We reported a rare case in which acute pulmonary thromboembolism (APTE) was the initial clinical manifestation of multiple endocrine neoplasia type 1 (MEN1). A 44-year-old male presented with chest tightness and dyspnea, and was subsequently diagnosed with acute pulmonary embolism on computed tomography pulmonary angiography (CTPA). Medical history revealed a long-standing pituitary adenoma. During the etiologic evaluation, the patient was found to have a hypercalcemic crisis, hyperparathyroidism, and a pancreatic neuroendocrine tumor. Genetic testing confirmed a pathogenic MEN1 mutation (c.1664G>A), which established the diagnosis of MEN1. Along with regular anticoagulation therapy, the patient underwent multidisciplinary evaluation. Oral bromocriptine was continued for the pituitary adenoma, and parathyroidectomy was performed after correction of the hypercalcemic crisis. The pancreatic neuroendocrine tumor is being closely monitored, with elective surgery or somatostatin analogue therapy planned as appropriate to eliminate the underlying cause of pulmonary embolism. Through a brief literature review, we explored how MEN1 may contribute to a hypercoagulable state. The case highlighted the importance of endocrine and genetic screening in patients with unexplained pulmonary embolism.

The recognition of mislocalized DNA and RNA by cGAS-STING, RIG-I/MDA5, the OAS-RNase L axis, and endosomal TLR3/7/8 has emerged as a unifying paradigm linking cancer, autoinflammation, and antiviral immunity. Counterbalancing these sensors is a structurally heterogeneous nuclease repertoire whose distinct substrate specificities, subcellular compartments and pH optima constrain ligand availability in space and time. Disruption of this equilibrium drives disease through two mirror-image mechanisms. In cancer, DNASE1 is inactivated by tumor-derived G-actin, DNASE1L3 is transcriptionally silenced in hepatocellular, colorectal and lung adenocarcinomas, and DNASE2 is upregulated in immunologically "cold" tumors, together permitting neutrophil-extracellular-trap-mediated exclusion of cytotoxic T cells and suppression of cytosolic DNA sensing. In autoimmunity, biallelic loss of DNASE1L3, TREX1, RNase H2, ADAR1 or RNase T2 produces the interferonopathies of systemic lupus and Aicardi-Goutières syndrome. Diagnostically, nuclease-specific cleavage signatures have matured into cell-free DNA fragmentomics validated across 13 cancer types in a 3,021-patient cohort; therapeutically, the field now spans engineered actin-resistant DNASE1/DNASE1L3 biologics, selective TREX1 and ADAR1 inhibitors entering first-in-human evaluation, STING-activating nanomedicines, RNase Fc-fusions such as RSLV-132 in phase 2a lupus, and JAK1/2 inhibition as standard of care in Aicardi-Goutières syndrome. We synthesize this evidence as a two-fate problem: whether an endogenous nucleic acid accumulates at these sensors to drive autoinflammation or is cleared by nucleases before detection is set by the balance between sensor engagement and clearance capacity. The therapeutic corollary acts on the ligand rather than the enzyme, restoring ligand availability where disease is malignant and restoring clearance where disease is self-directed.

The low response rate to immunotherapy in patients with lung adenocarcinoma is primarily due to tumor immune evasion. The tumor immunosuppressive microenvironment orchestrates this evasion, yet the underlying mechanisms remain elusive. Here we identify non-specific cytotoxic cell receptor protein 1 (NCCRP1) as a critical and previously uncharacterized regulator of this process.

Cancer is the most common cause of disease-related mortality in children, highlighting the urgent need for improved care in this population. It is estimated that >15% of children diagnosed with cancer harbour a germline pathogenic variant in a cancer predisposition gene which confers an increased risk to develop cancer. There are over 100 genes associated with cancer predisposition syndromes (CPSs) and greater availability and acceptability of genetic testing in the last decade has facilitated their recognition in childhood. However, individually, each of these CPSs is rare, impeding robust research and advancement of clinical care. Once a specific CPS is diagnosed, current recommendations for clinical care are based primarily on expert consensus with a 'one size fits all' approach to management. Detailed knowledge of genotype-phenotype associations and the impact of genetic modifiers is lacking, and due to strong ascertainment bias of children already diagnosed with cancer predominantly being tested for a CPS, the true cancer risk is likely overestimated.

