Identifying upstream molecular regulators linking tumor proliferation with immune-related alterations remains an important challenge in cancer therapy. NTMT1 (METTL11A), a protein N-terminal methyltransferase, has been implicated in tumorigenesis; however, its role in coordinating tumor-immune interaction is poorly understood.

To investigate the association between polycystic ovary syndrome (PCOS) and miscarriage risk and to explore the potential causal effect.

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant genetic disorder caused by activating germline mutations in the RET proto-oncogene, typically arising during embryogenesis. The syndrome is characterized by the coexistence of medullary thyroid carcinoma, pheochromocytoma, gastrointestinal ganglioneuromas, and diffuse mucosal neuromas, the latter representing a pathognomonic clinical feature. In pediatric patients, mucosal neuromas most commonly involve the oral cavity, whereas laryngeal or other airway involvement is exceedingly rare and often underrecognized.

Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) harboring TP53 mutations are defined by extreme genomic instability, complex karyotypes (CK), and poor prognosis. While large-scale chromosomal imbalances are common in CK-MDS/AML, the synergy between focal amplifications of signaling drivers and the disruption of transcriptional regulators remains poorly elucidated.

MET exon 14 skipping is an actionable oncogenic driver in non-small cell lung carcinoma (NSCLC); however, noncanonical splice-region variants are frequently classified as variants of unknown significance (VUS), which may result in missed therapeutic opportunities and highlight limitations in current DNA next-generation sequencing (NGS) reporting criteria. We report a patient with pulmonary sarcomatoid carcinoma harboring a noncanonical MET splice donor-proximal indel (c.3022_3028 + 13delinsA), initially interpreted as a VUS, who achieved a rapid and durable response to capmatinib. Subsequent RNA sequencing and droplet digital PCR (ddPCR) confirmed MET exon 14 skipping, supporting the value of orthogonal transcript-level validation for exon-adjacent variants.

Programmed cell death represents a fundamental process in maintaining organismal homeostasis and responding to pathological challenges. The traditional view considered apoptosis, pyroptosis, and necroptosis as independent death pathways. However, recent research has revealed extensive interactions and synergies among these pathways, leading to the emergence of a novel form of cell death termed "PANoptosis." Triggered by specific stimuli, PANoptosis involves the assembly of a large multiprotein complex called the PANoptosome. This complex integrates key molecules and morphological features from apoptosis, pyroptosis, and necroptosis, culminating in a highly efficient and coordinated inflammatory cell death program. Concurrently, non-coding RNAs, as crucial regulators of gene expression, participate extensively in the regulation of cellular fate at the post-transcriptional and epigenetic levels. This review systematically summarizes the molecular mechanisms by which non-coding RNAs regulate the core components of PANoptosis and its upstream signaling pathways. It further delves into the pathological role of this regulatory axis in infectious diseases, cancer, neurodegenerative disorders, and autoimmune diseases. Additionally, the article explores the diagnostic potential of non-coding RNA-based approaches and therapeutic strategies targeting the non-coding RNA-PANoptosis axis, while also addressing current challenges related to mechanistic complexity, delivery technologies, and safety assessment. This review aims to establish a systematic framework for the "non-coding RNA-PANoptosis-disease" regulatory axis, providing a theoretical basis for understanding the interactive logic of cell death networks and for developing precise interventions for related diseases.

The 2021 WHO classification permits diagnosis of glioblastoma in IDH-wildtype diffuse astrocytic tumors with TERT promoter mutation, EGFR amplification, or chromosome 7 gain/10 loss, even without necrosis or microvascular proliferation. The clinical behavior of these molecularly defined glioblastomas (molGBM) remains uncertain.

LIMD1, a tumour suppressor located at chromosome 3p21.3, is frequently lost in non-small-cell lung cancer, yet its role in tumour-immune interactions remains unclear. Here, we show LIMD1 loss increases PD-L1 protein abundance across multiple lung cancer models and primary airway epithelial cells. Mechanistically, LIMD1 restrains PD-L1 through post-transcriptional and post-translational mechanisms. LIMD1 loss can relieve microRNA-mediated repression of the CD274 3'UTR, and LIMD1 loss can also disrupt ARIH1-PD-L1 association, reduce PD-L1 polyubiquitination, and stabilise PD-L1 protein without a commensurate increase in CD274 transcript levels in isogenic models. Functionally, LIMD1-deficient tumour cells suppress CD8+ T-cell activation in vitro and show enhanced sensitivity to PD-1/PD-L1 blockade in tumour-PBMC co-culture assays. Analysis of TRACERx non-small-cell lung cancer samples revealed clonal LIMD1 loss of heterozygosity in ∼40% of lung adenocarcinomas, where it is associated with increased tumour PD-L1 expression. Across independent patient cohorts receiving immune checkpoint blockade, low LIMD1 expression was enriched among responders. We identify LIMD1 as a tumour-intrinsic regulator of PD-L1 turnover and suggest that tumour suppressor loss can shape immune checkpoint biology and influence immunotherapy response.

