoid constructs have produced all the cell types and structures that previously required 28 days to achieve. These tissues are then transplanted into rodents that are genetically modified to minimize rejection risk.
All of the transplanted tissues engrafted in rodents, the co-authors state. After growing in the rodents, the team produced as much as eight cm of functioning small intestine tissue, compared to approximately one cm of tissue using previous protocols. Not only were the structures much larger than previous methods, but now their neuromuscular function was also similar to native human tissue, representing a major advance.
“We are now able not only to generate complex gastrointestinal organoids at scale, but also to guide their differentiation into functional tissues with integrated enteric neuronal networks,” noted senior author Maxime Mahe, PhD. “By leveraging a defined growth environment, the intrinsic self-organization capacity of the cells drives the formation of tissue structures that closely resemble the human gastrointestinal tract.”
Jim Wells, PhD, a study co-author and chief scientific director at CuSTOM says the new technology overcomes key barriers to scale and function in organoid research and biomanufacturing.
“This platform’s simplicity, reproducibility, and versatility make it accessible for widespread adoption,” said Wells. “In addition, the emergence of a self-organized nervous system within these organoids is particularly important for further studies of neurodevelopmental disorders.”
Another step closer to human clinical trials
Michael Helmrath, MD, a surgeon-scientist at Cincinnati Children’s who co-directs CuSTOM, has been working for more than a decade to develop intestine organoids sophisticated enough for transplantation in human patients.
In 2017, Helmrath and colleagues demonstrated how to combine neural crest cells with intestinal tissue cells in a layered process to make the first human organoids with nerve function. His team also showed how intestine organoids could be grown larger by implanting them in a mouse to provide a blood supply. Ever since, intestine organoids have been getting more sophisticated, including versions with immune cells in addition to the specialized organ cells and nerves.
Now the new process—involving rats instead of mice—produces larger amounts of tissue.
“It is still not possible to grow complete, full-sized human organs in some sort of tank, but research like this has produced significant amounts of tissue that can be matched directly to individual patients,” explains Helmrath. “We believe such tissues, once transplanted, would further grow and multiply as part of the patient’s own organ to restore functions.”
More research and development is needed before “CCS organoids” will be ready for human clinical trials, according to Helmrath. But if successes continue, organoid medicine may allow more infants and children with dysfunctional organs to be treated without ever needing a full organ transplant.
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Enzymes Involved in Cholesterol Transport May Point to New Cancer Therapies
Some types of cancer have a relentless appetite for the metabolite cholesterol, using as much as they can access to accelerate their growth beyond the capabilities of normal cells. Research by scientists at Sanford Burnham Prebys Medical Discovery Institute and collaborators at the University of Illinois Chicago have now unveiled a potential method for turning the table on these tumors by subverting their cholesterol cravings.
The researchers’ studies, in mice and in human cancer cells, revealed new insights into enzymes known as phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) that help move cholesterol around cells. The researchers showed that without the help of these enzymes, a cholesterol traffic jam occurs, blocking the cancer cell’s ability to fuel tumor growth.
Headed by Brooke Emerling, PhD, the director of and associate professor in the Cancer Metabolism and Microenvironment Program at the Sanford Burnham Prebys NCI-Designated Cancer Center, the team reported on its findings in Science Advances, in a paper titled “Noncanonical PI(4,5)P2 coordinates lysosome positioning through cholesterol trafficking.”
The TP53 gene is mutated in roughly half of all cancers. Emerling and first author Ryan Loughran, PhD, a postdoctoral associate in the Emerling lab, focus on difficult-to-treat forms of breast cancer, where TP53 mutations are found in more than 84% of triple-negative breast cancers and three of every four HER2-amplified breast cancers.
Cancer cells with a mutation in the tumor-suppressing TP53 gene are known to produce extra cholesterol. This may make them more vulnerable to starvation if scientists can put a stop to the steady supply of the lipid. “We need more ways to treat cancers with this common mutation,” said Emerling. “One of our main goals with this work was to find new treatment possibilities for the large subset of breast cancers harboring TP53 mutations,” said Loughran. “We recognized a real opportunity in targeting the enzymes that control cholesterol transport, especially since cancer cells depend on this process far more than normal cells do.”
To better understand how to turn these cancers’ cholesterol consumption into a weakness, the research team turned to a family of cell membrane lipids known as phosphoinositides and the kinase enzymes that regulate them. The investigators had shown that a branch of the lipid enzyme family known as PI5P4Ks were required for the growth of cancers with TP53 mutations in mice, and they suspected that this tumor prevention was due to the enzymes’ role relocating cholesterol in the cell. “Our group has shown that suppression of the most catalytically active PI5P4K isoforms (α and β) in TP53-deficient cancer cells inhibits proliferation, and the deletion of these enzymes in Trp53-knockout mice confers protection from tumorigenesis,” the investigators wrote.