Chromosome 4q12 rearrangements are recurrent in hematologic malignancies, most frequently involving PDGFRA. Fluorescence in situ hybridization (FISH) is routinely used for detecting 4q12 rearrangements. This study aimed to clarify 4q12 rearrangements misdiagnosed by FISH and explore the transcriptomic profile of acute myeloid leukemia (AML) with CHIC2 rearrangements.

In IDH-wildtype glioblastoma, prognosis is conventionally interpreted through established molecular, clinical, surgical and anatomical factors, whereas the prognostic meaning of the mode of onset is less defined. We hypothesized that neurocognitive/neuropsychiatric presentation identifies an adverse clinical phenotype, potentially reflecting diagnostic delay and/or early disruption of distributed cerebral networks.

Corticotroph pituitary neuroendocrine tumours (PitNETs)/adenomas are heterogeneous sellar neoplasms. Currently established histopathological classification approaches are often considered limited in fully capturing the clinical and biological complexity of these tumours. Thus far, a molecular-based classification has not been established in corticotroph PitNETs. We compile molecular data of 270 corticotroph PitNETs (111 internal, 159 external), encompassing epigenome, transcriptome, and proteome profiles. Comprehensive integrative analyses are performed to identify, validate and characterise definitive molecular subgroups. Corticotroph PitNETs separate into four robust and clinicopathologically distinct molecular subgroups, which are broadly distinguishable by microscopy using SSTR1, GATA3 and SSTR5 immunohistochemistry. An integrated stratification model incorporating these molecular subgroups demonstrates significant prognostic utility. Our findings support the establishment of a refined molecular-based corticotroph PitNET classification, the full clinical value of which will require validation in prospective studies. To facilitate future research, we provide an easy-to-use epigenomic classifier for corticotroph PitNETs.

Cancer and inflammatory diseases are critically influenced by dynamic interactions between pathological tissues and the host immune system. The precise migration of immune cells into the local microenvironments of tumors or inflammation is a fundamental prerequisite for them to exert their functions. Immune reservoirs, including tertiary lymphoid structures, secondary lymphoid structures, bone marrow and the intestinal tract, serve as critical mobilization hubs for diverse lymphoid and myeloid populations to infiltrate tumors or inflamed sites. The directional migration of immune cells is orchestrated through complex regulatory networks involving chemokine or cytokine-receptor pairs, adhesion molecule interactions, extracellular vesicle signaling, metabolic reprogramming and microbiota modulation. In both tumors and inflammation, immune cell trafficking shapes the local immune landscape, contributing to either immune protection or pathological progression. Contemporary therapeutic strategies targeting immune cell migration encompass the following axes: precision modulation of chemokine or cytokine networks, architectural reprogramming of lymphatic structures or extracellular matrix, dietary intervention and strategic manipulation of microbiome. Nevertheless, clinical translation remains hindered by microenvironmental heterogeneity, suboptimal migratory efficiency, and technical limitations in longitudinal tracking of cellular dynamics. This review integrates recent findings from oncology and inflammatory diseases to explore the origins, phenotypes and trafficking mechanisms of migratory immune cells, highlighting how advances in understanding immune migration across cancer and inflammation can inform therapeutic innovation and precision immunomodulation.

This systematic review with functional meta-synthesis and exploratory meta-analysis evaluated the clinical utility of molecular testing in ameloblastoma, focusing on diagnostic, genotype-phenotype, prognostic, liquid-biopsy, and precision-therapy implications.

