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PubMed2026

Immunohistochemical evaluation of Ki-67 and GLI1 in sporadic and nevoid basal cell carcinoma syndrome-associated odontogenic keratocysts.

INTRODUCTION: Odontogenic keratocyst (OKC) is a developmental odontogenic cyst that may occur sporadically (OKCsp) or in association with nevoid basal cell carcinoma syndrome (NBCCS) (OKC-sy). NBCCS is an autosomal dominant disorder characterised by morphological abnormalities and an increased predisposition to several neoplasms, including basal cell carcinomas. Mutations in the tumour suppressor gene PTCH1 have been reported in patients with OKC and NBCCS. PTCH1 participates in a signalling cascade that culminates in the translocation of GLI transcription factors to the nucleus, thereby activating target genes involved in cell proliferation. Aberrant GLI1 expression has been associated with increased proliferation in lung adenocarcinoma and other cancers. OBJECTIVE: To compare GLI1 and Ki-67 protein expression in OKCs associated with NBCCS versus sporadic OKCs. MATERIALS AND METHODS: We included 13 OKCsp and 9 OKCsy from a children's hospital and university ... Immunohistochemistry was performed using anti-GLI1 and anti-Ki-67 to assess GLI1 expression and cell proliferation. RESULTS: No significant differences were observed in GLI1 or Ki-67 expression in the epithelial component of OKCsy versus OKCsp. A positive correlation between GLI1 and Ki-67 expression was detected in the total sample (r = 0.71, p < 0.05). CONCLUSION: The positive correlation between GLI1 and Ki-67 expression in OKCs suggests an association between SHH pathway activity and cell proliferation in both sporadic and syndromic lesions.

GLI1↗

PubMed2026

Obinutuzumab or Tacrolimus in Primary Membranous Nephropathy.

BACKGROUND: Studies of obinutuzumab, a type II anti-CD20 antibody, have shown efficacy in the treatment of hematologic cancers and autoimmune diseases. An evaluation of the efficacy and safety of obinutuzumab in patients with primary membranous nephropathy is needed. METHODS: In a phase 3 trial, we randomly assigned adults with primary membranous nephropathy in a 1:1 ratio to receive intravenous obinutuzumab or oral tacrolimus. The primary end point was complete remission (defined as a urinary protein-to-creatinine ratio of 0.3 or lower and a stable estimated glomerular filtration rate [eGFR]) at week 104. Key secondary end points were complete or partial remission at week 104, complete remission at week 76, a sustained reduction in the eGFR of at least 30%, duration of complete remission, and change in the Patient-Reported Outcomes Measurement Information System Fatigue T score from baseline to week 104. Fixed-sequence hierarchical testing was performed. Safety was assessed. RESULTS: A total of 142 patients underwent randomization. At week 104, complete remission was observed in 26 of 71 patients in the obinutuzumab group and in 4 of 70 patients in the tacrolimus group (37% vs. 6% with multiple imputation for missing data; adjusted difference, 31 percentage points; 95% CI, 18 to 44; P<0.001). The analyses of complete or partial remission at week 104 and complete remission at week 76 also showed a significant treatment effect. The analysis of a sustained eGFR reduction did not show a significant treatment effect; thus, subsequent end points in the hierarchy were not formally tested for significance. Adverse events of grade 3 or higher were reported in 16 patients (22%) in the obinutuzumab group and in 13 patients (19%) in the tacrolimus group; serious adverse events occurred in 12 (17%) and 10 (14%), respectively. There were 61 and 57 infections per 100 patient-years in the obinutuzumab and tacrolimus groups, respectively; 3 and 4 serious infections per 100 patient-years; and 11 and 14 serious adverse events per 100 patient-years. Adverse drug reactions with obinutuzumab included infusion-related reactions, respiratory tract infections, and neutropenia. One patient in each group died during escape therapy. CONCLUSIONS: Obinutuzumab was superior to tacrolimus in inducing complete remission in patients with primary membranous nephropathy. (Funded by F. Hoffmann-La Roche; MAJESTY ClinicalTrials.gov number, NCT04629248.).

