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PubMed2026

Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

PPAR gamma↗

PubMed2026

Azithromycin-resistant Salmonella enterica Typhi with AcrB R717L/Q mutations in the United States.

BACKGROUND AND OBJECTIVES: Azithromycin is a critical oral treatment for typhoid fever caused by Salmonella enterica serovar Typhi (Salmonella Typhi), since XDR has rendered other first-line treatment options ineffective. Azithromycin resistance conferred by amino acid changes in AcrB, an AcrAB-TolC efflux pump component, represents an emerging public health concern. Leveraging phenotypic and genotypic data from U.S. Salmonella Typhi surveillance systems, this study describes the prevalence, phenotype and genomic epidemiology of Salmonella Typhi with AcrB mutations in U.S. patients since the first detection in 2015. METHODS: AST and WGS data of >3000 Salmonella Typhi isolates were used to identify all cases with an AcrB mutation in the United States (2015-2025). We calculated annual prevalence and MIC ranges. Phylogenetic analysis was used to contextualize U.S. cases of Salmonella Typhi with an AcrB mutation within all globally reported cases. RESULTS: While the prevalence of AcrB mutations in the United States is low (1.5%), it has risen significantly in recent years, from 0.2% in 2016-2022 to 2.2% in 2023-2025. This increase is predominantly driven by clonal expansion of existing strains circulating in South Asia. AcrB mutations do not reliably confer resistance to azithromycin (MIC ≥ 32 mg/L), complicating clinical interpretation. CONCLUSIONS: The prevalence of AcrB mutations in Salmonella Typhi is increasing in the United States, and likely globally, given that U.S. data function as an informal proxy for regions without routine surveillance infrastructure. Clinical outcomes data are needed to inform Salmonella Typhi treatment guidelines and potentially amend clinical breakpoints for azithromycin.

Journal Article↗

PubMed2026

Metabolic and endocrine modulation of the gut-adipose tissue axis via pro-, pre-, and postbiotics in overweight dogs: A systematic review.

Canine obesity is a complex metabolic disorder driven by luminal dysbiosis, impaired gut barrier function, and metaflammation. Following PRISMA 2020 guidelines, this systematic review evaluated the efficacy of pro-, pre-, and postbiotics in modulating the gut-adipose tissue axis in overweight dogs (BCS ≥ 6/9) or diet-induced obesity models. Searches across PubMed and Dimensions (April 2026) identified seven eligible experimental trials. Results suggest that postbiotic Bifidobacterium animalis subsp. lactis CECT 8145 reduced postprandial glucose AUC by 6 % strictly during energy restriction. Pasteurized Akkermansia muciniphila postbiotics limited diet-induced weight gain, though glucoregulatory impacts were highly strain-specific (AKK2 reduced fasting glucose and insulin resistance indexes, whereas EB-AMDK19 exerted no significant effect). Specific probiotics (including Enterococcus faecium, Bifidobacterium lactis, Lactiplantibacillus plantarum and Bifidobacterium breve) attenuated fasting hyperinsulinemia and preserved circulating adiponectin, but lipid profile improvements (triglycerides and total cholesterol) were inconsistent across trials. In dogs, increased luminal short-chain fatty acids are not consistently mirrored by endocrine responses, so the coupling between microbial metabolites and incretin signaling remains incomplete. A critical lack of standardized reporting for species-validated insulin sensitivity metrics was identified. In conclusion, microbiome-targeted therapies, particularly inanimate postbiotics, may represent useful adjunctive strategies to mitigate metabolic dysregulation in obesogenic environments. However, clinical efficacy remains strictly strain-specific and dependent on host energy balance. Given the scarcity of high-certainty evidence, future trials must integrate dynamic physiological assessments with species-validated surrogate indexes alongside standardized dietary controls.

Animals↗

PubMed2026

Regional and statewide hysterectomy-corrected endometrial cancer incidence and five-year relative survival in Texas.