Cancer type classification is challenging due to tumor heterogeneity and undefined tissue of origin (TOO), particularly in cancers of unknown primary (CUP) and multiple primary cancers (MPC). Accurate TOO identification is critical for guiding treatment and prognosis. We developed a stacked ensemble machine learning classifier that integrates 11 multidimensional cfDNA features spanning genomic, fragmentomic, methylation/repeat, and microbial signals. Base models were constructed using five algorithms, including Deep Learning, Distributed Random Forest, Gradient Boosting Machine, Generalized Linear Model, and XGBoost, within a five-fold cross-validation framework, and their predictions were aggregated into a final ensemble optimized for top-1 accuracy. The classifier achieved robust performance across 17 cancer types, with top-1 and top-2 accuracies of 78% and 89% in the training cohort (n = 1,814), and 80% and 90% in an independent validation cohort (n = 1,221). Notably, predictive performance was retained in samples with low tumor fraction (71% top-1, 85% top-2). Sensitivity varied across tumor types, with the highest performance observed in head and neck and colorectal cancers. Among CUP cases, 11 of 15 (73.3%) predictions matched clinically inferred primary sites based on multimodal diagnostics. Feature importance analysis identified nucleosome positioning, fragment size distribution, and repeat elements as key contributors to model performance. Collectively, this cfDNA-based classifier provides a robust and non-invasive approach for accurate cancer type identification and has the potential to support clinical decision-making.

IDH1/2 mutations are prevalent genetic alterations in gliomas that facilitate metabolic reprogramming and epigenetic modifications, which are essential for glioma progression. However, their exact contributions to tumorigenesis remain to be fully elucidated. Cellular senescence is a known precursor to tumorigenesis, and multiple oncogenes can initiate this senescence program. Our study demonstrated that the IDH1 mutation inhibits the proliferation of astrocytes and glioma cells, inducing cellular senescence through mechanisms involving DNA damage and increased production of reactive oxygen species (ROS). Notably, these effects were mitigated by the addition of exogenous glutamine. Within cells, glutamine synthetase (GS) serves as the sole enzyme responsible for glutamine synthesis. We found that D-2-hydroxyglutarate (D-2HG), an oncometabolite generated by mutant IDH enzymes, directly inhibits GS activity by binding to the glutamate site, substantially reducing endogenous glutamine production and exacerbating senescence in IDH1-mutant glioma cells. Additionally, in human glioma samples, a greater prevalence of GS-positive astrocytes was detected in IDH-mutant gliomas, likely providing adequate glutamine to sustain growth and mitigate senescence in these cells. Our findings suggest that D-2HG promotes senescence in IDH1-mutant glioma cells by inhibiting GS activity and that disrupting glutamine transport between astrocytes and glioma cells may constitute a promising therapeutic strategy for targeting IDH-mutant gliomas.

MECOM rearrangements (MECOM-r) are high-risk events in myeloid neoplasms often cryptic or incompletely characterized by conventional karyotype analysis. We used optical genome mapping (OGM) to define the frequency and spectrum of MECOM-r in an unselected, consecutively collected cohort of individuals with high-grade myeloid neoplasms (HGMNs) and compared these findings with standard cytogenetic approaches.

KRAS mutations are common in colorectal cancer, but the impact of KRAS mutation subtypes on treatment response remains poorly understood. This research aimed to investigate whether different KRAS mutations influence pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC).

Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity. This study developed a robust prognostic signature integrating ferroptosis- and lipid metabolism-related genes to investigate the role of CRY2 in CRC progression.

IntroductionSOX2, a key pluripotency gene, plays a central role in breast cancer stem cell (BCSC) biology, driving tumor aggressiveness. Although SOX2 dysregulation has been widely studied across various cancers, its specific regulatory mechanisms in breast cancer (BC) remain incompletely elucidated. This study examined the regulatory axis of the SOX2 gene and associated molecular mechanisms underlying BCSC maintenance and prognosis.MethodsThis retrospective cross-sectional study analyzed breast tumor tissues and adjacent normal controls collected consecutively from two tertiary hospitals. SOX2 promoter methylation was assessed using methylation-Specific PCR, and expression of SOX2, DNMT3b, TET3, miR-200b-3p, and TGFβ1 was quantified by qPCR.ResultsAberrant methylation of the SOX2 promoter, linked to increased expression, was observed in the BC cohort. Notably, several samples exhibited a poised promoter state, reflecting an epigenetic configuration associated with stemness. Upregulation of DNMT3b in miR-200b-reduced cells was significantly associated with SOX2 promoter methylation, suggesting a feedback loop modulating methylation dynamics. Additionally, a positive association between deregulated TET3 and TGFβ1 highlights a positive feedback loop in the dynamic tumor microenvironment. SOX2 methylation emerged as a strong prognostic marker, characterized by a low hazard ratio and high diagnostic sensitivity. Its combination with DNMT3b improved specificity (SE = 90%, SP = 79%). Reduced TET3 and miR200b expression correlated with poor outcomes, and their integration with SOX2 formed a tri-gene signature that enhanced patient stratification. Correlation analyses revealed coordinated expression among SOX2, TET3, and TGFβ1, supporting their role in methylome regulation.ConclusionThe findings underscore the clinical significance of this axis and its embedded feedback circuits in shaping BC progression and therapeutic response.

