Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

Resistance to lenvatinib remains a major barrier in the treatment of advanced hepatocellular carcinoma (HCC), underscoring the urgent need to elucidate the underlying mechanisms and identify actionable therapeutic targets. In this study, we identified a neurosecretory factor derived from HCC cells, Nerve Growth Factor (NGF), as a critical mediator of lenvatinib resistance. Utilizing an innovative in vivo-in vitro cross-circulated strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR-cells). Through proteomic screening of conditioned media and subsequent functional validation, we demonstrated that NGF secretion progressively increases with the acquisition of resistance. Mechanistically, we uncovered that the SRPK1-SRSF1 axis drives enhanced NGF production by regulating alternative splicing of its precursor transcript, specifically promoting the expression of a shorter, translationally efficient isoform (proNGF-B). Elevated NGF subsequently activates the non-canonical MAPK pathway (MEK5-ERK5) via its high-affinity receptor TrkA, thereby sustaining tumor cell viability and proliferation under sustained tyrosine kinase inhibitor pressure. Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

Perineural invasion (PNI), a prominent pathological feature of pancreatic ductal adenocarcinoma (PDAC), is closely associated with poor prognosis. Clarifying its mechanism is therefore critical for developing new therapies. Recent research has focused on the crosstalk between tumors and Schwann cells (SCs), particularly the role of SC dedifferentiation in facilitating PNI. In this study, by integrating RNA-seq, spatial transcriptomics, and single-cell analysis of clinical samples, we identified significant enrichment of dedifferentiated SCs and upregulation of key markers (p75NTR, SOX2, and c-Jun) in PNI regions. Moreover, PTGES was more highly expressed in the central region of the PNI than in the other regions of the PNI. Coculture experiments revealed that PANC-1 and BxPC-3 cells enhanced SC dedifferentiation, and this process facilitated pancreatic cancer cell malignancy. Furthermore, PTGES upregulation in the coculture system mediated prostaglandin E2 (PGE2) synthesis. Functional experiments revealed that PGE₂ drove morphological alterations in SCs-characterized by bipolar stretching-and elevated the expression of dedifferentiation markers, including p75NTR, c-Jun, SOX2, and GDNF. In the 3D coculture model, treatment with a PTGES inhibitor (CAY10526), siPTGES or PTGES-KO impaired the directional migration and neurite outgrowth of SCs toward PDAC cells. Mechanistically, PGE₂-stimulated SCs secrete elevated levels of LIF and ADAMTS-1, factors that promote extracellular matrix degradation and neural remodeling to facilitate tumor invasion. In summary, we delineate a novel paracrine axis in which PDAC-derived PGE₂ drives SC dedifferentiation and the production of proinvasive factors (LIF and ADAMTS-1), collectively establishing a microenvironment conducive to PNI. Our findings suggest that the PTGES-SC axis is a promising therapeutic target for inhibiting PNI in PDAC.

Accumulating evidence shows that bacteria influence cancer homeostasis, yet the effects of tumor‑associated microbes and their products remain largely unexplored. We previously reported that P. aeruginosa-cancer crosstalk suppresses tumors via the bacterial cupredoxin azurin, and we developed an azurin‑derived peptide that was tested in clinical trials. Building on our previous studies, we studied tumor-resident bacteria for novel therapeutics and targets. Photosynthetic bacteria from the phylum Chloroflexota, including a member of the class Chloroflexia, identified in tumors, carry the cupredoxin auracyanin gene. Based on the structural and chemical characteristics of auracyanin, we designed a novel cell-penetrating peptide, aurB. Plant chloroplasts are thought to have evolved from a bacterial endosymbiont, and both chloroplasts and mitochondria possess shared proteins essential for ATP-dependent energy production, indicating that these bacterial-derived proteins may influence mitochondrial function. Consistent with this model, we demonstrated that aurB, a peptide from cupredoxin auracyanin B, localized at mitochondria, blocked energy production by targeting ATP synthase in prostate cancer cells, thereby significantly inhibiting tumor growth. More strikingly, combination treatment with aurB and radiation therapy significantly inhibited tumor growth in a tibial bone metastasis model. Moreover, the number of metastatic lesions in the lungs was also significantly lower upon aurB treatment. Multiplex RNA-expression profiling revealed that the inhibition of ATP production by aurB increased the efficacy of radiation therapy by modulating multiple pathways involving HIF-1α. Our findings indicate that electron transfer proteins could represent an important source of promising novel peptide-based agents that target the aberrantly activated mitochondrial energy system in cancer.

Gastric synovial sarcoma (GSS) is an exceptionally rare mesenchymal malignancy, with only 51 cases reported. We present a case of a man in his 50s with dyspeptic symptoms and epigastric pain. Gastroscopy revealed an ulcerous tumour below the gastro-oesophageal junction. Histology, immunohistochemistry and molecular analysis confirmed SS18::SSX1 fusion, diagnostic of synovial sarcoma. The patient underwent successful robot-assisted partial gastric resection with negative margins. No recurrence was noted at 6-month follow-up. This case underscores the diagnostic challenge of GSS, the critical role of molecular techniques and the efficacy of minimally invasive surgical management.

