The PAPSS1 gene is a modulator of response to cisplatin by regulating estrogen receptor alpha signaling activity in ovarian cancer cells.

BACKGROUND: Cancer cells may develop resistance to cisplatin by various mechanisms. Yet, the exact mechanism of cisplatin in ovarian cancer remains unclear. Recent studies have shown that 3'-phospoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) inhibition combined with low-dose cisplatin increases DNA damage. The aim of this study was to determine the value of targeting PAPSS1 as a cisplatin modulator in epithelial ovarian cancer (EOC). RESULTS: Increased expression of PAPSS1 was observed in both EOC cells and tissues. Also, its higher nuclear expression was distinctly associated with FIGO (The International Federation of Gynecology and Obstetrics) stage, histological subtype, metastasis, and recurrence. Down-regulation of the PAPSS1 gene increased the cisplatin sensitivity of EOC in vitro and in vivo. Expression of PAPSS1 was negatively correlated with estrogen receptor α (ERα) in EOC. Also, low nuclear PAPSS1 and high nuclear ERα expression in EOC were associated with longer overall survival and progression-free survival in all ovarian cancer and ovarian cancer patients who received platinum-based chemotherapy. PAPSS1 silencing increased the activity of ERα-signaling in EOC cells, thus sensitizing tumors to cisplatin. CONCLUSIONS: These findings characterize a novel interplay between PAPSS1-mediated sulfation and ERα-signaling in EOC cisplatin resistance. PAPSS1 may be exploited as a cisplatin-sensitizing therapeutic target.

Association between per- and polyfluoroalkyl substances exposure and risk of diabetes: a systematic review and meta-analysis.

BACKGROUND: Emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the etiology of diabetes. OBJECTIVES: This study aimed to systematically review the epidemiological evidence on the associations of PFAS with mortality and morbidity of diabetes and to quantitatively evaluate the summary effect estimates of the existing literature. METHODS: We searched three electronic databases for epidemiological studies concerning PFAS and diabetes published before April 1, 2022. Summary odds ratio (OR), hazard ratio (HR), or ß and their 95% confidence intervals (CIs) were respectively calculated to evaluate the association between PFAS and diabetes using random-effects model by the exposure type, and dose-response meta-analyses were also performed when possible. We also assessed the risk of bias of the studies included and the confidence in the body of evidence. RESULTS: An initial literature search identified 1969 studies, of which 22 studies were eventually included. The meta-analyses indicated that the observed statistically significant PFAS-T2DM associations were consistent in cohort studies, while the associations were almost non-significant in case-control and cross-sectional studies. Dose-response meta-analysis showed a "parabolic-shaped" association between perfluorooctanoate acid (PFOA) exposure and T2DM risk. Available evidence was rated with "low" risk of bias, and the level of evidence for PFAS and incident T2DM was considered "moderate". CONCLUSIONS: Our findings suggest that PFAS exposure may increase the risk of incident T2DM, and that PFOA may exert non-monotonic dose-response effect on T2DM risk. Considering the widespread exposure, persistence, and potential for adverse health effects of PFAS, further cohort studies with improvements in expanding the sample size, adjusting the covariates, and considering different types of PFAS exposure at various doses, are needed to elucidate the putative causal associations and potential mode of action of different PFAS on diabetes. IMPACT STATEMENT: A growing body of evidence suggests that per- and polyfluoroalkyl substances (PFAS) are endocrine disruptors and may contribute to the development of diabetes. However, epidemiological evidence on the associations of PFAS and diabetes is inconsistent. We performed this comprehensive systematic review and meta-analysis to quantitatively synthesize the evidence. The findings of this study suggest that exposure to PFAS may increase diabetes risk among the general population. Reduced exposure to these "forever and everywhere chemicals" may be an important preventative approach to reducing the risk of diabetes across the population.

Association Between Exposure to Per- and Polyfluoroalkyl Substances and Birth Outcomes: A Systematic Review and Meta-Analysis.

