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PubMed2026

Transcriptome analysis of brown adipose tissue in Brandt's vole treated with tannic acid under cold exposure.

BACKGROUND: Tannic acid (TA) is a hydrolysable plant secondary metabolite known to influence multiple physiological processes in animals; however, its role in regulating brown adipose tissue (BAT) thermogenesis remains poorly understood. Notably, the overwinter food caches of Brandt's voles predominantly consist of Artemisia species, which are rich in TA. This study aimed to determine whether TA contributes to cold tolerance in Brandt's voles by activating BAT thermogenesis. Adult male voles were administered TA, after which the masses of BAT and inguinal white adipose tissue (iWAT) were measured, and temperature changes in BAT, the body surface, and the rectum were recorded following exposure to - 20 °C. In addition, transcriptomic analyses of BAT were performed, and the expression and protein levels of key thermogenic markers were assessed. RESULTS: The results showed that TA reduced iWAT mass while exerting minimal effects on BAT mass. TA-treated voles exhibited significantly elevated temperatures in BAT, the body surface, and the rectum after cold exposure. Histological analyses revealed that TA treatment reduced adipocyte area in iWAT while increasing the number of nuclei in brown adipocytes in BAT. In BAT, differentially expressed genes (DEGs) in voles receiving a low TA dose were significantly enriched in pathways related to fat digestion and absorption and peroxisome proliferator-activated receptor (PPAR) signaling. In contrast, DEGs in voles administered a high TA dose were predominantly associated with brown adipocyte differentiation and the upregulation of cold-induced thermogenesis. Moreover, TA administration increased the expression of FFAR4 and UCP1, as well as the protein levels of PGC-1α, PPARγ, and UCP1 following cold exposure. CONCLUSIONS: Collectively, these findings demonstrate that TA enhances cold tolerance in Brandt's voles by promoting thermogenic gene expression and stimulating brown adipocyte differentiation in BAT, providing novel insights into the role of plant secondary metabolites in mammalian cold adaptation and herbivore-plant interactions.

Animals↗

PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗

PubMed2026

The bioinformatics approach to identifying pathogenic variants for colorectal cancer (CRC).

Colorectal cancer (CRC) is the third most prevalent cancer globally, accounting for 9.6% of newly diagnosed cases and 9.3% of cancer-related deaths. It develops from the uncontrolled proliferation of glandular cells in the colon and rectum and is categorized into three primary types: sporadic, hereditary, and colitis-associated. While genetic susceptibility is a key factor in CRC pathogenesis, identifying high-impact pathogenic variants remains a significant challenge. This study integrates bioinformatics and population genetics approaches to identify CRC-associated single-nucleotide polymorphisms (SNPs) with potential clinical significance. CRC-associated SNPs were extracted from the Genome-Wide Association Studies (GWAS) Catalog, functionally annotated via HaploReg, and validated via Ensembl. In addition, expression quantitative trait locus (eQTL) data from the GTEx database were used to assess the effects of these variants on gene expression across human tissues. Our analysis identified three high-priority SNPs (rs9379084, rs3184504, and rs11557154) associated with the RREB1, ATXN2, SH2B3, and DCAF12 genes, which exhibited marked allele frequency differences among populations. These findings suggest potential biomarkers for CRC risk assessment and highlight the importance of genetic screening across diverse populations.

Bioinformatics↗

PubMed2025

Clinicopathologic and Molecular Analysis of Colorectal Carcinomas With Spectrum of Neuroendocrine Carcinoma Components.