Molecular classification has refined risk stratification in endometrial cancer and is now incorporated into the 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system. However, prospective real-world data on its impact on multidisciplinary tumor board (MDT) decision making remain limited. We evaluated the impact of molecular information on adjuvant treatment recommendations in stage I to II endometrial cancer.

Breast cancer represents a major public health burden in Sudan, where most patients are diagnosed at advanced stages and access to comprehensive diagnostic and molecular services remains limited. Current treatment strategies are largely extrapolated from non-African populations, despite the substantial genetic diversity across African populations that may significantly influence drug response, efficacy, and toxicity. Pharmacogenomics offers a promising approach to optimize breast cancer therapy through genetically informed treatment decisions; however, its clinical application in Sudan and across Africa remains limited. This narrative review synthesizes published evidence on pharmacogenetic determinants influencing breast cancer treatment, with a particular focus on African and Sudanese populations. Relevant studies published between 2005 and 2026 were identified through searches of PubMed, Google Scholar, and PharmGKB. A qualitative synthesis was conducted to summarize key pharmacogenes, population-specific genetic variability, and their potential clinical and therapeutic implications. Considerable interethnic variability has been reported in pharmacogenes involved in drug metabolism and transport, including CYP2D6, CYP3A4, CYP2B6, DPYD, and ATP-binding cassette transporter genes. African populations exhibit distinct allele frequency patterns that may substantially affect drug disposition, therapeutic efficacy, and toxicity, particularly for endocrine therapies and commonly used chemotherapeutic agents. These differences limit the direct applicability of pharmacogenomic data derived from European and Asian populations and underscore the need for population-specific evidence. Integrating pharmacogenomics into breast cancer management has the potential to improve treatment effectiveness and safety in Sudan. Achieving this goal requires the generation of locally relevant pharmacogenomic data, strengthened diagnostic and laboratory infrastructure, and a stepwise, context-appropriate incorporation of pharmacogenomic principles into clinical practice. Such an approach is important to support equitable and effective precision oncology for Sudanese and African populations.

Motivated by the rising incidence of cancers at younger ages, this study compares tumor genomic alterations between adolescents and young adults (AYAs; 18-39 years) and non-AYAs (40 years and older) and explores the relationship with continuous age in patients with relapsed/refractory ovarian, breast, and colorectal cancers accrued to the NCI-MATCH trial.

Metronomic chemotherapy with oral capecitabine + vinorelbine (Cape + VNL) provides synergistic cytostatic activity and antiangiogenic and immunomodulatory effects, potentially offering prolonged disease control with limited toxicity in HER2-negative metastatic breast cancer (MBC). However, efficacy in the real-world (RW) setting, especially in late lines, and the impact of dihydropyrimidine dehydrogenase (DPYD) polymorphisms on dose reduction and safety remain limited.

Chemoradiotherapy (CRT) is a standard treatment for rectal cancer, yet patients show marked variability in response. Identifying reliable biomarkers that predict CRT response remains an unmet clinical need.

Ropeginterferon alfa-2b, a novel monopegylated interferon with improved pharmacokinetics, has emerged as a promising cytoreductive agent for managing polycythemia vera (PV). Despite increasing adoption, evidence synthesis of its efficacy and safety compared to standard care remains limited. The manuscript aimed to evaluate the efficacy of ropeginterferon alfa-2b in comparison to standard treatment options, including hydroxyurea and phlebotomy, in achieving complete hematologic response, partial molecular response (PMR), and reducing JAK2V617F allele burden in patients with PV.

There is a growing number of research suggesting that there is an association between gut microbiota and central nervous system (CNS) tumor. However, the causal relationships and the mediation effects of inflammatory proteins in the associations are unclear. We extracted genetic variants associated with gut microbiota, inflammatory proteins, and 4 subtypes of CNS tumors from published genome-wide association studies and performed a Mendelian randomization analysis to identify potential causal effects. The inverse variance weighted method was used as the main method. Mediation analysis and single-cell RNA-seq analysis were performed to explore the mediation effects and the expression in cells. This study identified 73 gut microbial taxa and 11 inflammatory proteins that were significantly associated with CNS tumors. The inflammatory proteins may act as intermediate mediators in the potential causal association between gut microbiota and 4 CNS tumor subtypes. Mediation analysis suggested that CX3CL1 may partially mediate the relationship between gut microbiota and Glioblastoma, while Eotaxin, CSF-1, IL-15RA and the other 5 cytokines may serve as subtype-specific potential mediators for the remaining 3 tumor types. Our research supports a hypothesized "gut-immune-brain" axis that may mediate the effects of gut microbiota on different CNS tumor subtypes, with distinct immune proteins implicated for each. These findings strongly suggest potential targets for microbiome therapy and immune therapy, though the underlying mechanistic links require experimental validation.

