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PubMed2025

Integrating necroptosis and immune landscapes: a multi-omics-derived NecropImmScore stratifies prognosis and therapy in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) remains the deadliest gynecologic malignancy, largely due to its immunosuppressive tumor microenvironment (TME) and resistance to therapy. Necroptosis, a regulated lytic cell death pathway mediated by the RIPK1-RIPK3-MLKL axis, can trigger immunogenic cell death, but its specific role in shaping the OC immune landscape and its clinical translation potential are posorly understood. METHODS: We employed multi-omics analysis (transcriptomics, genomics, clinical data) from TCGA-OV (n = 380), ICGC OV-AU, and IMvigor210 cohorts, combined with rigorous in vitro functional validation using OC cell lines (SKOV3, HEY), macrophages (THP-1 derived), and T cells (Jurkat). Computational immunology approaches (ESTIMATE, CIBERSORT, ssGSEA) quantified immune infiltration. We identified MLKL-associated immune genes, performed survival analysis (Kaplan-Meier, Cox regression), and constructed a necroptosis-immune signature (NecropImmScore) using consensus clustering and PCA of 102 prognostic genes. Drug sensitivity was predicted via pRRophetic and CellMiner. RESULTS: MLKL emerged as a protective prognostic biomarker (p = 0.018), significantly correlated with enhanced immune infiltration (ImmuneScore, StromalScore, ESTIMATEScore; p < 2.22e-16), M1 macrophage polarization (p = 0.006), activated CD4 + T cells (p = 0.003), and elevated immune checkpoint expression (PD-L1, CTLA4, LAG3, TIGIT). In vitro, MLKL overexpression in OC cells promoted M1 polarization (p < 0.05), activated Jurkat T cells (upregulated CCR4/5/7/9, CD69, CD3D/E, GZMB; p < 0.05), and induced key chemokines (CXCL9/10/11/13) critical for immune cell recruitment. Integration of MLKL-related and immune-related DEGs (n = 632) revealed enrichment in T-cell activation, chemokine signaling, and antigen presentation pathways (FDR < 0.05). Consensus clustering based on 102 survival-associated genes defined three molecular subtypes (Clusters A-C) with divergent survival (p = 0.019), necroptosis activity, and immune infiltration (Cluster C: best prognosis, highest MLKL/ImmuneScore). The derived NecropImmScore robustly stratified patients: high-score correlated with superior overall survival (TCGA: p < 0.001; ICGC: p = 0.014), inflamed TME phenotype, elevated checkpoint expression, and improved response to anti-PD-L1 in IMvigor210. Critically, high NecropImmScore predicted higher BRCA1 mutation frequency (AUC = 0.802), synergy with BRCA1 status for prognosis, higher homologous recombination deficiency (HRD) score, sensitivity to cisplatin (p = 0.014), paclitaxel (p = 0.016), gemcitabine (p = 0.017), and provided superior prognostic stratification when combined with TMB and HRD score (p < 0.001). CONCLUSION: This study establishes MLKL as a master regulator of anti-tumor immunity in OC, driving chemokine-mediated immune cell recruitment and TME reprogramming. The novel NecropImmScore is a multifaceted biomarker that effectively predicts prognosis, immunotherapy response, BRCA1 deficiency, and chemosensitivity, offering significant potential for guiding precision therapeutic strategies in OC.

Humans↗

PubMed2026

Recent Advances in Surveillance Strategies for Nasopharyngeal Carcinoma.

PURPOSE OF REVIEW: Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by a distinct geographical distribution. Effective surveillance is crucial for the early detection of recurrence or metastasis and for improving patient prognosis.This review systematically examines current NPC follow-up protocols and recent developments to inform individualized precision surveillance. RECENT FINDINGS: This review focuses on two main aspects. 1) We compare and analyze current major NPC follow-up guidelines, with key discussions covering follow-up frequency, imaging modalities (including magnetic resonance imaging [MRI] and positron emission tomography [PET]), plasma Epstein-Barr virus DNA (EBV-DNA) monitoring, and functional assessments. 2)We elaborate on the application prospects and research progress of genomics, radiomics, and artificial intelligence in NPC surveillance. Studies suggest that risk-stratified, individualized follow-up strategies, such as those based on conditional survival models, can enhance the cost-effectiveness of surveillance. Additionally, emerging technologies, including radiomics and artificial intelligence, show promise for improving recurrence risk assessment, prognostic stratification, and individualized surveillance in NPC. Concurrently, advances in genomics and radiomics offer new opportunities for predicting complications and guiding treatment adjustments. Future efforts should focus on integrating multidisciplinary expertise to develop dynamic monitoring systems that enable precise follow-up and ultimately improve patient survival outcomes.

