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Cancer of unknown primary site(CUPs) is a metastatic syndrome with an unidentifiable primary tumor, even after extensive workup to seek the primary site. CUPs accounts for about 3%-5% of the total number of all cancer diagnoses worldwide. The current precision medicine era has reclassified patients with CUPs into the favorable and unfavorable prognostic subset. In this study clinical characteristics and treatment of patients of CUPs were retropactively analysed. Thirty-two patients treated from July 2016 to October 2021 were included in the Affiliated Tumor Hospital of Tianjin Medical University(Tianjin, China).Common symptoms were anemia, fever, enlarged lymph nodes, abdominal pain, edema/multiple serous cavity effusion. Patients with good prognostic factors achieved good outcomes with treatment, conversely, patients with poor prognosis were generally treated empirically and had poorer outcomes. After anti-tumor treatment, the total effective rate was 41 percent(41% was the percentage of patients who achievedtumour respons). To the end of follow-up, after anti-tumor treatment, the median Overall Survival(OS) of patients was 5.4 months. [ABSTRACT FROM AUTHOR]

Background: To understand the clinical characteristics of and explore the risk factors for mortality in patients with severe fever with thrombocytopenia syndrome (SFTS).Methods: Data from SFTS patients diagnosed by laboratory examination at Chaohu Hospital affiliated with Anhui Medical University from June 2017 to January 2021 were retrospectively analysed. According to the clinical results, all confirmed patients were divided into the surviving group (80 patients) and non-surviving group (20 patients). The two groups were compared in terms of general characteristics, clinical symptoms and signs, laboratory indicators and other aspects. The independent risk factors for mortality in SFTS patients were analysed by multivariate binary logistic regression.Results: Univariate analysis showed a significant difference in age and the incidence of consciousness disturbance, respiratory failure, haemorrhagic manifestations, renal dysfunction, shock, aspartate aminotransferase (AST) ≥400 U/L, creatine kinase (CK)≥1000 U/L, creatine kinase isoenzymes (CK-MB) ≥100 U/L, lactate dehydrogenase (LDH) ≥1000 U/L, serum creatinine ≥100 mmol/L, blood urea nitrogen ≥7.5 mmol/L and C-reactive protein ≥8 mg/L between the two groups (P < 0.05).Conclusions: Consciousness disorder, haemorrhagic manifestations, renal dysfunction, AST ≥ 400 U/L, and LDH ≥ 1000 U/L are independent risk factors for mortality in SFTS patients and merit close attention in clinical treatment to avoid fatal consequences. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown.Methods: The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot.Results: We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance.Conclusions: Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Recognising that excessive dietary salt intake is associated with high blood pressure and adverse cardiovascular health, the Ministry of Health Malaysia conducted the Malaysian Community Salt Survey (MyCoSS) among Malaysian adults. This paper introduced MyCoSS projects and presented findings on the salt intake of the Malaysian adult population.Methods: MyCoSS was a nationally representative survey, designed to provide valuable data on dietary salt intake, sources of salt in the diet, and knowledge, perception, and practice about salt among Malaysian adults. It was a cross-sectional household survey, covering Malaysian citizens of 18 years old and above. Multi-stage-stratified sampling was used to warrant national representativeness. Sample size was calculated on all objectives studied, and the biggest sample size was derived from the knowledge on the effect of high salt on health (1300 participants). Salt intake was estimated using a single 24-h urine collection and its sources from a food frequency questionnaire. Knowledge, attitude, and practice were determined from a pre-tested questionnaire. All questionnaires were fully administered by trained interviewers using mobile devices. Anthropometric indices (weight, height, and waist circumference) and blood pressure were measured using a standardised protocol. Ethical approvals were obtained from the Medical Research Ethics Committee, Ministry of Health Malaysia, and Queen Mary University of London prior to conducting the survey.Results: Findings showed that the average sodium intake of Malaysian adults (3167 mg/day) was higher than the WHO recommendation of 2000 mg/day. Daily intake was significantly higher among males and individuals with higher BMI and higher waist circumference.Conclusion: Salt intake in the Malaysian population was higher than the WHO recommendation. MyCoSS's findings will be used for the development and implementation of national salt reduction policy. A successful implementation of a national salt reduction programme in Malaysia will benefit the whole population. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer (ESCA) is one of the most common cancers worldwide and has a very poor prognosis. Hypoxia-inducible factor 1 (HIF1) signaling pathway plays a critical role in tumorigenesis and is therefore considered a potential therapeutic target in the treatment of many cancers. Activating transcription factor 5 (ATF5) facilitates the expression of various genes and has been extensively studied for its potential role in cancer treatment. Methods: The expression level of ATF5 in clinic sample was detected by quantitative real time PCR and immunohistochemistry. ATF5 biological function was investigated by western blot, cell cycle analysis, cell viability assay, luciferase reporter assays, colony formation assay, transwell assay, wound healing assay, tube formation assay, and ELISA assay. CHIP and Re-CHIP assay, GST-pulldown, and RNA-sequencing were used to study the cross-talks between ATF5 and HIF1 complex. Mouse xenograft study was utilized to study the correlation of ATF5 and tumor growth in vivo. Student's t-test or Chi-square test was used for statistical analysis. Results: Here, we first found ATF5 was dramatically upregulated in ESCA cancer and related with poor survival time. Next, we found that the expression level of ATF5 had a positive relationship with the proliferation, migration, and invasion ability of ESCA cells. Besides, we innovatively found that ATF5 functions as a novel coactivator in HIF1 transcription complex by binding to HIF1α. Further, we demonstrated that silencing ATF5 phenocopies HIF1α knockdown in tumorigenic properties in vitro and inhibited ESCA tumor angiogenesis and proliferation in vivo. Conclusion: Herein, we found ATF5 as a novel component of the HIF1 transcription complex. The findings of the present study may provide new insights into the development of a novel and more efficient therapeutic strategy against ESCA. AdnowYwCvGQPELyR7fEPbo Video abstract [ABSTRACT FROM AUTHOR]

