Citations

Alzheimer’s disease (AD) is characterized by profound metabolic dysfunction and disturbances in gut–brain axis signaling. Ketogenic diet (KD) has demonstrated metabolic and cognitive benefits in both preclinical and clinical studies. However, factors that determine individual responsiveness or non-responsiveness to KD interventions remain poorly understood. Emerging evidence suggests that gut microbiome composition plays a critical role in modulating these factors. This study examined how KD responsiveness, determined by fecal microbiota transplantation (FMT) derived from human KD responders (RES) or non-responders (nRES)- influences cognition, gut barrier function, neuroinflammation, and microbial structure in 3xTg-AD mice. We further evaluated whether supplementing KD with a novel Synbiotic Yogurt (SY) formulated by our team could augment or restore responsiveness. We hypothesized that RES microbiota would confer superior KD-driven benefits and that KD-SY would synergistically improve metabolic and neurobiological outcomes, particularly among nRES recipients. Adult 3xTg-AD mice were antibiotic-cleansed and randomized to receive Control-, RES-, or nRES – FMT, while maintained on KD for four weeks. A second cohort received KD supplemented with SY or non-fat milk along with RES- or nRES-FMT. Behavioral tests, gut permeability assay, serum inflammatory markers, brain amyloid beta (Aβ), intestinal morphology, gene expression, and 16S rRNA microbial profiling were measured. RES-FMT recipients showed early improvements in spatial memory (Y-maze and novel object recognition) and consistently lower Aβ accumulation in cortex and hippocampus. They also showed higher synaptophysin and IL-10 expression. In contrast, nRES-FMT mice exhibited distinct microbiome clustering, lower microbial diversity, enrichment of Proteobacteria, and impaired gut barrier function relative to RES-FMT recipients. Functionally, specific taxa like Enterococcus, Enterobacter, and Paenibacillus were associated with greater vulnerability to AD-related pathology, while Akkermansia, Bifidobacterium, and Muribaculum were linked with lower vulnerability. SY supplementation improved metabolic and gut barrier indices across groups characterized by increased circulating ketone levels, lowered fasting glucose and glucose-ketone index, and decreased gut permeability. nRES-SY mice showed the strongest gains in recognition memory and reductions in brain Aβ1–42 burden. SY increased expression of barrier- and inflammation-modulating genes, including occludin, APLP2, and IL-10. Microbiome analysis demonstrated higher microbial diversity and enrichment of beneficial genera such as Paralactobacillus, Eubacterium, and Muribaculum. These findings show that KD responsiveness is strongly determined by gut microbiota composition and that SY supplementation can enhance or rescue metabolic, cognitive, and microbial outcomes, particularly in nonresponders. This supports a precision-microbiome strategy combining metabolic and Synbiotic interventions to improve gut–brain axis function in AD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in type 2 diabetes mellitus (T2DM); however, their association with post-stroke outcomes following acute ischemic stroke (AIS) remains uncertain. Methods We conducted a retrospective propensity score-matched (PSM) cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and AIS between January 2020 and January 2025 were included. Pre-stroke GLP-1 RA users were compared with non-users. Primary outcomes were all-cause mortality, intracerebral hemorrhage (ICH), ICD-10-coded stroke severity (NIHSS categories), and transient ischemic attack (TIA). Results After PSM, GLP-1 RA use was associated with significantly lower all-cause mortality at all time points (RR 0.44–0.52; HR 0.43–0.45; all p<0.001). ICH risk was reduced within 1–3 days (RR 0.683; 95% CI 0.496–0.940; p=0.019) and within 7 days (RR 0.575; 95% CI 0.516–0.641; p<0.001). A severity-dependent gradient was observed across NIHSS categories, with risk reductions ranging from 37% for minor strokes (NIHSS 0–5; RR 0.626) to 67% for very severe strokes (NIHSS >20; RR 0.327; all p<0.001). TIA risk was 29% lower (RR 0.712; 95% CI 0.668–0.759; p<0.001). E-value analysis demonstrated that an unmeasured confounder would need to be associated with both GLP-1 RA use and 30-day mortality by a risk ratio of at least 3.95 to fully explain the observed association, and by a risk ratio of at least 3.53 to shift the confidence interval to include the null. Conclusions In this large real-world cohort, pre-stroke GLP-1 RA use was associated with lower post-stroke mortality, reduced ICH, and a severity-dependent reduction in ICD-10-coded stroke severity among patients with T2DM. Residual confounding cannot be excluded, and these findings warrant confirmation in prospective randomized trials.

Measles virus (MeV) infection is mediated by two cellular receptors: signaling lymphocytic activation molecule family member 1 (SLAMF1, also known as CD150), expressed by immune cells, and nectin-4, expressed by epithelial cells. Infection of immune cells causes systemic disease and immune suppression, while infection of airway epithelial cells results in efficient transmission. In rare cases, MeV reaches the brain and slowly spreads in cells that do not express bona fide receptors, causing subacute sclerosing panencephalitis (SSPE). In the brains of persons with SSPE, multiple mutations of the MeV membrane fusion apparatus are selected that enable its triggering by host proteins acting as surrogate receptors. These mutations favor cell-to-cell spread, which promotes population-based MeV genome evolution and the formation of collective infectious units (CIUs). CIUs, which can rebalance their components and rapidly adapt to new environments, may support neuropathogenesis of other nonintegrating RNA viruses, in particular those with nonsegmented negative-strand genomes.

