GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress.

Doxorubicin (DOX), which is widely used for the treatment of cancer, induces cardiomyopathy associated with NADPH oxidase-derived reactive oxygen species. GSK2795039 is a novel small molecular NADPH oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte necroptosis in DOX-induced heart failure through NADPH oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2'-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum lactate dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.

High anti-Müllerian hormone (AMH) is associated with increased risks of ectopic pregnancy in women undergoing fresh embryo transfer cycle, a cohort study.

BACKGROUND: Ectopic pregnancy is more common amongst assisted reproduction cycles and is a cause of significant maternal morbidity. Few predictive markers exist to help identify and modify risk of ectopic pregnancy in preparing for embryo transfer. The relationship between serum and AMH and ectopic pregnancy rate is unknown. METHODS: This was a retrospective cohort study investigating women who underwent fresh embryo transfer cycles from January 2017 to December 2019 in Peking University Third Hospital. The primary outcome was ectopic pregnancy. Restricted cubic splines with four knots for AMH concentration (0-3, 3-6, 6-12, 12-max) were used to map out the non-linear relationship between the predicted ectopic pregnancy rate and the serum AMH concentration. Log binomial regression was used to test the crude risk ratio (cRR) and the adjusted risk ratio (aRR) after adjustment for confounders with 95% confidence intervals (CI) to determine the difference across various groups. RESULTS: A total of 13,718 cycles in women undergoing fresh embryo transfer were eligible for analysis. The ectopic pregnancy rate was 1.3% per embryo transfer cycle initiated and 3.3% per pregnancy. Serum AMH concentrations were higher amongst women with ectopic pregnancy than in women with a confirmed intrauterine pregnancy or heterotopic pregnancy or who did not become pregnant (Mean levels: 4.0 ng/ml vs 3.2 ng/ml, 1.7 ng/ml, and 2.8 ng/ml). An AMH concentration of 7 ng/ml represented the best cut-off value to predict ectopic pregnancy. The ectopic pregnancy rate was 3.4% per cycle and 7.5% per pregnancy in women with AMH levels ≥ 7 ng/ml; and 1.2% per cycle and 2.9% per pregnancy in women with AMH levels < 7 ng/ml. Serum AMH concentration ≥ 7 ng/ml was associated with an increased risk of ectopic pregnancy in all fresh embryo transfer cycles started (aRR = 2.35 (1.45, 3.58)) as well in women who became pregnant (aRR = 2.23 (1.49, 3.33). CONCLUSIONS: Baseline AMH concentration ≥ 7 ng/ml is associated with an increased risk of ectopic pregnancy in fresh embryo transfer cycles.

Association between ambient air pollution and blood sex hormones levels in men.

Concerns are growing over time on the adverse health effects of air pollution. However, the association between ambient air pollution and blood sex hormones in men is poorly understood. We included 72,917 men aged 20-55 years from February 2014 to December 2019 in Beijing, China in this study. Blood testosterone, follicle stimulating hormone, luteinizing hormone, estradiol, and prolactin levels of each participant were measured. We collected exposure data of daily ambient levels of particulate matter ≤10 µm (PM10) and ≤2.5 µm (PM2.5), nitrogen dioxide, sulfur dioxide (SO2), carbon monoxide, and ozone. Generalized linear mixed models were used to analyze the potential association between ambient air pollution exposure and blood sex hormone levels. The results showed that both immediate and short-term cumulative PM2.5, PM10, and SO2 exposure was related to altered serum sex hormone levels in men, especially testosterone. An increase of 10 µg/m3 in PM2.5 and PM10 in the current day was related to a 1.6% (95% confidence interval [CI]: 0.9%-2.3%) and 1.1% (95% CI: 0.5%-1.6%) decrease in testosterone, respectively, and a decreasing tendency of accumulated effects persisted within lag 0-30 days. The present study demonstrated that it is important to control ambient air pollution exposure to reduce effects on the reproductive health of men.

