Search Results (2,179)

Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair (pMMR) and microsatellite stability (MSS) metastatic colorectal cancer (mCRC). Inhibition of vascular endothelial growth factor (VEGF) or cytotoxic chemotherapy can boost immunogenicity and has the potential to upregulate ICI efficacy. Methods: A comprehensive electronic literature search was conducted up to April 2025 to identify randomized controlled trials comparing cytotoxic chemotherapy plus bevacizumab with or without ICI. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), objective response rate (ORR), and severe adverse events (AEs: grade 3 or more). A meta-analysis was performed using random-effects models to calculate hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four studies involving 986 patients (With-ICI group, n = 651; Without-ICI group, n = 335) were included. The meta-analysis demonstrated a significant improvement in PFS in the With-ICI group compared with the Without-ICI group, with an HR of 0.82 (95% CI: 0.70–0.96, p = 0.01) without statistical heterogeneity. No significant improvements were observed between the With- and Without-ICI groups in OS and ORR meta-analyses, but the With-ICI group had a favorable trend in OS. A significant increase in serious AEs was not observed in the With-ICI group. Conclusions: This meta-analysis suggests a potential benefit of adding ICIs to chemotherapy plus bevacizumab in pMMR mCRC; however, the evidence remains preliminary and hypothesis-generating, warranting further investigation in biomarker-driven trials and clarification of long-term outcomes. Full article

Accounting for 15–30% of colorectal cancer cases, the serrated pathway remains poorly characterized compared to the adenoma–carcinoma sequence. It involves sessile serrated lesions as precursors and is characterized by BRAF mutations (BRAF^V600E), CpG island hypermethylation, and microsatellite instability (MSI). Using label-free proteomics, we compared normal tissue margins from patients with diverticular disease, sessile serrated lesions, low-grade adenomas, and high-grade adenomas. We identified S100A14 as significantly overexpressed in sessile serrated lesions compared to low-grade adenomas, high-grade adenomas, and normal tissues. This overexpression was confirmed by immunohistochemical scoring in an independent cohort. Gene expression analyses of public datasets showed higher S100A14 expression in BRAF^V600E-mutated and MSI-H colorectal cancers compared to microsatellite stable BRAF^wt tumors. This finding was confirmed by immunohistochemical scoring in an independent colorectal cancer cohort. Furthermore, single-cell RNA sequencing analysis from the Human Colon Cancer Atlas revealed that S100A14 expression in tumor cells positively correlated with the abundance of tumoral CD8⁺ cytotoxic T cells, particularly the CD8⁺ CXCL13⁺ subset, known for its association with a favorable response to immunotherapy. Collectively, our results demonstrate for the first time that S100A14 is a potential biomarker of serrated neoplasia and further suggests its potential role in predicting immunotherapy responses in colorectal cancer. Full article

In the traditional classification system of the Lauraceae family based on morphology and anatomy, the phylogenetic position of the genus Sassafras has long been controversial. Chloroplast (cp) evolution of Sassafras has not yet been illuminated. In this study, we first sequenced and assembled the complete cp genomes of Sassafras, and conducted the comparative cp genomics, phylogenomics, and divergence time estimation of this ecological and economic important genus. The whole length of cp genomes of the 10 Sassafras ranged from 151,970 bp to 154,011 bp with typical quadripartite structure, conserved gene arrangements and contents. Variations in length of cp were observed in the inverted repeat regions (IRs) and a relatively high usage frequency of codons ending with T/A was detected. Four hypervariable intergenic regions (ccsA-ndhD, trnH-psbA, rps15-ycf1, and petA-psbJ) and 672 cp microsatellites were identified for Sassafras. Phylogenetic analysis based on 106 cp genomes from 30 genera within the Lauraceae family demonstrated that Sassafras constituted a monophyletic clade and grouped a sister branch with the Cinnamomum sect. Camphora within the tribe Cinnamomeae. Divergence time between S. albidum and its East Asian siblings was estimated at the Middle Miocene (16.98 Mya), S. tzumu diverged from S. randaiense at the Pleistocene epoch (3.63 Mya). Combined with fossil evidence, our results further revealed the crucial role of the Bering Land Bridge and glacial refugia in the speciation and differentiation of Sassafras. Overall, our study clarified the evolution pattern of Sassafras cp genomes and elucidated the phylogenetic position and divergence time framework of Sassafras. Full article