Background: A large body of emerging evidence suggests that per- and polyfluoroalkyl substances (PFAS) affect birth outcomes in various pathways, but the evidence is inconsistent. Therefore, this study aimed to systematically review the epidemiological evidence on PFAS exposure and birth outcomes. Methods: Three electronic databases were searched for epidemiological studies through February 13, 2021. We used random-effects meta-analysis for eight birth outcome indicators to calculate summary effect estimates for various exposure types. The risk of bias and the overall quality and level of evidence for each exposure-outcome pair were assessed. Results: The initial search identified 58 potentially eligible studies, of which 46 were ultimately included. Many PFAS were found to have previously unrecognized statistically significant associations with birth outcomes. Specifically, birth weight (BW) was associated with PFAS, with effect sizes ranging from -181.209 g (95% confidence interval (CI) = -360.620 to -1.798) per 1 ng/ml increase in perfluoroheptanesulfonate (PFHpS) to -24.252 g (95% CI = -38.574 to -9.930) per 1 ln (ng/ml) increase in perfluorodecaoic acid (PFDA). Similar patterns were observed between other PFAS and birth outcomes: perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with birth length (BL) and ponderal index (PI), PFOS and perfluorododecanoic acid (PFDoDA) with head circumference (HC), PFHpS with gestational age (GA), and perfluorononanoic acid (PFNA) and PFHpS with preterm birth (PTB). Additionally, PFDA showed a statistically significant association with small for gestational age (SGA). The level of the combined evidence for each exposure-outcome pair was considered to be "moderate". Conclusion: This study showed that PFAS exposure was significantly associated with increased risks of various adverse birth outcomes and that different birth outcome indicators had different degrees of sensitivity to PFAS. Further studies are needed to confirm our results by expanding the sample size, clarifying the effects of different types or doses of PFAS and the time of blood collection on birth outcomes, and fully considering the possible confounders.

Downregulation of LINC01508 contributes to cisplatin resistance in ovarian cancer via the regulation of the Hippo-YAP pathway.

BACKGROUND: Some long non-coding RNAs (lncRNAs) have been found to contribute to cisplatin resistance. Here, we identified a novel lncRNA that was downregulated in cisplatin-resistant to ovarian cancer (OC) cells and aimed to examine the contribution of LINC01508 to cisplatin resistance in OC cells. METHODS: Differences in the lncRNA expression profile between OV2008 and C13K cells were assessed by lncRNA expression microarray. The expression of LINC01508 in ovarian epithelial cells, four OC cells, and OC, benign ovary tumor and normal ovary, cisplatin-resistant and non-resistant OC specimens were evaluated by quantitative real-time polymerase chain reaction (qPCR). The role of LINC01508 in OC cisplatin-resistant was evaluated by cell counting kit-8 (CCK-8), flow cytometry, colony formation, wound healing, Transwell, and tumor growth inhibition study in vivo. The clinical associations of LINC01508 in OC were evaluated using correlation analysis. The effects of verteporfin (VP) on cisplatin were explored to reveal the function of the hippo-YAP pathway on the cisplatin tolerance of C13K. RESULTS: LINC01508 was downregulated in cisplatin-resistant OC cells and platinum-resistant OC tissue (p<0.01). LINC01508 downregulation was correlated with tumor size, residual tumor, and platinum resistance. The overexpression of LINC01508 improves in vitro and in vivo sensitivity to cisplatin while predicts the poor overall survival which need further follow-up research. The increased level of LINC01508 could suppress the cisplatin resistance of OC cells through the inhibition of the hippo-YAP pathway. CONCLUSIONS: The study proposes that dysregulation of LINC01508 expression results in resistance of OC to cisplatin through the inhibition of the hippo-YAP pathway.

Proton pump inhibitors can reverse the YAP mediated paclitaxel resistance in epithelial ovarian cancer.

BACKGROUND: Several reports indicated that the expression of Yes-associated protein (YAP) was associated with multi-drug resistance. Acidic microenvironment increased by the overexpression of vacuolar-ATPase (V-ATPase) was also observed in tumor growth and drug resistance. We hypothesize that proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. Thus, our objective is to explore the reversal of drug resistance by the inhibition of YAP through specific PPIs in the epithelial ovarian carcinoma (EOC) cells. . RESULTS: We found that V-ATPase D1 was a positive regulator of YAP. Sub-lethal doses of the proton pump inhibitor esomeprazole (EMSO) in combination with paclitaxel (PTX) increased the PTX sensitivity in PTX-resistant EOC cells, as compared to PTX single treatments by inhibiting YAP and reserving pH gradient created by the V-ATPase D1. Moreover, sub-lethal doses of EMSO combined with PTX decreased autophagy and improved caspases independent apoptosis of PTX-resistant EOC cells. CONCLUSIONS: These results suggested that sub-lethal doses of esomeprazole reverse YAP-mediated PTX resistance through the inhibiting of both YAP expression and acidic tumor microenvironment created by the V-ATPase D1. Therefore, we think the use of PPIs represents a promising strategy to improve the effectiveness of anti-EOC.

A case report for severe hand-foot skin reaction caused by chemotherapy with actinomycin D in a patient with oculocutaneous albinism.