Anti-Müllerian hormone in guiding the selection of a freeze-all versus a fresh embryo transfer strategy: a cohort study.

PURPOSE: To explore an interaction effect between serum anti-Müllerian hormone (AMH) levels and the relative treatment effect of a freeze-all versus a fresh embryo transfer strategy on live birth. METHODS: This was a retrospective cohort study investigating couples with infertility and eligible for both freeze-all and fresh embryo transfer between 2017 and 2019. Women with an absolute indication for a freeze-all strategy were excluded. Multivariable fractional polynomial interaction analysis within a logistic regression model was used to evaluate whether the treatment effect of a freeze-all versus a fresh transfer strategy varied at different AMH levels. Non-linear interactions were also considered. The primary outcome was the live birth after the first transfer. RESULTS: A total of 13,503 women underwent a fresh embryo transfer and 2247 women underwent a freeze-all strategy. Live birth rates were slightly higher in the freeze-all group compared to those in the fresh embryo transfer group (35% vs 33%). There was a non-linear interaction between baseline serum AMH levels and the relative treatment effect of a freeze-all strategy versus a fresh transfer strategy on live birth (P = 0.0161). The benefit on live birth from a freeze-all embryo transfer strategy was greatest in women with a high serum level (> 7 ng/ml). The interaction remained valid when different imputation methods were used. CONCLUSION: As serum AMH level increased, there was a nonlinear increase in relative treatment effect of a freeze-only transfer versus a fresh transfer strategy on live birth, and such an effect reaches its maximum in women with high AMH levels.

Investigation on the risk factors for late-onset OHSS: a retrospective case-control study.

BACKGROUND: The pathophysiology of ovarian hyperstimulation syndrome (OHSS) is largely unknown. High ovarian response is acknowledged as a risk factor. However, in our clinical practice, the incidence of OHSS is not necessarily linked to the degree of such response among women. Here, we aimed to screen for potential risk factors other than those associated with ovarian response. METHODS: A total of 21,222 ovarian stimulation cycles were collected among women undergoing assisted reproductive technology, among which 84 patients with late-onset OHSS were identified as cases; corresponding matched control cases were obtained from the remaining 21,138 cycles. A multivariable logistic regression with the best subset method was performed to screen for significant risk factors. RESULTS: First, control samples were obtained with a case-to-control ratio of 1:4. The matching criteria were mainly ovarian response-related factors including age, body mass index, number of oocytes retrieved, standard or mild ovarian stimulation, and specific ovarian stimulation protocols. After matching the five ovarian response-related factors, 81 cases and 318 controls were obtained. The best model was selected after analysis as above. Basal serum low-density lipoprotein cholesterol (LDL-C), basal total cholesterol (TC), and estradiol (E2) concentrations on the day of triggering ovulation were included in the model, with odds ratios of 0.3410 (95% confidence interval, CI, 0.1618-0.7186), 2.2008 (95% CI 1.1192-4.3275) and 1.0000 (95% CI 1.0000-1.0001), respectively. CONCLUSION: Basal LDL-C was a risk factor negatively associated with late-onset OHSS, while basal TC and triggering E2 levels during ovarian stimulation were positive risk factors.

Thoracoscopic versus open resection for symptomatic congenital pulmonary airway malformations in neonates: a decade-long retrospective study.

