Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Boosting activity of γ-alumina-supported vanadium catalyst for isobutane non-oxidative dehydrogenation via pure V3.

The vanadium-based dehydrogenation (DH) catalyst is becoming a promise alternative to the industrial used Pt- and Cr-based catalysts, due to lower cost and less environmental threat. However, the low DH activity hampered the industrial application of vanadium-based catalysts. Herein, for the first time, we introduce a method to prepare high-efficiency vanadium-based catalyst by constructing pure V3+ species on γ-Al2O3 through treatment of as-prepared thiovanadate. The V3+ species contributes to not only enhancing the DH activity, but also fabricating the V3+-O/S acid-base pair with ideal strength and stability. The isobutene yield can reach as high as 56.9 wt%. Only Lewis acid is recognized on V3+/Al2O3 catalyst, while no Brønsted acid remains. The side-reactions are consequently inhibited, and the selectivity to isobutene is improved. Besides, with the increase of vanadium loadings, the Lewis acid content increases at first and then decreases, and the content of acid sites in middle strength keeps decreasing. Though the deposited coke on V3+/Al2O3 was just 2.5 wt% during 8.5 h consecutive DH reaction, the valence state of vanadium was still influenced and the fraction of inert V4+ species increased steadily. This study will improve the potential for industrial application of vanadium-based DH catalyst, and offer theoretical guidance for optimization of ideal DH catalysts.

Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002).

PURPOSE: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. PATIENTS AND METHODS: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. RESULTS: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0-44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7-21.7)] in the ET group and 14.8 months (12.8-16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71-1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. CONCLUSIONS: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Anxiety and depression-like behaviours are more frequent in aged male mice conceived by ART compared with natural conception.

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.

Isobutane dehydrogenation over high-performanced sulfide V-K/γ-Al2O3 catalyst: Modulation of vanadium species and intrinsic effect of potassium.

Compared with industrial used Pt- and Cr-based catalyst in dehydrogenation (DH) of light alkanes, the sulfide V-K/γ-Al2O3 catalyst reported in this study shows lower cost and toxicity, and significant DH performance. The yield to isobutene reached as high as 52.9%, which is among the highest reported to date. We attribute such high isobutene yield to the precise modulation of polymerization degree for vanadium species via doping of potassium and indicating that the synergy between vanadium species and acid sites is critical to enhance the DH performance. Our previous work showed sulfidation promoted the increase of DH performance for vanadium-based catalyst, and we go further in this study to explore the correlation between increased range of DH performance and the added potassium. The different loaded potassium leads to variation in sulfidation degree, affecting the properties of vanadium species and acid properties consequently. The potassium was distributed uniformly on surface of the sulfide vanadium-based catalyst and was predominantly bonded with the vanadium species rather than with the γ-Al2O3 support. With increasing the potassium amount from 0 to 3 wt%, the acid amount kept decreasing, and some specific strong acid sites appeared once adequate sulfur was introduced in the V-K/γ-Al2O3 catalyst. The characterization and DFT results both revealed that the doped potassium contributes to regulating the vanadium species in the oligomeric state. The synergy between vanadium species and acid properties was regulated by the added potassium simultaneously, and thus the DH performance was enhanced. This study provides promising strategy for preparation of environment-friendly model industrial DH catalyst.

Study protocol for the Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI): a multicentre, cluster-randomised, parallel-group, superiority trial of a multifaceted community-family-mother-child intervention to prevent childhood overweight and obesity.