BACKGROUND: Rising endometrial cancer (EC) incidence nationwide, particularly among Hispanic women, and high prevalence of risk factors such as obesity and comorbidities in Texas, motivated us to estimate EC incidence rates (IRs) and survival by age (<50 years/ early-onset, ≥50 years/late-onset), race-ethnicity (Non-Hispanic-White [NHW], -Black [NHB], Hispanic), histology (endometrioid, non-endometrioid), and area-based socioeconomic (SES) factors across Texas Health Service Regions (HSRs). STUDY DESIGN: Between 2000 and 2019, a total of 42,571 women (20-79 years) with EC were reported from Texas within the Surveillance, Epidemiology, and End Results Program. IRs and 5-year relative survival were calculated using SEER*Stat. IRs were corrected for hysterectomy using Behavioral Risk Factor Surveillance System data. RESULTS: Statewide EC IRs rose from 38.5 (2000-2009) to 44.5 (2010-2019), with the highest increase in the Upper-South (42.6 to 53.8). Across HSRs, Upper-South consistently had higher IRs among women < 50 (13.9) and ≥ 50 years (112.7). Among those < 50 years, Hispanics had the highest IRs (12.4), predominantly endometrioid tumors, whereas in women ≥ 50 years, NHB had the highest IRs (119.2) with a large proportion of non-endometrioid tumors. IRs were higher in areas with lower poverty, and higher education, income, and urbanization. Associations with unemployment were mixed. Worse survival outcomes were observed among NHBs, non-endometrioid, advanced-stage, and lower SES. Central Texas had more favorable survival outcomes compared to other HSR. CONCLUSION: EC IRs and survival rates in Texas largely mirror national trends, with regional differences likely reflecting sociodemographic and histologic distributions.

Humans↗

PubMed2026

A systematic literature review on low-grade myofibroblastic sarcoma of the trunk.

BACKGROUND: Low-grade myofibroblastic sarcoma (LGMS) is a rare malignant mesenchymal tumor, with primary trunk involvement being particularly uncommon. Due to its rarity, associated diagnostic challenges, and variability in management, a comprehensive evaluation of the available evidence is required. This study aims to systematically review the clinical characteristics, treatment strategies, and outcomes of truncal LGMS. METHODS: A systematic literature search was conducted using PubMed, Web of Science, and Embase for articles published from January 1998 to January 2026. The review included full-text articles involving patients with a pathologically confirmed diagnosis of truncal LGMS. The collected data included patient demographics, tumor features, treatment modalities, recurrence, and follow-up status. RESULTS: Of the 404 studies initially identified, 30 studies involving 59 patients with pathologically confirmed truncal LGMS met the inclusion criteria. Outcome analyses of therapeutic management and clinical course included 45 patients with complete follow-up data, including 42 surgically treated patients and 3 non-surgically managed patients. The final evidence base consisted solely of retrospective studies and case reports. No prospective studies or randomized controlled trials were identified. Consequently, a descriptive statistical analysis was conducted instead of a meta-analysis. CONCLUSION: Current evidence indicates that wide excision with negative margins may be a reasonable primary treatment option for truncal LGMS, with case-based reports showing numerically lower recurrence after wide excision, although the evidence is limited and potentially confounded by multiple factors. Radiotherapy or chemotherapy may be considered only on a highly individualized basis for selected unresectable, recurrent, metastatic, anatomically constrained, or margin-positive cases. Given the very limited sample size and heterogeneous treatment indications across published cases, treatment efficacy cannot be reliably estimated from the available data. Prolonged long-term regular follow-up is recommended for all patients, considering the risk of late recurrence.

Humans↗

PubMed2026

A 4-year longitudinal wastewater surveillance of five gastroenteritis viruses and the correlation with clinical cases in Alberta, Canada.