PURPOSE: The purpose of this study is to evaluate the potential advantages of thoracoscopic versus open resection for symptomatic congenital pulmonary airway malformation (CPAM) in neonates. METHODS: A retrospective review of the medical records of neonates (age ≤ 28 days) who underwent surgery for symptomatic CPAM from 2010 to 2020. RESULTS: Of the 24 patients, 14 patients underwent thoracoscopic resection and 10 patients underwent open resection. 4 patients with CPAM located in the upper or middle lobes underwent lobectomy, and 20 underwent lung-preserving wedge resection in the lower lobe. Between the two groups, there were no statistically significant differences in related preoperative variables, including gestational age at birth, body weight, head circumference, lesion size, cystic adenomatoid malformation volume ratio (CVR), and age at operation (P > .05). The differences in intraoperative variables were statistically significant. The length of the surgical incision was significantly shorter in thoracoscopic resection group than in open resection group (1.4 cm [1.3-1.8] vs. 6.0 cm [5.0-8.0], P = .000), along with significantly less operative blood loss (3 ml [1-6] vs. 5 ml [2-10], P = .030) but significantly longer operation time (159 min [100-220] vs. 110 min [70-170], P = .003). Regarding postoperative variables, ventilator days, duration of chest tube use and length of hospital stay were not statistically significant (P > .05). CONCLUSION: Both thoracoscopic and open resection for symptomatic CPAM achieve good clinical outcomes, even in neonates. Thoracoscopic resection has minimal aesthetic effects and does not increase the risk of surgical or postoperative complications. Lung-preserving resection may be feasible for neonatal CPAM surgery.

Exosomes derived from adipose tissue, bone marrow, and umbilical cord blood for cardioprotection after myocardial infarction.

Human mesenchymal stem cells (MSCs) have the potential for improving cardiac function following myocardial infarction (MI). This study was performed to explore the cardioprotection of bone marrow mesenchymal stem cells (BMMSCs), adipose tissue-derived mesenchymal stem cells (ADMSCs), and umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) for myocardium in rats after MI. MI models were established in rats, which were injected with PBS, BMMSCs, ADMSCs, and UCMSCs. Cardiac function was detected by ultrasonic cardiogram. TTC staining, TUNEL staining, and immunohistochemistry were adopted to determine infarction area, cardiomyocyte apoptosis, and microvascular density (MVD), respectively. Exosomes were derived from BMMSCs, ADMSCs, and UCBMSCs, and identified by morphological observation and CD63 expression detection. Neonatal rat cardiomyocytes (NRCMs) were isolated and cultured with hypoxia, subjected to PBS and exosomes derived from BMMSCs, ADMSCs, and UCMSCs. Flow cytometry and enzyme-linked immunosorbent assay were used to determine NRCM apoptosis and the levels of angiogenesis-related markers (VEGF, bFGF, and HGF). According to ultrasonic cardiogram, BMMSCs, ADMSCs, and UCMSCs facilitated the cardiac function of MI rats. Furthermore, three kinds of MSCs inhibited cardiomyocyte apoptosis, infarction area, and increased MVD. NRCMs treated with exosomes derived from BMMSCs, ADMSCs, and UCMSCs reduced the NRCM apoptosis and promoted angiogenesis by increasing levels of VEGF, bFGF, and HGF. Notably, exosomes from ADMSCs had the most significant effect. On the basis of the results obtained from this study, exosomes derived from BMMSCs, ADMSCs, and UCBMSCs inhibited the cardiomyocyte apoptosis and promoted angiogenesis, thereby improving cardiac function and protecting myocardium. Notably, exosomes from ADMSCs stimulated most of the cardioprotection factors.

Association of serum anti-Müllerian hormone and other factors with cumulative live birth rate following IVF.

