IntroductionDNA double-strand breaks (DSBs) are repaired via homologous recombination (HR) or the more error-prone non-homologous end joining (NHEJ). breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) are key genes in HR, and their mutations are associated with aggressive prostate cancer (PCa). While PARP inhibitors (PARPi) improve survival in BRCA-mutated PCa, their efficacy in late-stage disease is limited and often accompanied by serious side effects. This study aims to develop an in vitro model of BRCA-mutated PCa and evaluate the therapeutic potential of DNA-dependent protein kinase (DNA-PK) inhibitors that target the NHEJ pathway.MethodsThe genes BRCA1 and BRCA2 were targeted for knockout (KO) in lymphnode cancer of the prostate (cell line) [LNCaP] using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology. The KO were assessed via Western blot analysis. Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. The impact on cell proliferation was evaluated using the CellTiter-Glo assay and synergy of the treatments was analyzed with SynergyFinder. Cytotoxic effects were measured by flow cytometry using an Annexin V-fluorescein isothiocyanate (FITC) apoptosis detection kit. The presence of DSB was quantified using immunofluorescence.ResultsBRCA2 and BRCA1 protein expression were successfully downregulated in the knockout (KO) cell lines. After two days of treatment with talazoparib and/or nedisertib, a significant decrease in cell proliferation was observed. Additive effects of the combination treatment were detected exclusively in the BRCA KO cells. These cells also exhibited significantly higher rates of necrosis after treatment compared to scramble cells and, DNA DSB were significantly more prevalent in the BRCA KO cells. Additionally, BRCA1/2 loss is inversely correlated with DNA-PK, with knockout leading to increased DNA-PK expression to support NHEJ.ConclusionBRCA knockout LNCaP models were established, exhibiting increased DNA-PK activity and indicating greater susceptibility to DNA-PK inhibition. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination.

The subtle sequence diversity and mutually exclusive expression patterns of T cell receptor beta chain constant genes, TRBC1 and TRBC2, in mature human T cells, provide the basis for immune-targeting strategies designed to eliminate clonally expanded malignant T cells while sparing a subset of normal T cells capable of maintaining immunocompetence. The evolutionarily conserved gene arrangement and regulation of TRBC loci in mammals make these genes attractive targets for translational immune-targeting strategies in companion species, including dogs. However, available TRBC sequence data relevant to common dog breeds remains limited. In this study, we investigated the sequence diversity and mRNA expression profiles of canine TRBC1 and TRBC2 genes in peripheral blood mononuclear cell (PBMC) samples representing 14 different dog breeds, and in six established canine haematopoietic cell lines of both T-cell and non-T-cell origin (i.e., B and NK cell lines). Our analysis uncovered a previously unreported variation in the TRBC1 sequence encoding the transmembrane region but found no sequence diversity in the extracellular domain of TRBC1 and TRBC2. A nearly equal mRNA expression of TRBC1 and TRBC2 was consistently observed in bulk samples of canine PBMCs across all breeds, in contrast to canine cell lines, which exhibited a more skewed expression profile. Unexpectedly, germline mRNA expression of TRBC was present in some (i.e., CLB70, GL1) but not other (i.e., CLBL1) canine cell lines of B cell origin. In conclusion, our findings indicate that the fully conserved amino acid sequence in the extracellular domain of canine TCR beta chain variants presents a challenge for the development of differential therapeutic antibodies. Additionally, the presence of germline TRBC transcripts in certain canine B-cell neoplasms, but not others, may provide additional insights into the developmental stages from which these neoplasms originate.

The circadian rhythms, intrinsic 24-hour oscillations in physiological and cellular processes, serve as fundamental regulators of cellular function and metabolism. Although these rhythms are robust, they are susceptible to dysregulation, particularly in hematological diseases, where circadian misalignment exacerbates pathological conditions. The role of bone marrow adipose tissue mesenchymal stem cells (BMAT-MSCs), a dynamic component of the bone marrow microenvironment, in the pathogenesis of Fanconi anemia (FA), a genetic disorder characterized by a predisposition to myeloproliferative disease and acute myeloid leukemia (AML), remains poorly understood. This study explores the potential therapeutic applications of dexamethasone (DEX)-induced synchronization in BMAT-MSCs derived from healthy donors (HD), FA, and AML.