Viruses are common causes of acute gastroenteritis worldwide. They are detected in large quantities in raw sewage making them amenable to wastewater-based surveillance (WBS). To monitor the prevalence of gastroenteritis viruses in wastewater and assess their correlation with clinical cases, wastewater samples collected between July 2020 and June 2024 from 12 wastewater treatment plants across Alberta, Canada were analyzed for norovirus (NoV) GI & GII, rotavirus (RoV), adenovirus (AdV), sapovirus (SaV) and astrovirus (AsV). Among the 5726 wastewater samples tested, AdV (80.5%) had the highest detection rate followed by NoV GII (75.6%), SaV (63.2%), NoV GI (59.4%), RoV (42.2%) and AsV (20.2%). Winter and spring seasonality was found for NoV and RoV in both wastewater and clinical disease. Public health interventions especially in the 1st year of the COVID-19 pandemic had a significant impact on their burden with marked reduction in wastewater detected viruses and clinical cases. NoV showed a strong correlation between its level in wastewater and the number of clinical cases, while moderate correlation was observed for the other four viruses. Cross-correlation analysis showed that changes of viral RNA concentration in wastewater lagged behind reported gastroenteritis cases by approximately 6 days to 3 weeks. To our knowledge, this is the longest multi-region WBS study monitoring multiple gastroenteritis viruses spanning both COVID-19 pandemic and post-pandemic periods. The data obtained from this study supported WBS as a complementary tool to track population-based circulation of gastroenteritis viruses, providing actionable public health data.

Clinical cases↗

PubMed2026

Metabolic depot for nucleated erythrocyte degradation: molecular and structural elucidation of the teleost melanomacrophage center.

The function of melanomacrophage centers (MMCs) has long been controversial. While their foundational function is widely accepted as "metabolic dumps" for waste processing, a widely circulated hypothesis posits that they are primitive germinal centers (GCs) executing adaptive immunity. To elucidate this controversy, this study systematically evaluated the splenic MMCs in a higher teleost ( Micropterus salmoides) by combining transmission electron microscopy (TEM) and high-resolution spatial transcriptomics. Structurally, TEM revealed that the MMC comprises a core with characteristic sparse cellular density, filled with cellular debris and encapsulated by a fibrous layer. Molecularly, under physiological conditions, MMC regions exhibited low transcriptional activity. We did not detect clear enrichment of B cell and T cell lineage genes, and the key GC marker aicda was not observed. Conversely, its predominant molecular signature was characterized by macrophage-driven iron metabolism (e.g., ferritin) and erythrocyte degradation (e.g., hba1). Furthermore, the physicochemical properties of MMCs pigments (e.g., argyrophilia) suggest that traditional histological staining methods warrant cautious interpretation regarding potential non-specific signals. In conclusion, our findings characterize the MMC as a highly specialized metabolic processing and sequestration niche. This study provides new perspectives on the evolution of immune-metabolic homeostasis in poikilothermic vertebrates, advances comparative immunology, and offers a critical scientific reference for the accurate interpretation of MMCs as a biological indicator in pathology and ecotoxicology.

Animals↗

PubMed2026

Gut microbial diversity at baseline conditions the clinical, microbiome, and metabolic response to paraprobiotic Lactiplantibacillus plantarum LRCC5282 in overweight adults.

The gut microbiota is increasingly recognized as a target for obesity management; however, whether baseline gut microbial diversity conditions responsiveness to microbiota-targeted interventions remains unclear. We aimed to investigate whether baseline gut microbial diversity is associated with responsiveness to a paraprobiotic derived from Lactiplantibacillus plantarum LRCC5282 (LP5282-P) in overweight adults. In a 12-week, randomized, double-blind, placebo-controlled, multicenter trial of 120 overweight adults, LP5282-P produced no significant between-group differences in any clinical outcome across the overall per-protocol population. However, in the low-diversity subgroup, LP5282-P was associated with significant reductions in body weight, body mass index, and circulating leptin levels. These clinical changes were accompanied by compositional shifts in the gut microbiota, including higher relative abundances of Christensenellaceae, Faecalibacterium, and Alistipes. Fecal metabolite profiles showed elevated acetate and butyrate concentrations and altered bile acid composition. Within the low-diversity subgroup, changes in the relative abundances of Akkermansia and Eubacterium were inversely correlated with changes in body weight, body fat mass, and leptin levels. In contrast, the high-diversity subgroup exhibited no consistent response across the outcome domains examined. Overall, baseline gut microbial diversity was associated with differential responsiveness to LP5282-P, supporting its potential use as a stratification variable in future microbiota-targeted intervention trials. Further studies integrating direct measures of microbial activity and host response are warranted to elucidate the biological pathways underlying this diversity-dependent responsiveness. Trial registration: Clinical Research Information Service (CRIS), KCT0008119.

Humans↗

PubMed2026

Childhood Economic Mobility and Systemic Inflammation Among Men Who Experienced Low Income in Toddlerhood: The Moderating Role of Trait Hostility.