RESEARCH QUESTION: What are the optimal values of maternal age and body mass index (BMI), paternal age and BMI, number of oocytes retrieved, and serum AMH concentrations for cumulative live birth rate (CLBR) in IVF and embryo transfer (IVF-ET)? DESIGN: This retrospective cohort study included 9494 women who underwent their first IVF-ET cycle between January 2017 and July 2018. The primary outcome was the CLBR within one complete cycle. Cox regression analysis was used to test the hazard ratio, with 95% confidence intervals. RESULTS: CLBR was significantly lower when maternal age was over 35 (adjusted P < 0.01 for age 36-38 years, adjusted P < 0.00001 for all age groups above 38 years). CBLR increased with increasing serum AMH concentrations and number of retrieved oocytes up to peak values at 5-7 ng/ml AMH and 16-20 oocytes in all women. CLBR was significantly increased when serum AMH concentrations were 3-7 ng/ml (adjusted P < 0.001) and number of oocytes retrieved was more than five (adjusted P < 0.00001). Overweight had a negative effect on CLBR compared with normal BMI in women under 35 years of age (adjusted P = 0.037). In women aged over 35 years, paternal overweight had a negative effect on CLBR compared with normal paternal BMI (adjusted P < 0.01). CONCLUSIONS: Maternal age had an impact on optimal serum AMH concentrations and number of oocytes retrieved. Maternal overweight negatively affected CLBR in women under 35 years of age, and paternal overweight negatively affected CLBR in women over 35 years.

An Ovarian Reserve Assessment Model Based on Anti-Müllerian Hormone Levels, Follicle-Stimulating Hormone Levels, and Age: Retrospective Cohort Study.

BACKGROUND: Previously, we reported a model for assessing ovarian reserves using 4 predictors: anti-Müllerian hormone (AMH) level, antral follicle count (AFC), follicle-stimulating hormone (FSH) level, and female age. This model is referred as the AAFA (anti-Müllerian hormone level-antral follicle count-follicle-stimulating hormone level-age) model. OBJECTIVE: This study aims to explore the possibility of establishing a model for predicting ovarian reserves using only 3 factors: AMH level, FSH level, and age. The proposed model is referred to as the AFA (anti-Müllerian hormone level-follicle-stimulating hormone level-age) model. METHODS: Oocytes from ovarian cycles stimulated by gonadotropin-releasing hormone antagonist were collected retrospectively at our reproductive center. Poor ovarian response (<5 oocytes retrieved) was defined as an outcome variable. The AFA model was built using a multivariable logistic regression analysis on data from 2017; data from 2018 were used to validate the performance of AFA model. Measurements of the area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predicative value were used to evaluate the performance of the model. To rank the ovarian reserves of the whole population, we ranked the subgroups according to the predicted probability of poor ovarian response and further divided the 60 subgroups into 4 clusters, A-D, according to cut-off values consistent with the AAFA model. RESULTS: The AUCs of the AFA and AAFA models were similar for the same validation set, with values of 0.853 (95% CI 0.841-0.865) and 0.850 (95% CI 0.838-0.862), respectively. We further ranked the ovarian reserves according to their predicted probability of poor ovarian response, which was calculated using our AFA model. The actual incidences of poor ovarian response in groups from A-D in the AFA model were 0.037 (95% CI 0.029-0.046), 0.128 (95% CI 0.099-0.165), 0.294 (95% CI 0.250-0.341), and 0.624 (95% CI 0.577-0.669), respectively. The order of ovarian reserve from adequate to poor followed the order from A to D. The clinical pregnancy rate, live-birth rate, and specific differences in groups A-D were similar when predicted using the AFA and AAFA models. CONCLUSIONS: This AFA model for assessing the true ovarian reserve was more convenient, cost-effective, and objective than our original AAFA model.

A novel mathematical model of true ovarian reserve assessment based on predicted probability of poor ovarian response: a retrospective cohort study.

