Weill Cornell Medicine

Dietary fat composition modulates host physiology and the gut microbiome, but the long-term effects of specific fat sources and the extent to which these changes resolve after dietary reversal remain incompletely defined. Here, we present a longitudinal multi-omic resource of mice maintained for one year on a purified control diet, seven high-fat diets differing in predominant fat source, or reversal regimens in which animals were switched from high-fat to control diet after 4 or 9 months. We further incorporated two cohorts with distinct pre-existing microbiome configurations to determine how baseline community structure shapes diet-induced remodeling of the gut microbiome ecosystem. By integrating longitudinal phenotyping, fecal metagenomics, fecal metabolomics, plasma metabolomics and lipidomics, and intestinal single-cell RNA sequencing, we defined the shared and dietary fat-specific responses across host and microbiome compartments. Baseline microbiome composition strongly influenced microbial responses to diet, indicating that pre-existing community structure is a major determinant of dietary ecosystem remodeling. Although many altered features shifted toward baseline after dietary reversal, only approximately half of diet-associated microbial changes recovered within the study window. A subset of taxa exhibited persistent alterations, including sustained depletion of Lactobacillus johnsonii and Bifidobacterium pseudolongum and sustained enrichment of Alistipes finegoldii, consistent with a "microbiome memory" of prior high-fat diet exposure. This memory effect is mirrored in the host, by sustained suppression of major histocompatibility complex class II (MHC-II) gene expression in intestinal epithelial cells after dietary reversal. These findings indicate that dietary fats leave a lasting imprint on the host-microbiome interactome that survives dietary intervention. Together, these data establish a resource for defining how dietary fat source, baseline microbiome composition, and dietary history shape host-microbiome states. The entire resource is available online as an RShiny app.

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in the treatment of solid tumors, reinforcing the need to elucidate the invivo biodistribution of these engineered T cells. Here, we integrate the anti-DOTA huC825 reporter ("Thor") platform into newly developed human anti-interleukin-13 receptor α-2 (IL13Rα2)-single-cell fragment variable (scFv)-derived CAR-T cells and investigate its utility for mapping CAR-T cell distribution in a xenograft mouse model of melanoma. Methods: We engineered anti-IL13Rα2-scFv-derived CAR-T cells expressing huC825 (KLG3BBz-huC825), evaluated detection sensitivity, and monitored CAR-T cell biodistribution via weekly [86Y]Y-aminobenzyl-DOTA PET/CT and therapeutic efficacy. Results: KLG3BBz-huC825 T cells demonstrated potent antigen-specific cytotoxicity and cytokine release invitro. The Thor radiohapten capture platform offered exquisite detection sensitivity of only 3,000 engineered T cells and enabled prolonged spatiotemporal assessment of CAR-T cell kinetics up to 7 wk after infusion, corroborated by histopathology. Treatment with KLG3BBz-huC825 resulted in an overall survival benefit. Conclusion: The Thor platform offers a versatile and highly sensitive approach to study the real-time kinetics of CAR-T cells invivo.

Prostate cancer progression is characterized by dysregulated lipid metabolism, with fatty acid synthase (FASN), the rate-limiting step in de novo lipogenesis (DNL), resulting in significant accumulation of saturated lipids. Here, we investigate whether pharmacologic FASN inhibition creates a metabolic state that increases reliance on exogenous polyunsaturated fatty acids (PUFAs). Inhibition of FASN profoundly alters membrane phospholipid composition, driving compensatory incorporation of PUFAs into membrane phospholipids, thus increasing susceptibility to lipid peroxidation and oxidative damage. Combined FASN inhibition and PUFA exposure increased reactive oxygen species, induced mitochondrial hyperpolarization, and enhanced lipid peroxidation in both hormone-sensitive and castration-resistant prostate cancer models. Marked inhibition of human and murine prostate cancer organoids is achieved ex vivo . In genetically engineered, DNL-reliant Hi-Myc mice, a diet enriched in PUFAs significantly inhibited invasive carcinoma compared to a saturated fat-enriched diet. Environmental PUFAs modulate and enhance the therapeutic efficacy of FASN-targeted strategies. These findings set the stage for pharmacologic and dietary intervention in prostate cancer patients.

