BackgroundDrug resistance, characterized by high heterogeneity and complex mechanisms, poses a significant challenge in cancer treatment. Stratifying resistant tumors into biologically and clinically meaningful subgroups can improve prognostic evaluation and help guide treatment decisions. However, the DNA methylation-based subtypes of resistant tumors have not yet been comprehensively characterized.ResultsDNA methylation profiles from resistant tumors were retrieved from public database including TCGA and GEO. For each tumor type resistant to a specific treatment drug, consensus clustering based on the most variable methylated probes was conducted to identify the DNA methylation subtypes of resistant tumors. For low-grade glioma (LGG) resistant to Temozolomide, consensus clustering of highly variable CpGs identified two subtypes: cancer resistance CpG island methylator phenotype-positive (CR_CIMP+) and -negative (CR_CIMP-). The CR_CIMP- subtype associates with poorer prognosis, reduced drug response, and more advanced histology, exhibiting higher tumor mutation burden and greater activity in drug resistance-related pathways, such as PI3K/AKT/mTOR signaling. CR_CIMP subtypes with distinct clinical or molecular features were also identified in pancreatic adenocarcinoma and bladder urothelial carcinoma resistant to Gemcitabine, as well as in non-small cell lung cancer resistant to anti-PD1/PD-L1 immunotherapy. Based on predicted drug responses, the study screens candidate drugs for each CR_CIMP subtype. Finally, a random forest model is proposed to predict CR_CIMP subtypes in LGG patients resistant to Temozolomide.ConclusionsThis study uncovers DNA methylation subtypes within resistant tumors, enabling more precise stratification to inform prognosis and therapy selection.

Triple-negative breast cancer (TNBC) exhibits addiction to chronic endoplasmic reticulum (ER) stress, which sustains an aggressive metastatic phenotype through activation of the unfolded protein response (UPR). Here, we identify a previously unrecognized "ER-stress addiction" axis in which the Hippo pathway effector TEAD4 directly transcriptionally upregulates the ER chaperone PDIA4. We further demonstrate that this axis can be pharmacologically targeted by a natural polysaccharide. Tetrastigma hemsleyanum polysaccharide (THP) selectively activates the Hippo kinase cascade, leading to YAP phosphorylation, cytoplasmic sequestration, and subsequent degradation. This cascade attenuates YAP/TEAD4 interaction and abolishes TEAD4 DNA-binding activity. Moreover, THP downregulates TEAD4 expression. These combined effects drive transcriptional suppression of PDIA4, catastrophic disruption of ER proteostasis, and ultimately lethal ER stress in TNBC cells. Functionally, THP inhibits migration, invasion, angiogenesis, and intracellular Ca2 + flux in vitro, and-importantly-blocks metastasis in patient-derived organoids, zebrafish xenografts, and two syngeneic mouse models at non-toxic doses. Multi-omics analyses and rescue assays confirm the TEAD4-PDIA4 axis as the core functional module. Our findings establish THP as a first-in-class, natural-product-based therapeutic that disrupts ER-stress addiction in metastatic TNBC by targeting the Hippo-YAP/TEAD4-PDIA4 axis.

