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PubMed2026

Pharmacokinetics and safety of TBAJ-587, a novel antimycobacterial diarylquinoline, in healthy participants.

TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25-800 mg under fasting conditions and multiple doses of 50-200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.

Humans↗

PubMed2026

Discovery of NAT-6-321056 as a novel modulator of VEGFR2 signaling to suppress tumor angiogenesis.

Vascular endothelial growth factor receptor 2 (VEGFR2) is a master regulator of angiogenesis and cancer progression. However, current VEGFR2 modulators face significant challenges, including off-target toxicity and acquired resistance, underscoring the urgent need for novel therapeutic agents with improved efficacy and safety profiles. Here, we reported that virtual screening of 39,442 natural products from the ZINC natural products-derived library, coupled with molecular docking and molecular dynamics (MD) simulations to evaluate the binding stability of candidate compounds, identified NAT-6-321056 as a highly promising modulator of VEGFR2 signaling. Biological evaluations demonstrated that NAT-6-321056 exerted potent inhibition on the growth of a broad spectrum of cancer cells, including both solid tumors and hematological malignancies. In EA.hy 926 endothelial cells and SK-N-DZ neuroblast cells, the compound significantly suppressed proliferation, migration, and invasion. Microscale thermophoresis (MST) confirmed direct binding of NAT-6-321056 to VEGFR2 with favorable affinity. Kinase profiling against a panel of 33 kinases indicated that NAT-6-321056 exhibited a multi-kinase modulation profile. Mechanistic studies revealed that NAT-6-321056 suppressed the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and was associated with reduced VEGFR2 phosphorylation and attenuation of the downstream ERK/JNK/AKT signaling pathways. Moreover, NAT-6-321056 exhibited robust in vivo anti-angiogenic effects in both the chick chorioallantoic membrane (CAM) assay and transgenic zebrafish vascular fluorescence imaging models. Computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction suggested acceptable drug-like properties. Collectively, these findings demonstrated that NAT-6-321056 is a promising modulator of VEGFR2 signaling with potent anti-angiogenic activity and represents a viable candidate for cancer therapy.

Vascular Endothelial Growth Factor Receptor-2↗

PubMed2026

Direct Initiation of Long-Acting Cabotegravir Plus Rilpivirine in People with HIV and Suboptimal Virologic Suppression: A Randomized Trial.

BACKGROUND: Long-acting injectable cabotegravir plus rilpivirine (LA CAB+RPV) is approved for virally suppressed people with human immunodeficiency virus (HIV), but evidence for its use in those with persistent viremia and adherence challenges remains limited. METHODS: We conducted a multicenter, open-label, randomized study involving oral antiretroviral therapy (ART)-experienced people with HIV who had been diagnosed with HIV for at least 12 months and a most recent HIV-1 RNA level of at least 200 copies per milliliter. Participants with resistance-associated mutations to CAB or RPV were excluded. Eligible participants were randomly assigned in a 1:1 ratio to receive immediate LA CAB+RPV or to continue standard oral therapy until Week 24 (delayed switch group). The primary endpoint was the proportion of participants with an HIV-1 RNA level of less than 200 copies per milliliter at Week 24. RESULTS: Of 61 randomized participants, 45 met eligibility criteria and were included in the analysis; 91% were male, and the median baseline HIV-1 RNA was 35,000 copies/mL. At Week 24, viral suppression was achieved in 88.0% (22/25) in the immediate LA group versus 55.0% (11/20) in the delayed switch group (relative risk for failure to achieve viral suppression, 0.27; 95% CI, 0.08-0.86; p = 0.026). The effect of LA CAB+RPV was sustained through Week 52. CONCLUSIONS: Among people with HIV and viremia associated with adherence challenges, immediate initiation of LA CAB+RPV resulted in higher rates of viral suppression than continued oral ART, supporting its use beyond populations with stable suppression.

HIV↗

PubMed2026

Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Consanguinity↗

PubMed2026

Circular RNAs in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here, we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on the most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.

Amyotrophic Lateral Sclerosis↗

PubMed2026

Tracing the evolution and diversity of human parvovirus B19 across human history.

