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Introduction Advanced oxidation protein products (AOPPs), which are novel markers of oxidant-mediated protein damage, are prevalent in numerous diseases. We previously demonstrated that AOPPs act as a new class of pathogenic mediators in preeclampsia by causing trophoblast damage and dysfunction. Herein, we explored whether AOPPs could regulate the Nrf-2/ARE/HO-1 anti-oxidative pathway to facilitate the progression of preeclampsia. Methods To investigate the pathophysiology of preeclampsia, we evaluated the effects of AOPPs on trophoblast damage, apoptotic proteins, and Nrf-2/ARE/HO-1 anti-oxidative pathway expression, as well as their underlying mechanisms. Results AOPPs directly increased the expression of apoptotic proteins and significantly inhibited the expression of Nrf-2/ARE/HO-1 pathway in trophoblasts. Nrf-2 silencing aggravated the AOPPs-induced cell apoptosis in vitro by activating p53 and caspase cascade, whereas Nrf-2 overexpression had the opposite effect. Moreover, Nrf-2 exerted cytoprotective effects by increasing HO-1. Discussion These findings suggest that AOPPs induce trophoblast apoptosis by triggering p53 and caspase activation via inhibition of the Nrf-2/ARE/HO-1 anti-oxidative pathway. Hence, Nrf-2/ARE/HO-1 pathway activation plays a protective role in AOPPs-induced cell apoptosis; thus, holding potential as a therapeutic target against preeclampsia.

Aim: Bone mesenchymal stem cell-derived exosomes (Exos) have been shown to exert therapeutic effects in spinal cord injury (SCI). In this study, we aimed to apply bioengineering approaches to promote Exo retention and their sustained release for SCI repair. Materials & methods: 3D gelatin methacrylate hydrogel (GelMA) was used as a transplanted Exo delivery system (GelMA-Exos). The viability, proliferation, and differentiation of neural stem cells cultured on hydrogel were assessed. Further, GelMA-Exos was injected into the damaged lesions to assess its repair potential. Results: GelMA hydrogel enhanced the retention of Exos, which promoted the neuronal differentiation and extension in vitro. Furthermore, GelMA-Exos promoted neurogenesis and attenuated glial scars in the damaged lesions. Conclusion: The injectable Exo-loaded 3D hydrogel induced neurological functional recovery post SCI.

BACKGROUND Glycogen storage disease type Ib (GSD-Ib) is a glycogen metabolism disorder that leads to the manifestations of inflammatory bowel disease (IBD), especially Crohn’s disease (CD)-like colitis. Although biological agents are effective for treating CD, their application in the treatment of GSD-Ib with CD-like colitis has been rarely reported. CASE SUMMARY A 13-year-old Han male was diagnosed with GSD-Ib with CD. The patient was treated with granulocyte colony-stimulating factor. When he had symptoms of CD-like colitis, he was continuously pumped with enteral nutrition and administered oral mesalazine for 2 wk; however, the symptoms did not improve significantly. Hence, infliximab (IFX) was administered. Hitherto, the patient has been followed up for 1 year, and no clinical manifestations have been observed. After 6 mo of treatment (fifth IFX treatment), the disease activity index and all inflammatory indexes decreased, and a review of the colonoscopy data showed that the ulcers appeared smooth. CONCLUSION In this study, the patient was successfully treated with IFX. In cases of GSD-Ib, IBD should be highly considered.

Purpose: To determine the molecular mechanism involved in the anti-migraine effect of Asari Radix et Rhizoma (ARR) using network pharmacology. Methods: The compounds present in ARR were identified through information retrieval from literature and public databases, and were screened based on absorption, distribution, metabolism, excretion and toxicity. Target genes related to the selected compounds and migraine were identified or predicted from public databases. Hub genes in ARR against migraine were identified through analysis of interactions in overlapping genes between compounds and migraine target genes, based on STRING database. Gene enrichment analysis of overlapping genes was performed using Database for Annotation, Visualization and Integrated Discovery. Results: A total of 138 compounds were selected as potential bioactive compounds in ARR. Target genes related to the selected compounds (611 genes) and migraine (278 genes) were obtained, including 71 overlapping genes. The hub genes in the anti-migraine effect of ARR were BDNF, IL6, COMT, APP and TNF. Gene enrichment analysis showed the top 10 biological processes or pathways involved in the mechanism of anti-migraine action of ARR. The tissue source of the overlapping genes was not limited to the brain. The results from gene enrichment analysis revealed that the effect of ARR on migraine was holistic, which is characteristic of traditional Chinese medicines. Conclusion: Network pharmacology has been used to decipher the molecular mechanism involved in the action of ARR against migraine. The results provide a scientific basis for the clinical effect of ARR on migraine.

Pulmonary fibrosis is a devastating disease, and the pathogenesis of this disease is not completely clear. Here, the medical records of 85 Covid-19 cases were collected, among which fibrosis and progression of fibrosis were analyzed in detail. Next, data independent acquisition (DIA) quantification proteomics and untargeted metabolomics were used to screen disease-related signaling pathways through clustering and enrichment analysis of the differential expression of proteins and metabolites. The main imaging features were lesions located in the bilateral lower lobes and involvement in five lobes. The closed association pathways were FcγR-mediated phagocytosis, PPAR signaling, TRP-inflammatory pathways, and the urea cycle. Our results provide evidence for the detection of serum biomarkers and targeted therapy in patients with Covid-19.

Recent evidence suggests that melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), a neuronal class regulating non-image forming (NIF) vision and generally thought to be injury resistant, are dysfunctional in certain neurodegenerative diseases. Although disrupted NIF visual functions have been reported in patients and animals with diabetes, it remains controversial whether ipRGCs exhibit remodeling during diabetes and if so, whether such remodeling is variable among ipRGC subtypes. Here, we demonstrate that survival, soma-dendritic profiles, and melanopsin-based functional activity of M1 ipRGCs were unaltered in streptozotocin-induced 3-month diabetic mice. Such resistance remained at 6 months after streptozotocin administration. In contrast, M2/M3 ipRGCs underwent significant remodeling in diabetic mice, manifested by enlarged somata and increased dendritic branching complexity. Consistent with the unaltered melanopsin levels, the sensitivity of melanopsin-based activity was unchanged in surviving M2 cells, but their response gain displayed a compensatory enhancement. Meanwhile, the pupillary light reflex, a NIF visual function controlled by M2 cells, was found to be impaired in diabetic animals. The resistance of M1 cells might be attributed to the adjacency of their dendrites to capillaries, which makes them less disturbed by the impaired retinal blood supply at the early stage of diabetes.

Preeclampsia is a pregnancy complication classified by new onset of elevated blood pressure and proteinuria after 20 weeks of gestation. During preeclampsia, extra villous trophoblasts fail to adequately invade the myometrial spiral arteries, leading to incomplete and impaired vessel transformation and initiating or aggravating preeclampsia. Although NF-κB and proinflammatory cytokines have been reported to be related to trophoblast dysfunction, the underlying mechanism remains unclear. Herein, we demonstrated the miR-138/RELA axis modulating the migratory ability, and invasive ability of HTR-8/SVneo and JEG-3 cells, as well as the inflammatory factor levels in response to LPS stimulation. miR-138 expression was upregulated in preeclampsia placenta and LPS-stimulated HTR-8/SVneo and JEG-3 cell lines. miR-138 overexpression rescued the migratory and invasive ability of HTR-8/SVneo and JEG-3 cells inhibited by LPS stimulation, and decreased LPS-induced TNF-α and IL-6 levels. By binding the 3’-UTR of RELA, miR-138 negatively regulated p65 expression. The silencing of p65 also improved LPS-induced HTR-8/SVneo and JEG-3 cell dysfunction and TNF-α and IL-6 levels. More importantly, p65 overexpression partially reversed the functions of miR-138 overexpression upon both cells, indicating that miR-138 exerted its biological effects through targeting RELA. In conclusion, miR-138 improves LPS-induced inflammation and oxidative stress on trophoblasts through targeting RELA and affecting NF-κB signaling. The miR-138/RELA axis might be involved in preeclampsia pathogenesis, which requires further in vivo and clinical researches.