Adult↗

PubMed2026

Integrated single-cell and bulk transcriptomic analysis identifies a novel senescent fibroblast subtype associated with poor prognosis in acral melanoma.

BACKGROUND: Acral melanoma (AM) exhibits significant intratumoral heterogeneity, but its tumor microenvironment (TME) and immune regulation remain unclear. This study aims to dissect TME heterogeneity and establish a prognostic model based on key cell subpopulations. METHODS: We collected AM single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). Unsupervised clustering, CellChat, and Scissor analysis were performed to characterize cellular heterogeneity, cell-cell communication, and prognosis-related cell subpopulations. Kaplan-Meier analysis was used to assess the prognostic value of key genes, which were further validated by multiplex immunohistochemistry (mIHC). RESULTS: In AM, Mel_C2, C7, and C9 with high SEMA6A and KIT expression were strongly linked to poor prognosis. We further identified a senescent fibroblast subpopulation (sCAF_CDKN2A) characterized by high fibroblast senescence signature (FSS) scores. Integrating Scissor analysis of fibroblast subtypes with bulk prognostic data, we identified COL3A1, VCAN, and KIT as prognosis-associated genes upregulated in poor-outcome-related fibroblast subsets. Cell-cell communication analysis revealed that sCAF_CDKN2A engages in an immunosuppressive network, interacting with regulatory T cells (Tregs) via MIF signaling and receiving signals from exhausted CD8+ T cells through PPIA-BSG interactions. Using transcription factor expression patterns from these fibroblast subtypes, we constructed a prognostic model that effectively stratified patients into distinct risk groups with significant differences in overall survival (OS). mIHC confirmed significantly higher protein levels of SEMA6A and COL3A1 in tumor tissues compared to matched normal tissues. CONCLUSIONS: We established a novel prognostic model for AM and identified sCAF_CDKN2A as an immunosuppressive senescent fibroblast subpopulation driving poor prognosis.

Acral melanoma↗

PubMed2026

Efficacy and safety of split-dose ultra-low-volume polyethylene glycol with ascorbic acid versus sodium picosulfate with magnesium citrate for bowel preparation: a systematic review and meta-analysis.

Colonoscopy remains the gold standard for early detection and prevention of colorectal cancer, with adequate bowel cleansing being pivotal for its success. This systematic review aims to evaluate the efficacy and safety of split-dose ultra-low-volume polyethylene glycol (PEG) with ascorbic acid (Asc) versus sodium picosulfate magnesium citrate for bowel preparation. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive literature search across Embase, PubMed, Web of Science, and Scopus from inception to July 2025. Data analysis was conducted using R version 4.2.2 (31 October 2022) and RStudio version 2022.07.2 (2009-2022, RStudio, Inc.) Our literature search yielded six eligible studies involving 3285 patients. Our findings indicate no significant differences in overall and right-sided colon adequate cleansing rates between the two regimens: risk ratio: 1.05, 95% confidence interval (CI): 0.99-1.12, P  = 0.1082; and risk ratio: 1.03, 95% CI: 0.99-1.08, P  = 0.1755, respectively. However, PEG + Asc demonstrated a significantly lower rate of vomiting compared to sodium picosulfate magnesium citrate (risk ratio: 2.58, 95% CI: 0.94-2.78, P  = 0.0008), suggesting better tolerability. Other secondary outcomes, including nausea, abdominal pain, and overall Boston Bowel Preparation Scale scores, did not show significant differences. The quality of the evidence varied across the outcomes. Our results support the comparable efficacy of both bowel preparation agents while highlighting PEG + Asc's potential advantages in tolerability. Our findings suggest that the choice between these two preparations can be tailored to the specific patient, considering their preferences or previous experiences, although some caution is advised in interpreting these findings.