Radiogenomics links quantitative features from routine CT and PET/CT with tumor genomics to non-invasively profile non-small cell lung cancer (NSCLC). This review synthesizes the current workflow-from image acquisition and segmentation to feature extraction and modeling-and emphasizes clinical use cases: triage when tissue is limited, risk stratification, therapy selection (including immunotherapy), and longitudinal monitoring. Despite promising results, clinical translation is constrained by non-standardized imaging/feature pipelines, limited multi-center validation and calibration, vulnerability to data leakage, and challenges in interpretability, uncertainty handling, and software and model governance. We advocate treating genomic burden-tumor mutational burden (TMB), intratumor heterogeneity (ITH), and copy-number alterations (CNA)-as first-class endpoints and covariates, and outline a pattern-aware framework for EGFR T790M to inform surveillance and treatment sequencing. We also provide a practical reporting checklist and a pitfall-to-remedy table to support reproducible, multi-center studies and regulatory-grade documentation. Radiogenomics is best viewed as a complement to biopsy rather than a replacement. Real-world impact now depends on harmonized protocols, leakage-free external validation, explainable and uncertainty-aware models, and integration with multi-omics decision support to deliver reliable, patient-centered lung cancer care.

Dermatofibrosarcoma protuberans (DFSP) is a rare, locally aggressive cutaneous sarcoma characterized by high recurrence rates and the development of resistance to imatinib. The scarcity of preclinical models hinders research into DFSP pathogenesis and the development of novel therapeutic strategies. In this study, we established and characterized a novel DFSP cell line, designated DFSP-DPH1, derived from a 47-year-old male patient with an abdominal tumor. Comprehensive characterization confirmed that DFSP-DPH1 retains key features of the original tumor, including the fibroblast-like spindle morphology and expression of diagnostic markers CD34 and vimentin, with absence of factor XIIIa. Short tandem repeat profiling confirmed the cell line's origin and excluded cross-contamination. Sanger sequencing revealed a COL1A1 exon 46-PDGFB exon 2 fusion transcript, a breakpoint not previously reported in established DFSP cell lines. Functionally, DFSP-DPH1 exhibits robust proliferative capacity, forms three-dimensional spheroids under anchorage-independent conditions, and demonstrates significant migratory and invasive capabilities. Drug sensitivity screening of a panel of 48 PDGFR inhibitors confirmed its resistance to imatinib and identified several compounds with superior efficacy compared to imatinib. Transcriptomic analysis confirmed the dominance of the COL1A1::PDGFB fusion transcript and revealed enrichment of pathways related to cancer, viral infection, and neuroactive ligand-receptor interaction. This novel imatinib-resistant DFSP cell line, DFSP-DPH1 provides a valuable preclinical model for investigating the molecular mechanisms underlying DFSP pathogenesis, drug resistance, and tumor progression, and for developing and evaluating novel therapeutic strategies.

Breast cancer progression is influenced by tumor subtype, metabolic environment, and patient factors, including menopausal status and BMI. In this study, we utilized publicly available data to investigate the prognostic relevance of PPARγ gene's expression across different subgroups. We also examined adipose tissue proliferation in patients with various tumor subtypes and phenotypic cohorts. We analyzed RNA-seq data from primary breast cancer patients in the TCGA-BRCA cohort, stratifying patients by PPARγ expression, menopausal status, and tumor receptor subtype. Kaplan-Meier analyses revealed that high PPARγ expression was associated with improved overall survival, particularly in premenopausal patients. Complementing this, we analyzed PET-CT scans from breast cancer patients in the ACRIN-6888 trial, focusing on standardized uptake value (SUV) metrics of a cell cycle tracer, 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) in visceral and subcutaneous adipose tissue. Postmenopausal patients had lower visceral adipose tissue SUVmean, and patients with ER+ or non-TNBC tumors showed lower SUVpeak and SUVmax of both adipose tissue types, indicating metabolic/proliferative reprogramming of adipose tissue based on tumor subtype. We hypothesize that PPARγ expression and adipose proliferation differentially affect survival across subtypes and menopausal status, providing deeper insight into PPARγ as a therapeutic target in breast cancer and the potential implications for precision medicine treatments.

Mantle cell lymphoma is a biologically and clinically heterogeneous subtype of non-Hodgkin lymphoma that affects predominantly older patients. The disease remains incurable with modern therapies. The integration of first- and now second-generation Bruton tyrosine kinase inhibitors (BTKis) into earlier-line settings appears to improve outcomes. Remaining questions in the field relate to the need for chemotherapy and the choice and duration of maintenance therapy, given its cost and infectious complications. In this review, we highlight clinical data showing BTKis targeting genetic vulnerabilities within mantle cell lymphoma cells. We then assess the integration of these agents into the first-line setting for all patients with newly diagnosed disease. Special consideration is given to patients with TP53-mutated disease, for which non-chemotherapy approaches are preferred.