Human parvovirus B19 (B19V) is an ubiquitously spread, exclusively human pathogen, mainly posing risks to children, as well as pregnant and immunocompromised individuals. Despite evidence of B19V infection of human populations as far back as 7,000 years, the evolutionary history of B19V remains poorly understood. In this study, we present B19V genomic data from the remains of 53 globally distributed individuals spanning more than 8,000 years, including 7 children. Our findings suggest that the most recent common ancestor of all present B19V lineages existed around 12,000 years ago, at the end of the last Ice Age. Additionally, we identified an extinct Eurasian clade that participated in the recombination event that led to the emergence of B19V genotype 2 (GT-2). We date this event to ∼3,200-1,800 BP, potentially in the greater Mediterranean area. Our study shows aspects of how ancient parvovirus variants arose, disseminated, and impacted human health through time.

ancient DNA↗

PubMed2026

Responding to a protracted tuberculosis outbreak: lessons from multiple rounds of investigation in a Chinese boarding school.

PURPOSE: This study analysed a multi-semester pulmonary tuberculosis (PTB) cluster outbreak in a Chinese boarding school to provide evidence for future epidemic control. METHODS: Contacts were screened via symptoms, infection tests and chest radiography. Screening expanded progressively from close contacts to same-floor contacts, then all students and staff. Whole-genome sequencing (WGS) with single nucleotide polymorphism (SNP) and bioinformatics analysis was used for lineage classification, transmission clustering (≤12 SNPs defining a cluster) and drug resistance prediction. RESULTS: From 2020 to 2022, 20 students were diagnosed with PTB, half laboratory-confirmed. Most cases clustered in class 16 and were epidemiologically linked to the primary case (case 0), who had household PTB exposure. Case 0 and case 1 had diagnostic delays exceeding 3 and 6 months, respectively. WGS of five isolates (case 1, 3, 4, 9 and 10) collected over three semesters showed all belonged to lineage 2 and differed by ≤12 SNPs, confirming the same transmission chain. The infection rate in class 16 (46.34%) was significantly higher than other case classes (19.05%) and classes without cases (8.27%) (χ2 = 61.169, p < 0.001). No new cases were detected during a one-year follow-up of students involved in the outbreak after the final round of screening, nor among household contacts of all cases followed up to the present. CONCLUSIONS: Lack of entry health examinations facilitated the outbreak. Delayed diagnosis, incomplete contact screening and absence of preventive treatment led to cross-semester persistence. The infection rate disparity confirms class 16 as the outbreak epicentre. Improving community case management, extending contact follow-up and enhancing cluster outbreak measures are recommended to prevent future outbreaks.

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

The impact of sex, age, and genetic ancestry on DNA methylation across tissues.

Understanding the consequences of individual DNA methylation variation is crucial for advancing our knowledge of human biology and disease, yet the collective impact of individual traits on DNA methylation and their downstream effects on gene expression across human tissues remains poorly understood. Here, we quantify the contributions of sex, age, genetic ancestry, and BMI on autosomal DNA methylation variation across nine human tissues and 424 individuals from the Genotype-Tissue Expression project. We show that genetic ancestry and age have a greater impact on DNA methylation compared with sex, with aging effects being more widespread but less pronounced. On average, <10% of the gene expression variation in sex, age, and ancestry is mediated by DNA methylation differences, with ancestry showing the largest proportion of mediation. We further show that ancestry-associated DNA methylation differences accumulate at CpG sites with extreme methylation states and are largely under genetic control. The female autosomal genome exhibits consistent hypermethylation across tissues at Polycomb-repressed regions. Ultimately, we show that age-related Polycomb target hypermethylation is observed across multiple tissues but not in the gonads. Our multi-individual, multitissue approach defines the key drivers of human DNA methylation variation in healthy conditions, establishing a baseline for the interpretation of DNA methylation changes in disease contexts.

Humans↗

PubMed2026

Multiomic insights into fungal polylactic acid degradation: Metabolic adaptation and hydrolytic mechanisms of Sporobolomyces pararoseus.