Humans↗

PubMed2026

An oxidative stress - and immunotherapy-related six-gene signature defines immune subtypes and predicts prognosis and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: Oxidative stress and the tumor immune microenvironment jointly shape hepatocellular carcinoma (HCC) progression and response to immunotherapy, yet integrated biomarkers linking these processes are lacking. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify oxidative stress- and immunotherapyrelated differentially expressed genes (OSIRDEGs). Functional enrichment, weighted gene co-expression network analysis (WGCNA) and LASSO-Cox regression were used to construct a prognostic signature. Consensus clustering, TIDE, CIBERSORT and ssGSEA characterized immune phenotypes. Somatic mutation, copy-number and drug-response data were integrated to assess genomic alterations and drug sensitivity. Expression of model genes was validated by qRT-PCR and western blotting in HCC cell lines. RESULTS: We identified 24 OSIRDEGs enriched in cell-cycle and mitotic pathways. WGCNA intersection yielded 18 module genes, from which a six-gene signature (BUB1B, CDKN2A, CENPE, HMMR, PTTG1, SPP1) was derived. The signature robustly stratified patients into high- and low-risk groups with significantly different progression-free and disease-free survival in both TCGA-LIHC and GSE14520. Based on signature expression, two molecular subtypes were defined, exhibiting distinct survival, immune landscapes and predicted immunotherapy responsiveness. Model genes harbored recurrent alterations and showed significant correlations with anticancer agents. All six genes were upregulated at mRNA and protein levels in metastatic HCC cell lines versus normal hepatocytes. CONCLUSIONS: We systematically explored the landscape of OSIRDEGs in HCC, and proposed a validated six-gene signature that refines prognostic stratification, delineates immunerelevant HCC subtypes and highlights candidate biomarkers for therapeutic selection and mechanistic investigation.

Humans↗

PubMed2026

Could the preoperative urethral curve be used to predict immediate urinary continence following Retzius-sparing robot-assisted radical prostatectomy? A retrospective multi-center study.

PURPOSE: Immediate urinary continence (UC) recovery following Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) remains highly variable, highlighting the need for reliable preoperative prediction. We aimed to develop and validate models to identify patients likely to achieve immediate UC recovery following RS-RARP. MATERIALS AND METHODS: A total of 580 prostate cancer patients who underwent RS-RARP from four medical centers were assigned to a training set (n=348), an internal validation set (n=103) and an external validation set (n=129). Independent predictors were identified through univariate analysis and LASSO regression. A nomogram was constructed using multivariate logistic regression. Its performance was evaluated with receiver operating characteristic (ROC) curve, calibration curves, and decision curve analysis. RESULTS: Immediate UC recovery was observed in 84.5% (294/348) of patients in the training cohort, 80.6% (83/103) in the internal validation cohort, and 81.4% (105/129) in the external validation cohort, respectively. Multivariate analysis identified membranous urethral length (MUL) (OR=1.23, P=0.029) and urethral curvature (OR=2.84, P<0.001) as independent predictors, while prostate volume (PV) (OR=0.84, P <0.001) as a protective factor. The nomogram integrating MUL, PV, and urethral curvature demonstrated superior predictive accuracy, with an AUC of 0.87 (95% CI, 0.83-0.91) in the training cohort. The bootstrap-corrected calibration slope was 0.96, and the Brier score was 0.08. Calibration curves and decision curve analysis confirmed the predictive accuracy and clinical utility of the nomogram. CONCLUSIONS: Our study introduces a novel quantitative method for assessing urethral curvature. The mpMRI-based model, integrating urethral curvature and prostate spatial configuration, offers enhanced predictive accuracy for postoperative immediate UC recovery.

Humans↗

PubMed2026

SGLF-Net:Staged Global-to-Local Cross-Scale Fusion Network for Colonoscopic Polyp Segmentation.

Polyp segmentation in colonoscopy images plays a pivotal role in computer-aided medical diagnosis and the early prevention of colorectal cancer. However, existing methods often suffer from performance degradation when confronted with extreme polyp scale variation and polyp boundary ambiguity. To address these challenges, we propose the Staged Global-to-Local Cross-Scale Fusion Network (SGLF-Net), which adopts a novel staged global-to-local learning paradigm to progressively refine segmentation from coarse global semantics to fine-grained local details. Specifically, the Global Semantic Perception Stage integrates a Swin Transformer Encoder and a Dynamic Attentive Decoder (DAD) to construct comprehensive multi-scale contextual representations. The Local Detail Refinement Stage employs an Edge-aware Dynamic Attentive Decoder (E-DAD) to enhance structural fidelity and boundary precision through explicit edge-guided supervision. Furthermore, we introduce the Cross Spatial-Scale Feature Aggregation and Reconstitution (CSSAR) module, equipped with hybrid attention mechanisms, to facilitate efficient semantic structural interaction between the two cascaded stages. Extensive experiments on five public benchmark datasets demonstrate that SGLF-Net consistently outperforms state-of-the-art methods in both segmentation accuracy and boundary preservation.