PURPOSE: To establish a mathematical model for assessing the true ovarian reserve based on the predicted probability of poor ovarian response (POR). METHODS: In this retrospective cohort study, a total of 1523 GnRH-antagonist cycles in 2017 were firstly analyzed. The ovarian responses were calculated based on the number of retrieved oocytes. The continuous variables were converted into categorical variables according to cutoff values generated by the decision tree method. The optimal model was identified using forward stepwise multiple logistic regression with 5-fold cross-validation and further verified its performances using outer validation data. RESULTS: The predictors in our model were anti-Müllerian hormone (AMH), antral follicle counts (AFC), basal follicle-stimulating hormone (FSH), and age, in order of their significance, named AAFA model. The AUC, sensitivity, specificity, positive predictive value, and negative predictive value of AAFA model in inner validation and outer validation data were 0.861 and 0.850, 0.603 and 0.519, 0.917 and 0.930, 0.655 and 0.570, and 0.899 and 0.915. Ovarian reserve of 16 subgroups was further ranked according to the predicted probability of POR and further divided into 4 groups of A-D using clustering analysis. The incidence of POR in the four groups was 0.038 (0.030-0.046), 0.139 (0.101-0.177), 0.362 (0.308-0.415), and 0.571 (0.525-0.616), respectively. The order of ovarian reserve from adequate to poor followed the order of A to D. CONCLUSION: We have established an easy applicable AAFA model for assessing true ovarian reserve and may have important implications in both infertile women and general reproductive women in Chinese or Asian population.

Screening for therapeutic targets of tumor angiogenesis signatures in 31 cancer types and potential insights.

Tumor vessel normalization can increase pericyte coverage, perfusion efficiency and immune infiltration, while reducing hypoxia, vessel leakage, CTC and metastasis. In this study, we systemically presented the expression pattern of tumor angiogenesis gene signatures in 31 cancer types and its association with immune infiltration and cancer metastasis. Specifically, READ, COAD etc. have relatively similar expression patterns with low GPAGs and high PPAGs. Patients with this expression pattern may benefit from tumor vessel normalization. COAD was selected for further investigation and we found GPAG CXCL12 was downregulated while PPAG EPHB3 was overexpressed in COAD, which were further validated using two independent colon cancer dataset. Further study indicated that CXCL12 expression was positively correlated innate inflammation pathways such as NFκB and negatively correlated with metastasis, while EPHB3 had a reverse result. Moreover, CXCL12 was positively correlated with cancer immune infiltration while EPHB3 was negatively correlated with cancer immune infiltration. Besides, the association between CXCL12/EPHB3 and mutation/CNA landscape were also explored. We also discussed the potential application of gut microbiota in cancer treatment. In summary, blood vessel normalization could promote immune infiltration and repress cancer metastasis while immune cell infiltration can promote blood vessel normalization through a positive feedback loop.

Predictive value of serum kisspeptin concentration at 14 and 21 days after frozen-thawed embryo transfer.

RESEARCH QUESTION: Can serum kisspeptin levels 14 and 21 days after frozen-thawed embryo transfer predict the early pregnancy outcome of patients? DESIGN: Prospective study, with 133 patients undergoing frozen-thawed embryo transfer. Patients were divided into non-pregnant group and pregnant group (including biochemical pregnancy, singleton pregnancy, miscarriage and twin groups). RESULTS: Serum kisspeptin levels on day 21 were significantly higher than day 14 in singleton pregnancy, miscarriage and twin groups (all P < 0.0001), but not in the biochemical pregnancy group. Similarly, serum human chorionic gonadotrophin (HCG) levels were higher on day 21 compared with day 14 except for the biochemical pregnancy group. Compared with the twin group (296.9 pg/ml), the other four groups showed significantly higher serum kisspeptin levels on day 14 (non-pregnant 548.9, biochemical pregnancy 440.4, miscarriage 434.9, singleton pregnancy group 420.9 pg/ml, P < 0.01, P = 0.016, P = 0.034, P = 0.036, respectively). The miscarriage (762.2 pg/ml), singleton pregnancy (730.8 pg/ml) and twin groups (826.3 pg/ml) had significantly higher kisspeptin levels than the biochemical pregnancy group (397.3 pg/ml) on day 21 (P < 0.001, P < 0.01, P < 0.001, respectively). Serum kisspeptin levels on day 14 were negatively correlated with embryo implantation rate (P = 0.035, R2 = -0.880). Serum kisspeptin levels on day 21 have a poor predictive value of miscarriage compared with serum HCG levels (area under the curve = 0.53 and 0.78, respectively). CONCLUSIONS: Serum kisspeptin levels on day 14 are negatively correlated with embryo implantation rate. Serum kisspeptin levels on day 21 have a poor predictive value of miscarriage.

ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver.

The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros region was not affected. The migration activity of ATF4(-/-) HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated expression of a panel of cytokines in ATF4(-/-) stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4(-/-) HSCs in the culture. Furthermore, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.

Retrospective cohort study: AMH is the best ovarian reserve markers in predicting ovarian response but has unfavorable value in predicting clinical pregnancy in GnRH antagonist protocol.

BACKGROUND: Various ovarian reserve markers have been used to predict ovarian response and pregnancy. However, concerning Chinese population, fewer trials have been performed using the combined ovarian reserve markers to predict ovarian response and pregnancy in GnRH antagonist protocols. METHODS: Data from a total of 373 patients' in vitro fertilization cycles using GnRH antagonist protocol was retrospectively included. According to our center's daily practice, circulating follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) were tested on menstrual cycle day 2-4 or hCG trigger day, and the concentration of AMH was determined despite of menstrual cycle. The antral follicle count (AFC) was assessed by transvaginal ultrasound on day 2-4 of menstrual cycle. Different ovarian response was defined as 0-4 and 5-15 and >15 oocyte retrieved for low and normal and high ovarian response, respectively. Gestational sac with fetal heartbeat detected by ultrasound was considered as clinical pregnancy. RESULTS: Serum AMH levels was the most accurate marker in predicting ovarian response [area under the receiver operating characteristic (ROC) curve = 0.767]. Significant difference was found in age between non-clinical pregnancy and clinical pregnancy groups (p < 0.001). CONCLUSIONS: Our data demonstrated that the circulating AMH despite of menstrual cycle was preferable in prediction of oocyte retrieved outcome during GnRH antagonist protocol than age, AFC and the other currently used hormone markers. Furthermore, age is the only marker in predicting clinical pregnancy.

Inhibition of STAT5a by Naa10p contributes to decreased breast cancer metastasis.

N-α-Acetyltransferase 10 protein (Naa10p, also called arrest-defective 1), the catalytic subunit of N-acetyltransferase A, is a critical regulator of cell death and proliferation. Naa10p is also shown to regulate cancer metastasis by inhibiting cell motility; however, its role in cancer metastasis is not fully understood. In this study, we found that high expression of Naa10p is positively correlated with the survival of patients with breast cancer, whereas negatively correlated with lymph node metastasis. Naa10p inhibits breast cancer cell migration and invasion in vitro and decreases the xenograft growth and metastasis in nude mice. Microarray screening revealed that Naa10p downregulates inhibitors of differentiation 1 (ID1) expression. Naa10p binds to signal transducer and activator of transcription 5a (STAT5a) and decreases STAT5a-stimulated ID1 expression in an acetyltransferase-independent manner. Moreover, Naa10p antagonizes Janus kinase 2-STAT5a signaling by lowering p65-activated interleukin-1ß expression. Our results demonstrate a novel mechanism through which Naa10p inhibits the metastasis of breast cancer cells by targeting STAT5a.

Preparation of Fe-BN-C catalysts derived from ZIF-8 and their performance in the oxygen reduction reaction.

Enhancing the oxygen reduction reaction (ORR) activity and stability of the fuel cell cathode electrocatalysts and reducing their costs are critical. In response to this need, Fe, B, and N co-doped hollow mesoporous carbon materials were prepared by a simple chemical doping one-step pyrolysis method using ZIF-8 as a precursor. The results showed that the optimized catalyst displayed a higher limiting current density (6.154 mA cm-2) and half-wave potential (0.859 V), which showed significant enhancement compared with the Pt/C catalyst (5.487 mA cm-2 and 0.853 V). Moreover, the optimized catalyst had outstanding long-term stability with a current density retention higher than 91% after 36 000 s of stability testing. This work provides a facile strategy for the design of outstanding ORR performance of non-precious metal oxygen reduction catalysts.

