Age at natural menopause and associated factors with early and late menopause among Chinese women in Zhejiang province: A cross-sectional study.

OBJECTIVES: Menopause is a significant life transition for women, impacting their physical and psychological health. The age at natural menopause (ANM) and its associated factors have differed by race and region. This study aimed to investigate ANM and associated factors of early and late menopause among Chinese women in Zhejiang province. METHODS: A cross-sectional study was conducted using a multi-stage stratified cluster sampling method to recruit 8,006 women aged 40-69 years who had resided in Zhejiang province for over 6 months between July 2019 and December 2021. Self-reported ANM and sociodemographics, lifestyle behaviors, reproductive history, and health-related factors were collected using questionnaires in face-to-face surveys. ANM were categorized into three groups: early menopause (<45 years), normal menopause (45-54 years), and late menopause (≥55 years). Kaplan-Meier survival analysis was utilized to calculate the median ANM. Multivariable multinomial logistic regression was employed to explore the associated factors of early menopause and late menopause. RESULTS: A total of 6,047 women aged 40-69 years were included for survival analysis, with 3,176 of them for the regression analysis. The overall median ANM was 51 years (Inter-quartile range [IQR]: 51-52). Women who were smokers (odds ratio [OR]:4.54, 95% confidence interval [CI]:1.6-12.84), had irregular menstrual cycles (OR:1.78, 95% CI:1.12-2.83) and hypertension (OR:1.55, 95% CI:1.09-2.21) had a higher odds ratio of early menopause, while central obesity (OR:1.33, 95% CI:1.03-1.73) and hyperlipidemia (OR:1.51, 95% CI:1.04-2.18) were factors associated with late menopause. CONCLUSIONS: This study revealed the associations between ANM and various factors among Chinese women. These factors included socio-demographic factors such as age; life behavior factors like current or prior smoking status; reproductive history factors such as irregular menstrual cycles, miscarriages, and breastfeeding; and health-related factors like central adiposity, hypertension, and hyperlipidemia. These findings provided a basis for understanding factors associated with ANM.

Comprehensive analysis of the relationship between ubiquitin-specific protease 21 (USP21) and prognosis, tumor microenvironment infiltration, and therapy response in colorectal cancer.

BACKGROUND: Ubiquitin-specific proteases family is crucial to host immunity against pathogens. However, the correlations between USP21 and immunosurveillance and immunotherapy for colorectal cancer (CRC) have not been reported. METHODS: The differential expression of USP21 between CRC tissues and normal tissues was analyzed using multiple public databases. Validation was carried out in clinical samples through qRT-PCR and IHC. The correlation between USP21 and the prognosis, as well as clinical pathological characteristics of CRC patients, was investigated. Moreover, cell models were established to assess the influence of USP21 on CRC growth and progression, employing CCK-8 assays, colony formation assays, and wound-healing assays. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP21 in CRC. The study also examined the impact of USP21 on cytokine levels and immune cell infiltration in the tumor microenvironment (TME). Finally, the effect of USP21 on the response to immunotherapy and chemotherapy in CRC was analyzed. RESULTS: The expression of USP21 was significantly upregulated in CRC. High USP21 is correlated with poor prognosis in CRC patients and facilitates the proliferation and migration capacities of CRC cells. GSVA indicated an association between low USP21 and immune activation. Moreover, low USP21 was linked to an immune-activated TME, characterized by high immune cell infiltration. Importantly, CRC with low USP21 exhibited higher tumor mutational burden, high PD-L1 expression, and better responsiveness to immunotherapy and chemotherapeutic drugs. CONCLUSION: This study revealed the role of USP21 in TME, response to therapy, and clinical prognosis in CRC, which provided novel insights for the therapeutic application in CRC.

Relationship between observation time and detection rate of focal lesions in Esophagogastroduodenoscopy: a single-center, retrospective study.