Journal Article↗

PubMed2026

Frequent mutations in the BIRC3 gene promote metastatic potential of nasopharyngeal carcinoma cells through the TRAF2-NF-κB pathway.

Nasopharyngeal carcinoma (NPC) is a head and neck cancer characterized by highly locoregionally invasive behavior attributable to the latent infection with Epstein-Barr virus (EBV) and genomic instability. It is well established that EBV-encoded oncogenic molecules actively contribute to the malignant behavior of NPC cells. However, the mechanism by which aberrant genomic alterations enable NPC cells to become aggressive remains largely unknown. In the present study, whole-exome sequencing (WES) revealed that the gene encoding the baculoviral IAP repeat-containing 3 (BIRC3) protein was frequently mutated in circulating tumor cells (CTCs) but not in paired primary tumor cells from patients with metastatic NPC. A minigene assay indicated that the c.637 A > G mutation disrupted normal mRNA splicing, resulting in the partial deletion of Exons 2 and 3 and altered stability of BIRC3 mRNA. In vitro experiments demonstrated that ectopic expression of the BIRC3c.637A>G mutant enhanced NPC cell invasive properties, including proliferation, resistance to apoptosis, migration, and invasion. Furthermore, overexpression of wild-type BIRC3 promoted invasive characteristics in NPC cells through the TRAF2-NF-κB signaling axis. In summary, BIRC3 acts as a regulator of the malignant features of NPC cells. Frequent BIRC3 mutations in CTCs, such as the c.637 A > G mutation, further enhance the metastatic potential of disseminated NPC cells by inducing aberrant alternative splicing. These findings suggest the therapeutic feasibility of targeting the BIRC3/TRAF2/NF-κB axis in the treatment of NPC.

Humans↗

PubMed2026

Development and validation of an LC-MS/MS method for the quantification of the KRASG12C inhibitor divarasib.

Divarasib is a newly developed covalent KRASG12C inhibitor, currently under clinical investigation in a phase 3 trial in patients with non-small cell lung cancer (NSCLC). At the moment, very limited pharmacokinetic data are publicly known. However, obtaining more insight into the pharmacokinetic properties of divarasib is important, since this may provide a better understanding of its efficacy and safety risks. Pre-clinical studies have been performed in mouse models to evaluate the effect of drug transporters and drug-metabolizing enzymes on the plasma exposure and tissue distribution of divarasib. Therefore, a reliable quantification method is required. To our knowledge, no bioanalytical assay of divarasib has been published yet. Therefore, in this study we developed and validated an assay to quantify divarasib in human plasma and in eight different mouse-related matrices, and partially in mouse plasma, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was initially evaluated over a concentration range of 1-10,000 nM. However, due to carry-over observed at 10,000 nM, the validated calibration range was established at 1-2000 nM, with matrix-dependent LLOQs of 1-10 nM. Erlotinib was used as an internal standard and acetonitrile was utilized to perform protein precipitation as sample pretreatment. Divarasib demonstrated stability in human plasma and in mouse plasma and tissue homogenates under various experimental conditions. A pilot in vivo study showed the applicability of our validated LC-MS/MS method. Ongoing clinical trials may collect plasma samples, and this developed method enables quantification of divarasib in both mouse and human plasma samples.

Animals↗

PubMed2026

METTL14-mediated m6A modification of CCNE1 accelerates progression of myelodysplastic syndromes via MAPK-ERK and PI3K-AKT signaling pathways.

BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification and plays a key role in the initiation, progression, and relapse of multiple cancers, including hematologic malignancies. However, the role of m6A and m6A regulatory genes in myelodysplastic syndromes (MDS) remains unclear. This study aims to elucidate the function and molecular mechanism of methyltransferase METTL14 in MDS. METHODS: RT-qPCR was used to assess the expression of multiple m6A regulators, focusing on METTL14 in MDS patients and cell lines. METTL14 overexpressing and knockdown cell lines were established, and CCK-8, EdU, and flow cytometry assays were performed to explore the biological functions of METTL14.Dot blot, MeRIP-Seq, MeRIP-qPCR, RT-qPCR, and Western blot were employed to investigate the underlying molecular mechanism. RESULTS: Dysregulation of multiple m6A regulators was observed in MDS, among which METTL14 was upregulated. Elevated METTL14 expression increases MDS risk and adverse prognosis, emerging as a biomarker for poor prognosis. METTL14 promoted proliferation and cell-cycle progression of MDS cells while inhibiting apoptosis; corresponding changes were observed in cell cycle and apoptosis markers. METTL14 regulated cellular m6A levels. Downstream targets of METTL14 were enriched in cell cycle-related pathways, with CCNE1 identified as a critical target. Knockdown of METTL14, actinomycin D, or S-adenosylhomocysteine treatment reduced CCNE1 mRNA and protein levels. Furthermore, METTL14 activated MAPK-ERK and PI3K-AKT signaling via CCNE1 in an m6A-dependent manner, thereby promoting proliferative MDS cells' capacity. CONCLUSIONS: This study delineates a METTL14/m6A/CCNE1 signaling axis in MDS progression and suggests that METTL14-mediated m6A modification may be a potential therapeutic target for MDS.

Humans↗

PubMed2026

Engineered MXene-based nanozyme platform: NIR-II photothermal and dual enzyme-mimetic potentiated chemodynamic synergy for precision tumor eradication.

The antioxidant defense barrier in the tumor microenvironment, particularly glutathione (GSH), considerably restricts the therapeutic efficacy of chemodynamic therapy (CDT). Moreover, CDT generally exhibits relatively mild therapeutic efficacy owing to its intrinsic reaction kinetics, making it difficult to achieve complete tumor eradication within a short time. To address these issues, we construct a functionalized nanotherapeutic platform, Nb2CTx@Ru-PEG2000-FA (NCRPF), for tumor photothermal ablation and enhanced CDT resulting from GSH depletion. NCRPF possesses three key advantages: 1. Efficient near-infrared II photothermal conversion (η = 42.08%), raising the tumor temperature above 45 °C within 90 s for rapid ablation; 2. Dual peroxidase-like and glutathione peroxidase-like activities, simultaneously depleting GSH and generating a burst of ·OH to eliminate residual tumors; 3. Targeted tumor accumulation with 2.9-fold higher efficiency than passive diffusion. Both in vitro and in vivo results confirm that this combined strategy achieves complete tumor eradication with favorable biosafety. Collectively, the NCRPF nanotherapeutic system provides a powerful new paradigm with high translational potential for the complete eradication of breast cancer.

Animals↗

PubMed2026

Long-term consequences of childhood sexual abuse: An umbrella review of diagnostic meta-analyses.

BACKGROUND: Childhood sexual abuse (CSA) is a public health issue with an estimated worldwide prevalence of 12.7%, potentially leading to a host of lifelong and significant mental, physical, and behavioral health. The aim of this study was to comprehensively map the long-term consequences of childhood sexual abuse on physical, psychiatric, and behavioral health outcomes. METHODS: An umbrella review of meta-analyses of observational studies, registered on PROSPERO, was conducted to examine the diverse repercussions of childhood sexual abuse on adult health. Three bibliographic databases (PsycINFO, PubMed and Scopus) were searched from the inception of the respective databases to November 1st, 2022. Thirty-eight meta-analyses representing about 20 million individuals were analyzed, revealing a range of long-lasting consequences associated with CSA. RESULTS: Among physical pathologies, cervical cancer and functional neurological syndromes emerged as the most prominent, exhibiting significantly elevated odds ratios (ORs) of 4.18 IC95% and 3.30 IC95%, respectively. Sleep disorders and borderline personality disorders were the most prevalent mental health disorders associated with CSA, with respective ORs of 16.17 IC95% and 5.96 IC95%. Early sexual initiation (OR=3.59 IC95%, sexual assault (OR=3.36 IC95%, and prostitution (OR=3.24 IC95%) emerged as the most common behavioral consequences. Notably, no significant differences in the consequences of CSA were observed between men and women, except for reproductive health outcomes. DISCUSSION: When faced with certain pathologies, clinicians should consider and discuss sexual abuse with their patients. The consequences of abuse have a multifactorial origin, which is a weakness, as are the problems of defining abuse. The strength of our study is that it lists the consequences published in high-quality studies. CONCLUSION: This umbrella review provides compelling evidence of the profound and far-reaching impact of childhood sexual abuse on a broad spectrum of physical, mental, and behavioral health issues.