This review explores recent findings concerning racial and ethnic disparities in radiation therapy (RT) for breast cancer. It highlights variations in treatment access, delivery, adverse effects, and outcomes, aiming to inform interventions that promote equity. Disparities persist in the receipt of RT following breast-conserving surgery, particularly among Black, Hispanic, and American Indian/Alaskan Native women. These groups are more likely to experience delays in care, higher rates of treatment noncompletion, and underrecognized side effects. Furthermore, differences in mean radiation dose and limited access to advanced RT techniques contribute to increased toxicities. Institutional, systemic, and interpersonal factors underlie these inequities. Mitigating disparities in RT for breast cancer requires comprehensive strategies—expanding access, culturally sensitive care, dose optimization, and improved communication. Evidence from initiatives like the Michigan Radiation Oncology Quality Consortium (MROQC) demonstrates how data-driven quality improvement can narrow equity gaps.

In the phase 2, double-blind, randomized controlled BEYOND trial (NCT03342404), luspatercept increased hemoglobin levels in patients with non-transfusion-dependent β-thalassemia (NTDT). This study assessed long-term effects of luspatercept on patient-reported outcomes (PROs), using data from BEYOND and patients who continued luspatercept treatment in the phase 3b long-term follow-up (LTFU) study (NCT04064060). In BEYOND, patients received luspatercept or placebo Q3W for ≥ 48 weeks. PRO instruments included NTDT-PRO (BEYOND only), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Survey (SF-36). Mixed-effects models with repeated measures estimated least squares mean changes from baseline in PROs. PROs were evaluable in 144 patients (luspatercept 95, placebo 49) from BEYOND and 58 (luspatercept) from LTFU. Luspatercept improved NTDT-PRO tiredness/weakness and shortness of breath domain, FACIT-F fatigue subscale, and SF-36 vitality scores versus placebo through double-blind treatment (generally maintained through week 96). In LTFU patients, significant, meaningful improvements from baseline in FACIT-F fatigue subscale and SF-36 vitality scores were observed within 12 weeks of treatment initiation and maintained for up to 5 years. Other FACIT-F and SF-36 domains improved or were maintained throughout LTFU. Luspatercept offers rapid and durable benefits by improving anemia-related symptoms and quality of life in patients with NTDT. Trial Registration: ClinicalTrials.gov Identifier: NCT03342404; NCT04064060.

Over 90% of people with hereditary cancer syndromes in the United States remain unidentified. The Genetic Cancer Risk Detector (GARDE) is an open-source, electronic health record (EHR)-integrated, digital health platform that can facilitate genetic cancer risk assessment and genetic testing. This study evaluates its budget impact on health care institutions. A budget impact analysis was performed from the perspective of a US health care provider system over a 3-year horizon. Data from the BRIDGE randomized controlled trial data from the University of Utah Health (UHealth) were used, where eligible primary care patients were screened for genetic cancer risk via GARDE. Costs of GARDE were categorized across planning, implementation, and operational phases. Revenue projections were based on Centers for Medicare & Medicaid Services reimbursement rates. Scenario analyses varied uptake of interventions, surveillance intervals, reimbursement rates, and implementation scale. Of 1,444 patients identified by GARDE at UHealth and enrolled in the BRIDGE trial, 205 completed genetic testing, with 15 found to carry pathogenic variants. The total 3-year implementation cost was $29,217 US dollars (USD). Revenue from guideline-recommended procedures totaled $86,563 USD, yielding a net positive budget impact of $57,347 USD. Most revenue (76.4%) was generated by surgical risk-reduction procedures. Scenario analyses revealed high sensitivity to cancer risk-reducing surgery uptake and implementation scale. Modeling 100% uptake of risk-reducing surgeries increased revenue to $128,102 USD, while 20-fold scaling of the implementation population increased revenue to $1.7 million USD. Commercial insurance reimbursement assumptions further amplified revenue. GARDE enables scalable hereditary cancer risk assessment within a health care provider system. Even with modest uptake, it yields a positive financial return, and significantly greater revenue is achievable with broader implementation. These findings support adoption of EHR-integrated tools to enhance clinical outcomes in precision cancer prevention and risk management, in an economically viable manner.