Frontiers of Medicine最新文献

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.

SMARCA4-deficient non small cell lung cancer (SMARCA4-dNSCLC) has recently garnered increasing attention due to its high malignancy and poor prognosis. The literature suggests that in non small cell lung cancer (NSCLC), the loss of SMARCA4 frequently co-occurs with mutations in KRAS, KEAP1, and STK11 rather than in EGFR, ALK, and ROS1. Herein, we present the first documented case of SMARCA4-dNSCLC accompanied with rare mutations of EGFR exon 20 S768I and exon 18 G719X. The patient achieved partial response with afatinib for 17 months. Our case highlights the importance of EGFR mutations in the precision targeted treatment of SMARCA4-dNSCLC.

Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.

Ovarian cancer is the most lethal malignancy affecting the female reproductive system. Pharmacological inhibitors targeting CDK4/6 have demonstrated promising efficacy across various cancer types. However, their clinical benefits in ovarian cancer patients fall short of expectations, with only a subset of patients experiencing these advantageous effects. This study aims to provide further clinical and biological evidence for antineoplastic effects of a CDK4/6 inhibitor (TQB4616) in ovarian cancer and explore underlying mechanisms involved. Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616. Potential key genes related to TQB3616 sensitivity were identified through RNA-seq analysis, and TRIM4 was selected as a candidate gene for further investigation. Subsequently, co-immunoprecipitation and GST pull-down assays confirmed that TRIM4 binds to hnRNPDL and promotes its ubiquitination through RING and B-box domains. RIP assay demonstrated that hnRNPDL binded to CDKN2C isoform 2 and suppressed its expression by alternative splicing. Finally, in vivo studies confirmed that the addition of siTRIM4 significantly improved the effectiveness of TQB3616. Overall, our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment. TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.

Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe^-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.

Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.

This study aimed to investigate the incidence and risk factors for female sexual dysfunction (FSD) in urban and rural China. A prospective cohort study was conducted from February 2014 to January 2016, with follow-up from June to December 2018. Women aged ≽20 years were recruited from urban and rural areas in six provinces of China using a multistage, stratified, cluster sampling method. Sexual function was assessed using the Female Sexual Function Index questionnaire. A total of 16 827 women without sexual dysfunction at baseline participated in this study, 9489 of them (urban, 5321; rural, 4168) who had complete information from baseline to follow-up were included in the final analysis. The rate of follow-up was 68.81%, and the median follow-up time was 4.13 years. The 4-year incidence of FSD was 43.07%, with an incidence density of 12.02 per 100 person-years. In particular, the 4-year incidence and incidence density of FSD were 41.03% and 11.88 per 100 person-years in the urban group and 45.68% and 12.17 per 100 person-years in the rural group. Among women with sexual dysfunction, difficulties in sexual desire, satisfaction, and arousal were the main symptoms. In urban women, the risk factors for FSD included age ≽45 years (adjusted relative risk 1.69, 95% confidence interval 1.57-1.81), hypertension (1.31, 1.14-1.49), previous delivery (1.26, 1.13-1.41), post-menopausal status (1.20, 1.10-1.32), pelvic inflammatory disease (1.13, 1.05-1.21), and multiparity (1.11, 1.03-1.19). In the rural group, the risk factors significantly associated with FSD were age ≽45 years (1.50, 1.40-1.61), previous delivery (1.39, 1.17-1.65), hypertension (1.18, 1.06-1.30), multiparity (1.16, 1.07-1.27), and post-menopausal status (1.15, 1.07-1.23). FSD is a hidden epidemic condition in China, and the development of prevention strategies should consider the distinct risk factors present in rural and urban areas.

Complementary and integrative healthcare (CIH) is increasingly recognized as a valuable approach to empowering and activating cancer patients. Studies have shown that higher patient activation is positively associated with improved health outcomes and reduced healthcare costs. The CCC-Integrativ study aimed to assess the implementation of an evidence-based counseling service on CIH at four Comprehensive Cancer Centers (CCC) in Germany. In this controlled implementation study, the patient-level intervention included three CIH consultations within a 3-month period delivered by interprofessional teams of physicians and nurses. The primary endpoint was patient activation using the PAM-13 at baseline (T1) and post-intervention (T2), and compared between control (CO, receiving routine care) and the intervention group (IG) using an analysis of covariance. Missing data were handled with multiple imputations. Maintenance effects at 6-month follow-up (T3) were investigated using a linear mixed model. A total of n = 1128 oncology patients (CO = 443, IG = 685) with diverse tumor entities and cancer stages were included in the study. The overall mean baseline PAM-13 score was 69.74 (SD = 14.24) (n = 959 (85.0%)). A statistically significant between-group difference in post-intervention PAM-13 scores was observed (F_group(1, 1866.82) = 8.634, P = 0.003), with an adjusted mean difference of 2.22 PAM-points. Age, gender, tumor entity, disease stage, or CCC study site did not significantly predict post-treatment PAM-13 scores. The maintenance effect of the intervention was not statistically significant (F_timeXgroup(1, 3316.04) = 2.337, P = 0.096). Individually tailored counseling on CIH, offered by specifically trained, interprofessional teams, significantly improved patient activation. Given the established positive effects of higher patient activation, the implementation of such a program at cancer centers may yield beneficial outcomes for both patients and the healthcare system.

Dysregulated RNA splicing events produce transcripts that facilitate esophageal squamous cell carcinoma (ESCC) progression, but how this splicing process is abnormally regulated remains elusive. Here, we unveiled a novel alternative splicing axis of BOLA3 transcripts and its regulator HNRNPC in ESCC. The long-form BOLA3 (BOLA3-L) containing exon 3 exhibited high expression levels in ESCC and was associated with poor prognosis. Functional assays demonstrated the protumorigenic function of BOLA3-L in ESCC cells. Additionally, HNRNPC bound to BOLA3 mRNA and promoted BOLA3 exon 3 inclusion forming BOLA3-L. High HNRNPC expression was positively correlated with the presence of BOLA3-L and associated with an unfavorable prognosis. HNRNPC knockdown effectively suppressed the malignant biological behavior of ESCC cells, which were significantly rescued by BOLA3-L overexpression. Moreover, BOLA3-L played a significant role in mitochondrial structural and functional stability. E2F7 acted as a key transcription factor that promoted the upregulation of HNRNPC and inclusion of BOLA3 exon 3. Our findings provided novel insights into how alternative splicing contributes to ESCC progression.