Polylactic acid (PLA), a biodegradable polyester from renewable resources, is a sustainable alternative to petrochemical plastics. However, its environmental degradation is inefficient naturally, requiring specific microbial activities. While bacterial PLA-degrading mechanisms are well documented, fungal degrading systems-particularly their molecular mechanisms-are underexplored.We isolated Sporobolomyces pararoseus ZRQ01 from the gut microbiota of PLA-fed mealworms. This fungal strain noticeably degraded PLA in PLA-containing medium supplemented with 2% glucose. Biodegradation assays revealed 22.8% loss of the PLA film weight after 35 days of incubation, and scanning electron microscopy confirmed extensive surface erosion and pore formation. Integrated transcriptomic and proteomic analyses, together with the reference genome of S. pararoseus ZRQ01, revealed that S. pararoseus ZRQ01 upregulates hydrolytic enzymes at both transcript and protein levels to cleave PLA into lactic acid. After lactic acid is transferred into S. pararoseus ZRQ01 cells by monocarboxylate transporters with increased abundance, it is assimilated by pathways of pyruvate metabolism and the TCA cycle with increased protein abundance. Intriguingly, upregulation of genes in autophagy-related and MAPK signaling pathways underscores an adaptive stress response potentially supporting cellular homeostasis and degradation-related gene expression. Our results highlight S. pararoseus ZRQ01's metabolic potential for bioremediation and offer insights into fungal bioplastic degradation pathways.

Polyesters↗

PubMed2026

Diving Deeper Into Mechanisms of Acrylamide-Induced Toxicity: RNA Sequencing Reveals Transcriptomic Alteration and Retrotransposon Expression in Drosophila melanogaster.

Given the inevitability of human and animal exposure to acrylamide, there is increasing concern regarding its potential health risks. While a number of molecular mechanisms have been proposed, the complexity of acrylamide toxicological pathways and interactions remains incompletely characterized. In this study, we employed a transcriptomic approach to investigate the transcriptional responses of Drosophila melanogaster following exposure to acrylamide (100 mg/kg). Our analysis identified 634 differentially expressed genes (DEGs), with 362 upregulated and 272 downregulated. Functional analysis revealed these DEGs are enriched in pathways related to reproduction, detoxification, cellular and metabolic processes, signaling, synaptic formation and organization. Notably, acrylamide exposure upregulated the expression of tau and beta-amyloid protein precursor-like genes, both implicated in Alzheimer's disease pathology. An aversive memory test further demonstrated that acrylamide impaired the short-term memory of treated flies. Additionally, acrylamide-induced toxicity altered the expression of nine long terminal repeat retrotransposons, belonging to the gypsy and pao superfamilies. By exploring the potential role of transposable element activity in acrylamide-mediated toxicity, this study provides novel insights into the molecular mechanisms underlying its effects. Collectively, these findings offer a more comprehensive understanding of the mechanisms and pathways associated with the toxic action and detoxification of acrylamide in D. melanogaster.

Animals↗

PubMed2026

Molecular evaluation of residual disease following neoadjuvant chemotherapy in triple-negative breast cancer CALGB 40603 (Alliance).

BACKGROUNDDespite therapeutic advances in early-stage triple-negative breast cancer (TNBC), residual disease (RD) following neoadjuvant therapy remains a key predictor of a worse prognosis and obstacle to improving patient outcomes.METHODSTo better characterize RD and identify survival-associated features, we performed comprehensive transcriptomic profiling of 340 pretreatment stage II/III TNBCs and 70 matched posttreatment RD samples from the randomized CALGB 40603 (Alliance) phase II clinical trial. To explore preclinical treatment strategies for RD, patient-derived xenograft (PDX) mouse models mimicking RD were treated with antibody-drug conjugates (ADCs).RESULTSOur study shows prognostic genomic features measured pretreatment may differ from prognostic features measured posttreatment from RD specimens. Patients with a genomic PAM50 subtype of basal-like in RD specimens had a poor survival outcome, and their matching pretreatment tumors were characterized by elevated chromosomal amplifications of oncogenic drivers and significantly reduced B and T cell expression features. Paired analyses of basal-like RD and matched pretreatment tumors revealed further lymphocyte depletion in RD, along with lower expression of MHC class I and interferon signaling, indicating an immune-cold RD microenvironment. Treatment of a basal-like and conventional chemotherapy-resistant PDX model, resembling basal-like RD, with sacituzumab govitecan or trastuzumab deruxtecan produced a marked antitumor response.CONCLUSIONRD biology differs from pretreatment tumors, with basal-like subtype RD following neoadjuvant chemotherapy being immune cold and associated with poor survival. Preclinical modeling suggests this high-risk group may benefit from adjuvant ADC therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT00861705.FUNDINGNIH NCI U10CA180821 (Alliance for Clinical Trials in Oncology), NCI U24CA176171 (Alliance for Clinical Trials in Oncology), NCI UG1CA233373 (Alliance for Clinical Trials in Oncology), NCI Breast SPORE program P50-CA058223; Susan G. Komen SAC-160074; Breast Cancer Research Foundation BCRF-23-127; NIH NCI R01-CA229409; UNC LCCC Triple Negative Breast Cancer Center.

