PARP inhibitors have been approved for treating a subset of breast cancer patients harboring BRCA1/2 mutations. However, TNBC patients with wildtype BRCA1/2 have limited targeted therapeutic options. Dysregulation of protein arginine methyltransferase 5 (PRMT5) has been implicated in the progression of various cancers, including breast cancer. This study investigates the effects of two classes of PRMT5 inhibitors, GSK3326595 and TNG908, on breast cancer cell lines with different BRCA1/2 statuses to evaluate their therapeutic potential and synergy with PARP inhibitors. A panel of seven breast cancer cell lines was treated with PRMT5 and PARP inhibitors, followed by cell viability measurements using an MTT assay. Drug interactions were analyzed using the Loewe method on the Combenefit Software. Additionally, RT-qPCR was conducted to measure the expression of known DNA damage response genes. Synergy was observed in all cell lines, with BRCA1/2 wildtype cell lines displaying higher synergy scores than BRCA1/2 mutant lines, while the synergy was independent of MTAP status. Mechanistically, PRMT5 inhibition did not alter the early gene expression of known DNA damage response genes as measured by RT-qPCR. Notably, short-term PRMT5 inhibition was sufficient to sensitize an isogenic pair of ovarian cancer cells to subsequent PARP inhibition. These findings highlight the potential of combining PRMT5 inhibitors with PARP inhibitors in a wide range of cancers beyond BRCA1/2 and MTAP mutants. Further investigation is warranted to elucidate the underlying mechanisms of sensitization and the timing of cellular responses to PRMT5 inhibition.

Glucose 6-phosphate dehydrogenase (G6PD) is crucial for redox balance and biosynthesis via the pentose phosphate pathway (PPP), driving non-small cell lung cancer (NSCLC) proliferation. This study assessed the cytotoxic and enzymatic effects of five 1,2-naphthoquinone (NQ) derivatives, including SJ006 derived from Usnea barbata, in NSCLC cell lines (A549 and NCI-H292) compared to traditional inhibitors (DHEA and 6AN). All 1,2-NQs demonstrated concentration-dependent cytotoxicity against NSCLC cells. Among them, NN02 exhibited the highest cytotoxicity comparable to 6-AN, followed by NN01, NN04, SJ006, and SJ007, which showed moderate effects comparable to DHEA. SJ006 uniquely inhibited G6PD activity without altering its mRNA or protein expression. Unlike DHEA and 6AN, SJ006 functioned as an uncompetitive inhibitor, decreasing both K_m and V_max, with molecular docking confirming strong G6PD binding. Additionally, SJ006 increased reactive oxygen species (ROS) levels, induced G2/M cell cycle arrest, and triggered late apoptosis in NSCLC cells. Its effects were reversed by D-(-)-ribose, confirming PPP disruption as the mechanism. These results highlight SJ006 as a novel G6PD inhibitor that disrupts redox homeostasis and biosynthesis-driven cell proliferation, showing promise as an anticancer agent for NSCLC.

The current analysis aimed to evaluate the cost-effectiveness of benmelstobart plus anlotinib and chemotherapy for patients with ES-SCLC from the Chinese health-care system perspective. A mathematical decision model that simulated patients' 3-week transition in 20-year time horizon was conducted to evaluate the economic value. Survival and safety data were gathered from ETER701 trial, cost and utility values were obtained from the local charges and previously published studies. Sensitivity and subgroup analyses were performed to examine the robustness of the model results and to support the health-decision making. For intention-to-treat (ITT) patients, benmelstobart plus anlotinib and carboplatin/etoposide could bring additional 0.60 and 0.71 QALYs with marginal cost of $91,424.86 and $98,504.86 compared with anlotinib plus carboplatin/etoposide and carboplatin plus etoposide, respectively, resulting in an incremental cost-effectiveness ratios (ICERs) were $153,444.29/QALY and $138,272.39/QALY, respectively, which were higher than the Chinese willingness-to-pay (WTP) threshold. Sensitivity analyses and subgroup analyses confirmed the robustness of the model results when parameters changed. Benmelstobart plus anlotinib and carboplatin/etoposide was unlikely to be the cost-effective first-line strategy compared with anlotinib plus carboplatin/etoposide and carboplatin plus etoposide for ES-SCLC patients in China. Reducing the price of benmelstobart could increase its cost-effectiveness.