Humans↗

PubMed2026

A spotlight on PTEN alterations in prostate cancer: A narrative review.

Among the molecular alterations observed in prostate cancer, PTEN loss represents a key event, functionally linked to aberrant activation of the PI3K/AKT/mTOR pathway. Loss of PTEN function contributes to disease progression, therapy resistance and poor prognosis. This review highlights the biological significance and the prognostic role of PTEN in prostate cancer, the biologically relevant crosstalk between the PI3K and androgen receptor pathways, and the implications of this interaction for tumour adaptation and treatment resistance. We also discuss current methodologies for PTEN assessment, including immunohistochemistry and genomic techniques, and provide an overview of clinical trials targeting the PI3K/AKT axis in prostate cancer. Understanding PTEN alterations is essential for improving prognostic stratification and guiding precision oncology approaches.

Humans↗

PubMed2026

The role of circulating tumor DNA (ctDNA) to detect minimal residual disease in locally advanced gastroesophageal carcinoma: the BUTTERFLY study.

BACKGROUND: Despite advances in perioperative and neoadjuvant strategies, patients with locally advanced gastroesophageal cancers remain at high risk of recurrence after curative intent treatment. No validated biomarkers are available to detect minimal residual disease (MRD) or to guide post-operative risk-adapted management. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool for disease monitoring; single-parameter or tumor-informed assays, however, may lack sensitivity in low-tumor burden settings. Multimodal, tumor-agnostic approaches may overcome these limitations. METHODS: The BUTTERFLY study is a prospective, multicenter observational study enrolling patients with stage II-III gastric, gastroesophageal junction, or esophageal cancer treated with perioperative chemotherapy or neoadjuvant chemoradiotherapy followed by surgery. It evaluates the diagnostic performance and prognostic value of an academic, tumor-agnostic, multimodal ctDNA assay for MRD detection and prognostic stratification. Serial plasma samples are collected from baseline through post-operative follow-up and at relapse. Cell-free DNA is analyzed using the Agnostic Liquid Biopsy Multimodal Advancement (ALMA) platform, integrating tumor fraction estimation, somatic copy number alterations, fragmentomic features, single-nucleotide variants, and whole-genome methylation profiling. Multimodal features are combined with clinical variables using machine learning-based models to enhance MRD detection and relapse risk stratification. The primary endpoint includes sensitivity and specificity of ALMA-defined ctDNA/MRD status at the 4-8 weeks after surgery landmark, whereas secondary endpoints assess diagnostic performance at other time points and associations between ctDNA status and dynamics with disease-free survival, overall survival, treatment response, and lead time to recurrence. FUTURE PERSPECTIVES: If validated, this tumor-agnostic, multimodal ctDNA approach may enable earlier molecular relapse detection and support personalized post-operative management strategies.

circulating tumor DNA (ctDNA)↗

PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗

PubMed2025

Clinicopathologic and Genomic Characterization of SMARCA4-Deficient Carcinoma of the Gallbladder.

As a key subunit of the SWItch/sucrose nonfermentable chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 nonsquamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and 4 large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, whereas a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%) but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892∗ and p.R979∗-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs 14 months) and overall survival (median, 11 vs 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWItch/sucrose nonfermentable complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.

Humans↗

PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗

PubMed2026

Epigenetic alterations induced by ionizing radiation: pathways to cancer and prognostic strategies.