BACKGROUND: Current studies have shown that longer observation time can improve neoplastic detection rate. This study aimed to clarify whether endoscopists with longer observation times can detect more focal lesions. METHODS: Based on the mean examination time for Esophagogastroduodenoscopy (EGD) without biopsy, endoscopists were divided into fast and slow groups, and the detection rate of focal lesions was compared between the two groups. Univariate analysis, multivariate analysis and restricted cubic spline were used to explore the factors of focal lesion detection rate. RESULTS: Mean examination time of EGD without biopsy was 4.5 min. The cut-off times used were 5 min. 17 endoscopists were classified into the fast (4.7 ± 3.6 min), and 16 into the slow (7.11 ± 4.6 min) groups. Compared with fast endoscopists, slow endoscopists had a higher detection rate of focal lesions (47.2% vs. 51.4%, P < 0.001), especially in the detection of gastric lesions (29.7% vs. 35.9%, P < 0.001). In univariate and multivariate analyses, observation time, patient age and gender, expert, biopsy rate, and number of images were factors in FDR. There is a nonlinear relationship between observation time and FDR. CONCLUSION: Longer examination time improves the detection rate of focal lesions. Observation time is an important quality indicator of the EGD examination.

ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/ß-catenin pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high lethality rate. ZMIZ2 is a transcriptional co-activator implicated in various human diseases. However, the role and molecular mechanism of ZMIZ2 in HCC remains to be elucidated. METHODS: The expression and prognostic value of ZMIZ2 in HCC was excavated from public databases and explored by bioinformatic analysis. Then the expression of ZMIZ2 and related genes was further validated by quantitative RT-PCR, western blotting, and immunohistochemistry. Loss and gain-of-function experiments were performed in vitro and in vivo to investigate the function of ZMIZ2 in HCC. In addition, transcriptome sequencing and immunoprecipitation was conducted to explore the potential molecular mechanisms of ZMIZ2. RESULTS: ZMIZ2 was highly expressed in HCC and associated with poor prognosis. Silencing ZMIZ2 significantly inhibited HCC cell proliferation, cell cycle process, migration, and invasion in vitro, and also inhibited the progression of HCC in vivo. Additionally, ZMIZ2 expression was correlated with immune cell infiltration in HCC samples. Somatic mutation analysis showed that ZMIZ2 and TP53 mutations jointly affected the progression of HCC. Mechanistically, ZMIZ2 interacted with LEF1 to regulate malignant progression of HCC by activating the Wnt/ß-catenin pathway. CONCLUSION: ZMIZ2 was overexpressed in HCC and associated with poor prognosis. The overexpression of ZMIZ2 was corelated with malignant phenotype, and it facilitated HCC progression via LEF1-mediated activation of the Wnt/ß-catenin pathway. Furthermore, ZMIZ2 could be served as a prognostic biomarker and a new therapeutic target for HCC.

Guanylate-binding proteins signature predicts favorable prognosis, immune-hot microenvironment, and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: The role of guanylate-binding proteins (GBPs) in various cancers has been elucidated recently. However, our knowledge of the clinical relevance and biological characteristics of GBPs in hepatocellular carcinoma (HCC) remains limited. METHODS: A total of 955 HCC patients were enrolled from five independent public HCC cohorts. The role of GBP molecules in HCC was preliminarily investigated, and a GBP family signature, termed GBPs-score, was constructed by principal component analysis to combine the GBP molecule values. We revealed the effects of GBP genes and GBPs-score in HCC via well-established bioinformatics methods and validated GBP1-5 experimentally in a tissue microarray (TMA) cohort. RESULTS: GBPs molecules were closely associated with the prognosis of patients with HCC, and a high GBPs-score highly inferred a favorable survival outcome. We also revealed high GBPs-score was related to anti-tumor immunity, the immune-hot tumor microenvironment (TME), and immunotherapy response. Among the GBPs members, GBP1-5 rather than GBP6/7 may be dominant in these fields. The TMA analysis based on immunohistochemistry showed positive correlations between GBP1-5 and the immune-hot TME with abundant infiltration of CD8+ T cells in HCC. CONCLUSIONS: Our integrative study revealed the genetic and immunologic characterizations of GBPs in HCC and highlighted their potential values as promising biomarkers for prognosis and immunotherapy.