One of the most prevalent oral cancers, oral squamous cell carcinoma (OSCC), is distinguished by its rapid growth, invasiveness, and high metastatic potential. Green AgNPs are important because they can reduce systemic toxicity by inducing oxidative stress, cytotoxicity, and apoptosis in cancer cells. The goal of this study was to use saponins as natural stabilizers to create AgNPs, and the detrimental apoptotic effects on cancer cells were examined using high-content screening (HCS) assays such as TNI, CMP, and VCC.

HPV types 16 and 18 are associated with 70% of invasive cervical cancers. Between these two types of HPV, HPV type 16 is more commonly found in cervical cancer patients, whereas HPV type 18 is less frequently reported. Currently, the molecular mechanism underlying the increased cancer risk in HPV type 16, compared to HPV type 18, has not yet been fully elucidated.

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies worldwide. The long non-coding RNA MEG3 functions as a tumor suppressor in several cancers, potentially influencing gene expression through transcriptional, translational, and epigenetic mechanisms. let-7i plays a role in leukemia progression. This study aimed to evaluate MEG3 gene expression in adult ALL patients and investigate its possible regulatory interaction with let-7i-3p and let-7i-5p.

This study aimed to create a genetic and clinical roadmap for the TGF-β pathway in an Iraqi population, focusing on the TGF-β1 (+869 C/T) polymorphism.

Lymphoma is the most common hematologic malignancy in Thailand, with diffuse large B-cell lymphoma (DLBCL) being the predominant subtype. Early prognostic indicators are essential for guiding clinical decisions. Genetic alterations, particularly in regulatory regions, may serve as potential biomarkers. This study investigated sequence alterations upstream of exon 1 of the OSBPL10 gene and their clinical relevance in a Northern Thai DLBCL population.

A key element of computational drug discovery is the precise prediction of drug-gene interactions, particularly when working with intricate biological systems where relational dependencies are essential. Because biological networks are graph-structured, traditional machine learning techniques frequently fall short. Graph Neural Networks (GNNs) have emerged as a viable approach for learning meaningful representations from this data type in response to this challenge. In this study, three state-of-the-art GNN architectures Graph Convolutional Networks (GCN), Graph Attention Networks (GAT), and GraphSAGE are comprehensively compared using a bipartite graph constructed from drug-target biochemical activity data.

The present study was planned to examine the possible association of polymorphisms in the superoxide dismutase and catalase genes with adverse normal tissue effects or injury resulting from radiotherapy in HNC patients.

The aim of the study was to determine how the chemotherapeutic alkylating agent dacarbazine, together with the application of the miR-204-5p mimic in vivo, affects the presence of disseminated melanoma cells in distant organs - the lungs and liver.

Brain metastases arise from the spread of cancer cells from tumors residing outside the brain. Immunotherapy and molecularly targeted therapeutics have improved outcomes for some patients with brain metastases, but many patients are still faced with a dismal prognosis. The inability to effectively treat these tumors and improve patient survival highlights the dire need for improved therapeutic strategies that ultimately depend on developing a greater understanding of the molecular underpinnings and inner wiring of these tumors. In this Review, we discuss current and emerging insights into the genetics and cellular signaling pathways that contribute to the spread of tumors to the brain. We also discuss potential therapeutic targets in the metabolic vulnerabilities of cells that metastasize to the brain and in the interactions between metastases and the microenvironment.

MOTS-c is a mitochondria-derived peptide associated with reduced insulin resistance and obesity. The m.1382A>C polymorphism of the MOTS-c gene is linked to an increased risk of type 2 diabetes in men. However, no studies have explored the relationship between this polymorphism and MOTS-c levels in adolescents with polycystic ovary syndrome (PCOS). This study aimed to investigate the differences in MOTS-c levels between adolescents diagnosed with PCOS and those without PCOS, as well as the associations with metabolic parameters. The association between the MOTS-c gene polymorphism and serum MOTS-c levels in adolescents with PCOS was also evaluated.

Pheochromocytomasand paragangliomas (collectively referred as PPGLs) are highly heritable neoplasms arise from chromaffin cells of neural crest tissues; 40% of patients with PPGLs harbour germline pathogenic variants (PV), which up to 45% of patients exhibit somatic mutations in similar susceptibility genes. Endothelial PAS domain-containing protein-1 [also known as hypoxia inducible factor-2α, HIF-2α] is encoded by EPAS1, and along with other hypoxia-inducible factors (HIFs) acts as a key mediator in the cellular response to hypoxia. Gain-of-function mutations in EPAS1 have been linked to the Pacak-Zhuang syndrome, congenital cyanotic heart disease and sickle cell anaemia. Hypoxia due to chronic anaemia and/or associated nephropathy in patients with sickle cell disease (SCD) may increase the expression of genes related to HIFs, thereby increasing susceptibility to the development of PPGLs. We describe a case of young female with a history of sickle cell anaemia and sickle cell nephropathy who was found to have a para-aortic mass. Histology confirmed the diagnosis of a paraganglioma. She did not exhibit somatic mutations of the common predisposition genes but demonstrated a likely pathogenic activating somatic EPAS1 variant mutation. This case illustrates the predisposition of patients with SCD to PPGLs due to somatic EPAS1 mutations, and should increase awareness of such tumours in these patients.