Background: Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Although several transcriptome studies have been done on placentae from PE patients, only a small number of differentially expressed genes have been identified due to very small sample sizes and no distinguishing of clinical subtypes. Methods: We carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for dysregulated genes and the molecular network and pathways they are involved in. Results: We identified two functionally distinct sets of dysregulated genes in the two major subtypes: 2,977 differentially expressed genes in early-onset severe preeclampsia, which are enriched with metabolism-related pathways, notably transporter functions; and 375 differentially expressed genes in late-onset severe preeclampsia, which are enriched with immune-related pathways. We also identified some key transcription factors, which may drive the widespread gene dysregulation in both early-onset and late-onset patients. Conclusion: These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors. A few regulators may be the key drivers of the dysregulated molecular pathways.

To investigate the incidence and clinical significance of chromosomal mosaicism (CM) in prenatal diagnosis by G‐banding karyotyping and chromosomal microarray analysis (CMA). This is a single‐centre retrospective study of invasive prenatal diagnosis for CM. From 5758 karyotyping results and 6066 CMA results, 104 foetal cases with CM were selected and analysed further. In total, 50% (52/104) of foetal cases with CM were affected by ultrasound‐detectable phenotypes. Regardless of whether they were singleton or twin pregnancies, isolated structural defects in one system (51.35%, 19/37 in singletons; 86.67%, 13/15 in twins) and a single soft marker (18.92%, 7/37 in singletons; 13.33%, 2/15 in twins) were the most common ultrasound anomalies. Mosaic autosomal trisomy (19.23%, 20/104) was the most frequent type, and its rate was higher in phenotypic foetuses (28.85%, 15/52) than in non‐phenotypic foetuses (9.62%, 5/52). There was no difference in mosaic fractions between phenotypic and non‐phenotypic foetuses based on specimen sources or overall classification. Discordant mosaic results were observed in 16 cases (15.38%, 16/104) from different specimens or different testing methods. Genetic counselling and clinical management regarding CM in prenatal diagnosis remain challenging due to the variable phenotypes and unclear significance. Greater caution should be used in prenatal counselling, and more comprehensive assays involving serial ultrasound examinations, different specimens or testing methods verifications and follow‐up should be applied.

Background. This study aims to systematically evaluate the effect of moxibustion on the level of inflammatory cytokines in animal models with rheumatoid arthritis (RA) and to provide evidence for the clinical application of moxibustion to the treatment of RA and related basic researches. Methods. The databases employed in this study include PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), SinoMed, and Wanfang Data Information Site. The retrieval time was from the establishment of these databases to March 2020. The reviewers made use of the CAMARADES 10-item checklist to evaluate the quality of each included study. The inflammatory cytokines were considered as the outcome measure. The Revman 5.3 software was used to conduct meta-analysis on the outcome indicators of the studies included. Results. A total of 648 articles were retrieved and 18 animal experiments were included in this study. The quality scores of the studies ranged from two to eight with a mean of 5.8. Compared with the effect of the control group, moxibustion reduced the expression of TNF-α (SMD 2.95, 95% CI: 1.99–3.92, P<0.00001), IL-1β (SMD 4.10, 95% CI: 2.37–5.84, P<0.00001), IFN-γ (MD 25, 95% CI: 16.17–33.82, P<0.00001), IL-6 (MD 11.83, 95% CI: 6.22–17.44, P<0.0001), and IL-17 (MD 99.3, 95% CI: 86.83–111.76, P<0.00001). At the same time, the level of IL-2 (SMD 8.89, 95% CI: 0.93–16.86, P=0.03), IL-4 (MD 1.79, 95% CI: 0.26–3.32, P=0.02), and IL-10 (MD 5.93, 95% CI: 1.37–10.49, P=0.01) increased after moxibustion treatment. Asymmetric funnel plots indicated that there was publication bias. Conclusion. The findings of the present review indicate that moxibustion can protect the synovium of joint in animal models with RA by upregulation of the level of anti-inflammatory cytokines and downregulation of the level of proinflammatory cytokines. Moxibustion has the potential to relieve inflammation of RA.

White matter lesions (WMLs) are the most common central nervous system changes observed during cochlear implant evaluation. However, its clinical significance in cochlear implantation (CI) remains unclear. The purpose of this study is to explore the effects of WMLs on hearing and speech rehabilitation of prelingually deaf children after CI. The data of forty-five children with WMLs who received CI from 2011 to 2014 were retrospectively reviewed. All patients underwent magnetic resonance imaging examination preoperatively. The categories of auditory performance (CAP) and speech intelligibility rating (SIR) scales were used to evaluate changes in the auditory and speech abilities of the patients, and the Fazekas scale was adopted to assess the extent of WMLs. The degree of WMLs was divided into four grades (none, mild, moderate, severe). We assessed hearing and speech abilities at the following time points: 6, 12, 24, 36, 48 and 60-months post-operation. No significant differences in CAP scores were observed between WMLs groups and the control group at 12 months post-CI (p = 0.099), but marked between-group differences were found at 6, 24, 48- and 60-months post-CI. (p

Background and Aims: The World Health Organization (WHO) Western Pacific Region set a target of eliminating mother-to-child transmission (MTCT) of hepatitis B virus (HBV) by 2030. To assess the feasibility of this target in China, we carried out an epidemiological study to investigate the status quo of MTCT in the real-world setting. Methods: One thousand and eight hepatitis B surface antigen-positive pregnant women were enrolled at 10 hospitals. Immunoprophylaxis was administered to infants. In addition, mothers with HBV DNA level >2,000,000 IU/mL were advised to initiate antiviral therapy during late pregnancy. A health application called SHIELD was used to manage the study. Results: Nine hundred and five of the enrolled mothers, with 924 infants, completed the follow-up. Birth-dose hepatitis B vaccine and hepatitis B immunoglobulin were received by 99.7% and 99.7% of infants, respectively, within 24 h after birth. There were 446 mothers who received antiviral therapy, including 72.3% of the mothers with HBV DNA level >2,000,000 IU/mL and 21.0% of the mothers with HBV DNA level

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric mood disorder that lacks objective laboratory-based tests to support its diagnosis. A class of microRNAs (miRNAs) has been found to be centrally involved in regulating many molecular processes fundamental to central nervous system function. Among these miRNAs, miRNA-134 (miR-134) has been reported to be related to neurogenesis and synaptic plasticity. In this study, the hypothesis that plasma miR-134 can be used to diagnose MDD was tested. Perturbation of peripheral and central miR-134 in a depressive-like rat model was also examined. By reverse-transcription quantitative PCR, miR-134 was comparatively measured in a small set of plasma samples from MDD and healthy control (HC) subjects. To determine its diagnostic efficacy, plasma miR-134 levels were assessed in 100 MDD, 50 bipolar disorder (BD), 50 schizophrenic (SCZ), and 100 HC subjects. A chronic unpredictable mild stress (CUMS) rat model was also developed to evaluate miR-134 expression in plasma, hippocampus (HIP), prefrontal cortex (PFC), and olfactory bulb. We found that plasma miR-134 was significantly downregulated in MDD subjects. Diagnostically, plasma miR-134 levels could effectively distinguish MDD from HC with 79% sensitivity and 84% specificity, while distinguishing MDD from HC, BD, and SCZ subjects with 79% sensitivity and 76.5% specificity. Congruent with these clinical findings, CUMS significantly reduced miR-134 levels in the rat plasma, HIP, and PFC. Although limited by the relatively small sample size, these results demonstrated that plasma miR-134 displays potential ability as a biomarker for MDD.