Gastrointestinal pan-cancer landscape of tumor matrix heterogeneity identifies biologically distinct matrix stiffness subtypes predicting prognosis and chemotherapy efficacy.

Gastrointestinal (GI) cancers are a heterogeneous group of primary solid tumors, arising in GI tract from the esophagus to rectum. Matrix stiffness (MS) is a critical physical factor for cancer progression; however, its importance in tumor progression remains to be comprehensively recognized. Herein, we conducted a comprehensive pan-cancer analysis of MS subtypes across seven GI-cancer types. Using unsupervised clustering based on literature-derived MS-specific pathway signatures, the GI-tumor samples were divided into three MS subtypes, termed as the Soft, Mixed and Stiff. Then, distinct prognoses, biological features, tumor microenvironments and mutation landscapes among three MS subtypes were revealed. The Stiff tumor subtype was associated with the poorest prognosis, the most malignant biological behaviors, and the immunosuppressive tumor stromal microenvironment. Furthermore, multiple machine learning algorithms were used to develop an 11-gene MS-signature to identify the MS subtypes of GI-caner and predict chemotherapy sensitivity, which were further validated in two external GI-cancer cohorts. This novel MS-based classification on GI-cancers could enhance our understanding of the important role of MS in tumor progression, and may have implications for the optimization of individualized cancer management.

Polyps are detected more often in early colonoscopies.

OBJECTIVE: To examine the time variation in polyp detection for colonoscopies performed in a tertiary hospital and to explore independent factors that predict polyp detection rate (PDR). METHODS: Data on all patients who underwent colonoscopy for the diagnostic purpose at our endoscopy center in Zhongnan Hospital of Wuhan University from January 2021 to December 2021 were reviewed. The start time of included colonoscopies for eligible patients was recorded. PDR and polyps detected per colonoscopy (PPC) were calculated. The endoscopists' schedules were classified into full-day and half-day shifts according to their participation in the morning and afternoon colonoscopies. RESULTS: Data on a total of 12116 colonoscopies were analyzed, with a PDR of 38.03% for all the patients and 46.38% for patients ≥50 years. PDR and PPC significantly decreased as the day progressed (both p < .001). For patients ≥50 years, PDR declined below 40% at 13:00-13:59 and 16:00-16:59. The PDR in the morning was higher than that in the afternoon for both half-day (p = .019) and full-day procedures (p < .001). In multivariate analysis, start time, patient gender, age, conscious sedation, and bowel preparation quality significantly predicted PDR (p < .001). CONCLUSIONS: The polyp detection declined as the day progressed. A continuous work schedule resulted in a subpar PDR. Colonoscopies performed in the morning had a higher PDR than that in the afternoon. Patient gender, age, conscious sedation, and bowel preparation quality were identified as the independent predictors of PDR.

Pyroptosis-Related Signature Predicts the Progression of Ulcerative Colitis and Colitis-Associated Colorectal Cancer as well as the Anti-TNF Therapeutic Response.

Ulcerative colitis (UC) is a complex intestinal inflammation with an increasing risk of colitis-associated colorectal cancer (CAC). However, the pathogenesis is still unclear between active UC and inactive UC. Recently, it has been reported that pyroptosis-related genes (PRGs) are closely associated with inflammatory disease activity. Nevertheless, the specific roles of PRGs in the progression and treatment of UC and CAC remain unclear. In this study, we identified 30 differentially expressed PRGs based on the immune landscape of active and inactive UC samples. Meanwhile, weighted gene coexpression network analysis was applied to explore important genes associated with active UC. By intersecting with the differentially expressed PRGs, CASP5, GBP1, GZMB, IL1B, and IRF1 were selected as key PRGs to construct a pyroptosis-related signature (PR-signature). Then, logistic regression analysis was performed to validate the PR-signature and establish a pyroptosis-related score (PR-Score). We demonstrated that PR-Score had a powerful ability to distinguish active UC from inactive UC in multiple datasets. Besides, PR-Score was positively correlated with immune cell infiltration and inflammatory microenvironment in UC. Lower PR-Score was associated with a better response to anti-TNF therapy for patients with UC. Additionally, high-PR-Score was found to suppress CAC and improve the survival outcomes of patients with colorectal cancer. Finally, the levels of the PR-signature genes were validated both in vitro and in vivo. These findings can improve our understanding of PRGs in UC and provide new markers for predicting the occurrence of active UC or CAC and the treatment of UC.