Liver fibrosis is a crucial and potentially reversible stage in the progression from chronic liver diseases towards liver cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress is closely related to hepatic stellate cell (HSC) activation and liver fibrosis. Liver fibrosis is frequently accompanied by a global increase in hepatic protein methylation. This suggests that there may be potential unexplored connections among ER stress, protein methylation, and liver fibrosis. Here, we identify PRMT1-mediated methylation of the ER chaperone GRP94 at arginine 395 as a critical event that drives HSC activation and liver fibrogenesis. Using proteomic profiling of liver tissues from mouse models induced by carbon tetrachloride (CCl4) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), combined with studies in human hepatic stellate cells (primary HSCs and the LX2 cell line), we identify that methylation of GRP94 stabilizes the protein by inhibiting its ubiquitination. This modification potentiates the PERK–eIF2α–ATF4 arm of the ER stress response, leading to upregulation of the fibrogenic genes ACTA2 and COL1A1 and promoting HSC activation. Pharmacological inhibition of PRMT1 with MS023 reverses GRP94 methylation, suppresses HSC activation, and attenuates fibrosis progression in both cellular systems and murine models. This finding positions the crosstalk between ER stress and protein arginine methylation as a central node in the pathogenesis of liver fibrosis, suggesting that targeting the methylation of GRP94 may be a potential therapeutic strategy of liver fibrosis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by rapid proliferation and a great propensity for metastasis. Therapeutic options for TNBC remain limited due to the absence of targetable hormone receptors. While BET bromodomain inhibitors (BBDIs) exhibit promising anticancer potential, the emergence of drug resistance presents a major challenge. Here, through leveraging single-cell RNA sequencing (scRNA-seq) data across continuous states of BBDI treatment in TNBC, this study conducts an extensive investigation into BBDI resistance, and develops two computational frameworks, FR20 and D-FR20, to quantify BBDI resistance at single-cell resolution and to screen potential BBDI re-sensitizer drugs, respectively. The accuracy and scalability of FR20 are confirmed through rigorous evaluation in nine independent datasets. In addition, cellular dynamic changes and ferroptosis inhibition are revealed in the evolution of BBDI resistance. Experimental validation demonstrates that GPX4 overexpression significantly reduces drug sensitivity in TNBC cells. Furthermore, in vitro and in vivo experiments validate the ability of the small molecule filgotinib, identified by D-FR20, to re-sensitize BBDI and effectively eliminate resistant TNBC cells. Collectively, this study provides two computational frameworks for predicting BBDI resistance and candidate re-sensitizer, as well as demonstrates the roles of ferroptosis in BBDI resistance, offering a promising avenue for TNBC treatment.

Glioblastoma (GBM) is a highly aggressive intracranial malignancy originating from neuroepithelial glial progenitors. The prominent intra- and intertumoral heterogeneity of GBM is a major driver of therapeutic resistance and frequent tumor recurrence. Cholesterol is an essential structural component of mammalian cell membranes and plays crucial roles in membrane trafficking and transmembrane signal transduction. As a key intracellular cholesterol transporter, the Niemann-Pick type C2 (NPC2) protein remains poorly characterized regarding its biological functions and clinical implications in GBM. In this study, immunohistochemical staining of clinical GBM specimens revealed that elevated NPC2 expression was significantly correlated with unfavorable patient prognosis. Consistent with clinical observations, genetic knockdown of NPC2 markedly suppressed the proliferation and invasion abilities of LN18 cells. Mechanistically, NPC2 silencing downregulated GPX4 expression at both transcriptional and translational levels, suggesting a potential regulatory relationship between NPC2 and the ferroptosis pathway. Collectively, these findings indicate that NPC2 may facilitate GBM malignant progression partially through modulating GPX4-mediated ferroptosis, thereby representing a tentative prognostic biomarker and a potential therapeutic target for GBM that requires further validation.

Although jet electrodeposition allows for the deposition of composite coatings at higher current densities, achieving high-efficiency electrodeposition of nanocomposite coatings remains challenging due to edge effects caused by excessive current density and nanoparticle agglomeration during composite electrodeposition. This study explored friction-assisted jet electrodeposition of nanocomposite coatings, focusing particularly on the friction-assisted process at high current densities. The developed friction-assisted electrodeposition is expected to be applicable and beneficial for the electrodeposition of nanocomposite coatings. The micromorphology, microstructure, microhardness and wear resistance of the composite coatings were systematically evaluated, and the mechanism of friction-assisted jet electrodeposition of nanocomposite coatings was revealed. The results indicated that the friction assistance effectively disperses the nanoparticle agglomeration, obtaining a more uniform and smoother nanocomposite coating. Furthermore, the friction-assisted process does not change the microstructure of the coating growth, yet it significantly improves their microhardness and wear resistance, Notably, the performance of the friction-assisted jet electrodeposited Ni-Co/YSZ composite coating is the best at a particle concentration in the bath of 4 gL-1. However, friction-assisted jet electrodeposition is still not suitable for the deposition of excessively high amounts of nanoparticles, mainly because the agglomeration of nanoparticles causes them to settle inside the electrolytic cell and cannot participate in the flow of the electrolyte for effective deposition. This work investigated the effect of friction assistance on the properties of nanocomposite coatings deposited by jet electrodeposition at high current densities. This study demonstrated that friction-assisted jet electrodeposition effectively enabled the deposition of nanocomposite coatings at high current densities, providing a new reference for achieving efficient, high-quality nanocomposite coatings through the brushing effect of insulating fibres on the cathode surface.