Obesity is a growing chronic health problem worldwide. Studies about acupuncture for obesity treatment are many. But there are some doubts about the effectiveness of acupuncture versus sham acupuncture in treating obesity due to its lack of medical evidence. Therefore, the aim of this study is to assess the efficacy of acupuncture for obesity treatment and provide clinic evidence. Four English databases (PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials) and four Chinese databases (China National Knowledge Infrastructure, Chinese BioMedical Database, Chinese Scientific Journal Database and Wan-Fang Data) were searched from their receptions to August 2019. Randomized controlled trials (RCTs) using the comparison between acupuncture and sham acupuncture to treat simple obesity were included. The primary outcome of body mass index (BMI) would be used to measure the effect of acupuncture on obesity. According to the trial data extraction form based on the Cochrane Handbook, two reviewers separately extracted the data. Risk of bias of the RCTs was assessed by the Cochrane Risk of Bias Tool. The study included 8 RCTs with 403 patients. When compared with sham acupuncture, acupuncture showed obviously effect in BMI reduction (MD=1.0kg/m2, 95% CI=0.6 to 1.4, P0.05) was not statistically and significantly different between the acupuncture and control groups. Adverse effects were reported in 3 studies. The review suggests that acupuncture is an effective therapy for simple obesity rather than a placebo effect. This potential benefit needs to be further evaluated by longer-term and more rigorous RCTs.

Autism spectrum disorder (ASD) is a neuronal developmental disorder with impaired social interaction and communication, often with abnormal intelligence and comorbidity with epilepsy. Disturbances in synaptic transmission, including the GABAergic, glutamatergic, and serotonergic systems, are known to be involved in the pathogenesis of this disorder, yet we do not know if there is a common molecular mechanism. As mutations in the GABAergic receptor subunit gene GABRA4 are reported in patients with ASD, we eliminated the Gabra4 gene in mice and found that the Gabra4 knockout mice showed autistic-like behavior, enhanced spatial memory, and attenuated susceptibility to pentylenetetrazol-induced seizures, a constellation of symptoms resembling human high-functioning autism. To search for potential molecular pathways involved in these phenotypes, we performed a hippocampal transcriptome profiling, constructed a hippocampal interactome network, and revealed an upregulation of the NMDAR system at the center of the converged pathways underlying high-functioning autism-like and anti-epilepsy phenotypes.

We, the Editors and Publisher of the journal Cell Cycle, have retracted the following article: Rui Li, Xia Qiu, Mei He, Jing Qiao, Jing He, and Mei Zhong. METTL3-mediated mature miR-497-5p/195-5p inhibits trophoblast migration and invasion by targeting WWP1 in preeclampsia. Cell Cycle. 2021. doi: 10.1080/15384101.2021.1982527. Since publication, the authors have raised significant concerns about the reliability of the data presented in the article. As the Editor and Publisher also have concerns about the integrity of the reported results, all parties have agreed to retract the article to ensure correction of the scholarly record. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

ObjectivePre-eclampsia (PE) is one of the malignant metabolic diseases that complicate pregnancy. Gut dysbiosis has been identified for causing metabolic diseases, but the role of gut microbiome in the pathogenesis of PE remains unknown.DesignWe performed a case–control study to compare the faecal microbiome of PE and normotensive pregnant women by 16S ribosomal RNA (rRNA) sequencing. To address the causative relationship between gut dysbiosis and PE, we used faecal microbiota transplantation (FMT) in an antibiotic-treated mouse model. Finally, we determined the microbiome translocation and immune responses in human and mouse placental samples by 16S rRNA sequencing, quantitative PCR and in situ hybridisation.ResultsPatients with PE showed reduced bacterial diversity with obvious dysbiosis. Opportunistic pathogens, particularly Fusobacterium and Veillonella, were enriched, whereas beneficial bacteria, including Faecalibacterium and Akkermansia, were markedly depleted in the PE group. The abundances of these discriminative bacteria were correlated with blood pressure (BP), proteinuria, aminotransferase and creatinine levels. On successful colonisation, the gut microbiome from patients with PE triggered a dramatic, increased pregestational BP of recipient mice, which further increased after gestation. In addition, the PE-transplanted group showed increased proteinuria, embryonic resorption and lower fetal and placental weights. Their T regulatory/helper-17 balance in the small intestine and spleen was disturbed with more severe intestinal leakage. In the placenta of both patients with PE and PE-FMT mice, the total bacteria, Fusobacterium, and inflammatory cytokine levels were significantly increased.ConclusionsThis study suggests that the gut microbiome of patients with PE is dysbiotic and contributes to disease pathogenesis.

Cancer is a hyper-proliferative disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains difficult to resolve. By tracking de novo transformation from normal hematopoietic progenitors expressing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneity among granulocyte–macrophage progenitors (GMPs) determines their probability of transformation. A fast cell cycle intrinsic to these progenitors provide permissiveness for transformation, with the fastest cycling 3% GMPs acquiring malignancy with near certainty. Molecularly, we propose that MLL-AF9 preserves gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling immature myeloid progenitors, this cell state becomes perpetuated, yielding malignancy. In humans, high CCND1 expression predicts worse prognosis for MLL fusion AMLs. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be a preventative approach against malignancy., Not all mutated cells become malignant, suggesting additional requirements for transformation. Here, the authors track blood progenitors from normal to malignancy driven by MLL-AF9, revealing a subset of myeloid progenitors predisposed to transformation dependent on their normal cycling state.

KRAS is an independent negative predictor for anti-epidermal growth factor receptor (anti-EGFR) treatment in colorectal cancers (CRCs). However, 30% to 50% of CRC patients are KRAS-positive and do not benefit from anti-EGFR therapy. In this study, we investigated the mutational features and clinical significance of KRAS-positive Chinese CRC patients. A total of 139 Chinese CRC patients who received clinical KRAS testing (Sanger sequencing) were examined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Fifty KRAS-positive specimens were further detected by next-generation sequencing (NGS). The most prevalent mutation in KRAS was G12D (46%), followed by G12V (20%), and G13D (18%). In addition to KRAS, 72 unique alterations in another 12 genes were also detected. The most common mutated genes were TP53 (62%), APC (46%), and PIK3CA (22%). The proportion of HER2 amplifications in KRAS-positive CRC patients was 4.4%, which was lower than that in KRAS -negative CRC patients (14.3%). No relationship was found between HER2 amplification and KRAS status (p = 0.052). However, the odds ratio is very low (0.279). In addition, these gene mutations were not significantly associated with age, sex, tumor size, lymph node metastasis, mismatch repair–deficient, or tumor differentiation. However, TP53 mutations were more prevalent in colon cancer with KRAS mutations than in rectal cancer (75.0% vs 28.6%, respectively, p = 0.004). The negative predictive value of the IHC analysis for predicting HER2 amplification reached to 98.39%, while the positive predictive value reached only 50%. Overall, the mutation profiling of Chinese CRC patients with KRAS mutations is different from that of Western CRC patients. Our results will help us to understand the molecular features of Chinese CRC patients.