Background: The relationship between genetic diversity and fitness is well understood, but few studies have investigated how behavior influences genetic diversity, or vice versa. We investigated the relationship between feeding behavior (on a pelleted diet) and genetic diversity in pikeperch, a piscivorous species. Methods: A total of 135 juvenile pikeperch from the same stock were grouped into three behavioral groups: pellet consuming, pellet refusing, and cannibalistic. Eighteen microsatellite markers were used to characterize the genetic diversity and structure of individuals. Results: The juveniles were classified into two genetic clusters: one dominated by pellet-consuming individuals and the other by pellet-refusing individuals containing equal proportions of cannibal individuals. Three of the microsatellite markers were under selection, but only one showed significant genetic segregation between the groups. For this marker, the pellet consumption was associated with low fragment length. Individual multilocus heterozygosity was significantly higher in the pellet-refusing group. Conclusions: These results suggest that pellet consumption acts as an uncontrolled selective force during domestication, influencing the genetic variability of domesticated populations. The ability to habituate to pellets has a significant genetic basis. Cannibalism does not affect genetic variability, and the emergence of the trait is independent of the propensity to consume pellets. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

This study investigates the genetic diversity and population structure of Castanopsis tribuloides, a vital tree species in Asian forest ecosystems. Understanding the genetic patterns of keystone forest species provides critical insights into forest resilience and ecosystem function and informs conservation strategies. We analyzed population samples collected from three distinct locations within Doi Suthep Mountain in northern Thailand using Short Tandem Repeat (STR) markers to assess both intra- and inter-population genetic relationships. DNA was extracted from leaf samples and analyzed using a panel of polymorphic microsatellite loci specifically optimized for Castanopsis species. Statistical analyses included the assessment of forensic parameters (number of alleles, observed and expected heterozygosity, gene diversity, polymorphic information content), population differentiation metrics (G_ST), inbreeding coefficients (F_IS), and gene flow estimates (N_m). We further examined population history through bottleneck analysis using three models (IAM, SMM, and TPM) and visualized genetic relationships through principal coordinate analysis and cluster analysis. Our results revealed significant patterns of genetic structuring across the sampled populations, with genetic distance metrics showing statistically significant differentiation between certain population pairs. The PCA and cluster analyses confirmed distinct population groupings that correspond to geographic distribution patterns. These findings provide the first comprehensive assessment of C. tribuloides population genetics in this region, establishing baseline data for monitoring genetic diversity and informing conservation strategies. This research contributes to our understanding of how landscape features and ecological factors shape genetic diversity patterns in essential forest tree species, with implications for managing forest genetic resources in the face of environmental change. Full article

Host genetic variability is relevant to understanding how parasites modulate natural selection in wild fish populations. Coastal lagoons are transitional ecosystems where knowledge lacks on relationships between genotypic diversity with parasitism. The aim of this study was to assess the effect of genetic diversity on host health and parasitological traits in fish inhabiting a Mediterranean lagoon. Black-striped pipefish Syngnathus abaster were collected in August 2023 and 2024 from the Mar Menor (Iberian lagoon, SE Spain). Genetic diversity was measured as Internal Relatedness (IR: a homozygosity index from microsatellite markers). Population frequency was lower for the medium IR level. For this same category, both health indices (external body condition and internal organs) indicated a worse status. Parasite prevalence, abundance and an index of life-cycle complexity (heteroxenous species) were greater for the medium level of genetic diversity. Such results are explained under a scenario of parasite-mediated disruptive selection: a higher disease pressure against the phenotypically intermediate individuals. Two contrasting strategies were detected to better control parasitism at the host genotypic level: (1) high homozygosity, and (2) high heterozygosity, which probably reflects better immuno-competence as a phenotypic trait. From an evolutionary perspective, parasites play a crucial role in shaping genetic diversity within host populations. Full article

In recent decades, fishery stock enhancement has been increasingly utilized as a restoration tool to mitigate population declines and enhance the resilience of marine fisheries. Nevertheless, persistent enhancement efforts risk eroding the evolutionary potential of wild populations via genetic homogenization and maladaptive gene flow. Using long-term monitoring data (2017–2023), we quantified the effects of large-scale Penaeus penicillatus stock enhancement (~10⁸ juveniles/yr) on wild population dynamics and genetic integrity in the Beibu Gulf ecosystem. Temporal genetic changes were assessed using eight highly polymorphic microsatellite loci, comparing founder (2017) and enhanced (2024) populations to quantify stocking impacts. Insignificantly lower expected heterozygosity was observed in the stocked population (He = 0.60, 2024) relative to natural populations (He = 0.62–0.66; p > 0.1), indicating genetic dilution effects from enhancement activities. No significant erosion of genetic diversity was detected post-enhancement, suggesting current stocking practices maintain short-term population genetic integrity. Despite conserved heterozygosity, pairwise Fst analysis detected significant genetic shifts between temporal cohorts (pre-enhancement—2017 vs. post-enhancement—2024; Fst = 0.25, p < 0.05), demonstrating stocking-induced population restructuring. Genetic connectivity analysis revealed that while the enhanced Beihai population (A-BH) maintained predominant self-recruitment (>90%), it experienced substantial stocking-derived gene flow (17% SW → A-BH). The post-stocking period showed both reduced genetic exchange with adjacent populations and increased asymmetric dispersal from A-BH (e.g., 5% to YJ), indicating that hatchery releases simultaneously enhanced population isolation while altering regional genetic structure. Our findings revealed the paradoxical dual effects of stock enhancement and allelic diversity while disrupting natural genetic architecture. This underscores the need for evolutionary-impact assessments in marine resource management. Full article