OBJECTIVE: Childhood economic upward mobility (ie, increases in family income across childhood) may attenuate links between childhood poverty and systemic inflammation in adulthood, the extent of which may vary depending on inter-individual differences in personality characteristics, including hostility. METHODS: Men who experienced low income in toddlerhood (N=171) were followed prospectively into adulthood. Annual family income was collected 12 times when men were 1.5 to 17 years old. Men completed the Cook-Medley Hostility Scale and had their fasting blood drawn to measure circulating levels of C-reactive protein (CRP) at age 32. Multiple linear regression analyses examined main and moderation effects of childhood economic upward mobility and adult hostility on CRP levels adjusting for income at 1.5 years, race, parent educational attainment, and adult income, education, waist circumference, and smoking status. RESULTS: Main effects were nonsignificant, but an interaction effect emerged. Counter to expectations, childhood economic upward mobility related to greater adult CRP as trait hostility decreased ( β =-0.203, P =.018). Simple slope analyses further revealed that childhood economic upward mobility was positively associated with CRP among men lower in hostility ( β =0.23, SE=0.09, P =.020) but was unrelated to CRP among men higher in hostility. Results of post hoc sensitivity analyses are also discussed. CONCLUSIONS: Counterintuitive findings suggest that for men who experience poverty in toddlerhood, the association between childhood economic upward mobility and adult CRP may be nuanced and even in the positive direction for men low in hostility, which aligns with work on unintended health consequences of upward mobility.

Humans↗

PubMed2026

Exercise and pathologic complete response to cancer treatment: a systematic review and meta-analysis.

PURPOSE: Neoadjuvant chemotherapy (NACT) is a commonly recommended approach for treating several cancers, and improving patients' outcomes to this therapy is important. This systematic review and meta-analysis assessed the impact of exercise on pathologic complete response (pCR), a key short-term marker of treatment efficacy, in patients with solid tumors receiving NACT. METHODS: Four electronic databases were searched for randomized controlled trials with physical exercise during NACT as an intervention published until May 2025. Risk of bias was assessed using Cochrane RoB 2.0 and the TESTEX scale. A random-effect meta-analysis using the inverse variance method synthesized the results. Heterogeneity was assessed using I2 and chi2 statistics. Risk ratio estimated the effect size. RESULTS: Eight studies involving 504 patients with breast, esophageal, gastric, or rectal cancer were included in the final analysis. Exercise interventions consisted of aerobic and resistance exercise. Overall, there were no significant differences between exercise and control groups in the rate of pCR to NACT (pooled risk ratio: 1.08 (95% CI: 0.82 to 1.43) Z = 0.56, p = 0.58). However, meta-regression data from breast cancer (BC) studies (4 studies, 367 participants) suggest exercise may be associated with enhanced tumor response to NACT in HR + /HER2- subtypes (regression coefficient: 0.83 (95% CI: -0.00 to 1.67), p = 0.05). CONCLUSION: Exercise during NACT did not improve pCR across cancer types. Exploratory meta-regression findings suggest a possible benefit of exercise in BC patients with the HR + /HER2- subtype. These results should be interpreted with caution due to the small number of studies and low certainty of the evidence.

Humans↗

PubMed2026

Precision Oncology in Hepatopancreatobiliary Cancer Surgery.

Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.

Humans↗

PubMed2026

Genetic evidence for a causal relationship between melatonin metabolism and depression.

To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.

Melatonin↗

PubMed2026

Characterization and application potential of two newly isolated phages targeting the prevalent multidrug resistant Salmonella serovars in China.