The accumulation of tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is associated with malignant progression in cancer. However, the mechanisms by which the hypoxic TME facilitates TAM infiltration are not fully understood. This study showed that high ZEB1 expression in hypoxic cervical cancer cell islets was positively correlated with CD163+ TAM accumulation. ZEB1 in hypoxic cancer cells promoted the migration of TAMs in vitro and altered the expression of multiple chemokines, especially CCL8. Mechanistically, hypoxia-induced ZEB1 activated the transcription of CCL8, which attracted macrophages via the CCR2–NF-κB pathway. Furthermore, ZEB1 and CCL8 were independent prognostic factors in cervical cancer patients based on The Cancer Genome Atlas (TCGA) data analysis. In conclusion, hypoxia-induced ZEB1 exerts unexpected functions in cancer progression by fostering a prometastatic environment through increased CCL8 secretion and TAM recruitment; thus, ZEB1 may serve as a candidate biomarker of tumour progression and provide a potential target for disrupting hypoxia-mediated TME remodelling.

Background With the comprehensive implementation of the second child policy in China, the proportion of multiparous women has increased dramatically in the past few years. As nearly half of them have a history of previous cesarean delivery, there is widespread concern regarding complications of their pregnancy. Methods The aim of this study was to evaluate the effect of the previous delivery mode on subsequent pregnancy outcomes in the real world based on data from a Chinese birth registry. Birth registry data from July 1, 2016 to June 30, 2017 among a Chinese population were collected and analyzed retrospectively. This study included 14 representative hospitals from 10 provinces of China. All delivery data were collected by an internet-based system using a birth registration platform. The study enrolled 36,355 multiparas. Information extracted for analysis included basic demographic characteristics, previous delivery mode, current delivery mode, major maternal complications, and neonatal outcomes. Pregnancy outcomes of women with previous cesarean delivery (PCS group, n=14,774) were compared with the outcomes of women with previous vaginal delivery (PVD group, n=21,581). Results There were statistically significant differences in the major pregnancy outcomes between the PCS group and the PVD group. The PCS group had a higher incidence of cesarean section (CS), placenta previa, postpartum hemorrhage, uterus rupture, hysterectomy, gestational diabetes, gestational hypertension, delivery before 37 weeks of gestation, low birth weight, and Apgar Score at 5 min ≤3. Conclusions Women with previous cesarean delivery had poorer pregnancy outcomes than women with previous vaginal delivery. Avoiding unnecessary CS, especially in primiparas is essential to improving maternal and neonatal outcomes in later pregnancies.

Mei Zhong,1,* Zhenwei Zhai,2,* Xing Zhou,1 Jingxia Sun,1 Hui Chen,1 Wensheng Lu1 1Department of Endocrinology, The Peoples Hospital of Guangxi Zhuang Autonomous Region, Guangxi, People’s Republic of China; 2Department of Endocrinology, Tongde Hospital of Yuncheng, Changzhi Medical College, Shanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wensheng Lu Tel +86 17634045555Email lwswxqz@163.comAim: Gitelman syndrome (GS) is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis. In this study, we investigated the clinical presentation and sequenced 26 exons of SLC12A3 gene in a patient with a clinical suspicion of GS.Methods: Clinical work-up including clinical examination, electrocardiography (ECG), chest X-ray, bone mineral density (BMD), and ultrasound examination was conducted and all exons of SLC12A3 gene were analyzed by whole-exome sequencing.Results: The patient showed hypokalemia, hypomagnesemia, and metabolic alkalosis and was found to have four novel homozygous missense mutations including one known mutation (c.1456 G>A in exon 12) and three novel mutations (c.366A > G in exon 2, c.791C > G in exon 6 and c.1027C > T in exon 8).Conclusion: Four mutation sites of SLC12A3 gene were found in the patient, three of which have not been reported before. These results may be useful for better understanding the function of this gene and can assist clinicians with treatment decision-making.Keywords: Gitelman syndrome, clinical characteristics, SLC12A3 gene, exome sequencing, gene mutation

BackgroundDuring intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children. The current study was designed to determine the dynamic profiles of differentially-expressed SVATs in circulating exosomes (EXs) derived from autistic children and pregnant women at different gestational ages.MethodsBlood samples were collected from autistic children and women with variant physiopathologic pregnancies. EXs were isolated with an ExoQuick Exosome Precipitation Kit and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The expression of lncRNAs and lncRNA-targeted mRNAs were quantified using real-time PCR.ResultsSVAT-associated lncRNAs-mRNAs were detected in autistic children and differentially expressed from the first trimester of pregnancy to the term of delivery. Pathologic pregnancies, including spontaneous preterm birth (sPTB), preeclampsia (PE), and gestational diabetes mellitus (GDM), were compared to normal physiologic pregnancies, and shown to exhibit specific correlations between SVAT-lncRNA and SVAT-mRNA ofSTX8,SLC18A2, andSYPwith sPTB; SVAT-lncRNA and SVAT-mRNA ofSTX8with PE; and SVAT-lncRNA and SVAT-mRNA ofSV2Cas well as SVAT-mRNA ofSYPwith GDM.ConclusionVariant complications in pathologic pregnancies may alter the GEP of SVATs, which is likely to affect the intrauterine development of neural circuits and consequently influence fetal brain development.

INTRODUCTION The effects of assisted reproductive technology on the outcomes of twin pregnancies are controversial. Therefore, the purpose of this study was to compare the maternal and perinatal outcomes of twin pregnancies conceived spontaneously and those conceived by assisted reproductive technology. MATERIAL AND METHODS This was a cross-sectional study performed at Peking Union Medical College Hospital (PUMCH). Data on twin pregnancies (conceived spontaneously and by in vitro fertilization [IVF]/intracytoplasmic sperm injection [ICSI]) were obtained from the National Birth Registry of China for the period between 1 October 2016, and 30 September 2017. The primary obstetric outcomes were compared between twin pregnancies conceived by different methods. Logistic regression analysis with 95% confidence intervals (95% CI) was used for the multivariate analysis. RESULTS A total of 3270 twin pregnancies (2003 and 1209 conceived spontaneously and by IVF/ICSI, respectively) were identified. The proportion of twin pregnancies among all pregnancies was 3.4% (3332/97 278). Multiple regression analysis indicated that the incidences of gestational diabetes mellitus (adjusted odds ratio [AOR] = 1.42, 95% CI 1.10-1.83, p = 0.007), preterm premature rupture of membranes (AOR = 1.65, 95% CI 1.21-2.25, p = 0.002), placenta accreta spectrum (AOR = 2.12, 95% CI 1.42-3.17, p

Background: Fibrosis is an important histological change occurring in preeclamptic placentas, and might depends on the excess deposition of collagen I. However, the role of fibrotic placentas and collagen I in the pathogenesis of preeclampsia remains unclear. Methods: Collagen deposition and the expression of Collagen I in human placentas were analysed by Masson staining, Sirius red staining and western blotting. The role of collagen I in preeclampsia pathogenesis was studied in C57BL/6 mice.HTR-8/SVneo cells were used to investigate the mechanisms underlying the effects of collagen I in trophoblasts by transcriptome sequencing and pharmacological agonists. Finding: Human preeclamptic placentas exhibited a higher degree of fibrosis in stem villi and terminal villi than normal placentas, and were characterized by collagen I deposition. In vivo, a single injection of collagen I on gestational day 0.5 led to an increase in systolic pressure of pregnant mice from gestational day 4.5 -17.5, to a decrease in weight and number of viable embryos, and to enhanced placental collagen I expression, and degree of fibrosis compared with control mice. In vitro, collagen I attenuated the proliferation and invasion of HTR-8SV/neo cells. This effect could be reversed by treatment with agonist s of ERK and β-catenin. Transcriptome sequencing demonstrated that pathways related to cell proliferation and invasion were significantly downregulated in HTR-8/SVneo cells. Interpretation: Collagen I induced preeclampsia-like symptoms by suppressing the proliferation and invasion of trophoblasts through inhibition of the ERK phosphorylation and WNT/β-catenin signalling pathways. Funding: National Natural Science Foundation of China and Guangdong Province. Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: The collection of placentas was approved by the Ethics Committee of Nanfang Hospital（NFEC-2017-055）. All participants gave written consent prior to donating their placenta.