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P&lt; .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P&lt; .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Abstract Background: Zedoresertib (zedo) and lunresertib (lunre) are oral, highly selective WEE1 and PKMYT1 inhibitors, respectively. Inhibition of these targets leads to premature mitotic entry, and in the presence of high replication stress causes mitotic catastrophe. In preclinical models, the combination of the zedo and lunre is synthetically lethal, supporting this first-in-class trial combination (NCT04855656). Methods: In this Phase 1 trial, patients (pts) with advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off), guided by preclinical modelling of the pharmacological contributions of WEE1 and PKMYT1 inhibition in achieving tumor regression. Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Results: As of 18 Nov 2025, 54 pts (55.6% female ; prior lines of therapy 1 - 9, main cancer types: ovarian (OC) (35.2%), colorectal (31.5%), pancreatic (7.4%) and breast (5.6%)) were treated at 5 dose levels (DL) from 150 mg to 260 mg of zedo plus 60 mg or 80 mg of lunre. The most common ≥G3 treatment related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%) and Palmar Plantar Erythrodysesthesia (PPE) (7.4%). There were no G5 TRAEs. 4 (9.3%) of 54 pts had a dose-limiting toxicity (G3 pain in extremity and G1 rash in same pt (zedo 150 mg / lunre 60 mg), G3 rash (200 mg / 80 mg), G3 PPE (260 mg / 60 mg), G3 vomiting (260 mg / 60 mg)). PK/PDy analyses showed dose-dependent exposures for both zedo and lunre and target engagement in most pts, with reductions in pCDK1 Thr14 and Tyr15 and yH2AX induction. 24 (55.5%) of 44 RECIST v1.1 evaluable pts showed tumor shrinkage (3 cCR, 5 uPR, 15 SD and 1 PD). Of 16 evaluable pts with advanced OC (12 platinum resistant , 2 unknown and 2 platinum sensitive) with CCNE1 amp (13 pts) or FBXW7 mut (3 pts), 13 (81.3%) showed tumor shrinkage (3 cCR, 3 uPR and 7 SD); clinical benefit rate (pts with CR, PR or SD) was 93.8%; 7 (43.8%) OC pts were on treatment for at least 16 weeks; 4 (25%) OC pts achieved GCIG CA-125 responses. Of 23 pts with a post baseline ctDNA analysis, a MRR of 39% was seen across all DLs. Conclusion: We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC. Further dose optimization of this combination is ongoing. Citation Format: Timothy A. Yap, Rahul Aggarwal, Elisa Fontana, Martin Hojgaard, Benedito A. Carneiro, Linda Duska, Patricia LoRusso, Siddhartha Yadav, Stephanie Lheureux, Cara Mathews, Ryan H. Moy, Nehal Lakhani, Mia Weiss, Joan Tymon-Rosario, Gerardo Colon-Otero, Ignacio Garrido-Laguna, Elisabeth K. Lee, Esteban Rodrigo Imedio, Jonathan Wessen, Luke Piggott, Vito Dozio, Noemie Luong, Christophe Mas, Alison M. Schram. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT022.

Importance Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. Objective To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Design, Setting, and Population Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Exposure Device-enabled TTVR. Main Outcomes and Measures Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Results Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P &amp;lt; .001) and mean KCCQ-OS score (22.4 points; P &amp;lt; .001) from baseline to 30 days. There were no significant differences in 30-day mortality ( P = .47), heart failure hospitalization ( P &amp;gt; .99), and functional outcomes ( P = .55) when patients were stratified by baseline CIED status. Conclusions and Relevance Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.

Background/Objectives: Non-typhoidal Salmonella (NTS) species are well-recognized causes of invasive infection in patients with sickle cell disease (SCD), with a particular predilection for the musculoskeletal system. Although Salmonella osteomyelitis is well described in this population, septic arthritis is uncommon, especially involving the shoulder joint. We describe a case of NTS bacteremia complicated by native shoulder septic arthritis in a patient with SCD and review its clinical implications. Methods: We report the clinical course, diagnostic evaluation, microbiologic findings, imaging studies, and management of a 22-year-old man with homozygous SCD who presented with a vaso-occlusive pain crisis and subsequently developed severe sepsis with persistent Salmonella enterica bacteremia following ingestion of undercooked poultry. Persistent bacteremia prompted further evaluation for metastatic infection using advanced imaging and diagnostic arthrocentesis. Results: Whole-body imaging identified septic arthritis of the native right shoulder, which was confirmed by synovial fluid cultures growing Salmonella species. The patient underwent arthroscopic irrigation and debridement for source control. Antimicrobial therapy was narrowed to intravenous ceftriaxone based on susceptibility data and continued for six weeks. The patient demonstrated clinical improvement with resolution of bacteremia and was discharged to rehabilitation to complete therapy. Conclusions: This case highlights the importance of a careful exposure history, including foodborne sources, in patients with SCD presenting with invasive Salmonella infection. Persistent bacteremia should prompt early investigation for metastatic foci, and timely surgical source control combined with targeted antimicrobial therapy is essential for optimal outcomes in this population.

ABSTRACT The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer (MBC) biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense of BC and LP across all three male donors. Male LC were distinguished from female by elevated ESR1 and PGR mRNA, enrichment of RNA processing and ribosome biogenesis programs, reduced inflammatory cytokine and growth factor signaling, elevated estradiol gene set enrichment scores, and higher inferred activity of developmental patterning transcription factors. This pattern was observed across differential expression, gene ontology, ligand profiling, and regulon-based analyses, and was not restricted to sex chromosome-linked gene expression. This is consistent with the near-universal estrogen receptor (ER) positivity that characterizes MBC clinically. This atlas provides the first cellular and transcriptional reference for the normal male breast and a resource for investigating sex differences in mammary biology, germline susceptibility variant interpretation, and modeling breast malignancies.

Background: Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. Objective: To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). Methods: Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. Results: Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve—AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome’s potential in CP diagnosis. Conclusion: Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.