Chinese sturgeon (Acipenser sinensis) is an endangered anadromous and rare fish. The ovary development from stage II to III is being challenged by captive conditions, which seriously hinders the artificial reproduction of Chinese sturgeon. A comparative proteomic analysis on the ovaries at stage II and stage III of Chinese sturgeon was conducted in this study using the label-free quantitative method to uncover the intricate physiological processes. The findings revealed 200 up-regulated differentially expressed proteins (DEPs) and 150 down-regulated DEPs in the ovary at stage III compared with stage II, and 11 DEPs (including UCHL1, VTG, CTSD, and ZP, etc.) involved in the vitellogenesis and oocyte growth. Moreover, the up-regulated DEPs exhibited significant enrichment in the pathways linked to protein synthesis (ribosome, protein processing in the endoplasmic), metabolism and energy production (valine, leucine and isoleucine degradation, TCA cycle, oxidative phosphorylation, and fatty acid degradation), suggesting more active protein processing and energy metabolism at stage III. Meanwhile, APOB was down-regulated while VTG was up-regulated in stage III ovary, indicating the uptake of yolk protein and lipid through VTG at this stage. The parallel reaction monitoring (PRM) quantification of 16 DEPs solidly validated the outcomes of label-free analysis. This study provided powerful information for understanding the physiological processes of ovarian development in Chinese sturgeon, and potential biomarkers in predicting the vitellogenic stage.

Increasing evidence indicates that non-coding RNAs (ncRNAs) have emerged as essential factors in most biological processes through diverse mechanisms. However, the biological functions of most ncRNAs are still poorly understood. Here, we developed ncFN, a novel and comprehensive framework for ncRNA function annotation based on a global and heterogeneous biomolecular network. Specifically, we constructed a Global Interaction Network (GIN) by integrating ncRNA-ncRNA, ncRNA-protein coding gene (PCG), and PCG-PCG interactions. The GIN consists of 565,482 edges connecting 17,060 PCGs and 12,616 ncRNAs, including 1095 microRNAs (miRNAs), 3563 long non-coding RNAs (lncRNAs), and 7958 circular RNAs (circRNAs). For each ncRNA, we quantified Association Strengths (ASs) between the ncRNA and PCGs through Random Walk with Restart in GIN. Then, Gene Set Enrichment Analysis was performed with ASs as input to annotate the function of the ncRNA. Compared to most conventional methods that only focus on a single ncRNA type, ncFN offers significant advantages in covering diverse ncRNA types and a larger number of ncRNA molecules. Moreover, we demonstrated the superiority of ncFN by comparing it with other methods in the annotation of well-acknowledged disease-relevant ncRNAs and differentially expressed ncRNAs in diseases. Finally, ncFN also facilitated enrichment analysis with multiple ncRNAs or pathways as input. In conclusion, ncFN is a comprehensive and reliable tool for functional annotation of miRNAs, lncRNAs, and circRNAs, making it highly suitable for widespread use in ncRNA research. ncFN is freely accessible at http://www.jianglab.cn/ncFN/, and all codes are deposited on GitHub (https://github.com/LongMin0705/ncFN).

Ni-Co alloy-based nanocomposite coatings are widely used in the engineering field due to their excellent physical and chemical properties. The co-deposition of Al2O3-reinforced Ni-Co alloy was successfully achieved using ultrasonic-assisted jet electrodeposition. The effects of ultrasonic power and Al2O3 concentration on deposition morphology, surface roughness, adhesion, microhardness, abrasion resistance and self-corrosion properties of Ni-Co coatings were systematically investigated. A favorable Al2O3 concentration of approximately 3 g/L in the electrolyte and an ultrasonic power density of 8 W cm-2 were found to result in improved micro-hardness, adhesion, wear resistance, corrosion resistance, and the highest Al2O3 incorporation within the tested range. Under these conditions, the coating exhibited a micro-hardness of 623 HV, an adhesion strength of 36.8 N, a wear track width of 346.8 mu m, and a corrosion current density of 5.20 mu A cm-2, indicating excellent comprehensive properties. This study provides valuable insights for the development of environmentally friendly industrial alternatives to conventional hard chromium coatings and demonstrates promising potential for applications in marine engineering.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet the response rate remains limited, with only about 30% of solid tumor patients benefiting. Identifying reliable biomarkers to predict ICIs response remains a significant challenge. In this study, we proposed a refined Hallmark gene set-based Approach for Predicting Immunotherapy Response (HAPIR). Through comprehensive multi-cohort analyses encompassing six TIGER cohorts (n = 352) and TCGA-SKCM (n = 472), we validated the optimal performance of HAPIR. Using transcriptomic data from a training cohort, we firstly refined seven Hallmark gene sets enriched with differentially expressed genes between responder and non-responder patients. Then, a logistic regression model trained based on the activities of these gene sets demonstrated superior predictive performance (AUROC = 0.778) in ten-fold cross-validation, significantly outperforming 13 existing biomarkers, including PD-1 (AUROC = 0.678) and PD-L1 (AUROC = 0.54). HAPIR’s robustness was further validated in the validation set and four independent cohorts spanning multiple cancer types (melanoma, NSCLC, and STAD), consistently achieving average AUROC = 0.745. Beyond well-known biomarkers, HAPIR surpassed both gene-based and alternative gene set-based models. Importantly, HAPIR scores correlated significantly with patient survival and effectively recapitulated the immune microenvironment, enabling the prediction of potential drug targets and drug candidates to overcome immunotherapy resistance. In conclusion, HAPIR is a promising tool for predicting ICIs response and guiding the development of new immunotherapy strategies.

