ATM deficiency is frequently observed in castration-resistant prostate cancer (CRPC). However, effective therapeutic vulnerabilities associated with this genetic alteration remain poorly defined. This study aimed to identify synthetic lethal strategies that selectively target ATM-deficient prostate cancer cells.

An unbiased small-molecule compound screening was performed to identify agents exhibiting selective cytotoxicity in ATM-deficient prostate cancer cells. Candidate vulnerabilities were validated across multiple prostate cancer cell lines with genetic depletion or restoration of ATM. Mechanistic studies were conducted using molecular and biochemical assays to assess DNA damage, replication stress, and PARylation dynamics. In vivo efficacy was evaluated using ATM-deficient xenograft tumor models.

ATM-deficient prostate cancer cells exhibited marked sensitivity to pharmacological inhibition of poly (ADP-ribose) glycohydrolase (PARG) using with PDD00017273, an effect that was consistently observed across multiple cell lines and partially restored by ATM re-expression. Mechanistically, PARG inhibition induced persistent PARylation in ATM-deficient cells, not via canonical DNA double-strand break signaling, but via misincorporated ribonucleotides processed by topoisomerase 1 during DNA replication. This replication-associated PARylation resulted in severe replication stress, checkpoint activation, and accumulation of DNA double-strand breaks, ultimately leading to cell death. This cytotoxic mechanism is distinct from classical PAR-dependent cell death pathways, including NAD⁺ depletion and parthanatos. In vivo, PARG inhibition significantly suppressed the growth of ATM-deficient xenograft tumors cells.

This study identifies PARG inhibition as a previously unrecognized synthetic lethal vulnerability in ATM-deficient prostate cancer. These findings establish a mechanistic link between ATM loss, aberrant ribonucleotide processing, and replication-associated PARylation, supporting the clinical development of PARG inhibitors as a precision therapeutic strategy for ATM-deficient prostate cancer and potentially other malignancies harboring ATM deficiency.

Early lymph node (LN) metastasis often precedes systemic metastasis and corresponds with significantly inferior survival for patients diagnosed with early-stage breast cancer (EBC). To understand the biological pathways involved in early LN metastasis, differential gene expression (DGE) analysis compared large tumors without evidence of LN metastasis (pT2-3pN0) to small tumors with LN metastasis (pT1pN+).

This study included 2,349 patients with EBC who underwent MammaPrint and BluePrint testing as part of the FLEX (NCT03053193). DGE was performed between pT2-3pN0/pT1pN + and across their MP/BP subtypes. Immune deconvolution was assessed using gene-signature-based methods, complemented by conventional tumor-infiltrating lymphocyte (TIL) analyses on a representative subset of patients.

Greater DGE was observed within the MammaPrint High Risk and BluePrint Luminal B subgroups compared to pathological stages. MammaPrint High Risk tumors saw 73 differentially expressed genes (DEGs), while 34 were found for Luminal B tumors. Gene set enrichment analysis (GSEA) of MammaPrint High Risk/Luminal B tumors showed upregulated proliferation pathways and downregulated epithelial-to-mesenchymal transition (EMT) and immune profiles in pT2-3pN0 vs. pT1pN+, respectively. Immune deconvolution analyses showed a higher abundance of T gamma delta cells and CD4 + Th1 cells and a lower abundance of T regulatory cells, M2 macrophages, and cancer-associated fibroblasts within pT2-3pN0 tumors. Conventional histological assessment revealed no significant differences in TILs.

This study lays the groundwork for exploring mechanisms of LN metastasis in EBC and their relation to MammaPrint High Risk and Luminal B subtypes. These data support previous studies' association of LN metastasis with EMT and immune dysregulation.

Primary infertility affects 15% of couples worldwide, yet many genetic causes remain unknown. Through whole-exome sequencing of a woman with primary infertility and repeated embryo implantation failure, we identified a novel homozygous frameshift mutation in GREB1 (c.5364delC, p.Ala1789Argfs∗42). Sanger sequencing confirmed heterozygous carrier status in both parents. Functional studies demonstrated the absence of nonsense-mediated mRNA decay but abnormal GREB1 protein expression via western blotting. Computational modeling predicted pathogenic structural alterations. This variant is absent in gnomAD/ExAC databases. Our findings establish GREB1 mutations as a novel cause of female infertility, highlighting its role in endometrial receptivity regulation.