PURPOSE: Ionizing radiation (IR) is widely used not only in cancer diagnosis and therapy, but its biological effects also extend beyond radiation-induced lethal lesions, e.g., specifically DNA double-strand breaks (DNA-DSBs). This review aims to summarize current evidence on IR-induced epigenetic alterations and to integrate mechanistic insights from radiation chemistry and radiation biology that link DNA damage to long-term epigenetic dysregulation. RESULTS: Experimental and clinical studies collectively show that IR induces persistent epigenetic reprogramming, including global and gene-specific DNA methylation changes, radiation-responsive histone modifications, chromatin remodeling, and dysregulation of non-coding RNAs. Aberrant RNA methylation, including modifications like N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanine (m7G), and N3-methylcytosine (m3C), is closely linked to tumorigenesis and progression. Due to its tumor-specific properties, RNA methylation markers, specifically m6A, m5C, m1A, m7G, and m3C, emerge as valuable markers in liquid biopsy. Radiation chemistry studies indicate that epigenetically modified bases, for example, m5C, are preferential targets of radiation-induced oxidative damage, thereby promoting mutational hotspots and genomic instability. By altering DNA repair, apoptosis, immune responses, and cellular differentiation, these epigenetic changes promote carcinogenesis, radioresistance, and tissue toxicity. CONCLUSION: IR-induced epigenetic alterations represent a critical interface between initial DNA damage and long-term biological outcomes. Improved understanding of radiation-associated epigenetic signatures may enhance risk assessment, inform prognostic stratification, and support the development of epigenetic-targeted strategies to optimize radiotherapy and reduce adverse effects.

Ionizing radiation↗

PubMed2026

Genomic profiling as an option for ovarian cancer diagnostics.

INTRODUCTION: Ovarian cancer (OC) is a highly heterogeneous and lethal gynecological malignancy. Precision oncology has shifted the management paradigm to comprehensive molecular profiling. Genomic-based diagnostics are now a clinical necessity for accurate prognostic stratification and the rational selection of targeted therapeutics, such as PARP and immune checkpoint inhibitors. AREAS COVERED: This review evaluates current literature regarding the distinct genomic landscapes defining OC histotypes to underlined the role of molecular profiling in the diagnostic field of OC. We discuss the practical implementation, technical aspect, and clinical validity of the main molecular diagnostic platforms, focusing on tissue-based Comprehensive Genomic Profiling (CGP) and Homologous Recombination Deficiency (HRD). Furthermore, we explore emerging translational data on liquid biopsy (LBx) applications. EXPERT OPINION: While current tissue-based methodologies provide critical baseline data, the OC diagnostic paradigm must pivot from static testing to proactive and longitudinal tracking. Integrating advanced LBx approaches enables a real-time monitoring of dynamic parameters as minimal residual disease (MRD) and acquired resistance. Integrating these dynamic blood-based assays with multi-omic profiling and artificial intelligence (AI)-driven tools allows a full understanding of the complex tumor behavior.

Humans↗

PubMed2026

Genetic regulation of CPEB3-mediated alternative polyadenylation associated with survival of patients with hepatocellular carcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a key post-transcriptional mechanism that regulates gene expression by modulating 3'UTR length, its dysregulation has been implicated in carcinogenesis. How genetic variants influence APA to affect hepatocellular carcinoma (HCC) prognosis remains unclear. METHODS: Prognosis-APA quantitative trait loci (apaQTL) were performed using genotype and APA profiling from TCGA data. A two-stage survival analysis in 848 Chinese and 369 TCGA LIHC patients and functional validation were used to identify prognostic apaQTL in HCC progression. RESULTS: A total of 2,025 and 817 significant APA events were identified in Chinese and TCGA cohort, respectively. Besides, 859 events were associated with poor prognosis in HCC and enriched in RNA splicing / metabolism pathways. We detected 32,034 significant apaQTLs, predominantly enriched in 3'UTRs and RBP-binding regions. CPEB3 was prioritized as a key APA regulator RBP; its low expression correlated with poor patient survival and promoted proliferation, migration, and invasion in HCC cells. Notably, a functional apaQTL variant rs2037547, located in GSK3B and mediated by CPEB3, demonstrated a poor survival of HCC patients in both cohort (pooled HR=1.29, p=0.016). Mechanistically, rs2037547 promoted aberrant APA at proximal poly(A) sites of GSK3B through CPEB3, leading to increased expression of short 3'UTR isoform. This regulatory alteration enhanced HCC cell proliferation, invasion, and migration, and contributed to HCC progression. CONCLUSION: These findings elucidated the distinct role of apaQTL-mediated APA dysregulation in HCC prognosis, providing insights for prognostic stratification and potential targets for personalized therapy in HCC.

RNA-binding proteins↗

PubMed2026

Prognostic value of lymphopenia in early breast cancer: learnings from the prospective CANTO cohort.