Comprehensive analysis of cuproptosis-related genes in prognosis, tumor microenvironment infiltration, and immunotherapy response in gastric cancer.

BACKGROUNDS: Cuproptosis is the most recently identified copper-dependent cell death form that influences tricarboxylic acid (TCA) cycle. However, the relationship between cuproptosis and clinical prognosis, tumor microenvironment infiltration (TME), and response to immunotherapy remains unclear. METHODS: Single-sample gene-set enrichment analysis (ssGSEA) was employed to construct cuproptosisScore (cpS) and 1378 gastric cancer (GC) patients from five independent public datasets were classified into high- or low-cpS groups according to the median of cpS. Then the impacts of cuproptosis on tumor microenvironment infiltration (TME), biological function, response to immunotherapy, and clinical prognosis of GC were evaluated. RiskScore and nomogram were constructed using Lasso Cox regression algorithm to validate its predictive capability in GC patients. RESULTS: Compared to patients with high cpS, patients with low cpS exhibited poorer prognosis, higher TNM stage, and stronger stromal activation. Meanwhile, the analysis of response to immunotherapy confirmed patients with high cpS could better benefit from immunotherapy and had a better susceptibility to chemotherapeutic drugs. Then, 9 prognosis-related signatures were collected based on differentially expressed genes (DEGs) of cpS groups. Finally, a riskScore model was constructed using the multivariate Cox (multi-Cox) regression coefficients of prognosis-related signatures and had an excellent capability of predicting 1-, 3-, and 5-year survival in GC patients. CONCLUSIONS: This study revealed the role of curproptosis in TME, response to immunotherapy, and clinical prognosis in GC, which highlighted the significant clinical implications of curproptosis and provided novel ideas for the therapeutic application of cuproptosis in GC.

NAPSB as a predictive marker for prognosis and therapy associated with an immuno-hot tumor microenvironment in hepatocellular carcinoma.

BACKGROUND: Napsin B Aspartic Peptidase, Pseudogene (NAPSB) was associated with CD4 + T cell infiltration in pancreatic ductal adenocarcinoma. However, the biological role of NAPSB in hepatocellular carcinoma (HCC) remains to be determined. METHODS: The expression of NAPSB in HCC as well as its clinicopathological association were analyzed using data from several public datasets. qRT-PCR was used to verify the relative expression of NAPSB in patients with HCC using the Zhongnan cohort. Kaplan-Meier analyses, and univariate and multivariate Cox regression were conducted to determine the prognosis value of NAPSB on patients with HCC. Then enrichment analyses were performed to identify the possible biological functions of NAPSB. Subsequently, the immunological characteristics of NAPSB in the HCC tumor microenvironment (TME) were demonstrated comprehensively. The role of NAPSB in predicting hot tumors and its impact on immunotherapy and chemotherapy responses was also analyzed by bioinformatics methods. RESULTS: NAPSB was downregulated in patients with HCC and high NAPSB expression showed an improved survival outcome. Enrichment analyses showed that NAPSB was related to immune activation. NAPSB was positively correlated with immunomodulators, tumor-infiltrating immune cells, T cell inflamed score and cancer-immunity cycle, and highly expressed in immuno-hot tumors. High expression of NAPSB was sensitive to immunotherapy and chemotherapy, possibly due to its association with pyroptosis, apoptosis and necrosis. CONCLUSIONS: NAPSB was correlated with an immuno-hot and inflamed TME, and tumor cell death. It can be utilized as a promising predictive marker for prognosis and therapy in HCC.