IntroductionThe Cancer Genome Atlas (TCGA) data has been extensively used for differentially expressed genes (DEGs) discovery and validation in high-grade serous ovarian cancer (HGSOC), however platinum-sensitivity biomarkers have not yet reached clinical application. We aimed to propose a robust analytical framework for TCGA platinum sensitivity studies and systematically demonstrate how patient characteristics influence DEG analyses between platinum-sensitive and resistant groups, while also considering experimental platforms and analysis pipelines, as their impact is recognized but not comprehensively evaluated.MethodsThis retrospective TCGA cohort study used publicly available microarray and RNA-seq gene expression data. TCGA-derived datasets were identified through a literature review, including only studies enabling unambiguous patient identification. Three TCGA-based cohorts were assembled-two directly from published studies and one curated through own selection-differing in patient numbers (230, 201 and 142 patients, respectively) and stage distribution. Data were analyzed using DESeq2, edgeR, limma-voom, and Wilcoxon rank-sum test to compare the impact of patient selection and pipeline choice on DEGs outcome. Genes with an adjusted p-value < 0.05 and an |log2 fold change| > 2 were considered differentially expressed.ResultsThe three cohorts showed partial overlap of DEGs across platforms and pipelines. Both patient selection and analytical workflow influenced which genes were identified, highlighting findings variability even when using the same TCGA dataset. We establish a robust analytical framework for TCGA HGSOC biomarker studies, including the provision of patient barcodes and openly shared workflows that enable straightforward replication of our analyses from data download to DEG analysis.ConclusionsReproducibility of TCGA studies is limited by variability in patient selection, platinum sensitivity definitions, data sources, and analysis pipelines. We addressed these factors by providing a robust framework that can serve as a template for data analysis and transparent reporting when identifying and validating predictive signatures of platinum sensitivity in HGSOC patients.

The mutant isocitrate dehydrogenase 1/2 inhibitor (mIDHi) vorasidenib was recently incorporated into clinical treatment guidelines for IDH-mutant gliomas, although its impact on chemoradiation is unclear. Specifically, it is unknown whether upfront mIDHi exposure alters subsequent chemoradiation efficacy. Addressing this critical question has been challenging because of limited clinical data and a paucity of mIDHi-responsive preclinical glioma models. We first established that a genetic mouse model of IDH-mutant astrocytoma developed by our group was responsive to vorasidenib monotherapy. We then used this mouse to address whether mIDHi alters the response to chemoradiation after progression on mIDHi. Mice that received upfront vorasidenib followed by chemoradiation at progression had improved survival compared with control mice receiving vehicle followed by chemoradiation. We then compiled real-world data and early outcomes from 29 patients who were among the first to receive mIDHi followed by radiation with or without chemotherapy. Our study directly addresses uncertainty surrounding therapy sequencing that has emerged after introduction of vorasidenib as a first-line treatment for IDH-mutant glioma. Our empirical preclinical data demonstrate that prior mIDHi treatment enhances chemoradiation sensitivity of IDH-mutant glioma.