INTRODUCTION: Childhood overweight and obesity (OWO) is a primary global health challenge. Childhood OWO prevention is now a public health priority in China. The Sino-Canadian Healthy Life Trajectories Initiative (SCHeLTI), one of four trials being undertaken by the international HeLTI consortium, aims to evaluate the effectiveness of a multifaceted, community-family-mother-child intervention on childhood OWO and non-communicable diseases risk. METHODS AND ANALYSIS: This is a multicentre, cluster-randomised, controlled trial conducted in Shanghai, China. The unit of randomisation is the service area of Maternal Child Health Units (N=36). We will recruit 4500 women/partners/families in maternity and district level hospitals. Participants in the intervention group will receive a multifaceted, integrated package of health promotion interventions beginning in preconception or in the first trimester of pregnancy, continuing into infancy and early childhood. The intervention, which is centred on a modified motivational interviewing approach, will target early-life maternal and child risk factors for adiposity. Through the development of a biological specimen bank, we will study potential mechanisms underlying the effects of the intervention. The primary outcome for the trial is childhood OWO (body mass index for age ≥85th percentile) at 5 years of age, based on WHO sex-specific standards. The study has a power of 0.8 (α=0.05) to detect a 30% risk reduction in the proportion of children with OWO at 5 years of age, from 24.4% in the control group to 17% in the intervention group. Recruitment was launched on 30 August 2018 for the pilot study and 10 January 2019 for the formal study. ETHICS AND DISSEMINATION: The study has been approved by the Medical Research Ethics Committee of the International Peace Maternity and Child Health Hospital in Shanghai, China, and the Research Ethics Board of the Centre Intégré Universitaire de Santé et Services Sociaux de l'Estrie-CHUS in Sherbrooke, Canada. Data sharing policies are consistent with the governance policy of the HeLTI consortium and government legislation. TRIAL REGISTRATION NUMBER: ChiCTR1800017773. PROTOCOL VERSION: November 11, 2020 (Version #5).

Association between gestational anemia in different trimesters and neonatal outcomes: a retrospective longitudinal cohort study.

BACKGROUND: Previous studies investigated the association between gestational anemia and neonatal outcomes. However, few studies explored whether the effects of gestational anemia could be eliminated by subsequent correction of anemia in the later stages of pregnancy. This study aimed to investigate the relationship between anemia in different trimesters and neonatal outcomes. METHODS: The study was conducted in Shanghai, China, with a sample of 46,578 pregnant women who delivered between January 1, 2016 and July 1, 2019. A multivariable logistic regression model was adopted to analyse the associations between maternal anemia and neonatal outcomes. RESULTS: The incidence of gestational anemia was 30.2%, including 4.4% in the first trimester, 9.6% in the second trimester, and 16.2% in the third trimester. Only 24.5% (507/2066) of anemia that occurred in the first trimester and 29.6% (1320/4457) that occurred in the second trimester could be corrected in the later stages of pregnancy. Anemia occurring in the first trimester was associated with small for gestational age [odds ratio (OR) 1.46; 95% confidence interval (CI) 1.20-1.78] and with fetal distress (OR 1.23; 95% CI 1.08-1.40). Anemia corrected in the first trimester also was associated with a higher risk of small for gestational age. CONCLUSIONS: Gestational anemia is a public health problem in China impacting neonatal health. Anemia in pregnancy could be corrected in only about a quarter of the women. Anemia in the first trimester, whether corrected or not, still led to lower birth weight; therefore, the prevention of anemia prior to pregnancy is important.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Association of high maternal triglyceride levels early and late in pregnancy with adverse outcomes: A retrospective cohort study.

BACKGROUND: Excess maternal triglyceride (mTG) exposure during early or late pregnancy increases risks of adverse pregnancy outcomes. However, it is inconclusive whether persistently high maternal triglyceride during whole pregnancy has more negative associations. OBJECTIVE: To explore whether persistently high maternal triglyceride (mTG) levels from early to late pregnancy further increases the risk of adverse pregnancy outcomes. METHODS: We included 12,715 women who had a singleton birth and who underwent routine serum lipid screenings in both early (9-13 weeks) and late (28-42 weeks) pregnancy during May 2018 to July 2019 in a university-based maternity center. Risks for gestational diabetes mellitus (GDM), preeclampsia, preterm delivery, small/large for gestational age (LGA) were estimated. RESULTS: Elevated mTG levels during early pregnancy were associated with increased risks of preterm delivery (AOR, 1.52; 95% CI, 1.21 to 1.90), preeclampsia (1.75; 1.29 to 2.36), gestational diabetes mellitus (1.95; 1.69 to 2.25), and LGA (1.28; 1.12 to 1.46). Compared with those with low mTG levels both in the 1st and 3rd trimesters, persistently high mTG levels increased the risks of preeclampsia (2.53; 1.66 to 3.84), GDM (1.97; 1.57 to 2.47), and LGA (1.68; 1.37 to 2.07). However, persistently high mTG levels only slightly increased risk of LGA when compared with high mTG levels during the 1st trimester alone (1.34, 1.01 to 1.77). CONCLUSIONS: Elevated mTG levels during early pregnancy not in late pregnancy could be the crucial risk factor associated with adverse pregnancy outcomes. These results suggest the importance of lipid screenings and preventions during early pregnancy, which may help to improve pregnancy outcomes.

