Expression and function of long non-coding RNA DLX6-AS1 in endometrial cancer

Background:LncRNA DLX6-AS1 has been uncovered to exert effects on various cancers.Nevertheless,the impacts of DLX6-AS1 on endometrial cancer(EC)development remained obscure.The study explored the influence of DLX6-AS1 on EC progression via the microRNA(miR)-374a-3p/zinc-finger protein(ZFX)axis.Methods:EC cell lines were collected and DLX6-AS1,miR-374a-3p,and ZFX levels in EC cell lines were detected.The EC cells were transfected with DLX6-AS1,miR-374a-3p,and ZFX constructs to examine the biological functions of EC cells.The xenograft model was established for detecting tumor growth.Rescue experiments were conducted to verify the interaction of DLX6-AS1,miR-374a-3p,and ZFX in EC cells.Results:DLX6-AS1 and ZFX levels were elevated,while miR-374a-3p exhibited a reduced level in EC cells.Silencing DLX6-AS1 and elevated miR-374a-3p expressions repressed the biological activities of EC cells.Reduced DLX6-AS1 repressed tumor development.MiR-374a-3p silencing reversed the impacts of DLX6-AS1 silencing,while ZFX overexpression abrogated the impacts of miR-374a-3p elevation on EC cell growth.Mechanically,DLX6-AS1 was found to bind to miR-374a-3p,and miR-374a-3p targeted ZFX.Conclusion:DLX6-AS1 depletion restricts the malignant phenotype of EC cells.The study might provide novel therapeutic biomarkers for EC treatment.

Microglia in neurodegenerative diseases

A major feature of neurodegeneration is disruption of central nervous system homeostasis,during which microglia play diverse roles.In the central nervous system,microglia serve as the first line of immune defense and function in synapse pruning,injury repair,homeostasis maintenance,and regulation of brain development through scavenging and phagocytosis.Under pathological conditions or various stimulations,microglia proliferate,aggregate,and undergo a variety of changes in cell morphology,immunophenotype,and function.This review presents the features of microglia,especially their diversity and ability to change dynamically,and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration.This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.

An appropriate level of autophagy reduces emulsified isoflurane-induced apoptosis in fetal neural stem cells

Autophagy plays essential roles in cell survival.However,the functions and regulation of the autophagy-related proteins Atg5,LC3B,and Beclin 1 during anesthetic-induced developmental neurotoxicity remain unclear.This study aimed to understand the autophagy pathways and mechanisms that affect neurotoxicity,induced by the anesthetic emulsified isoflurane,in rat fetal neural stem cells.Fetal neural stem cells were cultured,in vitro,and neurotoxicity was induced by emulsified isoflurane treatment.The effects of pretreatment with the autophagy inhibitors 3-methyladenine and bafilomycin and the effects of transfection with small interfering RNA against ATG5(siRNA-Atg5)were observed.Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,and apoptosis was assessed using flow cytometry.Ultrastructural changes were analyzed through transmission electron microscopy.The levels of the autophagy-related proteins LC3B,Beclin 1,Atg5,and P62 and the pro-apoptosis-related protein caspase-3 were analyzed using western blot assay.The inhibition of cell proliferation and that of apoptosis rate increased after treatment with emulsified isoflurane.Autophagolysosomes,monolayer membrane formation due to lysosomal degradation,were observed.The autophagy-related proteins LC3B,Beclin 1,Atg5,and P62 and caspase-3 were upregulated.These results confirm that emulsified isoflurane can induce toxicity and autophagy in fetal neural stem cells.Pre-treatment with 3-methyladenine and bafilomycin increased the apoptosis rate in emulsified isoflurane-treated fetal neural stem cells,which indicated that the complete inhibition of autophagy does not alleviate emulsified isoflurane-induced fetal neural stem cell toxicity.Atg5 expression was decreased significantly by siRNA-Atg5 transfection,and cell proliferation was inhibited.These results verify that the Atg5 autophagy pathway can be regulated to maintain appropriate levels of autophagy,which can inhibit the neurotoxicity induced by emulsified isoflurane anesthetic in fetal neural stem cells.