Background and objectives Drug resistance and off-target toxicity remain major challenges in cancer therapy. Due to rapid proliferating nature of malignant cells, microtubule-targeting agents (MTAs) are widely used for chemotherapy, although their clinical efficacy is often limited by drug resistance and adverse effects. Objective of this study was to identify a novel therapeutic agent capable of selectively targeting microtubules in cancer cells while minimising toxicity to normal cells. Present study evaluates the chemotherapeutic potential of Vibrio cholerae haemagglutinin protease (HAP) as a novel MTA for gastric and colon cancers by investigating its role in microtubule degradation and apoptosis induction. Methods Effects of HAP were evaluated in human gastric and colon cancer cells using cellular and molecular assays. Time-dependent live-cell imaging was employed to assess HAP internalisation and co-localisation within intracellular organelles. Explant cultures derived from human tumour tissues were used to replicate the tumour microenvironment and validate therapeutic responses. Results HAP treatment activated protease-activated receptor 1 (PAR1), which is overexpressed in malignant cells, leading to an increase in intracellular reactive oxygen species (ROS) and facilitated HAP internalisation. Once internalised, HAP induced microtubule degradation through four mechanisms: ROS-mediated degradation of MAP2 and tau, destabilising microtubule network; enhancing tubulin-PARKIN interaction, enabling microtubule ubiquitination; and activation of lysosomal and proteasomal pathways to degrade microtubules. Collectively these events triggered apoptotic cascades in cancer cells and explant tissues, while normal healthy cells remained unaffected. Interpretation and conclusions HAP demonstrates strong potential as a selective anticancer therapeutic by inducing microtubule degradation and apoptosis without compromising viability of normal cells.

Background and objectives Despite substantial research on immunotherapy, its efficacy and safety in treating advanced non-small cell lung cancer (NSCLC) without identifiable driver mutations remain unclear. The objective of this review was to examine the efficacy and safety of immunotherapy, used as monotherapy or alongside chemotherapy, vs. chemotherapy alone in patients with advanced driver mutation-negative NSCLC. Methods A comprehensive literature search of PubMed, Embase, Scopus, and CENTRAL databases was conducted until December 2024. The protocol was registered in PROSPERO (CRD42024585050). Randomised controlled trials (RCTs) evaluating the efficacy and safety of immunotherapy, either as monotherapy or in combination with chemotherapy, compared with chemotherapy alone, were included. A random-effects meta-analysis was performed. Risk of bias was assessed using the Cochrane RoB 2 tool, and the certainty of evidence was evaluated using the GRADE framework. Results Twenty-three RCTs (n=14605 participants) were included. Immunotherapy (± chemotherapy) significantly improved overall survival [22 RCTs; 14,375 participants, hazard ratio (HR): 0.77; 95% Confidence interval (CI): 0.72-0.83] and progression-free survival (22 RCTs; 14,003 participants, HR: 0.67; 95% CI: 0.58-0.76) compared with chemotherapy alone. The objective response rate was also higher with immunotherapy (23 RCTs; 12,967 participants, RR 1.38, 95% CI: 1.24-1.54). No statistically significant differences were observed between the groups in terms of overall adverse event rates. Interpretation and conclusions Immunotherapy, whether administered alone or in combination with chemotherapy, provides significant survival benefits in patients with advanced driver mutation-negative NSCLC.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer (GC) with characteristic clinicopathological and molecular features. EBVaGC exhibits a more extensive lymphocyte infiltration than EBV-negative counterparts, and expresses a range of EBV encoded viral products. However, the interactions between EBV-positive GC cells and immune cells within the tumor microenvironment are not well understood. Herein we found that EBV downregulates GSDMB, an executive molecule of pyroptosis, in EBV-positive GC cells and enables these cells to escape GSDMB cleavage-induced pyroptosis by NK cells and cytotoxic T lymphocytes. The pyroptosis is mainly executed through the full length GSDMB isoform (GSDMBiso3) in GC cells. We further found EBV-encoded miR-BART12-3p targets the GSDMB 3'-UTR to downregulate its expression in GC cells. Inhibition of miR-BART12-3p enhances antitumor efficacy of NK cells against EBV-positive GC cells by triggering GSDMB cleavage-induced pyroptosis, as demonstrated both in vitro and in vivo. In conclusion, this study elucidates the molecular mechanism by which EBV downregulates GSDMB to evade immune cell killing, and provides a rationale for combining killer lymphocyte-based therapies with a miR-BART12-3p inhibitor for the treatment of EBVaGC.