BACKGROUND: Lymphopenia has been associated with poor outcomes in metastatic breast cancer (BC), but its prognostic relevance in early-stage disease remains unclear. This study aimed to evaluate the prognostic value of baseline lymphopenia in patients with non-metastatic BC using data from the prospective French CANTO cohort (NCT01993498). METHODS: 10,854 patients with baseline absolute lymphocyte count (ALC) were analysed. Lymphopenia was defined as ALC < 1.0 × 10⁹ cells/L, measured before any cancer treatment. Relapse-free survival (RFS), overall survival (OS), and treatment-related toxicities were assessed using Kaplan-Meier estimates, piecewise-Cox regression models, and cause-specific hazard analyses considering pre-specified time periods. RESULTS: Baseline lymphopenia was observed in 342 patients (3.1%). It was associated with ECOG performance status > 0, hypoalbuminemia, and prior neoplasia. Lymphopenia correlated with inferior 5-year RFS (89.1% vs. 92.9%) and OS (92.5% vs. 96.4%). In multivariable analyses, lymphopenia was associated with increased risk of early relapse during the first 24 months (HR = 2.11; 95%CI: 1.28-3.48; p = 0.003), but not beyond, and no independent prognostic impact on OS was observed. No significant differences were found in surgical complications or chemotherapy dose intensity, though granulocyte colony-stimulating factor use was higher among lymphopenic patients. CONCLUSION: Baseline lymphopenia is uncommon in early BC but may serve as a marker of early relapse risk. Although it does not independently predict long-term survival, its presence could reflect underlying tumour aggressiveness or patient frailty. These findings support further investigation of lymphocyte subpopulations to refine prognostic stratification in early BC. TRIAL REGISTRATION: Approved by French ethics committee in 2011 (ID-RCB:2011-A01095- 36,11-039 /NCT01993498 [20FEB2012]).

Adult↗

PubMed1975

Pyritinol hydrochloride and cognitive functions: influence on children in slow learner classes.

Pyritinol-HCl was tested for its impact on the cognitive functions of children with learning disabilities. This study is a contribution to scientific discussion on the complicated methodologic problems in evaluating the clinical efficacy of psychopharmacologic agents. Sixty-seven pupils of slow learner classes between the ages of 11 and 16 years were treated for 6 months with 300 mg pyritinol-HCl/24 hr or placebo under strict double-blind conditions. Drug intake was stimulated and controlled by means of intense psychosocial interaction with the mothers of the subjects. The dependence variables used to test medication effects were 22 parameters of cognitive performance measured in psychologic tests for perceptual and intellectual functions which were administered immediately before and after the medication phase. First the gainscores before and after treatment with pyritinol or placebo within the 22 cognitive parameters were statistically compared. In addition, an analysis of covariance on the corrected results of the second test (treating the results of first testing as covariates) and a two group discriminant analysis for overall differences were performed. None of the 22 parameters showed statistically significant treatment effects with respect to average performance (t (pyritinol - placebo) = 1.96 to 1.31), neither could the two groups be separated by discriminant analysis (Hotelling's T2 = 35.4, df - 22 and 43, P = 0.465). With respect to a variability of gainscores, however, in four parameters there was a significantly higher variance in the pyritinol group (F = 1.85-2.33, P less than 0.05, less than 0.02, respectively). This fact may signify that pyritinol-HCl had different effects on different subjects. By means of prognostic stratification we therefore attempted to define objective criteria for a selection of subjects with probable positive treatment effects. None of the 15 tested criteria, such as body weight, age, perceptual handicaps, or reduced short term memory, IQ range, proved, however, to be critical for a prognosis of pyritinol effects within the present test population.

Adolescent↗

PubMed2026

Pathomics-based machine learning models for predicting METTL5 expression and prognosis in lung adenocarcinoma.

BACKGROUND: METTL5, an N6-methyladenosine (m6A) RNA methyltransferase, has been implicated in tumor progression, but its prognostic value and non-invasive prediction in lung adenocarcinoma (LUAD) remain unclear. This study aimed to develop a pathomics-based machine learning model to predict METTL5 expression from histopathological images and evaluate its prognostic significance in LUAD. METHODS: A total of 327 LUAD patients from The Cancer Genome Atlas (TCGA) with matched hematoxylin and eosin (H&E) slides, transcriptomic, and clinical data were included and randomly divided into training and validation sets (7:3). Quantitative histopathological features were extracted using PyRadiomics. Feature selection was performed via maximum relevance minimum redundancy (mRMR) and recursive feature elimination (RFE), followed by construction of a Gradient Boosting Machine (GBM) model. A pathomics score (PS) was generated to assess prognostic relevance. Survival analyses, gene set variation analysis (GSVA), tumor mutational burden (TMB), immune infiltration analysis, and in vitro functional assays were conducted. RESULTS: METTL5 overexpression was independently associated with poor overall survival [hazard ratio (HR) =1.637, P=0.007]. The model achieved good predictive performance [area under the curve (AUC) =0.847 in the training set and 0.752 in the validation set]. High PS was significantly associated with worse survival and remained an independent prognostic factor (HR =1.563, P=0.03). Elevated PS correlated with altered metabolic pathways, increased TMB, and immune microenvironment changes. METTL5 knockdown reduced proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in A549 cells. CONCLUSIONS: The pathomics-based model accurately predicts METTL5 expression and provides prognostic stratification in LUAD, supporting its potential as a practical imaging-derived biomarker.