Humans↗

PubMed2026

Revealing potential biomarkers and metabolic mechanisms of ovarian aging in hens during late laying period based on machine learning and metabolomics.

Ovarian function decline during the late laying period represents a major bottleneck for the economic efficiency of the global poultry industry. However, the underlying metabolic mechanisms and reliable early-warning biomarkers for ovarian aging remain poorly understood. In this study, we performed the first untargeted LC-MS/MS metabolomics analysis of ovarian tissues from Taihe silky fowls at peak laying (30 weeks) and late laying (50 weeks) stages, and employed an ensemble machine learning strategy integrating LASSO, random forest, and support vector machine (SVM) algorithms to identify high-confidence core biomarkers of ovarian aging. Gene expression analysis was further conducted to validate the potential molecular mechanisms. Our results showed that the metabolic profiles of ovarian tissues differed significantly between the two groups. A total of 6 core biomarkers were identified, 4 of which were long-chain acylcarnitines. Mechanistic analysis revealed that downregulation of key genes in the carnitine shuttle system led to impaired mitochondrial fatty acid β-oxidation, which in turn triggered excessive oxidative stress and compromised ovarian endocrine function. In conclusion, this study identifies long-chain acylcarnitines as potential metabolic biomarkers for ovarian aging in Taihe silky fowls. These findings provide novel insights into the metabolic basis of poultry ovarian aging and lay a theoretical foundation for the precise regulation of reproductive performance in indigenous poultry breeds.

Animals↗

PubMed2026

Targeted variant analysis of feline mediastinal lymphoma using MassARRAY and clinical associations.

Lymphoma is the most commonly diagnosed cancer in cats. This study used the Agena MassARRAY to genotype 40 variants across 17 genes in feline mediastinal lymphoma. These variants have previously been identified in tumors, including T- and B-cell lymphomas, acute and chronic lymphocytic leukemias, and mast cell tumors, in humans, dogs, and cats, using various methods. They were selected based on high prevalence reported in prior oncology studies, potential relevance to targeted therapy, and suitability for multiplex PCR amplification. Pleural fluid samples were collected from 76 cats with mediastinal lymphoma, including 69 domestic shorthairs, two Persians, two Siamese, two Wichienmaat, and one Scottish Fold. The most prevalent variants were found in the BCL2, KIT, STAT3, and ZEB1 genes. Specifically, BCL2 c.83275986G > A and c.83275992G > T were present in 71.1% and 57.9%, respectively. In cats with variant-positive in KIT c.163965724C > CT significantly reduced (11 days) compared to wild-type cats (94 days) (p < 0.001). In cats with variant-positive in STAT3 c.42942437C > CA, resulted in shorter median survival compared to wild-type cats (18 days vs. 77 days, p = 0.006). The findings suggest that the variant panel could be useful for the genomic landscape of feline mediastinal lymphoma and warrant further validation.

Animals↗

PubMed2026

Effects of CPAP on endothelial activation and fibrinolytic balance in coronary artery disease with obstructive sleep apnea: The RICCADSA randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) promotes endothelial activation and a prothrombotic milieu through intermittent hypoxia, oxidative stress, and systemic inflammation, mechanisms closely linked to atherosclerosis progression. The vascular effects of continuous positive airway pressure (CPAP) therapy in patients with established coronary artery disease (CAD) remain incompletely understood. OBJECTIVE: To evaluate the longitudinal effects of CPAP treatment on endothelial adhesion molecules and fibrinolytic balance in patients with CAD and OSA. METHODS: In this randomized controlled analysis from the RICCADSA trial, 210 revascularized CAD patients with moderate-to-severe OSA were assigned to CPAP (n = 104) or no-CPAP (n = 106) and had available biomarker measurements at baseline and 12 months. Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) were assessed. Linear mixed-effects models were used to examine longitudinal changes and time-by-treatment interactions adjusted for cardiometabolic covariates. RESULTS: For ICAM-1, no significant time-by-treatment interaction was observed. For PAI-1, a borderline time-by-treatment interaction suggested a numerically smaller increase in the CPAP group compared with no-CPAP (p = 0.09). CPAP treatment was associated with a significantly greater reduction in VCAM-1 over time compared with no-CPAP (time-by-treatment interaction p = 0.045 in adjusted models). CONCLUSIONS: CPAP treatment was associated with selective modulation of vascular biomarkers in patients with CAD and OSA, characterized by attenuation of endothelial activation reflected by reduced VCAM-1 levels, while fibrinolytic imbalance appeared largely resistant to intervention. These findings support pathway-specific vascular responses to CPAP and provide mechanistic insight into residual atherosclerotic risk in this high-risk population.