Gestational trophoblastic neoplasms (GTN) are highly curable tumors, with an overall patient survival of 90%, due to the individualized chemotherapy. However, chemotherapy regimens vary between different treatment centers and the comparable benefits and risks of these different regimens are unclear. Here, we reported a case of GTN with oculocutaneous albinism (OCA) is resistant to fluorouracil (5-FU), extremely sensitive to actinomycin D (Act-D) with severe hand-foot skin reaction (HFSR). We hypothesized that the known, or unknown, gene mutations might be correlated with drug resistance, supersensitivity and severe drug side effects in OCA patients. Thus, we considered that OCA related genes influence some drug sensitivity and that the absence of melanin likely contributes to some drug resistance. It is important to assess the OCA related gene mutations locus of drug sensitivity, and resistance in OCA patients in future research.

[Clinical application of in vitro maturation of human immature oocytes for infertile women with polycystic ovary syndrome].

OBJECTIVE: To investigate clinical effect and safety of in vitro maturation (IVM) of human immature oocytes in infertile women with polycystic ovary syndrome by comparing with conventional in vitro fertilization(IVF)and intracytoplasmic sperm injection(ICSI). METHODS: From Jan. 2003 to Dec. 2009, 157 infertile women with PCOS underwent 162 cycles IVM in Center for Reproductive Medicine, the First Affiliated Hospital of Anhui Medical University. In the mean time, 109 patients with PCOS underwent 114 IVF/ICSI cycles as control group 1 and 106 patients with other factors underwent 106 IVF/ICSI cycles as control group 2. Treatment and outcome of pregnancy and infant were compared among those 3 groups. RESULTS: No statistically significant difference were found in terms of the positive rate of hCG in urine [35.7% (56/157), 42.2% (46/109), 44.3% (47/106)], the rate of clinical pregnancy [29.3% (46/157), 37.6% (41/109), 41.5% (44/106)], the rate of entopic pregnancy [1.9% (3/157), 1.8% (2/109), 0.9% (1/106)], the rate of miscarriage [18.6% (8/43), 12.8% (5/39), 20.9% (9/43)] and the rate of live-birth [22.3% (35/157), 31.2% (34/109), 32.1% (34/106)] among three groups (IVM group, control group 1, control group 2, P > 0.05). The rate of preterm labor, low weight newborn, mean birth weight, ratio of male to female did not show significantly difference among 3 groups (P > 0.05). The average control ovarian stimulation was 6 days, the median dose of gonadotropin (Gn) was 675 IU, and the total hospital cost was (8392 ± 1328) RMB in IVM group, which were statistically lower than those in the other two control groups (P < 0.01). The rate of multiple pregnancy was 4.7% (2/43) and ovarian hyperstimulation syndrome (OHSS) 0 in IVM group, which were significantly lower than those in the other control group (P < 0.01). CONCLUSION: In vitro maturation is an effective treatment in infertile women with PCOS, it could obtain the similar pregnancy outcome and reduce total cost, the dosage of gonadotropin-releasing hormone and rate of OHSS compared with conventional IVF/ICSI.

[Association between recurrent miscarriages and insulin resistance: a meta analysis].

OBJECTIVE: To evaluate the association between recurrent miscarriages and insulin resistance. METHODS: The case-control studies on the association between recurrent spontaneous abortion and insulin resistance from June 1996 to April 2012 were collected from Medline, Elsevier, Chinese Journal Full-text Database, Chinese Biological Medicine Database, data base of Wanfang, Springer link and EMBASE. RevMan 5.1 software was used for Meta analysis. RESULTS: According to the included criteria, 7 clinical trials were finally selected. Total 467 cases with recurrent pregnancy loss were enrolled in study group, while 413 women with no history of abnormal pregnancies were enrolled in control group. No significant difference was found in average age and body mass index between the two groups (P > 0.05). Meta analysis results showed that the level of fasting glucose was no statistical difference between study group and control group (WMD = 2.27, 95%CI: -1.11 to 5.65, P > 0.05); fasting insulin level was higher 2.05 mU/L in study group than that of in control group, the difference was statistically significant (WMD = 2.05, 95%CI: 1.03 to 3.08, P < 0.01). Case number of study group on Homa-insulin resistance > 4.5 was more than that of control group (OR = 3.36, 95%CI: 1.72 to 6.57, P < 0.01). Case number of study group on glucose/insulin ratio < 4.5 was more than that of the control group, statistical difference was found (OR = 3.37, 95%CI: 1.90 to 5.99, P < 0.01). CONCLUSION: Insulin resistance is associated with the susceptibility to recurrent miscarriages, and it may contribute to the occurrence of recurrent miscarriages.