The genetics of colorectal carcinoma (CRC) with neuroendocrine differentiation remain poorly understood; recent studies focusing on pure neuroendocrine carcinomas (NECs) demonstrated mutation profiles closely resembling colorectal adenocarcinomas (ACAs) with more frequent BRAF mutations and Rb/p16 pathway dysregulation. However, pathogenesis of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and ACAs with minor NEC component (AMiNECs) remains controversial. We aimed to define the behavior and molecular underpinnings of these tumors in comparison with conventional ACAs. In total, 20 NECs, 10 MiNENs, and 8 AMiNECs were compared with 100 controls with ACAs. Well-differentiated neuroendocrine tumors of any grade were excluded. CRCs with NEC components presented at a slightly earlier age (mean, 59 vs 65 years; P = .24) in a similar sex distribution (male:female, 1:1.11 vs 1.04:1; P = .97). The majority of cases arose either from a precursor adenoma (42%) or in the setting of inflammatory bowel disease (18%), whereas 5 of 10 cases (50%) originating from the rectum were human papillomavirus driven. Despite similarity in tumor size and depth of invasion among all groups, CRCs with NEC components showed more frequent lymph node and distant metastases (P < .001 each), leading to more advanced disease stage (stage III/IV; P < .001) and worse 5-year survival outcomes (35.4% for NECs, 30% for MiNENs, and 41.6% for AMiNECs vs 85.1% for ACAs; P < .001), compared with ACAs. Next-generation sequencing revealed more frequent BRAF (40% vs 3%; P < .001) and BRCA1 alterations (15% vs 1%; P = .001) in NECs compared with ACAs. Genomic alterations in RB1 were exclusively found in NECs (10%) and MiNENs (20%). In conclusion, the presence of any NEC component (from AMiNEC to pure NEC) in CRC carries a dismal prognosis. Yet, these tumors are more likely to harbor potentially targetable mutations such as BRAF p.V600E and alterations in BRCA1/2, which are of therapeutic value.

Humans↗

PubMed2026

Multi-level aggregation analysis of microbiome composition and host gene expression reveals associations with systemic and local immunity.

The human gut microbiome plays a critical role in immune regulation, yet the molecular links between microbiome composition and host gene expression remain incompletely understood. We analyzed associations between host gene expression and microbiome composition in a cohort of 315 healthy individuals, integrating microarray-based gene expression data from three intestinal sites (ileum, transverse colon, and rectum) and six immune cell types with microbiome sequencing data. Using a hierarchical feature aggregation strategy combining principal component analysis, clustering, and covariate correction, we discovered significant associations primarily related to immunity. While microbial profiles were similar across the three intestinal sites, the transverse colon yielded the most "microbiome-host gene expression" associations. Among the immune cell types, CD8+ cells showed the highest number of associations. The first principal component of microbiome composition, reflecting a gradient from commensals (e.g., Ruminococcaceae and Christensenellaceae) to proinflammatory taxa ([Ruminococcus] gnavus and Lachnoclostridium), correlated with the expression of TNF-α-linked genes (HMOX1, CPI17, HSD3B2, and SLC5A1). Among individual genera, Catenibacterium abundance was associated with gene expression in both intestinal and immune cells, including negative associations with MRPS21 (related to mitochondrial function) in the transverse colon and with CD8+ gene programs related to T cell differentiation. These findings align with emerging evidence implicating mitochondrial dysfunction in intestinal inflammation. Our results identify multi-level associations between the gut microbiome and host gene expression, suggesting potential mechanisms by which microbiota shape local and systemic immunity and vice versa. The implicated genes and taxa represent candidates for experimental validation to improve understanding of host-microbiome homeostasis and its disruption in disease.IMPORTANCEThe gut microbiome and immune system are engaged in a complex interplay throughout human life. While most associative studies focus on case-control comparisons-typically examining patients with conditions such as inflammatory bowel disease or metabolic diseases-less is known about the molecular links between the microbiome and immune system in healthy individuals. In this study of a large cohort of healthy individuals, we addressed this gap by applying multiscale modeling to tackle the high dimensionality of host-microbiome data. We identified multi-level associations between microbiome composition and host gene expression in both intestinal tissues and immune cells. These findings offer a valuable reference for understanding baseline host-microbiome communication and highlight molecular candidates-such as TNF-α-related genes and mitochondrial pathways-for future experimental validation.

Humans↗

PubMed2026

Treatment of localized rectal cancer in the Nordic countries-comparison of Nordic to Dutch, ESMO, and NCCN guidelines.