Microsatellite instability (MSI) is a clinically important biomarker for predicting responses to immune checkpoint inhibitors and identifying individuals with Lynch syndrome. Although MSI detection has been incorporated into Illumina’s next-generation tumor sequencing workflows, interpretation of the results remains challenging due to the absence of standardized thresholds and reporting criteria. In this retrospective study, we assessed the performance of MSI detection using Illumina’s targeted NGS panels—TruSight Tumor 170 and TruSight Oncology 500. The NGS-based MSI results were compared to those obtained by the reference method, MSI-PCR, across multiple tumor types in a real-world cohort of 331 cancer patients. The NGS method demonstrated high concordance overall (AUC = 0.922), though sensitivity was lower in colorectal cancers (AUC = 0.867) due to broader score variability and overlapping distributions. Our findings support the clinical utility of Illumina’s NGS-derived MSI scores for identifying MSI-H tumors, with a recommended MSI score cut-off value of ≥13.8%. Additionally, a borderline group was introduced, defined by an MSI score ranging from ≥8.7% to <13.8%. Within this range, the integration of TMB into the MSI classification workflow significantly improves diagnostic accuracy. For samples that remain inconclusive, orthogonal confirmation using MSI-PCR is advised to ensure accurate MSI classification. Full article

Endometrial carcinoma (EC) is the most common gynaecological malignancy in developed nations, exhibiting significant molecular heterogeneity that impacts prognosis and treatment response, particularly in advanced or recurrent settings. Traditional classification is increasingly supplemented by molecular subtyping (POLE-ultramutated, MSI-high/dMMR, NSMP, p53-mutated/CNH), which provides crucial prognostic information and predicts benefit from immunotherapy. This review summarizes the landscape of predictive biomarkers for immune checkpoint inhibitor (ICI) therapy in EC, emphasizing a new therapeutic scenario for advanced and recurrent EC. Mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), leading to high tumor mutational burden (TMB) and increased neoantigen production, is the most established predictor, resulting in FDA approvals for pembrolizumab and dostarlimab in this subgroup. POLE mutations also confer hypermutation and high immunogenicity, predicting a favorable ICI response. Other biomarkers, including PD-L1 expression and TMB, show variable correlation with response and require further standardization. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs), also influences treatment outcomes. Clinical trials have demonstrated significant survival benefits for ICIs combined with chemotherapy (e.g., dostarlimab/pembrolizumab + carboplatin/paclitaxel) in first-line settings, especially for dMMR/MSI-H EC, and for ICI combinations with targeted agents (e.g., lenvatinib + pembrolizumab) in previously treated patients. Integrating molecular classification and validated biomarkers is essential for optimizing patient selection and developing personalized immunotherapy strategies for EC. Full article

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI-HOPE-JAK-STAT, a novel conversational artificial intelligence platform built to enable the real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis-generating analyses for precision oncology. Methods: AI-HOPE-JAK-STAT combines large language models (LLMs), a natural language-to-code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age < 50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with significantly more favorable trends (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusions: AI-HOPE-JAK-STAT establishes a new standard for pathway-level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports the scalable, real-time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts. Full article

In this study, we investigated the expression of TIM-3 and Galectin-9 (Gal-9) in colorectal cancer (CRC) and their associations with oncogenic mutations, MSI status, cytokine profiles, and transcriptional data. TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to matched non-tumor margins (p < 0.05 and p < 0.001, respectively). TIM-3 protein concentration was notably higher in PIK3CA-mutated tumors (p < 0.05), while no associations were found with KRAS, NRAS, BRAF, AKT1, or MSI status. Multiplex cytokine profiling revealed strong correlations between TIM-3 and Gal-9 levels and key immunomodulatory pathways, including IL-10, IL-17, and chemokine signaling. We also observed significant associations with cytokine subsets involved in protumor activity and immune regulation. Gene set enrichment analysis (GSEA) demonstrated that high TIM-3 and Gal-9 expression was associated with upregulation of cell cycle-related pathways, and downregulation of immune signatures, such as interferon responses and TNF-α/NFκB signaling. These findings suggest that increased TIM-3 and Gal-9 expression reflects a shift toward proliferative activity and immune suppression in the CRC tumor microenvironment, highlighting their potential as biomarkers of immunoevasive tumor phenotypes, especially in PIK3CA-mutant CRC tumors. Full article