Laparoscopic repair of uterine rupture following successful second vaginal birth after caesarean delivery: A case report

BACKGROUND With the increasing trend of vaginal birth after caesarean delivery(VBAC),evaluation of the feasibility and safety of a second VBAC with grand multiparity is worth considering.Intrapartum uterine rupture is diagnosed in approximately one-fifth of all VBAC cases following successful vaginal delivery.To our knowledge,no report is available on the application of laparoscopy to repair postpartum uterine rupture after a successful second VBAC in China.CASE SUMMARY A 31-year-old woman(gravida 5,para 2)at 39 wk and 5 d of gestation was admitted to the hospital in labour.After a successful VBAC and observation for approximately 13 h,the patient complained of progressive abdominal pain.Given the symptoms,signs,and auxiliary examination results,intraperitoneal bleeding was considered.Because the patient was stable and ultrasound imaging was the only method available to assess the possibility of rupture,we recommended laparoscopy to clarify the diagnosis and for prompt laparoscopic uterine repair or exploratory laparotomy if necessary.Operative findings included transverse uterine scar rupture at the lower uterine segment of approximately 5.0 cm in length and 800 mL of intraoperative pelvic haemoperitoneum.Finally,she successfully underwent laparoscopic repair of uterine rupture and recovered very well according to three-dimensional magnetic resonance imaging at 42 d postpartum.CONCLUSION Routine postpartum intrauterine exploration is not beneficial to the mother and may even increase the risk of rupture.This case highlights a laparoscopic approach for repairing uterine rupture in the immediate postpartum period.

Roles of protein tyrosine phosphatases in reproduction and related diseases

Protein tyrosine phosphatases(PTPs)remove phosphate groups from protein tyrosine residues to regulate various cell signaling processes,subsequently affecting the growth,metabolism,differentiation,immune response,and other cellular processes.Several studies have investigated the functions of PTPs in tumor and organism immunity.However,only a few studies have focused on their roles in reproductive disorders.Therefore,in this review,we summarize the roles and underlying molecular mechanisms of PTPs in infertility,spontaneous abortion,pregnancy-induced hypertension,gestational diabetes mellitus,early embryonic developmental abnormalities,and preterm birth.This review can contribute to future research on PTPs and their potential applications as targets in the treatment of reproductive diseases.

System analysis based on the T cell exhaustion‑related genes identifies CD38 as a novel therapy target for ovarian cancer

Ovarian cancer(OV)is highly heterogeneous tumor with a very poor prognosis.Studies increasingly show that T cell exhaustion is prognostically relevant in OV.The aim of this study was to dissect the heterogeneity of T cell subclusters in OV through single cell transcriptomic analysis.The single RNA-sequencing(scRNA-seq)data of five OV patients were analyzed,and six major cell clusters were identified after threshold screening.Further clustering of T cell-associated clusters revealed four subtypes.Pathways related to oxidative phosphorylation,G2M checkpoint,JAK-STAT and MAPK signaling were significantly activated,while the p53 pathway was inhibited in the CD8+exhausted T cells.The standard marker genes of CD8+T cell exhaustion were screened to develop a T-cell related gene score(TRS)based on random forest plots in TCGA cohort.The patients with low TRS have better prognosis compared to the patients with high TRS in both TCGA and GEO.In addition,most genes included in the TRS showed significant differences in expression levels between the high-and low-risk groups.Immune cell infiltration was analyzed using the MCPcounter and xCell algorithms,which revealed significant differences between the two risk groups,indicating that the different prognoses may stem from the respective immune landscapes.In addition,CD38 knockdown in OV cell lines increased apoptosis and inhibited invasion in vitro.Finally,we performed a drug sensitivity analysis and identified six potential drug candidates for OV.To summarize,we identified the heterogeneity and clinical significance of T cell exhaustion in OV and built a superior prognostic model based on T cell exhaustion genes,which can contribute to the development of more precise and effective therapies.

Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer:a retrospective population-based study in China

To the Editor:In China,very young breast cancer patients(≤35-year-old)make up approximately 10%of all breast cancer cases,compared to 2%in Western countries.This suggests that different morbidity may be caused by different geographic regions and ethnicities,even leading to different clinicopathological characteristics and prognoses.Tang et al[1]reported that very young breast cancer patients had poor disease-free survival(DFS),and the risk of disease progression was 1.557-fold higher than that for the elderly patients,but no difference was observed in overall survival(OS).However,few studies have focused on very young patients with breast cancer in China.Therefore,we conducted a retrospective population-based study to investigate the oncological outcomes of very young breast cancer patients.The studies involving human participants were reviewed and approved by the Ethics Committee of the International Peace Maternity and Child Health Hospital([No.GKLW]2021-37).

Clinical significance of nuchal translucency measurement in routine prenatal examination

To the Editor:Measurement of nuchal translucency(NT)is a validated marker for aneuploidy,fetal abnormalities,and other pathologic conditions,[1] which makes it crucial to ensure the accuracy of NT measurement in clinical treatment.Ever since 2012,all the pregnant women visiting our hospital(The International Peace Maternity&Child Health Hospital Affliated to Shanghai Jiao Tong University School of Medicine,China)need to receive a routine first-trimester sonographic marker assessment.