Background: The benefit of blood cholesterol reduction for secondary prevention of ischemic stroke remains undetermined in Chinese patients. The purpose of this meta-analysis was to determine whether lipid-lowering agents including statins, fibrates, nicotinic acid, and ezetimibe reduced the risk of recurrent stroke in ischemic stroke patients in China and whether such findings could inform treatment decisions for blood lipid-lowering treatment in China.Methods: The English electronic databases PubMed, EMBASE, Cochrane Library and Chinese databases CNKI, Sino-Med, Wan Fang, and VIP were searched for studies published between January 1990 and April 2020. This meta-analysis included published data from trials that randomly assigned patients to groups treated with either blood lipid-lowering regimens or placebo. Effect comparisons were made using fixed effects model in meta-analysis and linear and spline regression were performed to identify the relative risk of stroke recurrence. The primary outcome was the reduction of total ischemic stroke events, and relative risk values were obtained using a risk prediction equation developed from the control groups of the included trials.Results: Five studies including 4,999 individuals with available data met the inclusion criteria. Relative to the control groups, the pooled estimated odds ratio (OR) for recurrent stroke among those who received lipid-lowering therapy was 0.79 (95% confidence interval [CI]: 0.63–1.00). A 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) significantly reduced the risk of ischemic stroke recurrence (OR: 0.15 [95% CI: 0.11–0.20]). The overall beneficial effect of statin therapy was confirmed to prevent ischemic stroke with an OR of 0.51 (95% CI: 0.36–0.72).Conclusions: Effective lipid-lowering therapy could decrease the blood LDL-C level, which had a protective effect against stroke recurrence. These results support the use of predicted baseline cerebrovascular disease risk equations to inform decisions regarding blood lipid-lowering treatment in ischemic stroke patients in China.

Basing on the simplest hydrothermal system containing deionized water, hexa-ammonium molybdate, and thiourea, hydrothermal mechanism on preparation of MoS2 was studied by DFT calculation. Hydrothermal process was divided into four steps which covered ionization equilibrium, the hydrolysis of CS(NH2)2, the formation of intermediates, and the formation of MoS2. Ionization equilibrium occurs at normal condition and determines the existence of Mo in the form of molybdic acid. Thiourea hydrolysis is rate-determining step in the process of hydrothermal which contains 10 elementary reactions. The formation of intermediates includes hydrogen transfer, dehydration, and vulcanization three steps which contain 18 elementary reactions, and the energy barrier of vulcanization is the highest. The formation of MoS2 is divided into two steps, the first step is that MoO(OH)(SH)3.H2O reacts with MoO (SH)4.H2O to form layer MoS2, and the second step is a very fast process that can affect the morphology of the products.

Background Preeclampsia is characterized by an excessive inflammatory response. Recent studies have shown that vagus nerve stimulation (VNS) has anti-inflammatory properties in vivo. This study aims to investigate whether VNS is safe for use during pregnancy and to explore the therapeutic potential and underlying mechanisms of VNS in PE. Methods Pregnant Sprague-Dawley rats were randomly chosen to receive N-nitro-L-arginine methyl ester (L-NAME)-containing water (preeclampsia-like mouse model) or saline (normal pregnancy control) daily at gestational days 14.5–20.5. VNS and the α7nAChR antagonist methyllycaconitine citrate (MLA, 1 mg/kg/d) were given daily at the same time. Results VNS decreased the high systolic blood pressure and urinary protein observed in the PE rats. In addition, VNS mitigated abnormal pregnancy outcomes. Moreover, VNS alleviated the inflammatory response by decreasing the levels of inflammatory cytokines. VNS significantly increased the expression of α7nAChR and attenuated the activation of NF-κB p65 in the placenta. Discussion Our findings indicate that maternal VNS treatment is safe during pregnancy and has a protective effect in a pregnant rat model of preeclampsia induced by L-NAME.

Lung cancer is the leading cause of cancer-associated death worldwide. In recent years, the advancement of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapies has provided clinical benefits for lung cancer patients with EGFR mutations. The response to EGFR-TKI varies in patients with lung cancer, and resistance typically develops during the course of the treatment. Therefore, understanding biomarkers which can predict resistance to EGFR-TKI is important. Overexpression of GLI causes activation of the Hedgehog (Hh) signaling pathway and plays a critical role in oncogenesis in numerous types of cancer. In the present study, the role of GLI1 in erlotinib resistance was investigated. GLI1 mRNA and protein expression levels were determined using reverse transcription-quantitative PCR and immunohistochemistry (IHC) in lung cancer cell lines and tumor specimens, respectively. GLI1 mRNA expression levels were found to be positively correlated with the IC50 of erlotinib in 15 non-small cell lung cancer (NSCLC) cell lines. The downregulation of GLI1 using siRNA sensitized lung cancer cells to the erlotinib treatment, whereas the overexpression of GLI1 increased the survival of lung cancer cells in the presence of erlotinib, indicating that Hh/GLI activation may play a critical role in the development of TKI resistance in lung cancer. Combined treatment with erlotinib and a GLI1 inhibitor reduced the cell viability synergistically. A retrospective study of patients with NSCLC treated with erlotinib revealed that those with a high IHC score for GLI1 protein expression had a poorer prognosis. These results indicated that GLI1 is a key regulator for TKI sensitivity, and patients with lung cancer may benefit from the combined treatment of TKI and GLI1 inhibitor.

Accumulating evidence suggests that the pathogenesis of preeclampsia involves poor placentation caused by insufficient trophoblast invasion and impaired uterine spiral artery remodeling, yet the underlying molecular mechanism remains unclear. We carried out transcriptome profiling on placentae from preeclamptic patients and normal subjects, and identified about four hundred long non-coding RNAs differentially expressed in placentae of patients with early-onset severe preeclampsia. Here, we report our identification of lncRNA SH3PXD2A-AS1 as a potential causal factor for this disease and its downstream pathways involved in placentation. We found that expression level of SH3PXD2A-AS1 in the placentae is positively correlated with clinical severity of the patients. We demonstrated that SH3PXD2A-AS1 inhibited invasion and migration through recruiting CCCTC-binding factor (CTCF) to the promoters of SH3PXD2A and CCR7 to inhibit their transcription. Therefore, we conclude that the upregulation of lncRNA SH3PXD2A-AS1 may contribute to the pathogenesis of preeclampsia through prohibiting trophoblast invasion during placentation.