Circulating levels of Elabela and Apelin in the second and third trimesters of pregnancies with gestational diabetes mellitus.

We design this study to detect levels of Elabela (ELA) and Apelin (APLN) in women with and without gestational diabetes mellitus (GDM) in the second and third trimesters, and to identify whether there is any association between ELA, APLN, and metabolic parameters. Seventy-nine GDM and 80 control subjects in the second trimester and 87 GDM and 88 healthy subjects in the third trimester were included. In the second trimester, lower ELA levels [(14.1 versus 16.9) ng/ml, p = .025] and higher APLN levels [(1021.8 versus 923.5) pg/ml, p = .046] were observed in GDM patients compared to controls. ELA levels were positively correlated with fasting plasma glucose (FPG) (r = 0.423, p < .001) in the control group, and APLN levels were negatively correlated with triglycerides (TG) (r = -0.251, p = .025) in the control group and total cholesterol (TC) (r = -0.227, p = .044) in the GDM group. ELA appeared to be related to glucose metabolism and APLN is involved in lipid metabolism during pregnancy. The expression of ELA is significantly downregulated from the second trimester to the third trimester.

The casein kinase 2α promotes the occurrence polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by hyperandrogenism, polycystic ovaries, and anovulation. Previous studies have revealed that androgen receptors (ARs) are strongly associated with hyperandrogenism and abnormalities in folliculogenesis in patients with PCOS. However, the kinases responsible for androgen receptor activity, especially in granulosa cells, and the role of casein kinase 2α (CK2α) specifically in the pathogenesis of PCOS, remain unknown. Here, we show that both CK2α protein and mRNA levels were higher in luteinized granulosa cells of patients with PCOS compared with non-PCOS, as well as in the ovarian tissues of mice with a dehydroepiandrosterone-induced PCOS-like phenotype, compared with controls. In addition, CK2α not only interacted with AR in vivo and in vitro, but it also phosphorylated and stabilized AR, triggering AR and ovulation related genes excessive expression. CK2α also promoted cell proliferation in the KGN cell line and inhibited apoptosis. Collectively, the finding highlighted that the CK2α-AR axis probably caused the etiology of the PCOS. Thus, CK2α might be a promising clinical therapeutic target for PCOS treatment.

Association between higher levels of serum estradiol and elevated levels of fibrin (fibrinogen) degradation products in late pregnancy following assisted reproductive technology treatment.

INTRODUCTION: Assisted reproductive technology (ART) treatment is a risk factor for pregnancy-related venous thromboembolism (VTE). This study aims to explore the risk factors for elevated fibrin (fibrinogen) degradation products (FDPs), an indicator of hypercoagulability, in late pregnancy among women who underwent ART treatment. MATERIALS AND METHODS: This retrospective case-control study recruited 227 women who spontaneously conceived and 214 women who underwent ART treatment and gave birth. A subgroup analysis of the 214 pregnant women after ART treatment was performed. 156 women with elevated FDP levels and 58 women with normal FDP levels were designated as the case and control groups, respectively. RESULTS: We found that ART treatment was a risk factor for higher FDP. After adjustments were made for confounders in the group of 214 women after ART treatment, fresh embryo transfer (adjusted odds ratio (aOR) = 3.33, 95% confidence interval (CI), 1.57-7.03) and >10 oocytes retrieved (aOR = 2.09, 95% CI, 1.10-3.99) were associated with elevated FDP in late pregnancy. Serum estradiol (E2) levels on human chorionic gonadotropin (hCG) trigger day were higher in the high-FDP group. A positive correlation between E2 on hCG trigger day and FDP was found for both fresh embryo transfer (r = 0.67, p < 0.001) and frozen embryo transfer (FET) (r = 0.53, p < 0.001). CONCLUSIONS: A higher E2 level on hCG trigger day is closely associated with dysfunction of coagulation and fibrinolysis in late pregnancy. When performing the thromboprophylaxis assessment during pregnancy, clinicians should pay more attention to patients who had previous ART treatment and had a high E2 level on hCG trigger day.