“Normally, when mice lose TP53 as the guardian of their genomes, they are fated to die from cancer in four-to-eight months,” said Emerling. “When you delete these kinases, the animals are 100% protected and never develop a tumor—and cholesterol turned out to be one of the missing pieces in this puzzle.”
The scientists conducted experiments in mouse and human cancer cells showing that PI5P4Ks influenced the movement and behavior of organelles that carry cholesterol around our cells. In cancer cells with TP53 mutations and PI5P4Ks, cholesterol-laden lysosomes were found near the exterior cell membrane. Without PI5P4Ks, lysosomes remained in the interior of the cells, near the nucleus.
Location is critical for lysosomes transporting cholesterol. While positioned near the edge of the cell, lysosomes and their cargo are in proximity with many receptor proteins, enzymes and signaling molecules that exist around the cell membrane. This includes mechanistic target of rapamycin complex 1 (mTORC1), an enzyme that governs cell growth and runs amok in cancer. “When lysosome positioning is biased towards the cell nucleus, mTORC1 activation is suppressed,” said Loughran. “This connects directly to our previous work, where we found that the loss of these kinases triggers starvation-like states in cancer cells. “When PI5P4Ks are absent, the link between lysosomal cholesterol and mTORC1 is compromised, a bit like two ships passing in the night.”
The change in lysosome position towards the cell’s interior that occurs without PI5P4Ks reduced interaction with mTORC1 and prevented it from sending signals associated with tumor growth. “The mTOR activation pathway is really what drives tumorigenesis, and so mTOR is an important target for cancer drug development,” said Emerling. “If we can target mTOR activity in aggressive cancers by blocking the sensing of cholesterol, that would be a promising treatment strategy.”
In their report the authors noted in summary, “The dependence of p53-deficient tumor cells on PI5P4Ks has been previously attributed to their roles as critical modulators of cellular stress responses, including protection from oxidative stress, maintenance of mitochondrial health, and regulation of autophagy. We now identify a previously undescribed role for PI5P4Ks in maintaining lysosomal cholesterol homeostasis and mTORC1 signaling.”
Previous research has looked at the use of statins as cancer drugs due to their ubiquity and safety as treatments for patients with high cholesterol. While more research is needed, studies so far suggest that tumors eventually acquire resistance to statins. “While cholesterol synthesis inhibitors such as statins have shown initial success, their efficacy is often compromised by the development of acquire resistance,” the team noted in the paper. “Consequently, strategies are being explored to disrupt cholesterol homeostasis more comprehensively by inhibiting its synthesis and intracellular transport.”
Loughran added, “It is important for us to find other ways to more comprehensively cut cancer cells off from cholesterol to impede their growth.” Emerling further stated, “We’ll continue to explore blocking PI5P4Ks as a more targeted approach tailored to how tumors operate.”
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Skape Bio Unlocks Generalizable GPCR Drugs Using AI Protein Design
The year was 2022. Chris Norn, PhD, was wrapping up his time as a postdoctoral researcher at the Institute for Protein Design (IPD) at University of Washington (UW). AlphaFold was taking the field by storm, while a new generation of deep learning tools was rapidly advancing de novo, or from-scratch, protein design with unprecedented success rates validated at atomic resolution. Within just a few years, these AI breakthroughs, widespread applications across pharmaceuticals, nanomaterials, biosensors, and more, would help earn Norn’s mentor, David Baker, PhD, the Nobel Prize in Chemistry.
“There’s so much dark space in biology. The precision of protein design was becoming incredible.” said Norn in an interview GEN. “Designing function from scratch is going to be incredibly impactful for treating diseases.”
Norn’s research investigated the subtle structural differences that caused G-protein-coupled receptors (GPCRs) to change conformation from a healthy state to disease driver. These integral membrane proteins are the largest protein family encoded by the human genome and represent approximately one-third of drug targets, across cancer, metabolic disease, and neurological disorders. Yet, they are traditionally difficult to hit because their accessible regions barely protrude from the cell membrane.
Today, Norn is co-founder and CEO of Skape Bio, a Copenhagen-based AI protein design company building a generalizable platform to target underexplored GPCRs and treat diseases once deemed undruggable. The team has published a new study in Nature demonstrating the design of functional miniproteins that target 11 GPCRs across a diversity of receptor families implicated in itch and pain, cancer, metabolic disorders, and migraine, with examples that penetrate deeply into hard-to-reach GPCR pockets. Notably, agonists were validated against three targets.