SLIT2, a member of neuronal guidance cues, has been reported to regulate inflammation and cancer progression. Periodontitis is an oral inflammatory disease that degenerates periodontal tissue, alveolar bone and tooth. This study aims to explore the expression pattern of SLIT2 in periodontitis and its role in disease progression and bone loss. Gingival tissue of 20 periodontitis patients and 20 healthy-controls was obtained. Ligature-induced periodontitis (LIP) mice-model was developed in Slit2-Tg and wild-type mice. The effect of SLIT2 on inflammation, immune cell infiltration, M1 macrophage polarization, and alveolar bone loss in periodontitis was analyzed extensively. In periodontitis-affected gingival-tissue, SLIT2 expression was 4.4-fold higher compared to healthy-volunteers. LIP enhanced SLIT2 expression in mice periodontitis-affected periodontal tissue (PAPT) and blood circulation of wild-type mice by 4. 6-, and 5.0-fold, respectively. In Slit2-Tg-mice PAPT, SLIT2 expression was 1.8-fold higher compared to wild-type mice. Micro-CT and histomorphometric analysis revealed a 1.3-fold higher cement-enamel-junction to the alveolar-bone-crest (CEJ-ABC) distance and alveolar bone loss in LIP Slit2-Tg-mice compare to LIP wild-type mice. Results from RNA-sequencing, RT-qPCR, and ELISA showed a higher expression of Cxcr2, Il-18, TNFα, IL-6, and IL-1β in Slit2-Tg-mice PAPT compared to wild-type-mice. Slit2-Tg-mice PAPT showed a higher number of osteoclasts, M1 macrophages, and the upregulation of Robo1 expression. Slit2-Tg-mice PAPT showed upregulation of M1 macrophage marker CD16/32 and osteoclastogenic markers Acp5, Ctsk, and Nfatc1, but osteogenic markers (Alp, Bglap) remained unchanged. Immunohistochemistry unveiled the higher vasculature and infiltration of leucocytes and macrophages in Slit2-Tg-mice PAPT. RNA-sequencing, GO-pathway enrichment analysis, and western blot analysis revealed the activation of the MAPK signaling pathway in Slit2-Tg mice PAPT. In conclusion, SLIT2 overexpression in periodontitis intensifies inflammation, immune cells infiltration, M1 macrophage polarization, osteoclastogenesis, and alveolar bone loss, possibly via activation of MAPK signaling, suggesting the role of SLIT2 on exacerbation of periodontitis and alveolar bone loss.

With a high incidence and high mortality rate, ovarian cancer presents a challenge for clinical practice. It is thus extremely urgent to investigate new diagnosis and therapy methods for the treatment of ovarian cancer. Ternary copper-based chalcogenide nanomaterials are attractive owing to their near infrared (NIR) response for cancer theranostic fields. However, improving the theranostic efficiency of these nanomaterials is challenging. Herein, CuS-MnS2 nano-flowers were easily synthesized and under NIR irradiation exhibited a relatively high photothermal conversion efficiency of 67.5% and a simultaneous reactive oxygen species (ROS) generation effect. Owing to these outstanding photothermal/photodynamic effects, excellent tumor ablation results could be achieved by the combined use of CuS-MnS2 nano-flowers and 808 nm NIR laser treatments. The main anticancer mechanism of CuS-MnS2 nano-flowers + NIR was likely necroptosis. In addition, the nano-flowers showed remarkable contrast enhancement according to magnetic resonance imaging (MRI). These CuS-MnS2 nano-flowers could thus serve as a promising multifunctional nanotheranostic agent for MRI and as a photothermal/photodynamic cancer therapy agent through necroptosis.

Selective intrauterine growth restriction (sIUGR) is a severe complication in monochorionic (MC) twin pregnancies, and it carries increased risks of poor prognosis. Current data suggest that vascular anastomoses and unequal placental sharing may be the key contributor to discordant foetal growth. While MC twins derive from a single zygote and have almost identical genetic information, the precise mechanisms remain unknown. DNA hydroxymethylation is a newly discovered epigenetic feature associated with gene regulation and modification. Here, we investigate discordant hydroxymethylation patterns between two placental shares of sIUGR and analyse the potential role of aberrant hydroxymethylation of angiopoietin-like 4 (ANGPTL4) in placental dysplasia. Hydroxymethylation DNA immunoprecipitation (hMeDIP)-chip and mRNA sequencing were performed to identify hydroxymethylation-associated genes. Real-time qPCR, western blotting, and immunohistochemistry were used to confirm ANGPTL4 expression. The mechanisms regulating ANGPTL4 were investigated by cell migration assay, invasion assay, viability assay, and apoptotic ratio assays, western blotting and hMeDIP-qPCR. Decreased ANGPTL4 was detected in the smaller placental shares of sIUGR. ANGPTL4 knockdown suppressed trophoblast invasiveness and migration, which possibly occurred through hypoxia inducible factor 1α (HIF-1α) and HIF-1 signalling pathway. Hypoxia leads to aberrant expression of ANGPTL4 and HIF-1α, positively correlated with their aberrant hydroxymethylation levels in promoter regions. Aberrant hydroxymethylation of ANGPTL4 may contribute to placental impairment by the HIF-1 signalling pathway in smaller placental shares of sIUGR.

To explore the mechanisms through which hypoxic tumor microenvironment (TME) modulates the transition of tumor-associated macrophages (TAMs). The migration ability of RAW264.7 macrophages was determined by transwell assay. Flow cytometric, western blot and immunofluorescence analyses of CD206 further validated the M2 polarization of macrophages. Immunofluorescence, western blot and qRT-PCR were performed to detect the expression of neuropilin-1 (Nrp-1) and carbonic anhydrase IX (CAIX). An intermittent hypobaric hypoxia (IH) animal model was established to evaluate the role of hypoxia in activating M2-like TAMs in vivo. We also used immunohistochemistry to analyze the association between CAIX, CD163+ macrophages and Nrp-1 in a series of 72 human cervical cancer specimens. We found that the hypoxic cervical TME educated the recruited macrophages to transform into the M2 phenotype. Nrp-1 expression was significantly increased in hypoxia-primed cervical cancer cells. Blocking Nrp-1 expression prevented hypoxic cells from recruiting and polarizing macrophages towards the M2 phenotype. Hypoxia exposure significantly increased the expression of Nrp-1 as well as the infiltration of macrophages in vivo. Consistently, immunochemical staining in serial tissue sections of cervical cancer revealed upregulated levels of Nrp-1 in CAIX-positive hypoxic regions along with a concurrent significant elevation of M2 macrophages. Nrp-1 and M2-like TAMs were related to the malignant properties of cervical cancer, such as the FIGO stage and lymph node metastasis. Nrp-1 plays critical roles in hypoxic TME-induced activation and pro-tumoral effects of TAMs in cervical cancer. Interfering with Nrp-1 may be a potential therapeutic strategy in treating cervical cancer.

The clinical relevance of uniparental disomy (UPD16) for chromosome 16 is currently unclear.We performed chromosome microarray analysis on two fetus and their placentas, fluorescence in situ hybridization (FISH) to exclude the hidden chr16 trisomy mosaicism in the fetuses, and clinical whole-exome sequencing to assess for homozygosity mutations of autosomal-recessive diseases.Microarray analysis of two fetuses had UPD16. The membranous placenta of the case 1 had confined placental mosaicism (CPM) for trisomy 16. Clinical whole-exome sequencing on chromosome 16 revealed three potentially pathogenic single nucleotide polymorphisms (SNPs). Gap-polymerase chain reaction (PCR) and MLPA for a-thal deletions demonstrated that case 2 was homozygous for the -SEA deletion.The poor outcome in these fetuses may be attributed to other factors, the membranous placenta and the -SEA deletion, respectively. Fetal UPD16 itself might be not correlated with intrauterine growth restriction (IUGR) and thus is not the basic cause of IUGR.

Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.

BACKGROUND The present study explored the patterns of physical comorbidities and their associated demographic and clinical factors in older psychiatric patients prescribed with antidepressants in Asia. METHODS Demographic and clinical information of 955 older adults were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Standardized data collection procedure was used to record demographic and clinical data. RESULTS Proportion of physical comorbidities in this cohort was 44%. Multiple logistic regression analyses showed that older age (OR = 1.7, P

// Ruo-Ting Xu 1, 2, * , Qing-Xian Chang 3, * , Qi-Qiong Wang 4 , Jian Zhang 5 , Lai-Xin Xia 6 , Nanbert Zhong 3, 7, 8 , Yan-Hong Yu 3 , Mei Zhong 3 and Qi-Tao Huang 3 1 Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 First School of Clinical Medicine, Southern Medical University, Guangzhou, China 3 Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China 4 Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, China 5 Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China 6 Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China 7 March of Dimes Global Network for Maternal and Infant Health, White Plains, NY, USA 8 Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA * These authors contributed equally to this work Correspondence to: Qi-Tao Huang, email: 15920454515@163.com Mei Zhong, email: zhongm1960@163.com Keywords: autism; childhood; pre-eclampsia; hypertensive disorders of pregnancy Received: June 05, 2017 Accepted: September 21, 2017 Published: December 07, 2017 ABSTRACT Background: Autism spectrum disorder (ASD) is a common severe pervasive neurodevelopmental disorder of undetermined etiology. Environmental exposures, especially pregnancy complications, have been increasingly recognized as a potential risk factor for ASD. Our aim was to (1) systematically evaluate the association between hypertensive disorders of pregnancy (HDP) and the risk of ASD in offspring, (2) specifically draw a subgroup analysis of disease severity in patients with HDP to achieve more sufficient evidence on this issue. Results: A total of 21 studies were identified with more than 6.5 million participants, including 31,027 ASD probands. A comparative meta-analysis established that offspring born premature to HDP were significantly associated with ASD than matched controls (OR = 1.42, 95% CI: 1.34–1.50). Subgroup analysis of clinical classification include: (1) gestational hypertension, (2) pre-eclampsia, (3) chronic hypertension complicating pregnancy (CHP). The offspring of mothers with pre-eclampsia and CHP have slightly higher risk (OR = 1.43; OR = 1.48, respectively) of ASD than those of mothers with gestational hypertension (OR = 1.37). In consistence with most previous researches, higher ASD prevalence was observed in male than female (OR = 1.38), indicating a potential role for gender in the pathophysiology of ASD. Materials and Methods: We conducted a systematic literature search on PubMed, EMBASE, Web of Science, PsycINFO database and China National Knowledge Infrastructure up to Jun. 2017. Statistical analysis was performed using Stata 10.0. Conclusions: This meta-analysis implies a possible link between HDP and the risk of ASD in offspring. However, further investigation should be conducted to confirm this conclusion, and intensive prenatal surveillance and early prediction for ASD is needed.

Contiguous microdeletions of the Norrie disease pseudoglioma (NDP) region on chromosome Xp11.3 have been widely confirmed as contributing to the typical clinical features of Norrie disease (ND). However, the precise relation between genotype and phenotype could vary. The contiguous deletion of NDP and its neighbouring genes, MAOA/B and EFHC2, reportedly leads to syndromic clinical features such as microcephaly, intellectual disability, and epilepsy. Here we report a novel contiguous microdeletion of the NDP region containing the MAOB and EFHC2 genes, which causes eye defects but no cognitive disability. We detected a deletion of 494.6 kb at Xp11.3 in both the proband and carrier mother. This deletion was then used as the molecular marker in prenatal diagnosis for two subsequent pregnancies. The deletion was absent in one of the foetuses, who remain without any abnormalities at 2 years of age. The proband shows the typical ocular clinical features of ND including bilateral retinal detachment, microphthalmia, atrophic irides, corneal opacification, and cataracts, but no symptoms of microcephaly, intellectual disability, and epilepsy. This familial study demonstrates that a deficiency in one of two MAO genes may not lead to psychomotor delay, and deletion of EFHC2 may not cause epilepsy. Our observations provide new information on the genotype–phenotype relations of $${\textit{MAOA/B}}$$ and EFHC2 genes involved in the contiguous deletions of ND.

Cervical cancer is the most frequent cause of gynecologic cancer-associated death worldwide. Animal models that demonstrate metastatic patterns consistent with the clinical course of cervical cancer are urgently needed to conduct studies focused on understanding the mechanisms of the disease and identifying optimal treatments. To address this, we established an orthotopic xenograft model of cervical cancer in female NOD-SCID mice using SiHa and ME180 cell lines stably expressing green fluorescent protein to evaluate the role of microRNA-21 (miR-21) in spontaneous lymph node metastasis in vivo. In this case, SiHa and ME180 cells were transduced by lentivirus to stably express green fluorescent protein and miR-21. Overexpression of miR-21 promoted proliferation, migration, and invasion of SiHa and ME180 cells in vitro. Finally, an orthotopic xenograft model of human cervical cancer was successfully established in NOD-SCID mice. Using this model, we confirmed that overexpression of miR-21 resulted in an increase in the size of primary tumors and in the frequency of spontaneous lymph node metastasis at the time of excision. Therefore, the use of the orthotopic xenograft model should allow for the investigation of novel factors that affect metastasis of cervical cancer and presents an opportunity to evaluate potential therapeutic agents that may inhibit the spread of the disease.

Background and Aims: Published data on the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer are controversial. We conducted this meta-analysis to obtain a more accurate assessment of prognostic significance of NLR in ovarian cancer. Materials and Methods: We conducted a systematic literature search using the electronic databases PubMed, Web of Science, and Embase up to May 2016. Hazard ratio (HR) and odd ratio (OR) with 95% confidence interval (95% CI) were calculated. Subgroup analyses were carried out to explore the source of heterogeneity. Statistical analysis was performed using Stata 10.0. Results: A total of 12 studies, consisting of 3,854 patients, which met our criterion were selected in this meta-analysis. Our pooled results showed that high pre-treatment NLR level was significantly associated with poorer overall survival (OS) (HR: 1.69, 95% CI 1.29-2.22) and shorter progression free survival (PFS) (HR 1.63, 95% CI 1.27–2.09). Additionally, increased NLR was also significantly correlated with advanced FIGO stage (OR 2.32, 95% CI1.79-3.00), higher serum level of CA-125 (OR 3.33, 95% CI 2.43-4.58), more extensive ascites (OR 3.54, 95% CI 2.31-5.42) as well as less chemotheraputic response (OR 0.53, 95% CI 0.40-0.70). The findings from most of subgroup meta-analyses were consistent with those from the overall meta-analyses. Conclusions: Elevated pre-treatment NLR could served as a predicative factor of poor prognosis for ovarian cancer patients.