The escalating global threat of multidrug resistant (MDR) Salmonella, a foodborne pathogen with animal-derived foods serving as the primary transmission vehicle, underscores the urgent need for effective lytic phages for biocontrol. From 142 environmental and farm samples in Shandong Province, we isolated 103 phages active against MDR S. Enteritidis and S. Typhimurium, which were the most prevalent Salmonella serovars in China. Two Siphoviridae phages vB-SenS-S1 and vB-SenS-SEC2 were selected for further study. With optimal multiplicities of infection (MOIs) of 10-2 (vB-SenS-S1) and 10-5 (vB-SenS-SEC2), both phages exhibited a 20 min latent period, yielding burst sizes of 52 and 37 PFU/cell, respectively. They also demonstrated stability across a range of temperatures (50-60 °C), pH levels (5-11), and after 1 h of UV exposure. Genomic analysis identified vB-SenS-S1 (43,002 bp, 47.04% GC) and vB-SenS-SEC2 (42,948 bp, 47.65% GC) as novel double-stranded DNA phages. Functional annotation confirmed the presence of genes essential for structural assembly, host lysis, and DNA replication/metabolism, and also verified the absence of resistance, virulence, and lysogeny-associated genes. Both phages vB-SenS-S1 and vB-SenS-SEC2 exhibited synergy with colistin and tetracycline. The synergy with colistin was particularly potent, leading to complete bacterial eradication in vitro. The in vivo therapeutic efficacy was further validated in both Galleria mellonella larvae and murine models of MDR Salmonella infection. Combination therapy with vB-SenS-SEC2 and colistin not only dramatically increased survival but also achieved a significant reduction in bacterial burden across multiple visceral organs of infected mice. Moreover, vB-SenS-S1 (108 PFU/mL) completely inhibited MDR Salmonella on chicken meat at 4 °C and -20 °C when initial contamination was ≤103 CFU/mL. This study not only expands the diversity of Salmonella phages but also highlights their potential as biocontrol agents in both clinical veterinary use and food decontamination, thereby enhancing food quality and safety at both the meat production source and the terminal product.

Animals↗

PubMed2026

Sugar rationing during the first 1000 days and early onset cancer: a natural experiment.

BACKGROUND: The "first 1000 days" of life is a critical window for metabolic programming, while the long-term oncological consequences of nutritional exposures during this period remain understudied. OBJECTIVES: We aimed to evaluate whether restricted sugar intake in utero and during early childhood reduces risk of early onset cancer diagnosis and mortality in adulthood, utilizing a natural experiment. METHODS: We analyzed 63,819 United Kingdom Biobank participants born between October 1951 and March 1956, spanning the end of United Kingdom sugar rationing (September 1953). Leveraging a quasi-experimental birth cohort design, we compared participants exposed to sugar rationing in utero and during infancy with those unexposed. Early onset cancer incidence (≤50 y) and mortality were ascertained via integrated national Cancer Registry and hospital inpatient records. Multivariable Cox proportional hazards models (including Gompertz distribution) were used to estimate hazard ratios (HRs), with exploratory site-specific analyses. RESULTS: Among 63,819 participants (56.3% female), 40,397 were exposed to rationing and 23,422 were unexposed. Early life sugar restriction significantly reduced early onset cancer risk (HR: 0.66; 95% confidence interval: 0.53, 0.81; P < 0.001). A dose-response relationship was observed, with peak protection in individuals exposed for ≤24 mo postnatally. This protection was observed systemically across solid tumors, independent of specific cancer sites. Specificity was corroborated by null associations with negative controls (herpes zoster and cataract). No significant difference was found for cancer-specific mortality. CONCLUSIONS: Restricting sugar intake during the first 1000 days is associated with a reduced risk of early onset cancer, extending the disease-free lifespan. The divergence between reduced incidence and unchanged mortality suggests early life metabolic environments primarily influence tumor latency rather than biological aggressiveness. These findings highlight the potential long-term public health implications of early life dietary guidelines against the rising burden of early onset cancer.

Humans↗

PubMed2026

Metabolomic Signatures of Inflammation in Chronic Kidney Disease.