Chronic myelomonocytic leukemia (CMML) is largely a disease of individuals older than 50 years; its occurrence in patients aged 50 years and younger is rare. The authors sought to characterize the clinicopathologic features and genetic profile of young-onset (age 50 years and younger) CMML (y-CMML) compared with older onset (older than 50 years) CMML (o-CMML).

In recent years, microRNA (miRNA) aberrations have gained particular attention in cancer pathogenesis. In our previous study using global miRNA expression microarray, we identified overexpression of miR-9-5p and miR-125-5p in multiple myeloma (MM) patients. To date, the roles of miR-9-5p and miR-125-5p are not well understood and require further clarification. This study aimed to investigate the functional role of miR-9-5p and miR-125b-5p in MM by in vitro cell-based assays. Synthetic mimics or inhibitors were transfected into the KMS-28BM MM cell line using nucleofection. The relative miRNA expression level was detected using RT-qPCR. Cell proliferation was measured with MTS assay, while apoptosis was analysed by flow cytometry using Annexin V-FITC/ PI double staining technique. The study findings revealed that suppression of miR-9-5p with inhibitor decreased cell proliferation significantly, while enforced expression of miR-9-5p by synthetic mimics increased proliferation of these cells compared to the scrambled negative control (P < 0.05). Moreover, transfection of miR-9-5p inhibitor and mimic increased (P < 0.01) and decreased (P < 0.05) the proportion of early apoptotic cells, respectively. Apart from that, repression of miR-125b-5p significantly increased the number of late apoptotic cells while overexpression reduced the number of early apoptotic cells compared to the negative control (P < 0.05). Inhibition of miR-9-5p and miR-125b-5p exert apoptotic and/ or antiproliferative effects in KMS-28BM cells, suggesting their possible role in the treatment of MM.

B7-H4 is an immune-regulatory molecule increasingly recognized for its role in tumor progression and immune evasion in epithelial ovarian cancer. To clarify its clinical relevance, we conducted a systematic review and meta-analysis evaluating the prevalence of B7-H4 expression and its association with survival outcomes. Nineteen eligible studies were included, of which sixteen provided data on expression proportions and eight reported progression-free or overall survival outcomes. The pooled prevalence of high or positive B7-H4 expression was 73%, though with considerable inter-study variability. High B7-H4 expression was associated with a significantly increased risk of disease progression (pooled unadjusted hazard ratio: 1.43), while its relationship with overall survival remained inconclusive due to limited data. Despite methodological differences among studies, the findings suggest B7-H4 is overexpressed and potentially prognostic in ovarian cancer. Additional studies are required to validate its clinical utility in patient risk assessment and as a therapeutic target.

Prostate Cancer (PCa) is a leading malignancy in men in developed countries. The lack of reliable prognostic markers in PCa hinders effective treatment, leading to potential patient misclassification and overtreatment with associated side effects. Recent advances in high-throughput sequencing have enabled the identification of tRNA-derived fragments (tRFs), small non-coding RNAs derived from tRNA cleavage. tRFs regulate crucial cellular processes like viability, differentiation, and homeostasis, implicating them in disease development, particularly cancer. Their potential as biomarkers for early diagnosis and prognosis, as well as targets for precision therapies, is increasingly recognized. This review focuses on the key biological functions of tRFs, including RNA silencing, translation regulation, and epigenetic regulation. It summarizes recent findings on tRFs in PCa, exploring their potential as clinical biomarkers and therapeutic targets.

G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain. In the current study, comprehensive bioinformatics analysis revealed that GPATCH2 was markedly upregulated in HCC and positively correlated with aggressive clinicopathological features, including histologic grade, AFP, albumin level, and adjacent hepatic tissue inflammation, as well as miserable outcomes in HCC. GPATCH2 also has certain diagnostic value for HCC, histologic grade, and 1-, 3-, and 5-year survival outcomes. Functionally, loss-of-function experiments disclosed that silencing GPATCH2 suppressed HCC cell proliferation, migration, invasion, and xenograft tumor growth in the subcutaneous mouse model. Silencing GPATCH2 also resulted in an increase in the expression level of CDH1, while causing a decrease in the expression levels of FN1, TWIST1, SNAI1, and SNAI2. Rescue experiments further confirmed SNAI2 as a critical downstream effector mediating GPATCH2-driven oncogenic activity in HCC. Mechanistically, GPATCH2 was uncovered to be transcriptionally activated by the transcription factor Yin Yang 1 (YY1), and can mediate the role of YY1 in promoting HCC progression and elevating SNAI2 expression. Taken together, GPATCH2 is a YY1-regulated oncogenic driver that promotes HCC advancement through SNAI2, highlighting its potential as a diagnostic, prognostic, and therapeutic target for HCC.