Patients have a limited response rate to immune checkpoint inhibitors (ICIs) therapy. Although several biomarkers have been proposed, their ability to accurately predict the response to ICIs therapy remains unsatisfactory. In addition, mutational signatures were validated to be associated with ICIs therapy. Therefore, we developed a mutational signature-based biomarker (MS-bio) to predict the response to ICIs therapy. Based on differentially mutated genes, we extracted six mutational signatures (single-base substitution (SBS)-A, SBS-B, SBS-C, SBS-D, double-base substitution (DBS)-A, and DBS-B) as MS-bio, and constructed a random forest (RF) model to predict the response. Internal and external validations consistently demonstrated the excellent predictive capability of MS-bio, with an accuracy reaching up to 0.82. Moreover, MS-bio exhibited superior performance compared to existing biomarkers. To further validate the accuracy of MS-bio, we explored its performance in The Cancer Genome Atlas (TCGA) cohort and found that the predicted responders were immunologically "hot". Finally, we found that SBS-C had the highest importance in prediction and was related to T cell differentiation. Overall, here we introduced MS-bio as a novel biomarker for accurately predicting the response to ICIs therapy, thereby contributing to the advancement of precision medicine.

Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK+CD8+CD27+CCR7+ T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.

During the yolk stage, the nutrients of larvae consumed are from the yolk sac, which greatly affect the survival and quality of fish. The aim of this study was to investigate the metabolic changes, physiological characteristics and the related molecular mechanism of Chinese sturgeon ( Acipenser sinensis) larvae during yolk stage by biochemical analyses in combination with transcriptome analysis of larvae at three developmental stages (vertical, flat and benthic). The results showed that both total amino acid and protein contents showed a trend of first decreasing and then increasing. The lipid content was stable in the early stages, but decreased significantly in the benthic stage (P < 0.05). In terms of amino acid profile, the contents of leucine, isoleucine and lysine were relatively high in essential amino acids (EAAs), and the contents of glutamate, aspartate and serine were relatively high in non-essential amino acid (NEAA). As for fatty acid content, the most abundant fatty acids are C16:0 (palmitic acid), C18:1 (oleic acid), C18:2n-6 (linoleic acid) and C22:6n-3 (docosahexaenoic acid, DHA). The results of transcriptome analysis showed that 4936 genes were up-regulated and 3079 genes were down- regulated from vertical stage to flat stage, and 1703 genes were up-regulated and 837 genes were down- regulated from flat stage to benthic stage, respectively. According to KEGG enrichment analysis on the differentially expressed genes (DEGs), the up-regulated DEGs mGlu3, mGlu5, NMDAR, PepT1, TAT1, EAAT3, CYP51A1 and CYP7A1 were significantly enriched in pathways related to the nervous system, protein digestion and absorption, steroid synthesis, cholesterol metabolism and bile acid biosynthesis in early development of larvae. Down-regulated DEGs Drg1, NHP2, KRE33 and MPP10 were enriched in the ribosome biogenetic pathway. In late development, up-regulated DEGs, cGAS, IRF3, TRAF2, MHC-I, MHC-II and TAR2, were enriched in pathways associated with innate and adaptive immunity. Down-regulated DKK2 and FGFRs, ITGAs were enriched in Wnt signaling pathway and PI3K-AKT pathway, respectively. In summary, this study revealed that the larval fish consumed protein as the main nutrient from the vertical stage to the flat stage, while mainly consumed lipid from the flat stage to the benthic stage, and highlighted the pathways of DEGs involved in the nervous system and immune system, which would provide new ideal to the high quality larvae production in Chinese sturgeon, thus benefit species protection.