Mitochondria activate immunity, but the role in cancer is unknown. Here, we report that transgenic expression of Parkin, a regulator of mitochondrial fitness, induces inflammation and interferon (IFN) gene signatures, suppresses prostate cancer formation and generates CD8+ and CD20+ intraprostatic immune aggregates. These had hallmarks of mature tertiary lymphoid structures (TLS), expressing markers of B cell maturation (CXCL13, CCL21), germinal center formation (BCL6, GL7), mature dendritic cells (MHC-II/CD208) and high endothelial venules (LYVE-1). Parkin TLS showed high Ig gene expression, recruitment of CXCR5+ follicular T helper cells and expansion of CD69+/KLRG1+ effector T cells. Conditioned medium from Parkin-positive cells expanded memory B and plasma cells, increased IgG1 production, and sustained B and T cell migration. Finally, conditional expression of Parkin induced TLS formation, upregulated Ig chains and inhibited prostate cancer growth, in vivo, whereas Parkin reconstitution in IFNAR1, CD8 or CD20 knockout mice had no effect. Therefore, mitochondrial immunity orchestrates antitumor responses, and TLS formation contributes to tumor suppression.

The molecular mechanisms by which KMT2A-rearranged (KMT2A-r) leukemias maintain the oncogenic FLT3 expression remain largely unclear, limiting therapeutic opportunities. Here, we identify the RNA binding protein MBNL1 as an unexpected positive regulator of FLT3 by DepMap dataset exploration and combinatorial CRISPR screens. MBNL1 promotes leukemia cell survival in cell lines and primary tumors by sustaining FLT3 expression in a KMT2A-r context-dependent manner. Mechanistically, we discover that MBNL1 recognizes a structured single-stranded DNA (ssDNA) element containing five consecutive guanines within the FLT3 enhancer, through MBNL1's zinc finger domains and the carboxyl-terminal unstructured region. Such MBNL1 protein/ssDNA interaction was evident in KMT2A-r leukemia using ChIP-seq and KAS-seq. Mutations of key amino acids of MBNL1's ssDNA binding surface or the critical guanines in ssDNA markedly abrogate the protein-ssDNA interactions. These findings implicate MBNL1 as a distinct FLT3 activator by recognizing a structured enhancer ssDNA element, highlighting an unexpected role for RNA binding proteins in transcriptional regulation through direct ssDNA recognition.

Melanoma plasticity drives immune evasion and therapy resistance through dynamic cell-state transitions beyond genetic alterations. Although epigenetic remodeling is central to this process, its impact under therapeutic pressure remains unclear. We profiled longitudinal biopsies from patients with melanoma treated in the phase 1b NIBIT-M4 epi-immunotherapy trial [NCT02608437, DNA (cytosine-5)-methyltransferase 1 inhibitor plus anti-CTLA-4] using single-cell multiome and spatial transcriptomics. Seven malignant meta-programs were identified, including a rare Wnt/β-Catenin melanocytic state and a dedifferentiated neural crest-like state enriched in nonresponders. Spatial analyses showed that homotypic clustering stabilizes resistant programs, with neural crest-like cells forming compact niches. Responders displayed enrichment of antigen presentation/interferon program and coordinated T and B cell expansion, whereas nonresponders retained stable neural crest-like clusters. Epigenetic therapy reactivated transposable elements, priming innate immunity and enhancing immunogenicity. Nuclear factor of activated T cells, cytoplasmic 2 (NFATC2) emerged as a master regulator of neural crest-like states and resistance; its perturbation promoted differentiation and immunogenicity. These findings define mechanisms of resistance and nominate β-Catenin and NFATC2 as therapeutic vulnerabilities.

Epidermal Growth Factor Receptor (EGFR) is often present on the cell surface of a wide variety human malignancies, including non-small-cell lung cancer (NSCLC), glioblastoma (GBM), pancreatic ductal carcinoma (PDC), and castration-resistant prostate cancer (CRPC). Efforts to optimize immunotherapies targeting EGFR are limited by murine intolerance of human EGFR. To overcome this obstacle, we developed C57BL/6 mice in which a truncated variant of human EGFR (hEGFRt), lacking the ligand binding domain and cytoplasmic domain, is expressed from the CAG regulatory elements comprised of the CMV enhancer, β-actin promoter, and β-globin poly-adenylation signals. Cetuximab, a high-affinity, clinically available anti-human EGFR antibody, retains affinity for hEGFRt. The hEGFRt cDNA in the CAG-hEGFRt transgene is flanked by loxP sites to enable its excision thereby reducing interaction of hEGFRt-directed immunotherapies with normal tissues. The CAG-hEGFRt(f/f) transgene is abundantly expressed in hematopoietic lymphoid and myeloid cells, with low-level expression evident also in non-hematopoietic liver, lung, kidney, and brain. Mx1-Cre-mediated transgene excision in adult mice reduces hEGFRt ~ 5-fold in blood mononuclear cells. CAG-hEGFRt(f/f) adult mice are tolerant of syngeneic NSCLC, GBM, prostate, and PDC lines expressing hEGFRt. These mice retain hEGFRt tolerance after transgene deletion. CAG-hEGFRt(f/f) mice provide a new and important tool for the development of immunotherapies targeting hEGFR.

Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.