Methyltransferase-like 5↗

PubMed2026

Methylation-Associated Differentiation Features Define Biological and Prognostic Heterogeneity in CMS4 Colorectal Cancer.

Consensus molecular subtype 4 (CMS4) colorectal cancer (CRC) is associated with an aggressive clinical course and poor survival, yet the biological basis of heterogeneity within this subtype remains incompletely understood. DNA methylation is an epigenetic mechanism involved in transcriptional regulation, cellular differentiation, and colorectal tumorigenesis. Here, we integrated single-cell RNA sequencing (scRNA-seq), bulk data, and promoter DNA methylation data to characterize CMS4-associated cancer cell states and methylation-related features. Using the scAB algorithm, we integrated scRNA-seq with bulk CMS4 data and identified CMS4-related cells distributed across multiple patients. Single-cell analyses of cell-cell communication and transcriptional regulation revealed a CMS4-related cancer cell population characterized by macrophage migration inhibitory factor (MIF)-centered intercellular communication, enhanced caudal type homeobox 1 (CDX1) and Kruppel-like factor 5 (KLF5) regulon activity, and gene modules enriched in differentiation-related pathways. CytoTRACE analysis further stratified CMS4 cancer cells into poorly and well-differentiated states, yielding 802 differentially expressed genes (DEGs). Linking these differentiation-associated DEGs with bulk expression and promoter methylation data identified 218 methylation-associated DEGs showing significant inverse methylation expression correlations, suggesting a link between differentiation-related heterogeneity and promoter methylation. Univariable Cox regression followed by LASSO regression further prioritized eight genes for construction of the methylation and differentiation-related prognostic model (MeDiff-PM). MeDiff-PM consistently stratified overall survival in the TCGA CMS4 cohort and two independent validation cohorts, with cutoff-independent continuous Cox analyses further supporting its prognostic association across cohorts. And MeDiff-PM remained prognostically significant after adjustment for available clinical variables. High MeDiff-PM risk scores were associated with activation of P53, WNT, and ubiquitin-mediated proteolysis pathways and with consistent predicted drug response differences for compounds across three CMS4 cohorts. While individual in silico knockout analysis suggested links between MeDiff-PM genes and metallothionein-related and immune-associated transcriptional responses. Collectively, these findings indicate that methylation-associated differentiation features represent a molecular dimension of intra-CMS4 heterogeneity and provide a biologically informed framework for prognostic stratification within CMS4 CRC.

Humans↗

PubMed1977

[Treatment of acute leukemia].

Evaluations of 650 patients with acute lymphoblastic leukemias (A.L.L.) and of 596 patients with acute granulocytic leukemias (A.G.L.) ara analyzed. The patients were treated in the department of Professeur Jean Bernard at Saint-Louis Hospital between 1964 and 1976. In A.L.L., prognosis is influenced primarely by age, being worse in infants less than 1 year old and in adults: it is also influenced by the blastic load and by other parameters such as cytology and immunological markers which could not be studied in all patients. The correlation between high blastic load and the T lymphoblasts variety is noteworthy. Random studies are still necessary to find out the best drug combinations and the optimal duration of treatment, but the necessity for meningeal prophylaxis, reinduction treatments and of L-A sparaginase consolidation is no longer discussed. Prognostic stratification is useful for therapeutical evaluation and should load to therapeutical modulation. In acute granulocytic leukemias, age is also a significant parameter and remission rate is lower for patients over 50 years of age. Cytology and cytochemistry allow to recognize acute promyelocytic leukemias and acute monoblastic leukemias which bear specific initial risks (D.I.C. for A.P.L., renal failure for acute monoblastic leukemia) but which are highly sensitive to Daunorubicin and Rubidazone respectively. In A.M.L. remission duration is not influenced by age and seems to be improved by intermittent treatment. The role of immunotherapy is still under study.