Multiple myeloma (MM) remains incurable, as most patients relapse or become refractory (RRMM), and the molecular nexus among clonal evolution, immune escape and therapy response remains unknown. Bulk RNA-seq from 24 MM to 6 matched marrows (subset of 132) plus single-cell datasets were analysed by differential expression, pseudotime, WGCNA, enrichment, immune deconvolution and GDSC drug screens. PRKD2 was knocked down (KD) or over-expressed (OE) in H929, 8226 and U266 cells. Viability (CCK-8) and apoptosis (Annexin V/7-AAD) were assessed after 48 h of axitinib (1.25-10 µM). PRKD2 was the sole gene uniformly up-regulated in newly diagnosed MM, RRMM and poor-survival cohorts, rising along the malignant plasma-cell trajectory. High PRKD2 aligned with ISS-III stage, elevated mRNAsi/EREG_mRNAsi and worse 5-year survival (38% vs. 73%, P = 0.012). PRKD2-KD reduced proliferation (~ 30%) and restored HLA-E, whereas PRKD2-OE suppressed antigen-presentation genes and polarised macrophages toward an IL-6/MERTK tumour-promoting phenotype. PRKD2-high marrow contained more naïve/memory B cells but fewer mature plasma cells. PRKD2 expression correlated positively with axitinib sensitivity (- log₁₀ IC₅₀, r = 0.68; P < 0.001). Experimentally, PRKD2-OE cells showed a 1.4-fold increase in axitinib-induced apoptosis, while PRKD2-KD cells were intrinsically pro-apoptotic and further sensitised; axitinib abolished the growth advantage conferred by PRKD2-OE. PRKD2 integrates secretory stress, stem-like programmes and immune evasion, driving aggressive MM yet exposing a vulnerability to VEGFR/PDGFR blockade. Direct PRKD2 targeting or axitinib-based combinations-including proteasome inhibition-deserve clinical evaluation for high-risk MM.

Lung squamous cell carcinoma (LUSC), representing approximately 25% of all lung cancer cases, is the second most prevalent histological subtype. While Family with sequence similarity 83 member A (FAM83A) is recognized as an oncogene across various tumors, its prognostic impact and biological roles specifically in LUSC have yet to be comprehensively elucidated. Our investigation explored the expression variability of the FAM83A gene and its implications for both patient prognosis and immune system modulation, utilizing data sourced from TCGA and the GEO. The scope of this analysis encompassed cohorts comprising 509 patients internally and 225 patients externally, specifically aimed at determining the prognostic significance of FAM83A expression. For methodological rigor, the larger internal cohort was systematically divided, with 60% forming a training set and the remaining 40% constituting a validation set, all assigned randomly. Through multivariate analysis that included clinicopathological factors and FAM83A expression assessed via immunohistochemistry (IHC), we identified key predictors for developing a novel LUSC prognostic model. Both internal and external validation sets utilized ROC curves, calibration curves, and DCA to evaluate the model's precision and clinical applicability. High levels of FAM83A mRNA expression in tumor tissues were linked to unfavourable outcomes for LUSC patients in both the TCGA and GEO datasets. Detailed analyses indicated that this upregulation of FAM83A mRNA is associated with increased immune cell infiltration and higher levels of immune regulatory gene expression. Retrospective analyses of patient samples further validated the relationship between elevated FAM83A protein expression and poorer prognoses. From these multivariate analysis results, we formulated a prognostic model incorporating four independent risk factors: elevated FAM83A expression, male gender, advanced disease stage, and poor differentiation. This model demonstrated strong predictive accuracy, confirmed by ROC and calibration curves, and DCA highlighted its substantial clinical relevance. FAM83A has been validated as a biomarker for forecasting outcomes in LUSC patients, leading to the development of predictive models based on this marker. Furthermore, FAM83A likely contributes to immunomodulatory processes within LUSC tissues.