This work reported the in-situ fabrication of insulating and corrosion-resistant coatings on the surface of 6061 aluminum alloy using the plasma electrolytic oxidation (PEO) process associated with laser surface melting (LSM) pretreatment and the incorporation of nano-AlN particles. The results show that LSM pretreatment can significantly reduce the large surface pores in the PEO coating and thus enhance the resistance to corrosion. Furthermore, nano-AlN particles can also be embedded into the coating under electrophoretic forces and react with molten oxides at high temperature to form composite phases. These nanoparticles simultaneously act as inert fillers and seal discharge channels and micropores, thereby improving the coating corrosion resistance and insulating performance. When the Al substrate was pre-treated with a 30 W laser followed by 20 minutes of PEO treatment, the breakdown voltage was significantly increased to 1233 +/- 20 V during the electrical insulation performance test. The results demonstrate that the LSM pretreatment is extremely powerful and efficient to improve the insulation and corrosion resistance of 6061 Al substrate, and further property enhancement can be achieved via the incorporation of insulating nano-AlN particles in the PEO-coating.

Indisulam, a sulfonamide-based compound, is employed as a second-line therapy for NSCLC due to its anti-tumor activity. However, its clinical efficacy is hindered by acquired resistance, the molecular basis of which remains poorly understood. Here, we demonstrate that hypermethylation of RNA-binding protein 39 (RBM39), a specific target of Indisulam, is closely associated with Indisulam resistance. PRMT6 methylates RBM39 at R92. This methylation inhibits Indisulam-induced ubiquitination and proteasomal degradation of RBM39, increases RBM39 protein levels, promotes alternative splicing and expression of proto-oncogenes, and ultimately leads to malignant proliferation and metastasis of NSCLC cells and tumor growth in xenograft mouse models. Inhibiting PRMT6 with MS023 or mutating the RBM39 methylation site enhances Indisulam sensitivity in NSCLC and significantly improves its anti-tumor efficacy. Our findings identify methylated RBM39 as a key biomarker of Indisulam resistance and suggest a potential therapeutic strategy for NSCLC.

Space ionizing radiation is a major risk factor for astronauts, yet its molecular mechanisms remain poorly understood. This study employs an integrative approach to investigate the effects of space ionizing radiation on molecules, modules, biological functions, associated diseases, and potential therapeutic drugs. Using paired samples from five donors subjected to acute ex vivo 2Gy gamma-ray irradiation, we analyzed miRNA and gene expression profiles in human peripheral blood lymphocytes collected 24 h post-exposure, combined with heterogeneous network analysis, identifying 179 key molecules (23 transcription factors, 10 miRNAs, and 146 genes) and 5 key modules. Functional enrichment analysis revealed associations with processes such as cell cycle regulation, cytidine deamination, cell differentiation, viral carcinogenesis, and apoptosis. Radiation was also significantly linked to neoplasms and digestive system diseases. Furthermore, we predicted 20 potential therapeutic compounds, including small molecules (e.g., Navitoclax) and Traditional Chinese Medicine ingredients (e.g., Genistin, Saikosaponin D), which may alleviate radiation-induced damage such as pulmonary fibrosis and oxidative stress. These findings provide novel insights into the molecular mechanisms of space ionizing radiation and may contribute to developing effective strategies to protect astronaut health during space missions.

In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable the development of metabolism-targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long noncoding RNA small nuclear RNA host gene 17 (SNHG17) and unfavorable prognosis in breast cancer. SNHG17 promoted breast cancer cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the P65 subunit of NF-κB and phosphorylated P65 at the threonine 505 site. SNHG17 bound to P65 at its truncated loop2 site, recruited P65 to mitochondria, and coregulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an antisense oligonucleotide significantly reduced breast cancer tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting breast cancer progression by increasing ATP production and provided insights into the reprogramming of energy metabolism in solid tumors. Significance: SNHG17 cooperates with NF-κB to induce expression of mitochondrial DNA and boost ATP production in breast cancer, suggesting that targeting SNHG17 could reverse metabolic reprogramming to suppress tumor progression.