Systematic management of twin pregnancies to reduce pregnancy complications

Twin pregnancies have increased significantly over recent decades,mainly due to the growing rate of such pregnancies that have been achieved via assisted reproductive techniques.Twin pregnancies are associated with high infant morbidity and mortality.Maternal obesity has been found to be significantly related to an increased risk of pre-eclampsia and other adverse outcomes.Maternal weight gains during pregnancy may have important implications for maternal and fetus health.Women with excessive gestational weight gains(GWG)are more likely to increase their risk of gestational diabetes mellitus(GDM),macrosomia,preterm birth,and fetal growth restriction.As with singletons,GDM is also expected to be more frequent in pre-gravid obese mothers of twins.111 Although there are some guides for twin pregnancies,few researches are focused on the systematic management of twin pregnancies.

An alternative splicing variant of mineralocorticoid receptor discovered in preeclampsia tissues and its effect on endothelial dysfunction

The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical artery samples from normotensive and PE pregnancies.Mineralocorticoid receptor(MR)and its alternative splicing variant(ASV)expression and their biological effects on PE were examined.An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples(umbilical artery,~57.58%;placenta,~36.84%).The MR ASV expression was positively associated with blood pressure in both groups.The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways.The MR ASV can also impair the proliferation,migration,and tube formation ability of endothelial cells.These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology,especially in endothelial dysfunction,and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.

Characterization, isolation, and culture of spermatogonial stem cells in Macaca fascicularis

Spermatogonial stem cells(SSCs)have great applications in both reproductive and regenerative medicine.Primates including monkeys are very similar to humans with regard to physiology and pathology.Nevertheless,little is known about the isolation,the characteristics,and the culture of primate SSCs.This study was designed to identify,isolate,and culture monkey SSCs.Immunocytochemistry was used to identify markers for monkey SSCs.Glial cell line-derived neurotrophic factor family receptor alpha-1(GFRAl)-enriched spermatogonia were isolated from monkeys,namely Macaca fascicularis(M.fascicularis),by two-step enzymatic digestion and magnetic-activated cell sorting,and they were cultured on precoated plates in the conditioned medium.Reverse transcription-polymerase chain reaction(RT-PCR),immunocytochemistry,and RNA sequencing were used to compare phenotype and transcriptomes in GFRAl-enriched spermatogonia between 0 day and 14 days of culture,and xenotransplantation was performed to evaluate the function of GFRAl-enriched spermatogonia.SSCs shared some phenotypes with rodent and human SSCs.GFRAl-enriched spermatogonia with high purity and viability were isolated from M.fascicularis testes.The freshly isolated cells expressed numerous markers for rodent SSCs,and they were cultured for 14 days.The expression of numerous SSC markers was maintained during the cultivation of GFRAl-enriched spermatogonia.RNA sequencing reflected a 97.3%similarity in global gene profiles between 0 day and 14 days of culture.The xenotransplantation assay indicated that the GFRAl-enriched spermatogonia formed colonies and proliferated in vivo in the recipient c-Kitw/w(W)mutant mice.Collectively,GFRAl-enriched spermatogonia are monkey SSCs phenotypically both in vitro and in vivo.This study suggests that monkey might provide an alternative to human SSCs for basic research and application in human diseases.

Preterm Labor,a Syndrome Attributed to the Combination of External and Internal Factors

Preterm labor(before 37 weeks’gestation)is the leading cause of neonatal mortality and morbidity,which can be divided into iatrogenic preterm labor,infectious preterm labor,and spontaneous preterm labor(sPTL).Up to now,there continue to be great difficulties in prediction and prevention of sPTL,owing to multiple risk factors,pathogenesis,and pathologic processes contributing to the event,which have not been fully clarified.Pregnancy maintenance and parturition is a complicated process with continuous maternal-fetal dialogue,in which both maternal and fetal factors participate and affect the outcome of pregnancy,including sPTL.Besides,external factors can also participate in sPTL,individually or through the interaction with internal factors.In this article,we summarize recent studies regarding sPTL from our and other groups,and discuss the risk factors and pathogenesis of preterm birth from both external and internal(maternal and fetal)aspects,so as to provide theoretical evidences for the diagnosis,prevention,and treatment of sPTL in the future.

Genetic hypothesis for the developmental origins of health and disease theory

The developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an individual.Developmental plasticity is thought to be a possible underlying mechanism.Here,I discuss a contrasting but complementary genetic hypothesis regarding the developmental origins of health and disease theory:crosstalk between the genomes of the parents and offspring is responsible for shaping and adapting responses to environmental stresses,regulating early growth and predisposition to non-communicable diseases.Genetic variants that are beneficial in terms of responses to early life stresses may have pleiotropic detrimental effects on health later in life,which may change the allele frequencies driven by selection on a population level.Genetic studies on the cohort of children born after assisted reproduction could provide insight regarding the genetic mechanisms of the developmental origins of health and disease theory.