One such prevalent kind of cancer among women is cervical cancer (CC). Fatality rates and incidence are progressively increasing, mainly in developing countries, due to a lack of experienced specialists, inadequate public awareness, and limited screening facilities. Nevertheless, CC cells exhibit composite textural features, and smaller changes among dissimilar cell subcategories result in greater challenges for the higher-accuracy screening of CC. This systematic analysis aims to assess the predictive value of artificial intelligence (AI) technologies for diagnosing, screening, and predicting CC and precancerous lesions. Deep learning (DL) and AI generally have a positive impact on computer-aided clinical diagnosis, particularly with the increasing accessibility of larger amounts of medical data that can aid AI methods in achieving high performance on various medical tasks. In this paper, a Fusion of Advanced Feature Reduction and Deep Representation Learning Approaches for Cervical Precancerous Lesion Classification (FAFRDRL-CPLC) technique using biomedical image analysis is proposed. The primary purpose of the FAFRDRL-CPLC technique is to serve as a valuable tool for assisting clinicians in the initial study and treatment planning of cervical precancerous lesions. Initially, the FAFRDRL-CPLC approach applies an anisotropic diffusion filtering (ADF) method for pre-processing to reduce noise while preserving crucial edges and lesion details. Furthermore, the fusion of advanced feature reduction models, such as the maximally scalable vision transformer (MaxViT-v2), the simple framework for contrastive learning of visual representations (SimCLR), and the Twins-spatially separable vision transformer (Twins-SVT) models, is employed to capture diverse and complementary representations from the pre-processed images. Finally, the stacked auto-encoder (SAE) classifier is utilized for the precancerous lesion detection process. The FAFRDRL-CPLC method is examined through experimentation using the Malhari dataset. The comparison study of the FAFRDRL-CPLC method demonstrated a superior accuracy value of 98.62% over existing approaches.

Plant-associated fungal endophytes hold great potential to synthesize metabolites similar to their host, with potential anticancer effects. The present study aims to identify lead compound in the ethyl acetate (EA) extract of fungal endophyte, Penicillium oxalicum, associated with a medicinal plant Amoora rohituka, responsible for the anti-breast cancer activity. The crude extract of P. oxalicum was subjected to High-performance liquid chromatography (HPLC) analysis and further, bioactivity-guided fractionation was performed for HPLC fractions based on cell viability assay. The potential fraction further showed dose-dependent generation of nitric oxide in breast cancer cells that indicates their activity in the induction of oxidative stress. The characterization of potential fraction was done using different analytical techniques, such as liquid chromatography coupled with quadrupole time of flight mass spectrometry (LC-Q-TOF-MS), high-resolution mass spectrometry (HRMS), Fourier transform-infrared (FTIR) spectroscopy, and both ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy that validates the mass, structure, and functional groups of the lead compound, identified as Phytosphingosine. Further, DAPI assay revealed Phytosphingosine induced alteration of nuclear morphology in breast cancer cells, indicating apoptotic events. The blood compatibility of Phytosphingosine was evidenced through hemolysis assay, thus suggesting its safety profile. This is the first report of the purification and characterization of Phytosphingosine from P. oxalicum, exhibiting anti-breast cancer activity. The cytotoxic potential of Phytosphingosine against MDA-MB-231 and MCF-7 cells suggests further exploration to elucidate its molecular cross-talks and signalling pathways to develop targeted therapy against BC.