Humans↗

PubMed2026

Harnessing Polygenic Risk Scores to Refine Venous Thromboembolism Risk Stratification.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to evaluate the independent impact of a PRS on VTE susceptibility in adults and children. METHODS: We completed a retrospective, case-control study of two separate cohorts with evaluation of three VTE PRS models, with the primary analysis focused on a 293 single nucleotide polymorphism (SNP) PRS. The adult cohort included 597 VTE cases and 31 998 controls, and the pediatric cohort included 109 cases and 448 controls, both obtained from a de-identified databank with linked genetic data. Separate adult and pediatric multivariable logistic regressions were performed to measure the association of risk factors with VTE. RESULTS: Higher PRS in adults was significantly associated with increased odds of VTE, with each 1-standard deviation increase in PRS conferring an adjusted odds ratio of 1.25 (OR = 1.25, 95% CI 1.15-1.36, p < 0.001). Leading risk factors for adults were cancer (OR = 2.43, 95% CI: 2.04-2.89, p < 0.001) and recent surgery (OR = 2.16, 95% CI: 1.83-2.54, p < 0.001). The standardized PRS also exhibited increased risk for VTE in children (OR = 1.38, 95% CI 1.10-1.74, p = 0.003). Central venous catheterization (OR = 5.65, 95% CI 3.40-9.50, p < 0.001) was the foremost risk factor for pediatric VTE. CONCLUSION: VTE in adults and children is multifactorial, with clinical and genome-wide risk factors contributing. PRS may serve as a valuable adjunct to clinical risk factors for VTE risk stratification.

Humans↗

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

Epigenetic Gene Networks Governing Immune State Transitions Across the Lifespan.

Immune function across development, tissue repair, aging, and disease depends not only on signaling pathways but also on epigenetic architectures that determine whether coordinated transcriptional programs can be accessed and resolved. Increasing evidence indicates that epigenetic gene networks regulate the accessibility and reversibility of semi-stable immune states, shaping plastic, homeostatic, reparative, and degenerative configurations. We propose the concept of epigenetic transition windows, defined as temporally and contextually restricted intervals during which epigenetic constraints are relaxed, permitting coordinated and reversible transitions between immune states. During development, these windows are broad and support immune tolerance and adaptive plasticity. In adulthood they become spatially and temporally restricted, preserving stability while enabling conditional adaptation. With aging, they progressively narrow, contributing to chronic inflammation, impaired repair, and increased vulnerability to neurodegeneration. Conversely, pathological persistence of regulatory permissiveness may underlie immune evasion and sustained plasticity in cancer. We outline operational genomic readouts for quantifying transition windows, including chromatin accessibility variance, enhancer switching dynamics, reversibility metrics, and cross-cell coordination indices, and derive experimentally testable predictions that distinguish this model from pathway-centric or damage-centric explanations. By reframing immune dysfunction as a failure of regulated state transition rather than excessive signaling alone, this framework integrates inflammaging, trained immunity, immune resolution failure, and tumor immune escape within a unified regulatory architecture and provides a systems-level perspective on immune adaptability across the lifespan.

Epigenesis, Genetic↗

PubMed2026

Mechanistic insights into flavor deterioration in bitter sturgeon caviar: Evidence from lipidomics and metagenomics.