Acute Disease↗

PubMed2026

Lactylation-related immune-metabolic dysregulation defines prognostic and therapeutic stratification in lung adenocarcinoma.

BACKGROUND: Lactylation links lactate metabolism with inflammatory signaling and immune regulation in tumors. However, its cellular distribution and translational value in lung adenocarcinoma (LUAD) remain unclear. METHODS: Single-cell RNA-sequencing datasets GSE189357 and GSE171145 were integrated to characterize lactylation-related activity, intercellular communication, and malignant epithelial cell states in LUAD. Single-cell-derived lactylation-related differentially expressed genes were mapped to TCGA-LUAD and multiple GEO cohorts. Univariate Cox regression and machine learning algorithms were used to construct a lactylation-related prognostic signature (LRPS). The associations of LRPS with prognosis, immunotherapy response, drug sensitivity, genomic alterations, immune infiltration, and inflammation- and metabolism-related pathways were evaluated. KRT7 was further validated using virtual knockout analysis, spatial transcriptomics, and in vitro and in vivo experiments. RESULTS: lactylation-related transcriptional activity showed heterogeneous distribution across LUAD cell populations and was associated with altered cell-cell communication. In malignant epithelial cells, LRTS-high and LRTS-low states exhibited distinct metabolic, inflammatory, and tumor-related pathway activities. LRPS showed stable prognostic performance in TCGA-LUAD and multiple GEO cohorts and remained an independent prognostic factor. Low LRPS was associated with greater potential benefit from immunotherapy, whereas different LRPS groups displayed distinct drug sensitivity, genomic alteration, and immune microenvironment patterns. KRT7 was highly expressed in LUAD and associated with poor prognosis. KRT7 knockdown suppressed LUAD cell proliferation, migration, invasion, colony formation, and tumor growth in vivo. CONCLUSIONS: This study identifies lactylation-related immune-metabolic dysregulation as a clinically relevant feature of LUAD and develops a single-cell-guided LRPS for prognosis and therapeutic stratification. KRT7 emerged as an LRPS-related functional candidate with experimentally supported roles in malignant LUAD phenotypes.

Immunotherapy↗

PubMed2026

Development and internal validation of a six-gene prognostic model based on galactose metabolism for overall survival in lung adenocarcinoma.

BACKGROUND: Lung cancer remains a leading cause of cancer incidence and mortality globally. Metabolic reprogramming promotes tumor progression and shapes an immunosuppressive tumor microenvironment. Galactose metabolism is involved in multiple malignancies, but its prognostic value in lung adenocarcinoma (LUAD) remains unclear. This study aimed to develop and internally validate a galactose metabolism-related multigene prognostic model for LUAD. METHODS: A retrospective prognostic model development and internal validation study was performed using RNA sequencing (RNA-seq) and clinical data from 585 LUAD patients in The Cancer Genome Atlas (TCGA). Differential expression, functional enrichment, univariate and multivariate Cox regression were applied to construct a prognostic gene signature. Internal validation was performed using bootstrap resampling. Model performance was evaluated by time-dependent receiver operating characteristic (ROC), C-index, calibration, and Kaplan-Meier analysis. Associations between the model and immune infiltration, immunotherapy responsiveness, and tumor stemness were also analyzed. RESULTS: A six-gene prognostic model (GALT, GANC, PGM1, GALM, B4GALT1, PGM2) was developed. The model showed good discrimination with 1-, 3-, and 5-year area under the curve (AUC) values of 0.719, 0.693, and 0.684, respectively. The low-risk group exhibited significantly longer survival, increased antitumor immune infiltration (CD8+ T cells, M1 macrophages, activated CD4+ memory T cells), higher expression of T cell proliferation-related genes, lower immune checkpoint expression, better predicted immunotherapy response, and lower tumor stemness compared with the high-risk group. CONCLUSIONS: We developed and internally validated a six-gene prognostic model for LUAD based on galactose metabolism. The model shows moderate prognostic performance and is associated with antitumor immunity and tumor stemness. It may be used for prognostic risk stratification and to guide personalized immunotherapy in LUAD.

Galactose metabolism↗

PubMed2026

Somatic-only SDHD variant with tumor-specific loss of heterozygosity in metastatic carotid body tumor: a case report with review of literature.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

Carotid body tumor↗