Osteoporosis and osteosarcoma share certain molecular pathways, and identifying common hub genes could provide new insights into their pathogenesis. This study aimed to identify and validate hub genes involved in both osteoporosis and osteosarcoma and explore their potential as biomarkers and therapeutic targets.

Hepatocellular carcinoma (HCC) stands as the foremost contributor to cancer-related mortality, underscoring its profound significance in the oncological landscape. This study explores the potential regulatory mechanisms of lncRNA CKMT2-AS1 in the functionality of HCC cells, thereby providing a basis for therapeutic approaches in the treatment of HCC.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype among all breast cancer types. Its treatment remains a significant challenge due to the lack of clearly defined molecular targets. We previously reported that lung-metastatic cell lines, established via orthotopic transplantation of a TNBC cell line, showed high expression of the TIE1 receptor-tyrosine kinase. In this study, we demonstrated that TIE1 expression correlates with poor prognosis in breast cancer patients and is highly elevated in the Claudin-low subtype, which largely overlaps with TNBC. Notably, TIE1 expression promoted tumorigenicity in a breast cancer cell line. Furthermore, in primary tumors formed by TIE1-expressing cells, we observed TIE1 cleavage, reduced apoptosis, and activation of the AKT-p70S6K signaling pathway. Our findings suggest that TIE1 may serve as a potential molecular target and biomarker for Claudin-low type breast cancer, and further research could have significant implications for its treatment.

Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and tertiary lymphoid structures (TLSs) has not yet been sufficiently described. We examined whole tissue sections histopathologically for TLSs and immunohistochemically for CD20 and CD138. The B-cell immunoscore (B-IS) divided the cohort into five categories based on the expression of these two B-cell/plasma cell markers (CD20 and CD138, respectively). Patients with fewer TLSs had worse overall survival (OS) [hazard ratio (HR) = 2.17; 95% CI: 0.94-5; p = 0.069]. A significant association was identified between a high TLS diameter and the presence of a lymphocytic infiltrate [odds ratio (OR) = 2.2442; 95% CI: 1.1022-4.55; p = 0.0208]. Patients with low B-IS (HR = 1.89, 95% CI: 1.18-3.03, p = 0.008), a low number of CD20+ cells in the tumor center (HR = 1.67, 95% CI: 1.04-2.7, p = 0.035), and a low number of CD20+ cells at the tumor invasion front (HR = 1.69, 95% CI: 1.06-2.78; p = 0.028) had significantly worse OS. High B-ISs were strongly associated with a mutated p53 profile detected by immunohistochemistry (OR = 4.76, 95% CI: 1.32-25, p = 0.011), low T-cell immunoscores (OR = 0.49; 95% CI: 0.23-1.03; p = 0.051), and brisk lymphocytic infiltration (OR = 2.0417, 95% CI: 1.01-4.76; p = 0.037). High CD20+ cell counts at the invasion front were associated with histological grade 3 disease (OR = 2.44, 95% CI 1.15-5.26, p = 0.015). An association was also observed between low B-IS and mutations in KMT2D (OR 0.31, 95% CI: 0.07-1.21, p = 0.057) and EGFR (OR = ∞, 95% CI: 0.86-∞, p = 0.053). In conclusion, high numbers of tumor-infiltrating B cells within TLSs represent a favorable prognostic marker in pSCC. These findings emphasize the need to identify novel microscopic prognostic markers during pathological assessment to guide early and appropriate therapeutic strategies.