Thyroid hormone receptor-interacting protein 13 (TRIP13), an enzyme from the AAA-ATPase family, facilitates the assembly or disassembly of protein complexes and participates in various biological processes. However, its impact on cancer immune infiltration and pan-cancer prognosis remains largely unexplored.

Pan-cancer multi-omics data from publicly available resources were systematically analyzed to evaluate TRIP13 expression across various cancer types and its association with patient prognosis. In addition, functional enrichment analyses were conducted to investigate TRIP13-related biological processes and pathways. The analysis included GSEA enrichment, correlation with immune regulator expression, tumor immune cell infiltration, association with tumor mutational burden (TMB), and correlation with microsatellite instability (MSI). Additionally, single-cell data were used to explore the expression and potential role of TRIP13 at the single-cell level. We subsequently conducted a series of in vitro experiments.

Our comprehensive pan-cancer analysis reveals significantly elevated TRIP13 expression across multiple cancer types and links it to poor prognostic outcomes. TRIP13 primarily activates pathways such as ubiquitination, cell cycle regulation, and DNA repair to drive tumor progression. Additionally, TRIP13 expression exhibits complex associations with various immune regulators and immune cells. In prostate cancer, TRIP13 shows marked overexpression and is associated with unfavorable prognosis. We identified a significant upregulation of TRIP13 in proliferative tumor stem-like populations in prostate cancer. Consistently, prostate cancer cells that acquired resistance to CDK4/6 inhibitors displayed marked TRIP13 overexpression, and functional assays revealed that TRIP13 modulates cellular sensitivity to these agents. Mechanistically, we demonstrated that E2F1 transcriptionally activates TRIP13, which in turn drives the upregulation of the downstream ubiquitin ligase HECTD3.

This study reveals aberrant TRIP13 expression across multiple cancers and its association with immune modulation and tumor aggressiveness. The elevation of TRIP13 in palbociclib resistant prostate cancer, together with the regulatory E2F1-TRIP13-HECTD3 axis, highlights its potential as a prognostic biomarker and therapeutic target.

Uterine leiomyomas may arise from somatic stem or progenitor cells, leading to abnormal activation, proliferation, and clonal expansion. In organ cultures of myometrium and leiomyoma, differentiated cells decline after 7 days, whereas resident stem cells may persist within their niches and subsequently become activated, proliferate, and repopulate tissue slices. This study investigated gene expression programs that regulate the proliferation and differentiation of myometrial and MED12-mutant leiomyoma stem cells during long-term organ culture.

Comparison of normal and tumor tissues at baseline and after culture revealed several fibroid transcriptional signatures that were preserved during prolonged ex vivo culture. The MED12 mutation persisted in the repopulated fibroid slices, supporting the hypothesis that fibroids originate from stem or progenitor cells harboring MED12 mutation. Both tissues activated hypoxia and stemness-associated programs, including robust induction of HMGA1, HMGA2, and PLAG1. Myometrium induced KITLG/KIT expression, a limited number of CD49b (ITGA2)-stem-positive and Ki67-positive proliferating cells, indicating restrained proliferation, likely mediated by upregulation of ITGA2-AS1. Additionally, myometrial slice cultures were enriched for immune and endothelial/vascular programs, including several SOX family members. In contrast, leiomyoma cultures exhibited widespread CD24/CD73 expression, focal CD49b clusters, high Ki67 positivity, metabolic reprogramming toward complex carbohydrate degradation, SLC-mediated transport, and a low-PLIN2/high-ACLY signature. Uterine leiomyoma cultures repressed genes involved in vascular homeostasis (e.g., PLPP3) and preferentially activated pathways related to smooth muscle excitability and vesicle secretion. Extracellular matrix (ECM) remodeling was strongly pro-fibrotic in leiomyomas, with significant upregulation of several TGFB-regulated and related genes, a disrupted balance of KLF regulators, including loss of the anti-fibrotic repressor KLF10 and induction of the pro-fibrotic KLF5 factor, and broad upregulation of integrins. Differential expression of multiple HOX genes further distinguished ECM regulation between tissues. From niche survival to pro-fibrotic expansion, the study delineates checkpoints primed for intervention, highlighting potential therapeutic opportunities targeting profibrotic signaling, metabolic dependencies, and integrin-mediated ECM interactions.