In a key example, the study designed a chemokine receptor antagonist that mobilizes hematopoietic stem and progenitor cells in a mouse model at a level comparable to a clinically used drug, with fewer side effects.
At the core of Skape Bio’s technology stack is a proprietary high-throughput platform that screens GPCRs directly within their native membrane environment, enabling accurate measurement of how conformational changes influence cell signaling and function. The approach represents a significant advance over traditional screening methods, which remove GPCRs from their membrane-embedded context and can fail to capture native structural dynamics. Over 100,000 miniprotein designs can be screened per target on a single-platform campaign.
Edin Muratspahić, PhD, postdoctoral research scholar at UW and co-corresponding author of the Nature study, highlights that the rise of de novo models, such as Baker lab’s RFdiffusion, has fueled the growing momentum for protein-based GPCR drugs. Compared to small molecules, protein therapeutics offer high selectivity, protease stability, and extended half-life. Notably, the small size of miniproteins allows better tissue penetration compared to antibodies.
“Many GPCRs remain underexplored because we didn’t have the tools to look at their pharmacology,” Muratspahić told GEN. “We’re excited to illuminate new biology beneficial to developing better and safer protein-based therapeutics.”
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Fungal Adjuvant Mannadjuvant Extends mRNA COVID-19 Vaccine Protections
Researchers at Boston Children’s Hospital have found that combining an adjuvant with the mRNA COVID-19 vaccine prolonged immune protection and broadened responses against viral variants in animal models, a discovery that could reduce the need for repeated booster vaccinations. The study, published in Nature Immunology, examined the effects of pairing the original SARS-CoV-2 mRNA vaccine with a fungal-derived immune enhancer called “mannadjuvant,” a formulation made from fungal mannan and aluminum hydroxide.
“Our strategy takes advantage of the immune system’s innate ability to ramp up broadly in response to a variety of components found in and on pathogens,” says Ivan Zanoni, PhD chair in immunology at Boston Children’s. “Even though the mRNA technology is the biggest breakthrough for vaccine technology in the last two decades, we thought that there was still room for us to improve this platform.”
The research focused on whether tuning inflammation through activation of pattern recognition receptors, or PRRs, could improve the effectiveness and durability of mRNA vaccines. The researchers tested whether stimulation of these receptors using fungal mannan could enhance immune responses generated by an mRNA vaccine targeting the ancestral SARS-CoV-2 spike protein.
The current research builds on earlier findings from Zanoni’s lab studying the same adjuvant in protein-based influenza vaccines. In the current study, investigators evaluated whether the mannadjuvant could improve performance of the original monovalent BNT162b2 Comirnaty vaccine encoding the spike protein from the ancestral WA1 strain of SARS-CoV-2.
To conduct the study, the team first confirmed that the mRNA vaccine remained stable after being mixed with the adjuvant. Researchers then vaccinated mouse models with either the mRNA vaccine alone or the vaccine combined with mannadjuvant. Additional testing was later conducted in non-human primates and human immune cells.
The research evaluated durability of antibody responses, T-cell activity, inflammatory signaling, and immune recognition of SARS-CoV-2 variants. Vaccinated mice were also exposed to mutated spike proteins from omicron variants of the virus to find out if the immune response generated by the adjuvant-enhanced vaccine could also recognize strains that emerged after the original vaccine design.
The data showed that mice that received the vaccine with the mannadjuvant retained antibodies to the viral spike protein for up to two years, compared with only a few months for animals given the vaccine alone. The adjuvant combined with the original vaccine was also shown to create a strong immune responses against omicron variant spike proteins.
“In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting,” the researchers wrote adding that their findings suggested antifungal PRRs could be used to create more potent and durable mRNA-based vaccines.
The researchers also evaluated the safety of the combination in mice and non-human primates and found that the adjuvant improved immune response “without increasing reactogenicity or breaking self-tolerance in mice and NHPs.”
The clinical implications of this finding shows that adjuvants targeting innate immune pathways could make mRNA vaccines more durable and less dependent on repeated reformulation or booster administration. Rather than updating vaccines to match each new variant, the researchers believe that the broader immune training elicited by combining the vaccine with an adjuvant may allow vaccines to remain effective as viruses evolve.
Future studies will focus on clarifying the molecular mechanisms by which the adjuvant stimulates immunity, particularly because immune responses to fungi are not fully understood. The team also plans to further investigate how mannadjuvant regulates interferon and interleukin-1 signaling and controls inflammasome activation.
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How Colorectal Tumors Escape KRAS Inhibitors Identified
Researchers at University of Texas MD Anderson Cancer Center and Weill Cornell Medicine have identified key mechanisms that allow colorectal tumors to resist KRAS inhibitors, uncovering both genetic and non-genetic pathways that help cancer cells survive treatment.
