The roles of metallothioneins in carcinogenesis

Abstract Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer

Role of Lymphadenectomy for Uterine Sarcoma: A Meta-Analysis

ObjectiveUterine sarcomas are rare, highly aggressive tumors with an unfavorable prognosis. The role of lymphadenectomy (LAD) remains controversial for this particular tumor type. To examine whether LAD can assist in prognosis or clinical benefits for uterine sarcoma patients, we performed a meta-analysis based on published studies.MethodsWe initially identified published studies by searching the PubMed database up to 30 November 2015. Study quality was evaluated systematically using the Newcastle-Ottawa Scale for assessing the quality of studies for inclusion in meta-analyses. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using Stata software version 12.0.ResultsOur search retrieved 14 eligible studies, involving a total of 4867 patients, including 1356 (27.9%) patients who had LAD. The pooled RR for uterine leiomyosarcoma (uLMS) in patients with LAD in 5 trials was 0.90 (95% CI, 0.62–1.31) and for endometrial stromal sarcoma (ESS) in 11 trials was 0.96 (95% CI, 0.69–1.34), suggesting that there was no significant benefit of LAD in improving overall survival (P &lt; 0.05). A random-effects model was chosen to estimate the RRs in view of the significant heterogeneity in the included studies (uLMS: Cochran Q test: P = 0.022, I2 = 64.9%; ESS: Cochran Q test: P = 0.005, I2 = 60.1%). No publication bias was detected by the Egger and Begg tests (uLMS: Begg: P = 0.221, Egger: P = 0.148; ESS: Begg: P = 1.000, Egger: P = 0.928).ConclusionsBased on currently available evidence, the findings of this meta-analysis suggest that LAD bears little prognostic or therapeutic benefit in patients with uterine sarcoma. Systematic LAD may not be recommended in patients with uLMS or ESS unless the patient has obvious extrauterine involvement, clinically suspicious enlarged nodes, or advanced sarcomas.</jats:sec

Effects of Infertility Drug Exposure on the Risk of Borderline Ovarian Tumors: A Systematic Review and Meta-Analysis

Whether infertility drug exposure increases the risk of borderline ovarian tumors (BOTs) remains controversial. The present study was conducted with a comprehensive search for studies published from January 1990 to December 2021 in the online databases Cochrane Library, PubMed, Web of Science and EMBASE. We considered the first diagnosis of a BOT as the primary outcome. The odds ratio (OR) was calculated with corresponding 95% confidence intervals (CIs) for the risk of BOTs in patients who were treated with infertility drugs. Ten studies, a total of 2,779,511 women, qualified for inclusion in this meta-analysis. The pooled OR of 1.56 (95% CI: 1.09&ndash;2.22) revealed a significant positive association between infertility drugs and an increased risk for BOTs, but for specific drugs, only CC plus Gn had statistical significance. No publication bias was detected using the Egger and Begg tests (p &gt; 0.05). A significant difference in BOT incidence was observed among infertile women and nulliparous women who were treated with or without infertility drugs. In conclusion, the use of infertility drugs may increase the risk of BOTs, but a dose-dependent relationship was not observed between the number of assisted reproduction technology cycles and the risk of BOTs, and infertile women who successfully became pregnant might have a reduced risk. Registration: PROSPERO, CRD42022330775

Nomogram for Predicting Live Birth after the First Fresh Embryo Transfer in Patients with PCOS Undergoing IVF/ICSI Treatment with the GnRH-Ant Protocol

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. A better understanding of factors associated with pregnancy outcomes and successful prediction of live birth after IVF/ICSI are important to guide clinical practice. This was a retrospective cohort study investigating live birth after the first fresh embryo transfer using the GnRH-ant protocol in patients with PCOS between 2017 and 2021 at the Reproductive Center of Peking University Third Hospital. A total of 1018 patients with PCOS were qualified for inclusion in this study. BMI, AMH level, initial FSH dosage, serum LH and progesterone levels on the hCG trigger day, and endometrial thickness were all independent predictors of live birth. However, age and infertility duration were not significant predictors. We developed a prediction model based on these variables. The predictive ability of the model was demonstrated well, with areas under the curve of 0.711 (95% CI, 0.672&ndash;0.751) and 0.713 (95% CI, 0.650&ndash;0.776) in the training cohort and validation cohort, respectively. Additionally, the calibration plot showed good agreement between the prediction and the observation (p = 0.270). The novel nomogram could be helpful for clinicians and patients in clinical decision-making and outcome evaluation

Metabolic Syndrome Rather Than Other Phenotypes in PCOS as a Predictive Indicator for Clinical Outcomes in IVF: Comprehensive Phenotypic Assessment across All PCOS Classifications