BACKGROUND: Rectal cancer treatment in Nordic countries has traditionally differed, especially regarding neoadjuvant treatment. The aim of this review is to give an overview of the current rectal cancer guidelines in the Nordics and compare these to international guidelines. METHODS: Oncologists and colorectal surgeons from the Nordic countries (Denmark, Finland, Norway, and Sweden) and the Netherlands were invited to participate in this narrative review. Two consensus meetings were held to agree on the content. All authors provided recommendations from their national guidelines. In addition, recommendations from the European Society of Medical Oncology (ESMO) and from the US National Comprehensive Cancer Network (NCCN) guidelines were extracted. RESULTS: Several differences between the included guidelines were identified. The radiological "sigmoid take-off" definition for the upper margin of the rectum has been adapted in Denmark and the Netherlands, whereas the other guidelines rely on distance from the anal verge on rigid sigmoidoscopy. Indications for direct surgery vary considerably, where the NCCN guidelines recommend more aggressive neoadjuvant treatment, primarily total neoadjuvant therapy (TNT), the Nordic and European guidelines open for direct surgery more often, and reserve especially TNT for high-risk cases. European countries more often recommend short-course radiotherapy, whereas NCCN maintains chemoradiotherapy as the mainstay. Whereas intentional and opportunistic organ preservation is an established part of the Dutch, NCCN, and ESMO guidelines, its use is mostly restricted to clinical trials in the Nordics. The Nordics and the Netherlands are restrictive in terms of adjuvant treatment, which is frequently recommended in ESMO and NCCN. Whereas neoadjuvant immunotherapy is recommended for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer in NCCN, this use is off-label in Europe and not routinely recommended. CONCLUSION: Although all guidelines rely on the same evidence, there are considerable differences, especially in the indications and type of oncologic treatment, both in the neoadjuvant and in the adjuvant setting.

Rectal Neoplasms↗

PubMed2026

ACG Clinical Guideline: Diagnosis and Management of Adenomatous Colorectal Polyposis Syndromes.

The hereditary adenomatous colorectal polyposis syndromes are incurable, systemic, cancer risk predisposition syndromes with substantial morbidity and mortality. They differ in their mode of inheritance, age at disease onset, phenotypic expression, and cancer risk. The most common cancer risks involve the gastrointestinal tract including the colon, rectum, duodenum, ampulla, and stomach. Identifying these syndromes through personal and family history risk assessment and germline genetic testing, along with timely surgical and endoscopic management, can reduce cancer incidence and mortality. These guidelines use the Grading of Recommendations, Assessment, Development, and Evaluation methodology to provide clinical guidance on the selection of individuals who should undergo a risk assessment for a hereditary adenomatous colorectal polyposis syndrome, modality and timing of germline genetic testing, cancer risk mitigation through endoscopic and surgical interventions, and the role of chemoprevention. This document reviews the approach to genetic testing in patients with phenotypic colorectal polyposis and the impact of presymptomatic diagnosis in families with a known familial germline pathogenic variant or clinical features suggestive of a hereditary adenomatous polyposis syndrome. Management strategies for patients based on genetic test results or without genetic testing are provided. We also review colorectal and extracolonic phenotypic benign and malignant manifestations of the known hereditary syndromes with a focus on the 2 most common hereditary colorectal polyposis syndromes: familial adenomatous polyposis and MUTYH-associated polyposis. The document concludes with recommendations on polyposis and cancer risk mitigation strategies and highlights updates to management since the previous guideline was published.

Humans↗

PubMed2026

Prognostic value of genes associated with metastasis and propionate metabolism in rectal cancer.

BACKGROUND: Research indicates that alterations in propionate metabolic pathways play a critical role in cancer development and invasion. Postoperative metastatic recurrence remains a major cause of mortality in patients with rectal cancer. However, propionate metabolism-related genes (PMRGs) in rectal cancer remain insufficiently characterized. Therefore, this study aimed to identify prognostic biomarkers associated with lymph node metastasis and propionate metabolism and construct a risk‑prediction model for rectal cancer via bioinformatic analyses. METHODS: The Cancer Genome Atlas-Rectum Adenocarcinoma (TCGA-READ) and GSE87211 datasets, together with a curated PMRGs gene set, were used in this study. Pearson correlation analysis was performed to assess associations between overlapping genes (differentially expressed genes between READ and normal tissues, as well as between N0 and N1-N2 stages) and PMRGs, leading to the identification of candidate genes. Functional enrichment analyses were subsequently conducted to characterize the biological roles of these candidates. Prognostic biomarkers were identified using univariate Cox regression combined with least absolute shrinkage and selection operator (LASSO) regression, and a prognostic model was constructed accordingly. Independent prognostic validation was then performed. In addition, immune checkpoint profiling and immunotherapy response analyses were conducted across risk subgroups. Single-gene Gene Set Enrichment Analysis (GSEA) was applied to elucidate the pathways associated with the identified biomarkers. Finally, drug sensitivity analyses were performed. RESULTS: A total of 157 candidate genes were identified through the analytical pipeline. Functional enrichment analysis indicated that these genes were primarily involved in inflammatory response regulation and tumor necrosis factor (TNF) signaling pathways. Five prognostic biomarkers were subsequently identified and incorporated into a predictive model. External validation using the GSE87211 cohort confirmed the robustness of the model. Risk score and disease status were identified as independent prognostic factors. Six immune checkpoint molecules exhibited differential expression between risk groups. Correlation analyses revealed that the risk score was positively associated with most immune checkpoint genes. Single-gene GSEA demonstrated that the biomarkers were mainly enriched in ribosomal biogenesis and cell adhesion molecule-related pathways. Furthermore, 51 therapeutic agents exhibited significantly different half-maximal inhibitory concentration (IC50) values between risk subgroups. CONCLUSIONS: This study identified five biomarkers (CCL24, IGFBP3, ODC1, PYGM, and VKORC1) associated with lymph node metastasis and propionate metabolism pathways, providing a potential foundation for prognostic prediction in patients with rectal cancer.