The findings, published in Cancer Cell, suggest that combining KRAS inhibitors with therapies targeting early inflammatory responses may improve outcomes for patients with KRAS-mutant colorectal cancer.
KRAS mutations remain difficult to treat in colorectal cancer
KRAS is one of the most commonly mutated oncogenes in colorectal cancer, occurring in nearly half of all patients. Mutations in the gene drive tumor growth by continuously activating signaling pathways involved in cell proliferation and survival.
Although KRAS inhibitors such as Adagrasib and Sotorasib have transformed treatment options for some lung cancers, their clinical benefit in colorectal cancer has been more limited. Many patients either fail to respond or rapidly develop resistance after an initial response.
Previous studies have suggested that tumors may escape treatment by acquiring secondary pathway mutations, but the full picture of resistance has remained unclear.
To investigate this further, the research team analyzed patient-matched tumor samples collected before treatment, during KRAS inhibitor therapy, and after disease progression. The researchers combined targeted gene sequencing with single-cell spatial transcriptomics to examine how tumor cells evolved over time.
The team also used organoid models of KRAS inhibitor-resistant colorectal cancer to validate their findings experimentally.
Tumors evade KRAS inhibition through multiple mechanisms
The researchers discovered that resistant tumors do not rely on a single escape mechanism. Instead, colorectal cancer cells use both genetic mutations and adaptive cell-state changes to survive therapy.
Some resistant cancer cells acquired secondary mutations that bypassed KRAS blockade, while others altered their cellular behavior without acquiring new mutations. According to the authors, these non-genetic adaptations enabled tumor cells to tolerate treatment and remain viable despite continued KRAS inhibition.
Both resistance mechanisms could coexist within the same tumor, highlighting the complexity and heterogeneity of treatment resistance in colorectal cancer.
“Our findings uncovered the genetic and cell-state shifts that colorectal tumors use to escape KRAS inhibition,” said co-lead author Salvador Alonso Martinez, MD, assistant professor of Gastrointestinal Medical Oncology at MD Anderson.
“Targeting the adapted early inflammatory response may be the key to stopping resistance and improving the effectiveness of KRAS therapies for these patients,” he added.
Early inflammatory signaling helps cancer cells survive
One of the study’s most significant findings was the identification of an early inflammatory response triggered shortly after KRAS inhibitor treatment begins.
In tumor samples collected early during therapy, the researchers observed activation of inflammation-related signaling programs that appeared to help cancer cells adapt to therapeutic stress.
Rather than immediately dying in response to KRAS blockade, some tumor cells entered a survival state driven by inflammatory signaling pathways. This adaptive response allowed them to persist and eventually contribute to disease progression.
The investigators identified the protein kinase TBK1 as a central mediator of this inflammatory adaptation.
TBK1 is known to regulate innate immune and inflammatory signaling pathways, but the new findings suggest it may also play a critical role in enabling colorectal tumors to survive KRAS inhibition.
When the researchers blocked TBK1 activity in preclinical models, the inflammatory survival response was suppressed and tumor cells became more sensitive to KRAS inhibitors.
Combination therapy may improve treatment durability
The results suggest that combining KRAS inhibitors with TBK1 blockade could represent a new therapeutic strategy for patients with KRAS-mutant colorectal cancer.
Rather than focusing exclusively on secondary genetic mutations after resistance has already emerged, targeting the early adaptive inflammatory response may help prevent or delay resistance from developing in the first place.
In preclinical organoid models, dual inhibition strategies enhanced treatment sensitivity and overcame resistance mechanisms that limited the effectiveness of KRAS inhibition alone.
The study’s authors believe this approach could potentially produce more durable responses in patients, though clinical validation will still be required.
Implications for future colorectal cancer treatment
The findings add to growing evidence that cancer drug resistance is often driven not only by permanent genetic evolution, but also by reversible adaptive cell states that emerge under therapeutic pressure.
Understanding these early adaptive mechanisms may help researchers design combination therapies that suppress tumor survival pathways before resistant clones become dominant.
The study also demonstrates the increasing importance of single-cell and spatial transcriptomic technologies in oncology research, allowing scientists to observe how tumors dynamically respond to treatment at high resolution.
While TBK1 inhibitors are not yet standard therapies for colorectal cancer, the researchers believe their work provides a strong rationale for future clinical trials combining TBK1 blockade with KRAS-targeted therapies.
If successful, these strategies could expand the clinical impact of KRAS inhibitors in colorectal cancer, where durable responses have historically been difficult to achieve.
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