RATIONALE & OBJECTIVE: Inflammation is associated with adverse kidney, cardiovascular, and mortality outcomes. Investigation of the metabolic milieu as it relates to inflammation may provide important insights into these disease processes. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: African American Study of Kidney Disease and Hypertension (AASK), Atherosclerosis Risk in Communities (ARIC) study, and Boston Kidney Biopsy Cohort (BKBC) participants with available metabolomics and inflammatory protein data. PREDICTORS: Baseline blood levels of 718 metabolites. OUTCOMES: Baseline and longitudinal changes in blood levels of tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins 6, 8, and 10 (IL-6, IL-8, IL-10), uromodulin (UMOD), and epidermal growth factor (EGF). ANALYTICAL APPROACH: Multivariable linear regression and linear mixed-effects models. RESULTS: Among 491 AASK participants (mean age 54 years; 37% women; mean glomerular filtration rate, 45 mL/min/1.73 m2), 367 cross-sectional associations between metabolites and inflammatory proteins were significant after correction for multiple comparisons. The direction of association was mostly positive for TNFR1 (97%), TNFR2 (97%), IL-8 (77%), and IL-10 (100%); negative for UMOD (80%) and EGF (97%); and variable for TNF-⍺, IFN-γ, and IL-6. Pathways were distinct for several inflammatory proteins (eg, tryptophan metabolism for TNFR2). Forty-five associations between metabolites and longitudinal change in inflammatory proteins were identified. Notable metabolites included tigylcarnitine and N 2,N 5-diacetylornithine, which were associated with 2-year increases in TNFR1 and/or TNFR2, and 1,5-anhydroglucitol, where lower levels were associated with decreases in UMOD. In ARIC (n = 3,773) and BKBC (n = 413), replication of cross-sectional associations was excellent for TNFR1 (ARIC 83%; BKBC 85%) and TNFR2 (ARIC 64%; BKBC 79%) but poor for IL-8 (ARIC 3%; BKBC 3%). LIMITATIONS: Metabolite data limited to baseline visit; potential for residual confounding. CONCLUSIONS: Using an untargeted approach, multiple metabolites were cross-sectionally and longitudinally associated with inflammatory proteins in persons with chronic kidney disease.

Chronic kidney disease↗

PubMed2026

Somatic mutations: recent advances in brain aging and neurodegeneration.

Somatic mutations are genetic variants that occur after the single-cell phase of development and have been implicated in disease pathogenesis. While most DNA lesions are detected and repaired, examination of healthy tissue has revealed that some lesions escape repair, leading to somatic mutations that accumulate at a consistent rate, including in human brain tissue and postmitotic neurons. Emerging methodological and analytical advances have revealed the presence of persistent mutagenic mechanisms during healthy brain aging as well as mutational pattern shifts in the context of neurodegenerative diseases. Here, we highlight recent methodological advances, summarize our current understanding of somatic mutagenesis in neurotypical brain aging, and examine the role of somatic mutations in neurodegenerative diseases.

Humans↗

PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗

PubMed2026

Does co-administration of cannabidiol (CBD) influence the plasma availability of delta-9-tetrahydrocannabinol (THC) and its active metabolite in humans? A systematic review and meta-analysis.

BACKGROUND: Research on the pharmacokinetic influence of cannabidiol (CBD) on delta-9-tetrahydrocannabinol (THC) has produced equivocal results. METHODS: We conducted a systematic search following PRISMA guidelines (last search: 24th November 2025, PROSPERO: CRD42023480695). Included studies were acute dosing trials that administered a) a single, fixed dose of THC and b) a matched dose of THC co-administered with CBD. Our objective was to investigate between-group differences in the Cmax, AUCt and AUCinf of circulating THC and its active metabolite, 11-hydroxy-THC (11-OH-THC). Hedges' g and ratio of means (RoM) were pooled from random-effects meta-analyses. The dose-effects of CBD and THC on Hedges' g were explored using meta-regression. Risk of bias was assessed using the Cochrane Collaboration tool RoB 2. RESULTS: 14 studies were included (12 crossover, two parallel group; seven oral administration, five inhalation, one IV, one mixed IV and oral; total participants: 341). In meta-analyses, average AUCt of THC was significantly higher in CBD co-administration study arms versus THC-only (Hedges' g= 0.526, 95%CI= 0.222-0.830), with very low certainty evidence. Both Cmax and AUCt of 11-OH-THC were significantly higher in CBD co-administration study arms (Cmax: g= 0.428, 0.115-0.741; AUCt: g= 0.692, 0.284-1.099), both with medium certainty evidence. In meta-regression analyses, CBD demonstrated dose effects on the Hedges' g of the Cmax and AUCt of 11-OH-THC (P < 0.05), but not THC levels. CONCLUSIONS: Cannabis users and prescribers of cannabinoid-based products should be made aware of the potential for drug-drug pharmacokinetic interactions between CBD and THC.

Humans↗