Rectal cancer↗

PubMed2026

Non-linear predictive modeling and comprehensive meta-analysis of rectal temperature in Santa Inês sheep: a systematic review of thermal challenges and biometerological trends.

A systematic and bibliometric review, combined with a meta-analysis, was used to adjust an equation for estimating the physiological responses of Santa Inês sheep subjected to different thermal challenges. The systematic review compiled data on physiological responses and the thermal environment, which were then used in the meta-analysis to adjust regression models. The bibliometric analysis mapped the relationships among studies, highlighting their usefulness in interpreting research findings and biases. Addressing prior methodological critiques, the core of this study involves replacing the linear approach with a non-linear segmented regression model to accurately define the Thermal Neutral Zone (TNZ). The Segmented Regression Model was crucial, establishing the upper limit of the Thermal Neutral Zone (TNZ) at an air temperature (tair) of 34.64 °C, where trectal begins to increase abruptly. The model, while identifying a biologically significant breakpoint, exhibited a moderate Multiple R-squared of 0.3529, highlighting the high heterogeneity and methodological variability in the current Santa Inês literature. This non-linear approach offers a biologically superior tool for identifying the onset of thermal distress.

Animals↗

PubMed2025

Injury and inflammation promote cancer progression at the anorectal junction.

In anorectal cancer, epithelial tumors frequently develop in transition zones (TZs) between the anal and the rectal epithelia, a region subjected to inflammation and wounds. However, whether inflammation and wounds contribute to tumor development in the anorectal region remain totally unknown. Using mice with KRASG12D mutation selectively at the TZ cells, we found that recurrent wound and its associated sustained inflammation are essential to promote tumor development. We characterized at the single-cell level the malignant events that occurred at the TZ all along tumor development from early neoplastic, hyperplastic, to malignant transition. We showed that this tumoral development was under the influence of interleukin (IL)-17, a cytokine highly secreted by a γδ T lymphocyte subset, allowing the recruitment of neutrophils at the TZ, which was crucial for tumor progression. Hence, this study reveals the importance of wound and its associated IL-17/neutrophil inflammatory axis in cancer progression.

Animals↗

PubMed2026

Comprehensive analysis of metabolomics and transcriptomics of radiation-induced rectal injury.

Radiation-induced rectal injury (RRI) significantly affects the quality of life in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (NCRT). Non-targeted liquid chromatography-mass spectrometry metabolomics analysis and transcriptomic analysis were conducted to explore RRI characteristics. Hematoxylin-eosin and Masson staining confirmed radiation-induced injury in rectal tissue within the radiotherapy target region. Orthogonal partial least squares discriminant analysis identified 823 differentially expressed metabolites (DEMs). Transcriptomic analysis revealed 400 differentially expressed genes (DEGs). Enrichment analysis revealed that DEMs and DEGs were primarily involved in metabolic, immune, and signal transduction pathways. Integrated analysis demonstrated significant enrichment of DEMs and DEGs in the arachidonic acid metabolism pathway. Pearson's correlation and canonical correlation analyses were used to assess the association between DEMs and DEGs within this pathway. In conclusion, this study identified key biological regulatory pathways involved in RRI through a multi-omics approach, offering potential targets for its diagnosis and treatment.

Humans↗