Basonuclin 1 deficiency causes testicular premature aging: BNC1 cooperates with TAF7L to regulate spermatogenesis.

Basonuclin (BNC1) is expressed primarily in proliferative keratinocytes and gametogenic cells. However, its roles in spermatogenesis and testicular aging were not clear. Previously we discovered a heterozygous BNC1 truncation mutation in a premature ovarian insufficiency pedigree. In this study, we found that male mice carrying the truncation mutation exhibited progressively fertility loss and testicular premature aging. Genome-wide expression profiling and direct binding studies (by chromatin immunoprecipitation sequencing) with BNC1 in mouse testis identified several spermatogenesis-specific gene promoters targeted by BNC1 including kelch-like family member 10 (Klhl10), testis expressed 14 (Tex14), and spermatogenesis and centriole associated 1 (Spatc1). Moreover, biochemical analysis showed that BNC1 was associated with TATA-box binding protein-associated factor 7 like (TAF7L), a germ cell-specific paralogue of the transcription factor IID subunit TAF7, both in vitro and in testis, suggesting that BNC1 might directly cooperate with TAF7L to regulate spermatogenesis. The truncation mutation disabled nuclear translocation of the BNC1/TAF7L complex, thus, disturbing expression of related genes and leading to testicular premature aging. Similarly, expressions of BNC1, TAF7L, Y-box-binding protein 2 (YBX2), outer dense fiber of sperm tails 1 (ODF1), and glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) were significantly decreased in the testis of men with non-obstructive azoospermia. The present study adds to the understanding of the physiology of male reproductive aging and the mechanism of spermatogenic failure in infertile men.

Long interpregnancy interval and adverse perinatal outcomes: A retrospective cohort study.

We conducted a retrospective cohort study of 9,552 women experiencing their second delivery between 2014 and 2016 at the International Peace Maternity and Child Health Hospital to investigate the association between the interpregnancy interval (IPI) and adverse perinatal outcomes. With the 12-23-mon IPI as the reference category, logistic regression analyzes were used to examine associations between different IPIs (<12, 12-23, 24-59, 60-119, and ≥120 mon) and perinatal outcomes (gestational diabetes mellitus, premature membrane rupture, gestational hypertension, preterm birth, low birth weight, and macrosomia). Compared with the 12-23-mon IPI category, women with longer IPIs had a higher risk of adverse perinatal outcomes, and those with an IPI ≥120 mon had the highest risk of gestational diabetes mellitus and premature membrane rupture (adjusted odds ratio (OR) 1.76, 95% confidence interval (CI) 1.32-2.35 and adjusted OR 2.03, 95% CI 1.53-2.67, respectively). These results indicate that a longer IPI is associated with a higher risk of adverse perinatal outcomes and an IPI of ≥120 mon appears to be independently associated with a higher risk of gestational diabetes mellitus and premature membrane rupture.

Melatonin rescues impaired penetration ability of human spermatozoa induced by mitochondrial dysfunction.

Fertilization failure often occurs during in vitro fertilization (IVF) cycles despite apparently normal sperm and oocytes. Accumulating evidence suggests that mitochondria play crucial roles in the regulation of sperm function and male fertility. 3-Nitrophthalic acid (3-NPA) can induce oxidative stress in mitochondria, and melatonin, as an antioxidant, can improve mitochondrial function by reducing mitochondrial oxidative stress. The role of sperm mitochondrial dysfunction in fertilization failure during IVF is unclear. The present study revealed that spermatozoa with low, or poor, fertilization rates had swollen mitochondria, increased mitochondria-derived ROS, and attenuated mitochondrial respiratory capacity. 3-NPA treatment enhanced mitochondrial dysfunction in sperm. Spermatozoa with poor fertilization rates, and spermatozoa treated with 3-NPA, had reduced penetration ability. The concentration of melatonin was decreased in semen samples with low and poor fertilization rates. Melatonin, not only decreased excessive mitochondria-derived ROS, but also 'rescued' the reduced penetration capacity of spermatozoa treated with 3-NPA. Taken together, the study suggested that mitochondria-derived ROS and mitochondrial respiratory capacity are independent bio-markers for sperm dysfunction, and melatonin may be useful in improving sperm quality and overall male fertility.