Reduced human fecundity attributable to ambient fine particles in low- and middle-income countries.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) has been associated with reduced human fecundity. However, the attributable burden has not been estimated for low- and middle-income countries (LMICs), where the exposure-response function between PM2.5 and the infertility rate has been insufficiently studied. OBJECTIVE: This study examined the associations between long-term exposure to PM2.5 and human fecundity indicators, namely the expected time to pregnancy (TTP) and 12-month infertility rate (IR), and then estimated PM2.5-attributable burden of infertility in LMICs. METHODS: We analyzed 164,593 eligible women from 100 Demographic and Health Surveys conducted in 49 LMICs between 1999 and 2021. We assessed PM2.5 exposures during the 12 months before a pregnancy attempt using the global satellite-derived PM2.5 estimates produced by Atmospheric Composition Analysis Group (ACAG). First, we created a series of pseudo-populations with balanced covariates, given different levels of PM2.5 exposure, using a matching approach based on the generalized propensity score. For each pseudo-population, we used 2-stage generalized Gamma models to derive TTP or IR from the probability distribution of the questionnaire-based duration time for the pregnancy attempt before the interview. Second, we used spline regressions to generate nonlinear PM2.5 exposure-response functions for each of the two fecundity indicators. Finally, we applied the exposure-response functions to estimate number of infertile couples attributable to PM2.5 exposure in 118 LMICs. RESULTS: Based on the Gamma models, each 10 µg/m3 increment in PM2.5 exposure was associated with a TTP increase by 1.7 % (95 % confidence interval [CI]: -2.3 %-6.0 %) and an IR increase by 2.3 % (95 %CI: 0.6 %-3.9 %). The nonlinear exposure-response function suggested a robust effect of an increased IR for high-concentration PM2.5 exposure (>75 µg/m3). Based on the PM2.5-IR function, across the 118 LMICs, the number of infertile couples attributable to PM2.5 exposure exceeding 35 µg/m3 (the first-stage interim target recommended by the World Health Organization global air quality guidelines) was 0.66 million (95 %CI: 0.061-1.43), accounting for 2.25 % (95 %CI: 0.20 %-4.84 %) of all couples affected by infertility. Among the 0.66 million, 66.5 % were within the top 10 % high-exposure infertile couples, mainly from South Asia, East Asia, and West Africa. CONCLUSION: PM2.5 contributes significantly to human infertility in places with high levels of air pollution. PM2.5-pollution control is imperative to protect human fecundity in LMICs.

Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells.

BACKGROUND: Increasing evidence suggests that cancer is a metabolic disease. Here, we investigated the potential role of fructose-1,6-bisphosphatase-2 (FBP2), the enzyme that catalyses the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and inorganic phosphate in glucose metabolism, in gastric cancer (GC) development. RESULTS: Our data indicated that FBP2 was downregulated in GC tissues (86.2%, 100/116), and absent or low FBP2 expression in GC tissues was correlated with poor survival of GC patients (P = 0.019). Conversely, ectopic expression of FBP2 in GC cells activated AMP-activated protein kinase (AMPK) signalling, inhibited the Akt-mTOR pathway, suppressed glucose metabolism, enhanced apoptosis, and reduced cell proliferation. Bisulphite genomic sequencing (BGS) in gastric cancer cell lines revealed that the FBP2 promoter region was densely methylated, and treatment of GC cells with the demethylation reagent, 5-aza-2-deoxycytidine (5-Aza), led to an increase in FBP2 expression. Importantly, forced expression of FBP2 abrogated tumour formation of these GC cells in nude mice. CONCLUSION: Our results indicate that FBP2 does negatively regulate cell growth, and reduced expression of FBP2 may contribute to carcinogenesis for GC. These findings suggest that restoration of FBP2 expression can be a promising strategy for the target therapy of GC.