Life-prolonging targeted therapies are available based on alterations detected on next-generation sequencing (NGS); however, clinical data on NGS adoption are limited.

Role of environmental fungi and Aspergillus fumigatus in respiratory diseases remains evident; however, its contribution to directly influencing lung cancer progression remains obscure. In this study, we investigated the effect of Aspergillus fumigatus extract (AFE) on the development of tumor-promoting characteristics in human lung cancer cell lines. The organism was distinguished based on Lactophenol Cotton Blue staining and further distinguished with protein expression patterns via SDS-PAGE and BCA analysis. A549 and H1299 lung adenocarcinoma human cell lines were challenged with AFE, and various cellular responses were monitored simultaneously for cell viability, proliferative activity, inflammatory gene expression, DNA damage expression, and migratory responses. AFE caused increased cell viability and exhibited cellular characteristics of highly proliferating cells with significant expression of Cyclin D1 and c-MYC. Highly inflammatory gene expression responses and protein expressions of AKT, ERK1/2, and NF-κB signaling pathways were noticed at both the gene and protein expression levels with NF-κB nuclear translocation verified with confocal microscopy studies. DNA damage expression markers like γ-H2AX, p-ATM, and p53 significantly contributed with observable genomic DNA cleavage. Additionally, AFE-exposed cells exhibited faster wound closure and expression of Epithelial-mesenchymal transition-associated factors contributing to cell migration and therapeutic efficacy of this combined approach needs further investigation and development into a targeting therapeutic agent against lung cancer.

CD8+ T cell-mediated immune escape is a key mechanism in tumor progression. GPC3 has an impact on the progression of various tumors. However, its potential function and regulatory mechanism in the immune escape of gastric cancer (GC) are still unclear. GC clinical samples were collected to assess the expression of GPC3. The impact of GPC3 on GC prognosis was analyzed by bioinformatics analysis. CCK-8, colony formation, flow cytometry, and Transwell were utilized to detect changes in GC cell viability, proliferation, antiapoptosis, migration, and invasion ability. According to bioinformatics analysis, the linkage between N6 m6A modification, protein interactions, ubiquitination, and transcriptional regulation was revealed. The m6A modification effect of YTHDF1 on GPC3 was verified through MeRIP, RIP, RNA-pull-down assays, and multiribosome experiments. CO-IP and immunofluorescence were undertaken to validate the interaction between GPC3 and MUL1. The effect of GPC3 and MUL1 on HSF1 ubiquitination was assessed by the in vitro ubiquitination assay. Moreover, the transcriptional activation effect of HSF1 on CD276 was examined through ChIP and dual luciferase experiments. We constructed a co-culture system of tumor cells and CD8+T cells, detected CD8+T cell proliferation using CFSE, assessed cell toxicity using LDH, and evaluated the cytotoxicity of CD8+T cells by detecting the secretion of killing factors using ELISA. Finally, an allograft mouse model was constructed to validate the therapeutic effect of targeting GPC3 and CD276 monoclonal antibodies. Combining bioinformatics analysis, clinical sample testing, and cell experiments, it was confirmed that GPC3 was highly upregulated in GC, boosting malignant progression such as GC cell viability, proliferation, and antiapoptosis, and affecting the poor prognosis of GC. Mechanistically, YTHDF1 mediated m6A methylation to reinforce GPC3 translation. GPC3 interacted with MUL1 to repress ubiquitination degradation of HSF1, and HSF1 enhanced transcriptional activation of the immune checkpoint CD276. GPC3 depressed the antitumor activity of CD8+T cells through the MUL1/HSF1/CD276 axis, mediating GC tumor immune escape. YTHDF1 upregulates the expression of GPC3 in GC in an m6A-dependent manner. GPC3 interacts with MUL1 to depress the ubiquitination degradation of HSF1, thereby upregulating the immune checkpoint CD276 and affecting GC immune escape.

Modeling of medical interventions, such as preventive surgeries, on a survival outcome necessitates an accurate and flexible representation of the time-dependent effect of the intervention. We propose using B-splines to model the time-dependent effect of a binary time-dependent covariate on a survival outcome in the presence of correlated competing risks. The proposed B-splines can also help choose the best functional form for the time-dependent effect. Our simulation studies demonstrate that the proposed competing risks model with B-splines performs well in estimating the time-dependent effect of the intervention and the penetrance function in all scenarios considered. We applied our proposed method to families carrying a pathogenic variant in BRCA1 recruited through the Breast Cancer Family Registry and evaluated the time-dependent effects of risk-reducing salpingo-oophorectomy on breast cancer risk in the presence of ovarian cancer and death from other causes as competing events. We found that the B-splines model better captured the changes in the association between the intervention and breast cancer over time and provided better predictive ability than alternative parametric models, such as the permanent exposure model and the Cox and Oakes model. Our results indicate that risk-reducing salpingo-oophorectomy has a significant protective effect on breast cancer incidence over the follow-up period.