Partnered Educational Governance: Rethinking Student Agency in Undergraduate Medical Education.

Historically, students have been "consumers" of undergraduate medical education (UME) rather than stakeholders in its design and implementation. Student input has been retrospective, and although UME leaders have been open to feedback, matters most important to students have often been overlooked, leaving students feeling largely unheard. Student representation has also lacked structure and unity of feedback.A vision for effective student representation drove the creation of a partnered educational governance (PEG) model at McGill University in Montreal, Quebec, Canada, where sharing of expertise between student representatives and UME leadership has improved the UME program and the educational experience of students.The PEG model is grounded in the literature on student government, the student-as-partner framework, and theories of accountability. As part of the model, the student Medical Education Committee, an organized structure for discussion and reporting to student constituents, was established. This structure allows student representatives, entrusted by their peers and faculty, to proactively provide input to UME committees in the development of policies and curricula. The partnership between students and faculty facilitates a shared understanding of educational challenges and potential solutions.Within the first year, meaningful changes associated with the PEG model included increased student engagement in key program decisions, such as the redesign of a research course and an update to the absences and leaves policy. The PEG model enables unified student representation that is accountable and representative-and has a significant impact on outcomes-while maintaining the UME program's ownership of and responsibility for the curriculum and policies.

Frequency and risk factors for recurrent gestational diabetes mellitus in primiparous women: a case control study.

BACKGROUND: To investigate the frequency and risk factors for recurrent gestational diabetes mellitus (GDM) in Chinese primiparous women. METHODS: Case control study. We investigated primiparous women who experienced GDM complications and had a subsequent pregnancy in the same hospital from January, 2012 to January, 2017. Ultimately, 78 women with recurrent GDM and 64 women with no recurrence were included. Clinical characteristics and biochemical parameters such as fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and lipid profiles were collected from medical records. We used an independent t-test and Chi-square test or Fisher's exact test to compare each variable. Univariate and multivariate logistic analyses were used to compute each odds ratio (OR) and 95% confidence interval (CI). RESULTS: The frequency of recurrent GDM was 55%. We found postprandial 1-h glucose at the 75-g OGTT was positively related to GDM recurrence, whereas first-trimester FPG in first pregnancy was negatively related. The first-trimester HbA1c value was higher in the group with GDM recurrence than in the group with no recurrence, though the difference was not significant. Moreover, the group with GDM recurrence manifested significantly higher first-trimester triglyceride concentrations in subsequent pregnancies; the adjusted ORs (95% CI) were 1.43 (1.09-1.87), 0.24 (0.10-0.63), 3.59 (0.93-13.88) and 1.89 (1.13-3.16). CONCLUSIONS: GDM recurred in more than half of subsequent pregnancies. Women with lower first-trimester FPG and higher postprandial 1-h glucose in first pregnancy, and with higher first-trimester triglyceride in subsequent pregnancy were at increased risk for GDM recurrence.

Prenatal exposure to testosterone induces cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.

High circulating androgen in women with polycystic ovary syndrome (PCOS) may increase the risk of cardiovascular disease in offspring. The aim of the present study is to investigate whether maternal androgen excess in the rat PCOS model would lead to cardiac hypertrophy in offspring. Maternal testosterone propionate (maternal-TP)-treated adult female offspring displayed cardiac hypertrophy associated with local high cardiac dihydrotestosterone (DHT). The molecular markers of cardiac hypertrophy along with androgen receptor (AR) and PKCδ, were increased in the Maternal-TP group. Treatment of primary neonatal rat ventricular cardiomyocytes (NRCMs) and H9c2 cells with DHT significantly increased cell size and upregulated PKCδ expression, which could be attenuated by AR antagonist. Treatment with phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly increased cell size and upregulated myh7 level. Rottlerin, that may inhibit PKCδ, significantly reduced the hypertrophic effect of DHT and PMA on NRCMs and H9c2 cells. Chromatin immunoprecipitation revealed that AR could bind to Pkcδ promoter. Our results indicate that prenatal exposure to testosterone may induce cardiac hypertrophy in adult female rats through enhanced Pkcδ expression in cardiac myocytes.