Introduction Sepsis can cause decreased diaphragmatic contractility. Intracellular calcium as a second messenger is central to diaphragmatic contractility. However, changes in intracellular calcium concentration ([Ca2+]) and the distribution and co-localization of relevant calcium channels [dihydropyridine receptors, (DHPRα1s) and ryanodine receptors (RyR1)] remain unclear during sepsis. In this study we investigated the effect of changed intracellular [Ca2+] and expression and distribution of DHPRα1s and RyR1 on diaphragm function during sepsis. Methods We measured diaphragm contractility and isolated diaphragm muscle cells in a rat model of sepsis. The distribution and co-localization of DHPRα1s and RyR1 were determined using immunohistochemistry and immunofluorescence, whereas intracellular [Ca2+] was measured by confocal microscopy and fluorescence spectrophotometry. Results Septic rat diaphragm contractility, expression of DHPRα1s and RyR1, and intracellular [Ca2+] were significantly decreased in the rat sepsis model compared with controls. Discussion Decreased intracellular [Ca2+] coincides with diaphragmatic contractility and decreased expression of DHPRα1s and RyR1 in sepsis. Muscle Nerve 56: 1128–1136, 2017

To analyze the amino acids (AA) and acyl carnitine (AC) profiles in dry blood spot (DBS) specimens of low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA), and to compare the concentration difference of AA and AC with those without above.This is a retrospectively study. Eight thousand nine hundred and seventy-nine uncomplicated pregnant newborns were enrolled into the study. DBS were collected on the third day of life, and concentrations of 11 types of AA, free carnitine and 30 types of AC were detected by using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS). Shapiro-Wilk test and Kruskal-Wallis rank test were applied in statistical analysis.Concentrations of most AA and AC in infants born in SGA were significantly higher than those in non-SGA group, while lower in LBW and PTB groups than those in non-LBW and non-PTB groups (p 0.05).The difference of concentration of AA and AC in the subgroups suggested there may be a dysutilization of AA and AC in SGA, but an inborn insufficient of AA and AC in LBW and PTB neonates.

Tripterygium hypoglaucum(Levl.) Hutch (THH) shows well clinical effect on rheumatoid arthritis (RA), but the active ingredients and molecular mechanisms remain unclear. This work was designed to explore these issues by network pharmacology. Compounds from THH were gathered by retrieving literatures. Compound-related and RA-related genes were identified using databases, and the overlapping genes were identified by Venn diagram. The active ingredients and genes of THH against RA were confirmed by dissecting interactions between overlapping genes and compounds using Cytoscape. SystemsDock website was used to further verify the combining degree of key genes with active ingredients. Pathway enrichment analysis was performed to decipher the mechanisms of THH against RA by Database for Annotation, Visualization and Integrated Discovery. A total of 123 compounds were collected, and 110 compounds-related and 1871 RA-related genes were identified, including 64 overlapping genes. The target genes and active ingredients of THH against RA comprised 64 genes and 17 compounds, the focus of which was PTGS2, triptolide, and celastrol. SystemsDock website indicated that the combing degree of PTGS2 with triptolide or celastrol was very good. The mechanisms of THH against RA were linked to 31 signaling pathways, and the key mechanism was related to inhibition of inflammation response through inactivating TNF and NF-kappa B signaling pathways. This work firstly explored the active ingredients and mechanisms of THH against RA by network pharmacology and provided evidence to support clinical effects of THH on RA.

Despite the milder clinical severity of Hb H patients compared with those of Hb Bart’s hydrops fetalis or patients with β-thalassemia major (β-TM), a few cases of Hb H hydrops fetalis syndrome have been reported so far. Here, we describe, for the first time in the Chinese population, one case of a neonate with Hb H hydrops fetalis syndrome caused by the – –SEA (Southeast Asian) deletion in combination with the Hb Hirosaki (HBA2: c.132C>G, p.Phe43Leu) mutation. Our study highlights the importance of continuous fetal monitoring using ultrasonography and blood screening studies of fetuses. Appropriate genetic counseling and comprehensive clinical follow-up should be performed on a pregnant woman who carried an α0-thalassemia (α0-thal) deletion and had a Hb H or Hb Bart’s hydrops fetalis offspring, especially if the woman’s partner also carried a hemoglobinopathy.

Background: Lamiophlomis rotata (LR) showed favorable clinical effect and safety on rheumatoid arthritis (RA), but its active ingredients and mechanisms against RA remain unknown. The aim of this work was to explore the active ingredients and mechanisms of LR against RA by network pharmacology. Methods: Compounds from LR were identified using literature retrieval and screened by absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation. Genes related to the selected compounds or RA were identified using public databases, and the overlapping genes between compounds and RA target genes were identified using Venn diagram. Then, the interactions network between compounds and overlapping genes was constructed, visualized, and analyzed by Cytoscape software. Finally, pathway enrichment analysis of overlapping genes was carried out on Database for Annotation, Visualization, and Integrated Discovery (DAVID) platform. Results: A total of 148 compounds in LR were identified, and ADMET screen results indicated that 67 compounds exhibited good potential as active ingredients. A total of 90 compounds-related genes and 1,871 RA-related genes were identified using public databases, and 48 overlapping genes between them were identified. Cytoscape results suggested that the active ingredients and target genes of LR against RA consisted of 23 compounds and 48 genes, and luteolin and AKT1 were the uppermost active ingredient and hub gene, respectively. DAVID results exhibited that the mechanisms of LR against RA were related to 34 signaling pathways, and the key mechanism of LR against RA might be to induce apoptosis of synovial cells by inactivating PI3K-Akt signaling pathway. Conclusion: The active ingredients and mechanisms of LR against RA were firstly investigated using network pharmacology. This work provides scientific evidence to support the clinical effect of LR on RA, and a research basis for further expounding the active ingredients and mechanisms of LR against RA.

Dysregulated RNA editing is well documented in several diseases such as cancer. The extent to which RNA editing might be involved in diseases originated in the placenta remains unknown, because RNA editing has rarely been studied in the placenta. Here, we have systematically profiled RNA editome on the placentae from 9 patients with early-onset severe preeclampsia (EOSPE) and 32 normal subjects, and a widespread RNA editing dysregulation in EOSPE has been identified. The mis-edited gene set is enriched with known preeclampsia-associated genes and differentially expressed genes in EOSPE. The “RNA editing events” at two microRNA binding sites in 3’-UTR of the LEP mRNA were generated, which could lead to increased expression level of LEP in trophoblast cells. Upregulation of LEP were also observed in the placentae of PE patients. These results suggest that widespread placental RNA editing may be involved in placental development and dysregulation of RNA editing in the placenta may contribute to the pathogenesis of preeclampsia.

Patients with preeclampsia display a spectrum of onset time and severity of clinical presentation, yet the underlying molecular bases for the early-onset and late-onset clinical subtypes are not known. Since the root cause of PE is thought to be located in the placentae, we carried out RNA-seq on 65 high-quality placenta samples, including 33 from 30 patients and 32 from 30 control subjects, to search for molecular features. We identified two functionally distinct sets of dysregulated genes in two major subtypes: metabolism-related genes, notably transporter genes, in early-onset severe preeclampsia and immune-related genes in late-onset severe preeclampsia, while the late-onset mild preeclampsia could not be distinguished from normal controls. A small number of dysregulated transcription factors may drive the widespread gene dysregulation in both early-onset and late-onset patients. These results suggest that early-onset and late-onset severe preeclampsia have different molecular mechanisms, whereas the late-onset mild preeclampsia may have no placenta-specific causal factors.

Rett syndrome (RTT), mainly caused by mutations in the methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapeutics. Here, we used two-dimensional and three-dimensional human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, the treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in the chromatin binding of BRD4 and the enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed the cell type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids, which were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate BRD4 dysregulation is a critical driver for RTT etiology, and suggest targeting BRD4 could be a potential therapeutic opportunity for RTT.