Growing evidence has revealed that N6-Methyladenosine (m6A) modification is crucial in cancer development, yet its role in hepatocellular carcinoma (HCC) remains unclear. To address this, we developed a novel m6A regulator-based prognostic signature (m6A-RPS) using comprehensive bioinformatics analysis of TCGA, GEO, and ICGC datasets. Our analysis revealed widespread dysregulation of m6A regulators in HCC tissues. Unsupervised consensus clustering further revealed distinct m6A methylation subtypes with significant survival differences, indicating the potential of m6A modification patterns in prognostic stratification for HCC. Using TCGA-LIHC cohort, LASSO Cox regression selected five key hub regulators (VIRMA, YTHDF1, YTHDF2, YTHDC1, IGF2BP3) to construct the m6A-RPS model.​​ This model proved to be a powerful and independent prognostic indicator (HR = 2.849 (1.819-4.461), P < 0.001), and validated in external cohort (ICGC-LIRI-JP). Patients with high m6A-RPS scores exhibited significantly poorer overall survival and progression-free interval, and the scores were positively correlated with adverse clinical characteristics (e.g., advanced stage, vascular invasion). ​ To facilitate clinical translation, we developed a nomogram that integrated the m6A-RPS with key clinical variables for individualized survival prediction.​​ Genomically, the high-risk group exhibited higher tumor mutation burden and mutation rates in hub regulators. Functional enrichment analyses implicated dysregulation in critical pathways like Wnt signaling, DNA replication, and cell cycle. Crucially, m6A-RPS stratified the tumor immune microenvironment: high-risk patients displayed an immunosuppressive phenotype characterized by enriched Th2 cells and higher potential for immune escape, whereas low-risk patients showed enhanced cytotoxic immune infiltration and elevated immunophenoscores, suggesting greater potential responsiveness to immune checkpoint inhibitors. Differential sensitivity to chemotherapy agents was also predicted. Finally, we constructed a regulatory network linking miRNAs, hub regulators, and 2 downstream target genes. Our study establishes m6A-RPS as a robust tool for prognosis prediction and immune landscape assessment in HCC, offering significant potential to guide personalized therapeutic strategies, particularly immunotherapy selection.

Linked color imaging (LCI) was developed to detect gastrointestinal neoplasms. The current study aimed to determine whether the use of LCI, compared with white-light imaging (WLI), can improve the miss rates of colorectal polyp. A multicenter, randomized back-to-back study was conducted in 16 Japanese endoscopy units. Patients were randomized according to examination: tandem colonoscopy with WLI followed by LCI (WLI-LCI group) and with LCI followed by WLI (LCI-WLI group). The detected polyps were evaluated according to location, size, morphology, and histopathological diagnosis. The primary outcome was polyp miss rate per patient (PMR-PP) in total colonoscopy. The secondary outcome was adenoma detection rate (ADR) during the first assessment in each group. The full analysis set comprised 327 participants, and 320 were included in either two groups. The PMR-PPs were 9.3% and 20.6% in the LCI-WLI and WLI-LCI groups, respectively. Regarding location, the PMR-PP of LCI was significantly lower than that of WLI in the transverse and descending colons and rectum. In terms of diminutive adenomas (< 5 mm), the ADR of LCI (38.2%) was significantly higher than that of WLI (29.1%). LCI was superior to WLI in terms of polyp miss rate particularly in the transverse and descending colons and rectum.

Kidney renal clear cell carcinoma (KIRC), as one of the most angiogenically active urological tumors, has not yet been fully elucidated its molecular mechanisms. Molecules interacting with CasL-Like 2 (MICAL-L2), a unique oxidoreductase, is known to be involved in cytoskeletal regulation. However, its role and mechanism in tumor angiogenesis remain unclear. This study aims to reveal the specific mechanism by which MICAL-L2 regulates KIRC angiogenesis through cytoskeletal dynamics and to explore its clinical translational value and significance. Bioinformatics database analysis showed that MICAL-L2 was significantly overexpressed in various solid tumors and was closely associated with shorter overall survival in KIRC patients. Gene set enrichment analysis demonstrated that MICAL-L2 expression was significantly correlated with members of the hypoxia-inducible factor (HIF) family and was closely related to angiogenesis pathways. Analysis of human KIRC cell lines revealed that the upregulation of MICAL-L2 stimulated the release of various pro-angiogenic cytokines, primarily through the activation of a novel mTOR/HIF1α/VEGF pathway, promoting tumor angiogenesis. Further studies using cultured KIRC cell lines unveiled that MICAL-L2 co-localized with F-actin in the cytoplasm and promoted tumor angiogenesis remodeling in vitro. Additionally, analysis of clinical datasets indicated that high expression of MICAL-L2 was associated with drug resistance to various anti-angiogenic agents and actin inhibitors in cancer. This study reveals a new mechanism in which MICAL-L2, under the tumor hypoxic environment, promotes KIRC angiogenesis and progression by activating the "cytoskeletal remodeling-mTOR/HIF1α/VEGF signaling pathway" using integrated analysis of clinical samples and cell models, providing new theoretical evidence and potential intervention targets for the development of combination therapies targeting the tumor microenvironment.