Polycystic ovary syndrome (PCOS) is a well-recognized, multi-system metabolic disorder affecting fertility. Although various classification methods have been proposed to assess the phenotypic heterogeneity of PCOS, there is currently no reliable phenotype for predicting clinical IVF outcomes. This retrospective study, as a comprehensive phenotypic assessment across all PCOS classifications, aimed to identify dependable phenotypes that can serve as predictors for IVF and pregnancy outcomes. The study included 1313 PCOS patients who received their initial IVF treatment between January 2019 and December 2021. The phenotypes reflect the diverse metabolic and hormonal characteristics in this study. Phenotype A, within the Rotterdam criteria classification, exhibited the highest anti-M&uuml;llerian hormone levels (AMH), while phenotype D displayed the lowest Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) values. Both the hyperandrogenism (HA) phenotype within HA-based classification and the overweight phenotype within the body-mass-index-based classification showed increased HOMA-IR and metabolic syndrome (MetS). The MetS phenotype had higher free androgen index and a lower AMH. Notably, the MetS-based classification system demonstrated an independent association of MetS with cumulative live birth, preterm birth, and gestational diabetes mellitus as a contributing risk factor for PCOS patients undergoing IVF (p &lt; 0.05). These findings carry noteworthy implications for advancing clinical management strategies for PCOS

Adiposity and lipid metabolism indicators mediate the adverse effect of glucose metabolism indicators on oogenesis and embryogenesis in PCOS women undergoing IVF/ICSI cycles

Abstract Background Polycystic ovary syndrome (PCOS) women have high incidences of dyslipidemia, obesity, impaired glucose tolerance (IGT), diabetes, and insulin resistance (IR) and are fragile to female infertility. Obesity and dyslipidemia may be the intermediate biological mechanism for the associations between glucose metabolism dysfunction and abnormal oogenesis and embryogenesis. Methods This retrospective cohort study was performed at a university-affiliated reproductive center. A total of 917 PCOS women aged between 20 and 45 undergoing their first IVF/ICSI embryo transfer cycles from January 2018 to December 2020 were involved. Associations between glucose metabolism indicators, adiposity and lipid metabolism indicators, and IVF/ICSI outcomes were explored using multivariable generalized linear models. Mediation analyses were further performed to examine the potential mediation role of adiposity and lipid metabolism indicators. Results Significant dose-dependent relationships were found between glucose metabolism indicators and IVF/ICSI early reproductive outcomes and between glucose metabolism indicators and adiposity and lipid metabolism indicators (all P < 0.05). Also, we found significant dose-dependent relationships between adiposity and lipid metabolism indicators and IVF/ICSI early reproductive outcomes (all P < 0.05). The mediation analysis indicated that elevated FPG, 2hPG, FPI, 2hPI, HbA1c, and HOMA2-IR were significantly associated with decreased retrieved oocyte count, MII oocyte count, normally fertilized zygote count, normally cleaved embryo count, high-quality embryo count, or blastocyst formation count after controlling for adiposity and lipid metabolism indicators. Serum TG mediated 6.0–31.0% of the associations; serum TC mediated 6.1–10.8% of the associations; serum HDL-C mediated 9.4–43.6% of the associations; serum LDL-C mediated 4.2–18.2% of the associations; and BMI mediated 26.7–97.7% of the associations. Conclusions Adiposity and lipid metabolism indicators (i.e., serum TG, serum TC, serum HDL-C, serum LDL-C, and BMI) are significant mediators of the effect of glucose metabolism indicators on IVF/ICSI early reproductive outcomes in PCOS women, indicating the importance of preconception glucose and lipid management and the dynamic equilibrium of glucose and lipid metabolism in PCOS women

Additional file 1 of Adiposity and lipid metabolism indicators mediate the adverse effect of glucose metabolism indicators on oogenesis and embryogenesis in PCOS women undergoing IVF/ICSI cycles

Additional file 1: Table S1. Relative risk (RR) and 95% CI in early reproductive outcomes associated with adiposity and lipid metabolism indicators among PCOS women undergoing their first IVF/ICSI cycles based on GLMs (n = 917). Table S2. Odds ratio (OR) and 95% CI in pregnancy outcomes associated with adiposity and lipid metabolism indicators among PCOS women undergoing their first IVF/ICSI cycles based on GLMs (n = 917). Table S3. Mediating effects investigating whether serum TC mediated the associations between glucose metabolism indicators and IVF/ICSI early reproductive outcomes in PCOS women. Table S4. Mediating effects investigating whether serum HDL-C mediated the associations between glucose metabolism indicators and IVF/ICSI early reproductive outcomes in PCOS women. Table S5. Mediating effects investigating whether serum LDL-C mediated the associations between glucose metabolism indicators and IVF/ICSI early reproductive outcomes in PCOS women. Table S6. Mediating effects investigating whether BMI mediated the associations between glucose metabolism indicators and IVF/ICSI early reproductive outcomes in PCOS women

Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells <i>In Vitro</i> and <i>In Vivo</i>

<div><p>We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of γH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD. Blockage of ATM/ATR signaling led to the attenuation of RD-induced γH2AX, and to the partial recovery of cell proliferation. Furthermore, RD exposure resulted in the inactivation of BRCA1, suppression of HR and NHEJ repair activity, and downregulation of the expressions and DNA-end binding activities of Ku70/86. Consistent with the observations, microarray data displayed that RD triggered the changes in genes responsible for cell proliferation, cell cycle, DNA damage and repair, and apoptosis. Administration of RD to xenograft mice reduced tumor growth, and coordinately caused alterations in the expression of genes involved in DNA damage and repair, along with cell apoptosis. Thus, this finding identified a novel mechanism by which RD affects DNA repair and acts as a DNA damage agent in prostate cancer.</p> </div