Long-term organ culture recapitulates key molecular features of fibroids and reveals tissue-specific mechanisms governing stem cell activation and differentiation. These findings identify potential therapeutic opportunities and establish long-term organ culture as a robust, physiologically relevant platform for investigating normal and tumor biology.

Intercellular communication is critical for tissue homeostasis, development and immune responses, with its disruption often implicated in various diseases, particularly cancer. Secretory pathway kinases and kinase‑like proteins (SPKKPs) constitute a distinctive enzyme class operating within the luminal secretory pathway or extracellular space, positioning them as pivotal regulators of cellular communication. This review consolidates current insights into the role of SPKKPs, including the FAM20 family, four‑jointed box kinase 1 (FJX1) and others, in orchestrating intercellular interactions through the phosphorylation of secreted proteins, extracellular matrix components and extracellular vesicle (EV) cargo. The molecular mechanisms by which SPKKPs modulate key oncogenic signaling pathways, such as PI3K/AKT, ERK/MAPK and SMAD family member 2, across diverse cancer types are examined. Additionally, their involvement in EV‑mediated signaling, extracellular matrix remodeling and regulation of fundamental biological processes, including development, tissue homeostasis and immune coordination, is explored. The review further addresses SPKKP dysregulation in a range of pathologies, from nervous system tumors to gastrointestinal and reproductive cancers, and discusses emerging therapeutic strategies. These strategies include specific kinase inhibitors, FJX1‑targeted peptide vaccines and innovative approaches targeting exosomes carrying SPKKPs substrates. Ultimately, this work highlights the essential role of SPKKPs in intercellular communication networks and their promising potential as diagnostic biomarkers and therapeutic targets, particularly in cancer.

The present study aimed to investigate the effects of microRNA (miR)‑5590‑3p on the biological functions of hepatocellular carcinoma (HCC) cells through the homeobox B2 (HOXB2)/MYC axis. The expression levels of miR‑5590‑3p, HOXB2 and MYC were measured in HCC tissues and cell lines, and the relationships between miR‑5590‑3p, HOXB2, and the clinicopathological characteristics and prognosis of patients with HCC were analyzed. The Cell Counting Kit‑8 assay assessed cell proliferation, flow cytometry measured apoptosis rate, and the Transwell and wound healing assays evaluated the invasive and migratory abilities of cells. The targeting interactions between miR‑5590‑3p and HOXB2, and between HOXB2 and MYC were assessed. In addition, a subcutaneous HCC xenograft model was established to assess the effects of miR‑5590‑3p on tumor growth. The results revealed that miR‑5590‑3p expression was downregulated in HCC tissues and cells, whereas HOXB2 and MYC expression were upregulated. Notably, low miR‑5590‑3p expression and high HOXB2 expression were both associated with a poor prognosis in patients with HCC. miR‑5590‑3p directly targeted and suppressed HOXB2, whereas HOXB2 promoted MYC transcription. Furthermore, downregulation of miR‑5590‑3p enhanced the invasion, migration and proliferation of Huh7 cells, and reduced their apoptotic rate. By contrast, miR‑5590‑3p overexpression or HOXB2 silencing decreased invasion, migration and proliferation, while increasing apoptosis. Moreover, HOXB2 overexpression reversed the inhibitory effect of miR‑5590‑3p upregulation on HCC cell proliferation. HOXB2 appeared to promote Huh7 cell proliferation and motility through MYC transcriptional activation, whereas miR‑5590‑3p overexpression suppressed tumor growth in vivo. In conclusion, miR‑5590‑3p may inhibit HCC cell proliferation and motility, and induce apoptosis by targeting HOXB2 and suppressing MYC transcription.