Esophageal cancer is a highly prevalent malignancy worldwide. Although immunotherapy, particularly programmed cell death‑1/programmed cell death ligand 1 (PD‑1/PD‑L1) inhibitors, has notably improved patient outcomes, the overall response rate remains limited. This limited efficacy is largely attributed to complex immunosuppressive networks within the tumor microenvironment (TME). The present review systematically dissects the multifaceted regulatory mechanisms of the PD‑1/PD‑L1 signaling axis in the TME of esophageal squamous cell carcinoma (ESCC), and its impact on immunotherapeutic efficacy. Emerging evidence indicates that multiple immunosuppressive mechanisms within the TME shape the response to immune checkpoint inhibitors: Regulatory T cells enhance immunosuppression via the TGF‑β‑PD‑1/PD‑L1 axis; IL‑6/STAT3 signaling upregulates PD‑L1 expression and mitochondrial remodeling and amino acid network regulation exacerbate T cell exhaustion. Meanwhile, tertiary lymphoid structure (TLS) maturation is positively associated with clinical prognosis by promoting tissue‑resident memory T cell activation and enhancing antitumor immunity. By contrast, the predictive value of tumor mutational burden (TMB) is constrained by TME heterogeneity. Emerging strategies highlight the predictive potential of TLS maturity and TMB, although the predictive relevance of TMB in ESCC remains inconsistent. Combination approaches show promise in reversing T/natural killer cell exhaustion and remodeling immunosuppressive TMEs. Future research should combine multi‑omics data with clinical information to develop personalized immunotherapy models for ESCC.

Melanoma, a highly malignant form of skin cancer, poses significant challenges in oncology due to its aggressive nature and resistance to conventional therapies. Epigenetic modifications, especially acetylation, have emerged as critical regulators of gene expression that influence the pathogenesis and progression of melanoma. Acetylation is a novel post‑translational modification that involves the addition of an acetyl group to lysine residues both in histone and in non‑histone proteins. In the context of melanoma, acetylation has been shown to occupy a pivotal role in regulating cellular proliferation, autophagy, apoptosis and metastasis, as well as drug resistance. The identification of acetylation‑associated biomarkers and therapeutic targets in melanoma is currently an active area of research. The present review aims to elucidate the roles of acetylation modifications in melanoma, and to explore the potential of targeting these modifications for novel therapeutic interventions, with a unique perspective on the acetylation networks mediating therapy resistance.

Pancreatic cancer is characterized by short survival and poor treatment outcomes. Astragaloside IV (AST‑IV), the primary pharmacological component of Astragalus membranaceus, is a traditional Chinese medicinal component with demonstrated anticancer potential. The present study aimed to evaluate the therapeutic efficacy of AST‑IV against pancreatic cancer cells in vitro and to elucidate its underlying mechanisms of action, thereby providing novel insights for its clinical application in the treatment of pancreatic cancer. The effects of AST‑IV on PANC‑1 pancreatic cancer cell viability and migration were assessed using Cell Counting Kit‑8 and wound healing assays, respectively. Subsequently, RNA‑sequencing (RNA‑seq) analysis was performed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to investigate the mechanisms underlying the effects of AST‑IV. Finally, western blotting experiments were conducted to validate the potential molecular mechanisms of AST‑IV. The results revealed that AST‑IV effectively suppressed the proliferation and migration of the pancreatic cancer cells. In addition, GO and KEGG analyses of the differentially expressed genes identified by RNA‑seq analysis suggested that AST‑IV induced endoplasmic reticulum (ER) stress and influenced critical cellular processes, including cell cycle regulation and DNA damage repair. Furthermore, western blotting demonstrated that AST‑IV significantly activated the protein kinase R‑like endoplasmic reticulum kinase (PERK) signaling pathway, upregulated activating transcription factor 4 expression and induced the overexpression of CCAAT/enhancer‑binding protein homologous protein, indicating that it triggered apoptosis. In summary, these findings suggest that AST‑IV induced apoptosis in pancreatic cancer cells through PERK‑mediated ER stress. These results expand the potential therapeutic applications of AST‑IV and provide a theoretical foundation for the development of novel treatment strategies and therapeutic targets for pancreatic cancer treatment.

Leukemia is a group of hematologic malignancies characterized by the uncontrolled proliferation of abnormal white blood cells, posing significant challenges for diagnosis and treatment because of its complex etiology. Both genetic and environmental factors contribute to leukemogenesis, with recent research highlighting the critical role of epigenetic modifications, particularly histone acetylation and deacetylation, in regulating gene expression and disease progression. Dysregulation of histone deacetylases (HDACs) is frequently observed in leukemia and is correlated with poor prognosis and resistance to conventional therapies. This observation has led to the development of epigenetic drugs for leukemia treatment. The emergence of HDAC inhibitors (HDACis) as targeted therapeutics offers promising avenues for more selective and effective leukemia treatments. The present review covers basic aspects of histone modification and its role in leukemogenesis and evaluates the potential of peptide‑based HDACis as novel drugs for leukemia therapy.