Immunotherapy has emerged as a transformative approach in gastrointestinal (GI) cancers, addressing historically poor survival rates in advanced-stage disease. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis demonstrate remarkable efficacy in colorectal cancer with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), exemplified by trials like NICHE-2 achieving exceptional pathological response rates. However, significant limitations persist, including resistance in some dMMR/MSI-H tumors, minimal efficacy in proficient mismatch repair (pMMR) tumors, and low overall response rates across most GI malignancies due to tumor heterogeneity and immune evasion mechanisms. Predictive biomarkers such as tumor mutational burden (TMB) and PD-L1 expression are crucial for optimizing patient selection, while hypermutated pMMR tumors with POLE mutations represent emerging therapeutic opportunities. In pancreatic adenocarcinoma, where survival remains dismal, combination strategies with chemotherapy and novel approaches like cancer vaccines show promise but lack transformative breakthroughs. Esophagogastric cancers benefit from ICIs combined with chemotherapy, particularly in MSI-H and HER2-positive tumors, while hepatocellular carcinoma has achieved significant progress with combinations like atezolizumab–bevacizumab and durvalumab–tremelimumab surpassing traditional therapies. Biliary tract cancers show modest improvements with durvalumab–chemotherapy combinations. Despite these advances, immunotherapy faces substantial challenges including immune-related adverse events, acquired resistance through cancer immunoediting, and the need for biomarker-driven approaches to overcome tumor microenvironment barriers. This review discusses key clinical trials, therapeutic progress, and emerging modalities including CAR T-cell therapies and combination strategies, emphasizing the critical need to address resistance mechanisms and refine precision medicine approaches to fully realize immunotherapy’s potential in GI malignancies. Full article

Two germplasm collections, comprising 1026 peach accessions located in Italy, were analyzed with 12 simple sequence repeat (SSR) markers. SSR reactions were performed using the multiplex-ready PCR protocol, and 147 alleles were amplified with an average of 12 alleles per locus. BPPCT001 was the most informative marker displaying the highest discrimination power (0.734). The observed heterozygosity showed an average of 0.45 alleles per locus, lower than expected (0.61). The fixation index (F) values were positive in all loci, with an average of 0.27 alleles per locus, suggesting the presence of endogamy. The DNA fingerprinting data allowed the discrimination of 80.95% of the analyzed accessions. If we exclude known sport mutations, known synonymies, and cultivars with the same pedigree, 161 accessions are mislabeled, with an error rate of 16.56% within or between collections. Population structure analysis revealed three subpopulations: modern peach cultivars, modern nectarine cultivars, and a third group mainly comprising traditional peach cultivars. The results obtained in this work will be useful to efficiently manage Genebank, reducing unwanted redundancy, synonyms and homonyms, mislabeling, and spelling errors, as well as identifying parents in controlled crosses. Full article

Climate change is usually recognized as the most significant challenge facing viticulture in the 21st century. As a result, experts are increasingly emphasizing the need to explore the biodiversity within the species Vitis vinifera L. In this context, the present study investigated the intra-varietal biodiversity of two widely cultivated grapevine varieties on the Canary Islands of Lanzarote and Fuerteventura (Spain). These islands, characterized by desert-like climates, strong winds, volcanic soils, and phylloxera-free conditions, have presented uninterrupted grapevine cultivation for the past three to five centuries. Intra-varietal variability was detected in 93.46% of the 107 accessions analyzed. The most divergent samples were a Malvasia Dubrovacka (LNZ-87) and a Listan prieto (FTV-8), each exhibiting five distinct variations. Another Listan prieto accession (FTV-13) showed four variations. A group of seven individuals displayed three variations including two Malvasia volcanica accessions (LNZ-12, LNZ-72) and five Listan prieto accessions (FTV-1, FTV-2, FTV-7, FTV-9, FTV-12). A set of 100 SSR markers was used to analyze this grapevine collection, of which 17 revealed variability. The most informative markers were VChr15b, VVIp34, VVMD32, VChr9b, VVMD5, VVMD28, and VMC4F3, while the least informative was VVNTM1, which detected no variation. The parentage of Malvasia volcanica (Malvasia Dubrovacka × Bermejuela) was supported by all SSR markers, assuming that three of them may involve a mutated parent. Full article