Triple‑negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and a poor prognosis. The present study investigated the anti‑TNBC effects and underlying mechanisms of cepharanthine (CEP), an isoquinoline alkaloid derived from Stephania cephalantha. The findings showed that CEP inhibited colony formation and induced apoptosis in TNBC cells. Mechanistic investigations revealed that CEP upregulated the pro‑apoptotic protein phorbol‑12‑myristate‑13‑acetate‑induced protein 1 (NOXA), downregulated the anti‑apoptotic protein Bcl‑2 and reduced the mitochondrial membrane potential (ΔΨm). Using quantitative proteomics and limited proteolysis‑coupled mass spectrometry, the present study demonstrated that CEP bound directly to the lysosomal enzymes cathepsin B and cathepsin D, thereby impairing their maturation and suppressing lysosomal degradation. This inhibition triggered the nuclear accumulation of transcription factor EB (TFEB), a factor that regulates the expression of Bcl‑2 family members. These findings indicated that CEP induced apoptosis by inhibiting lysosomal function and activating TFEB, leading to the upregulation of NOXA and downregulation of Bcl‑2. In conclusion, the present study demonstrated the pro‑apoptotic effect of CEP in TNBC cells and identified lysosomal enzymes as the direct target for its mechanism of action. These findings provided a foundation for further investigation of the pharmacological mechanisms of CEP.

To provide an updated and robust assessment of the efficacy of the Twin-Block appliance in the treatment of pediatric obstructive sleep apnea (OSA). A previous meta-analysis indicated a potential benefit, but was limited by the quality of available evidence and is now outdated. This study aims to synthesize all current evidence, including recent high-quality randomized controlled trials (RCTs).

This systematic review and meta-analysis was conducted following PRISMA guidelines. A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science was performed up to October 2025. We included RCTs, non-randomized controlled trials (NRCTs), and case series evaluating the effect of the Twin-Block appliance on respiratory parameters in children (< 18 years) with OSA. The primary outcome was the change in the Apnea-Hypopnea Index (AHI). A random-effects model was used to calculate the pooled Mean Difference (MD) and 95% Confidence Intervals (CIs). Sensitivity analyses were performed, and the risk of bias was assessed using design-specific tools (RoB 2, ROBINS-I, and the JBI Critical Appraisal Checklist).

Eight studies, comprising a total of 259 patients, were included in the systematic review. The meta-analysis of seven studies (n = 219) demonstrated that Twin-Block therapy resulted in a statistically significant and clinically meaningful reduction in AHI (pooled MD: -6.68, 95% CI: -8.76 to -4.60; p < 0.0001). Significant heterogeneity was observed across studies (I² = 89.1%). A recent high-quality RCT, while not poolable due to a different outcome measure, provided mechanistic evidence by showing a significant increase in oropharyngeal airway volume with Twin-Block treatment compared to a control group. The findings remained robust in sensitivity and leave-one-out analyses.

This updated meta-analysis provides strengthened evidence that the Twin-Block appliance is an effective treatment for reducing the severity of OSA in appropriately selected children. The therapeutic effect is likely mediated by structural enlargement of the upper airway. Despite the heterogeneity and limitations in the primary literature, these findings support the consideration of the Twin-Block appliance as a viable non-surgical intervention for pediatric OSA, particularly in patients with mandibular retrognathia. Future large-scale RCTs are warranted to confirm these findings and establish long-term effectiveness.

To compare venous thromboembolism (VTE) events in patients undergoing open reduction and internal fixation (ORIF) of acetabular fractures who did and did not receive weight-based dosing of prophylactic enoxaparin.

This retrospective cohort study included patients with acetabular fractures treated with ORIF between 2013 and 2020 at a single level-1 trauma center. Patients with pre-existing VTE, allergy, no enoxaparin use, or receipt of other prophylactic agents were excluded. Patients were categorized as having received appropriate or inappropriate weight-based enoxaparin dosing based on institutional BMI-tiered protocol. The primary outcome was incidence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Group comparisons were performed with Pearson's Chi-square, and binomial logistic regression was used to adjust for additional VTE risk factors.

Among 363 patients, 198 (54.5%) received appropriate weight-based dosing and 165 (45.5%) did not. Overall, 20 patients (5.5%) developed VTE (4 PE, 11 DVT, 3 both PE and DVT). Of these, 13 had received appropriate dosing. VTE incidence did not differ significantly between groups (6.6% vs. 4.2%, p = 0.334). Rates of isolated PE, isolated DVT, and combined events were also not significantly different (all p > 0.05). Logistic regression confirmed no significant association between weight-based dosing and VTE when adjusting for patient and clinical risk factors.

Only half of patients with operative acetabular fractures received appropriate weight-based dosing of enoxaparin. Weight-based dosing was not associated with reduced VTE incidence, suggesting that receipt of prophylaxis itself may be the most important factor. Larger studies are warranted to verify these findings.