Background: Prostate cancer (PCa), a prevalent malignant neoplasm in men, has its biochemical recurrence-free survival (BCRFS) serving as a critical determinant for patient prognosis. PARP inhibitors have demonstrated potential therapeutic value in the management of PCa. Nevertheless, the precise influence exerted by their associated genes on BCRFS remains elusive. Methods: We selected the differentially expressed genes after treatment with olaparib and defined them as PARP inhibitor-related genes (PIRGs). Consensus clustering was employed to evaluate the relationships among different PIRGs clusters, prognosis, and the immune microenvironment. Univariate COX regression analysis was used to screen the prognosis-related PIRGs, which were then incorporated into multiple machine learning frameworks. The random forest algorithm with the highest C-index was chosen to construct a BCRFS prediction model. A prognostic nomogram was developed based on the risk score and clinical information, and the predictive performance of the model was assessed. Results: In C4 - 2B and LNCaP cell lines, 230 and 58 genes were differentially expressed, respectively. Consensus clustering results showed distinct survival prognoses and immune - infiltrated microenvironments among different groups. The random forest model had a high average C - index in both the training and validation sets. The prognostic model constructed in this study demonstrated a higher C-index compared to the prognostic models from previous studies. High - risk group patients had a poor immunotherapy response. A nomogram based on risk scores and clinical information accurately predicted PCa patients' BCRFS. Cell experiments revealed that KANK3 was downregulated in PCa and upregulated by olaparib treatment. KANK3 overexpression in PCa cell lines inhibited cell proliferation, migration, and invasion, suggesting its oncogenic role in PCa. Conclusion: Our study has described the correlations between PARP inhibitor-related genes and the immune landscape, recurrence after radical prostatectomy, as well as clinical characteristics. The risk score can improve the existing risk stratification system.

Dysregulation of adenosine-to-inosine (A-to-I) RNA editing has been implicated in cancer progression. However, a comprehensive understanding of how A-to-I RNA editing is incorporated into miRNA regulation to modulate gene expression in cancer remains unclear, given the lack of effective identification methods. To this end, we introduced an information theory-based algorithm named REMR to systematically identify 12,006 A-to-I RNA editing-mediated miRNA regulatory triplets (RNA editing sites, miRNAs, and genes) across ten major cancer types based on multi-omics profiling data from The Cancer Genome Atlas (TCGA). Through analyses of functional enrichment, transcriptional regulatory networks, and protein-protein interaction (PPI) networks, we showed that RNA editing-mediated miRNA regulation potentially affects critical cancer-related functions, such as apoptosis, cell cycle, drug resistance, and immunity. Furthermore, triplets can serve as biomarkers for classifying cancer subtypes with distinct prognoses or drug responses, highlighting the clinical relevance of such regulation. In addition, an online resource (http://www.jianglab.cn/REMR/) was constructed to support the convenient retrieval of our findings. In summary, our study systematically dissected the RNA editing-mediated miRNA regulations, thereby providing a valuable resource for understanding the mechanism of RNA editing as an epitranscriptomic regulator in cancer.

Guideline recommendations for the application of neoadjuvant chemotherapy (NACT) in T2N1M0 stage hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer are ambiguous. The debate continues regarding whether NACT or adjuvant chemotherapy (ACT) offers superior survival outcomes for these patients. Female patients diagnosed with HR + /HER2- breast cancer at T2N1M0 stage between 2010 and 2020, were identified from the Surveillance, Epidemiology, and End Results database and divided into two groups, the NACT group and the ACT group. Propensity score matching (PSM) was utilized to establish balanced cohorts between groups, considering baseline features. Kaplan–Meier (K-M) analysis and the Cox proportional hazards model were executed to assess the efficacy of both NACT and ACT in terms of overall survival (OS) and breast cancer-specific survival (BCSS). A logistic regression model was employed to examine the association between predictive variables and response to NACT. After PSM, 4,682 patients were finally included. K-M curves showed that patients receiving NACT exhibited significantly worse OS and BCSS when compared with patients undergoing ACT. Multivariable Cox analysis indicated that not achieving pathologic complete response (non-pCR) after NACT (versus ACT), was identified as an adverse prognostic factor for OS (HR 1.58, 95