Recent advances in mammalian reproductive biology

Reproductive biology is a uniquely important topic since it is about germ cells, which are central for transmitting genetic information from generation to generation. In this review, we discuss recent advances in mammalian germ cell development,including preimplantation development, fetal germ cell development and postnatal development of oocytes and sperm. We also discuss the etiologies of female and male infertility and describe the emerging technologies for studying reproductive biology such as gene editing and single-cell technologies.

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.

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.

Intrauterine hyperglycemia impairs endometrial receptivity via up-regulating SGK1 in diabetes

Diabetes is a complex metabolic disorder which can adversely affect reproductive function. SGK1 is found to be up-regulated in multiple tissues of diabetic patients. However, the effects of diabetes on endometrial SGK1 expression and endometrial receptivity remain unknown. In this study, we established a streptozotocin-induced diabetic mouse model and observed reduced implantation sites, retarded development of pinopodes, increased SGK1, and aberrant expression of LIF and MUC1 in the endometrial epithelium. We injected the uterine lumen of normal mice with high-glucose solution and cultured endometrial cells in high-glucose medium to mimic intrauterine hyperglycemia. Both studies provided compelling evidence that hyperglycemia could lead to diminished embryo implantation and dysregulated SGK1, LIF and MUC1. Additionally, through over-expression of SGK1 in vivo and in vitro, we found that enhanced SGK1 also decreased LIF expression, increased MUC1 expression, and attenuated embryo implantation rate. We further identified that hyperglycemia-activated SMAD2/3 might be responsible for the enhancement of SGK1 and verified directly the interaction between SMAD3 and corresponding SMAD binding elements within SGK1 promoter. Taken together, our study confirmed the association between diabetes-related hyperglycemia and endometrial receptivity defects. Hyperglycemia-induced SGK1 has a tremendous role in this pathological process, rendering it as an attractive therapeutic target for diabetes-related reproductive disorders.

配子源性成人疾病的表观遗传机制

The events occurring before and soon after birth appear to impact an individual’s health throughout adulthood significantly.The pioneering work of David J.P.Barker studied the nutritional status of 2414 pregnant women and their offspring during the Dutch famine between 1944 and 1945,and convincingly connected undernutrition during pregnancy to the predisposition of offspring to many adult-onset diseases,including cardiovascular disease.

Epidemiology and region-specific risk factors for low Apgar scores in China:a nationwide study

Background Neonatal asphyxia is a serious public health issue.This study aimed to determine the epidemiology and region-specific risk factors for low Apgar scores,an important proxy for neonatal asphyxia,in China from 2015 to 2016.Methods The China Labor and Delivery Survey was a multicenter cross-sectional study including 96 hospitals distributed in 24(out of 34)provinces.Logistic regression analysis was performed to examine the risk factors for a low Apgar score(<7).Correspondence analyses were performed among neonates with low Apgar scores to explore the relationship between risk factors and geographical regions.The population attributable risk percentage(PAR%)was calculated for each region-specific risk factor.Results A total of 72,073 live births,including 320 births with low Apgar scores,were used for the analysis,giving a weighted rate of 3.9/1000 live births.There was a substantial difference in the incidence of low Apgar scores by geographic region,from 2.3/1000 live births in East China to 10.9/1000 live births in Northeast China.Maternal and obstetric factors are the major region-specific risk factors.In Southwest China,hypertensive disorders in pregnancy were more important contributors,with PAR% being 74.47%;in North and Northwest China,pre-pregnancy underweight was a more significant factor,with PAR% of 62.92%;in East China,infants born between 0:00 a.m.and 7:59 a.m.were a key factor,with PAR% of 80.44%.Conclusion Strategies based on region-specific risk factors should be considered to reduce the burden of low Apgar scores in China.

Toll-Like Receptor-Dependent Antiviral Responses at the Maternal-Fetal Interface

The maternal-fetal interface is a key barrier to protect the fetus from infection.Toll-like receptors (TLRs) at the maternal-fetal interface are involved in antiviral responses.TLRs are expressed in both maternal decidua and fetal trophoblasts.Virus-induced activation of TLR signaling pathways triggers the release of interferon-related antiviral molecules and other inflammatory cytokines and/or chemokines by the host innate immune system,which may disrupt immune tolerance at the maternal-fetal interface and lead to pregnancy complications.In this review,we summarize the state of knowledge on the most common viral infections during pregnancy,antiviral TLR responses at the maternal-fetal interface,and TLR-associated pregnancy complications.