Aged↗

PubMed2026

Exercise prehabilitation in head and neck cancer patients proposed for definitive chemoradiotherapy: The FIT4TREAT randomized controlled trial.

BACKGROUND: Patients with head and neck cancer (HNC) initially scheduled for definitive chemoradiotherapy (CRT) often experience early functional decline and deterioration in health-related quality of life (HRQoL) even before treatment initiation. Evidence for prehabilitation in this non-surgical setting remains limited. This study evaluated whether exercise prehabilitation (EP) initiated before CRT improves functional capacity compared with usual care (UC). METHODS: FIT4TREAT (ClinicalTrials.gov: NCT05418842) was a prospective, single-center, randomized clinical trial. Adults with HNC proposed for definitive CRT were randomly assigned (1:1) to EP or UC. EP consisted of supervised combined aerobic and resistance exercise performed three times per week from baseline until radiotherapy initiation. The primary outcome was the six-minute walk distance (6MWD) at the end of the pre-treatment period. Secondary outcomes included muscle strength, lower-limb functionality, body composition, and HRQoL assessed using the EORTC QLQ-C30 and QLQ-HN43. RESULTS: Between May 2021 and February 2025, 47 patients were enrolled; 40 were included in the primary analysis. After adjustment for baseline 6MWD and the randomization stratification variables, EP resulted in a significantly greater pre-treatment 6MWD than UC (adjusted between-group difference, 28.6 m; 95 % CI, 4.1-53.1; P = 0.023). EP also improved lower-limb functionality (P < 0.001) and was associated with better preservation in the QLQ-C30 summary score (P = 0.008), social functioning (P = 0.038) and body image (P = 0.011). CONCLUSION: EP before definitive CRT improves functional capacity and may help preserve HRQoL in patients with HNC, supporting its potential integration into routine oncology care.

Humans↗

PubMed2026

Integrative multi-omics reveals a fibroblast-centered, ZFHX3-prioritized regulatory framework linking sick sinus syndrome and atrial fibrillation.

OBJECTIVE: To define shared genetic and multi-scale mechanisms underlying comorbidity between sick sinus syndrome (SSS) and atrial fibrillation (AF). METHODS: We integrated genome-wide association study (GWAS) summary statistics for SSS and AF with Genotype-Tissue Expression (GTEx) expression and splicing quantitative trait loci (eQTL/sQTL), atrial single-cell and spatial transcriptomics, and epigenomics. We identified trait-relevant tissues and pathways, prioritized shared cell types, quantified genome-wide and local genetic sharing, detected joint loci by cross-trait meta-analysis, and linked loci to regulatory programs via colocalization and cell-prioritized co-expression networks. RESULTS: Both traits showed strongest enrichment in cardiac tissue, especially Heart Atrial Appendage. Fibroblasts from the left atrial appendage were consistently prioritized as the key shared cell population. SSS and AF displayed significant positive genome-wide genetic correlation, with multiple locally shared regions, including six major loci. Cross-trait meta-analysis identified eight joint-phenotype SNPs implicating four susceptibility genes. ZFHX3 was the leading tissue-cell-gene candidate, acting as a hub in fibroblast co-expression modules and colocalizing with cardiac regulatory signals. CONCLUSION: Shared liability for SSS and AF is highly tissue- and cell-specific, converging on regulatory networks in atrial appendage fibroblasts, with ZFHX3 serving as a central mechanistic and biomarker node.

Humans↗

PubMed2026

Trio-based whole-exome sequencing identifies convergent epithelial junction-related pathways in syndromic hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

Journal Article↗