Postconditioning in patients treated with primary percutaneous coronary intervention: an updated meta-analysis.

OBJECTIVE: The aim of present analysis was to evaluate the effect of postconditioning in primary percutaneous coronary intervention (pPCI). BACKGROUND: Although postconditioning in pPCI has shown potential favorable effects on reperfusion injury, recent trials have yielded divergent results. METHODS: Randomized controlled trials were identified using relevant databases published up to August 15, 2012. Weighted mean difference (WMD) and standardized mean difference (SMD) were calculated using meta-analysis through fixed- or random-effects models. Statistical analysis was performed using RevMan 5.17 and Stata 12.0. RESULTS: Thirteen studies providing myocardial biomarkers, left ventricular ejection fraction (LVEF) or infarct size evaluated by cardiac magnetic resonance (CMR) in a total of 725 ST-elevation acute myocardial infarction (STEMI) patients were identified. Compared with usual care, postconditioning significantly reduced myocardial injury biomarkers (SMD = -0.61; 95% Confidence Interval (CI): [-0.98, -0.23]; P = 0.001; I(2) = 78%). Univariate meta-regression analysis suggested potential source of heterogeneity were the type of biomarkers and the use of glycoprotein IIb/IIIa inhibitors (I(2) reg = 44.84% and 67.24%, respectively; R(2) = 91.53% and 49.46%, respectively). Secondary analysis showed statistical significant improvement of LVEF with postconditioning (WMD = 3.22%; 95%CI: [0.88%, 5.57%]; P = 0.007; I(2) = 60%) relative to usual care. The effect diminished during medium (<6 months) and long terms (≥6 months) (P = 0.86 and 0.15, respectively). There was no significant decrease in infarct size among patients treated with postconditioning compared to usual care (SMD = 0.20; 95%CI: [-0.03, 0.43]; P = 0.08; I(2) = 46%). CONCLUSION: In STEMI patients undergoing pPCI, postconditioning is associated with significant lower level of myocardial injury biomarkers and a statistical significant improvement of LVEF relative to usual care. However, this adjunctive therapy may fails to reduce infarct size evaluated by CMR.

NEDD4 attenuates oxidized low­density lipoprotein­induced inflammation and dysfunction in vascular endothelial cells via regulating APEX1 expression.

Atherosclerosis chiefly results from inflammation as well as vascular endothelial cell dysfunction. Methylation levels of neuronally expressed developmentally downregulated 4 (NEDD4) were found to be fortified in atherosclerosis patients and NEDD4 deficiency enhanced vascular calcification. However, the exact function of NEDD4 in inflammation and vascular endothelial dysfunction remains to be elucidated. In the present study, CCK-8 assay was used to estimate cell viability. Reverse transcription-quantitative PCR was adopted to examine the expression of NEDD4, inflammation-associated enzymes and apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1). Western blotting was used to test NEDD4, endothelial nitric oxide synthase, inducible nitric oxide synthase and APEX1 protein levels. Cytotoxicity was detected by a lactate dehydrogenase (LDH) kit. Reactive oxygen species level was tested by a corresponding kit. Vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 contents were examined with ELISA. Cell adhesion assays evaluated the adhesion of endothelial cells. Co-immunoprecipitation assay was used to test the relationship between NEDD4 and APEX1. The data revealed that NEDD4 expression rapidly declined in oxidized low density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs). Following NEDD4 overexpression, the active damage, inflammatory release and endothelial cell dysfunction in ox-LDL-induced HUVECs were attenuated. After co-transfection of APEX1 interference plasmids and NEDD4 overexpression plasmids, cell damage, inflammatory release and endothelial cell dysfunction in ox-LDL-induced HUVECs were improved again. Taken together, NEDD4 attenuated ox-LDL-induced inflammation and endothelial dysfunction by regulating APEX1 expression.