This study systematically compared the flavor and multi-omics differences between normal caviar and bitter caviar based on quantitative descriptive analysis (QDA), volatile compounds (VOCs) analysis, untargeted lipidomics, and metagenomics. The results showed that bitter caviar was characterized not only by increased bitterness, but also by decreased positive sensory attributes, including buttery, nutty, and marine fresh. VOCs analysis indicated that the volatile profile of bitter caviar was reorganized. Compounds such as 3-hydroxy-2-butanone, 1-octen-3-ol, and (E, Z)-2,6-nonadienal showed higher relative odor activity values (rOAVs); however, these changes did not improve its overall sensory experience. Untargeted lipidomics identified 492 differential lipids. These changes were mainly characterized by decreased PC and increased DG and LPC in bitter caviar. KEGG pathways analysis showed that these differential lipids were mainly associated with glycerophospholipid metabolism, choline metabolism in cancer, and retrograde endocannabinoid signaling. Metagenomic analysis showed that bacteria dominated the microbial community of caviar. Among them, Bacillus and Micromonospora showed relatively high abundance in the caviar microbiota. They were also closely associated with lipid metabolic changes involving PC, DG, and LPC, suggesting their potential as candidate targets for future microbiota-directed regulation of caviar quality. These findings provide new insights into the mechanisms underlying sensory deterioration and flavor formation in bitter caviar, and offer a theoretical basis for improving caviar quality in industrial production.

Animals↗

PubMed2026

The mighty microproteins: from versatile cellular regulators to precision medicine therapeutics.

Microproteins, are tiny proteins encoded by small open reading frame (sORF), translation of these non-canonical open reading frames (ncORFs) has been implicated in diverse biological processes and diseases. This review summarizes recent developments in the discovery, biogenesis, and functional characterization of microproteins, and their involvement in various disease, with special focus on their roles in cancer, cardiovascular, metabolic, neurodegenerative and immune-related disorders. We emphasize the regulation of key cellular pathways by microproteins, including mitochondrial homeostasis, apoptosis, metabolic reprogramming, and immune signaling, all of which affect disease initiation and progression. Emerging evidence also supports their potential as disease biomarkers and therapeutic candidates for precision medicine. Finally, the review critically discusses the current challenges including discrepancies in microprotein annotation, the limitations of ribosome profiling and proteogenomic approaches, the gap between computationally predicted and experimentally validated microproteins, and the need for rigorous orthogonal validation by means of CRISPR-based genome editing, ribosome release assays, mutational analysis, high-resolution mass spectrometry, and functional studies. Finally, we review recent development of AI-assisted ORF prediction, single-cell translatomics, spatial proteomics, and integrated multi-omics as emerging technologies reshaping. Microprotein discovery and functional annotation. Finally, we discuss the translational potential of microproteins and highlight the remaining challenges to clinical application, including peptide stability, pharmacokinetics, tissue-specific delivery, immunogenicity, and the need for rigorous preclinical and clinical validation. Together, this review provides an updated and critical overview of the rapidly evolving microprotein field and highlights future research priorities for translating these molecules into clinically useful biomarkers and precision therapeutics.

Microproteins↗

PubMed2026

Assessment of Genetic Correlations Between Tobacco or Alcohol Use and Neurodegenerative Diseases Using East Asian Genetic Ancestry Genome-Wide Association Study Results.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent late-onset neurodegenerative diseases worldwide. Both are influenced in part by genetic factors and are currently incurable. Tobacco and alcohol, the two most common substances used among the general adult population, are potential AD/PD risk factors and are also heritable. Although important progress has been made, most existing research on the genetics of AD and PD has been carried out in individuals of European genetic ancestry. Investigations in a broad range of groups are crucial to understand disease mechanisms. Given the current availability of ancestry-specific tobacco and alcohol use as well as AD and PD genome-wide association study summary statistics, we performed global and local genetic correlation analyses using East Asian datasets. Genes within the correlated genetic regions were subsequently used to identify potentially enriched biological pathways between substance use and neurodegenerative diseases. We identified a global genetic correlation between smoking cessation and PD, which we confirmed in complementary European genetic ancestry data. Gene set enrichment analyses highlighted potentially shared genetic mechanisms between breast cancer and AD, which warrants further exploration. This work aims to promote further analyses across genetic ancestry groups.

Female↗