Role of metformin in functional endometrial hyperplasia and polycystic ovary syndrome involves the regulation of MEG3/miR­223/GLUT4 and SNHG20/miR­4486/GLUT4 signaling.

Metformin (MET) can effectively treat endometrial hyperplasia (EH), and the expression of glucose transporter type 4 insulin­responsive (GLUT4) is closely associated with the development of EH. The present study aimed to verify the effect of MET in functional EH and polycystic ovary syndrome (PCOS). H&E staining was performed to analyze the severity of EH, and immunohistochemistry was performed to evaluate the expression of GLUT4 in the endometrium of PCOS rats. Reverse transcription­quantitative PCR was used to calculate the expression of long non­coding (lnc)RNA­maternally expressed gene 3 (MEG3), lncRNA­small nucleolar RNA host gene 20 (SNHG20), GLUT4 mRNA, microRNA (miR)­223 and miR­4486. Sequence analysis and luciferase assays were performed to explore the regulatory relationship among certain lncRNAs, miRNAs and target genes. EH in PCOS rats was efficiently inhibited by MET administration. The increased expression of GLUT4 in PCOS rats was attenuated by MET treatment. Moreover, the expression levels of lncRNA­MEG3 and lncRNA­SNHG20 were significantly inhibited in the endometrium of PCOS rats. MET treatment also showed remarkable efficiency in restoring the expression of lncRNA­MEG3 and lncRNA­SNHG20. Meanwhile, the expression levels of miR­223 and miR­4486 were notably elevated in the endometrium of PCOS rats, while MET treatment reduced the expression of miR­223 and miR­4486 in PCOS rats. Furthermore, a luciferase assay confirmed the inhibitory relationship between miR­223 and lncRNA­MEG3/GLUT4 expression, as well as between miR­4486 and lncRNA­SNHG20/GLUT4 expression. GLUT4 knockdown restored the decreased viability of HCC­94 cells induced by overexpression of lncRNA­MEG3. To conclude, MET exhibited a therapeutic effect in the treatment of EH by modulating the lncRNA­MEG3/miR­223/GLUT4 and lncRNA­SNHG20/miR­4486/GLUT4 signaling pathways. This work provides mechanistic insight into the development of EH.

[Pathogenesis and clinical significance of interleukin-8 and tumor necrosis factor-alpha in cervicitis].

OBJECTIVE: To investigate the relationship between local immune status of vagina and the occurrence of disease in patients with cervicitis. METHODS: ELISA were used to detect the level of interleukin (IL)-8 and tumor necrosis factor (TNF)alpha in vaginal douche of patients with cervicitis due to ureaplasma urealyticum, mycoplasma hominis, chlamydia trachomatis, neisseria gonorrhoeae and cervical erosion. RESULTS: Compared with the control group, the level of IL-8 in vaginal douche of patients with mycoplasma hominis cervicitis, chlamydia trachomatis cervicitis and neisseria gonorrhoeae cervicitis was significantly higher and there was significant difference ng/L: 371 +/- 34, 369 +/- 31, 339 +/- 36, vs 341 +/- 32, 338 +/- 33, 316 +/- 24, (all P < 0.01). Comparing the level of IL-8 in vaginal douche of patients with ureaplasma urealyticum cervicitis and cervical erosion with that of control group, there was no statistical difference (all P > 0.05). The level of TNF-alpha in vaginal douche of each group was remarkably higher than that of control group except for patients with cervical erosion. And statistically significant difference was found between them (all P < 0.01). CONCLUSION: With regards to the pathogenesis of cervicitis, local immune mechanism of vagina plays an important role in the occurrence of cervicitis. The role of IL-8 in pathogenesis of mycoplasma hominis cervicitis, chlamydia trachomatis cervicitis and neisseria gonorrhoeae cervicitis is likely to be more important.