Background: Understanding lignin biosynthesis and composition is of central importance for sustainable bioenergy and biomaterials production. Species of the genus Miscanthus have emerged as promising bioenergy crop due to their rapid growth and modest nutrient requirements. However, lignin polymerization in Miscanthus is poorly understood. It was previously shown that plant laccases are phenol oxidases that have multiple functions in plant, one of which is the polymerization of monolignols. Herein, we link a newly discovered Miscanthus laccase, MsLAC1, to cell wall lignification. Characterization of recombinant MsLAC1 and Arabidopsis transgenic plants expressing MsLAC1 were carried out to understand the function of MsLAC1 both in vitro and in vivo. Results: Using a comprehensive suite of molecular, biochemical and histochemical analyses, we show that MsLAC1 localizes to cell walls and identify Miscanthus transcription factors capable of regulating MsLAC1 expression. In addition, MsLAC1 complements the Arabidopsis lac4–2 lac17 mutant and recombinant MsLAC1 is able to oxidize monolignol in vitro. Transgenic Arabidopsis plants over-expressing MsLAC1 show higher G-lignin content, although recombinant MsLAC1 seemed to prefer sinapyl alcohol as substrate. Conclusions: In summary, our results suggest that MsLAC1 is regulated by secondary cell wall MYB transcription factors and is involved in lignification of xylem fibers. This report identifies MsLAC1 as a promising breeding target in Miscanthus for biofuel and biomaterial applications. [ABSTRACT FROM AUTHOR]

In essence, the β2 adrenergic receptor (β2AR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through Gαs coupling, but interestingly, β2AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the β2AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired β2AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of Gαs and Gαi, and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in Gαs-Gαi coupling to β2AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This Gαi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of β2AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6′-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in Gαs-Gαi coupling to β2AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in β2AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. 7HWufKwpH5ZfY_hx8fyY6a Video Abstract [ABSTRACT FROM AUTHOR]

Background: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action.Methods: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified.Results: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p.Conclusion: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways. [ABSTRACT FROM AUTHOR]

Background: Temporomandibular joint osteoarthritis (TMJOA) is characterized by abnormal subchondral bone remodeling and cartilage degeneration. As a non-invasive biophysical technology, pulsed electromagnetic field (PEMF) treatment has been proven to be efficient in promoting osteogenesis. However, the potential bone protective effect and mechanism of PEMF on abnormal subchondral bone remodeling in TMJOA are unknown.Methods: Unilateral anterior crossbite (UAC) was used to create TMJOA model in rats, and 17β-estradiol (E2) were injected daily to mimic patients with high-physiological levels of estrogen. Mouse osteoblast-like MC3T3-E1 cells treated with recombinant murine IL-1β was used to establish inflammatory environment in vitro. The treatment group were subjected to PEMF (2.0mT, 15 Hz, 2 h/d). Micro-CT scanning, histological staining, real-time PCR and western blotting assays were preformed to observe the changes in the subchondral bone.Results: Abnormal resorption of subchondral bone induced by UAC, characterized by decreased bone mineral density, increased osteoclast activity and expression of osteoclast-related factors (RANKL) and down-regulated expression of osteogenesis-related factors (OPG, ALP, Runx2 and OCN) at the early stage, could be reversed by PEMF exposure, which was similar to the effect of estrogen. In addition, PEMF exposure and E2 supplement may have a synergistic effect to some extent. Moreover, PEMF exposure could promote the ALP activity and osteogenic mineralization ability of MC3T3-E1 cells. PEMF promoted the expression of factors related to Wnt/β-Catenin signal pathway both in vivo and in vitro.Conclusions: Appropriate PEMF exposure have a protective effect on subchondral bone in TMJOA at early stage, in which canonical Wnt/β-Catenin pathway may be involved. PEMF may be a promising biophysical approach for early intervention of TMJOA in clinic. [ABSTRACT FROM AUTHOR]

Background: The deciphering of cellular networks to determine susceptibility to infection by HIV or the related simian immunodeficiency virus (SIV) is a major challenge in infection biology. Results: Here, we have compared gene expression profiles of a human CD4+ T cell line at 24 h after infection with a cell line of the same origin permanently releasing SIVmac. A new knowledge-based-network approach (Inter-Chain-Finder, ICF) has been used to identify sub-networks associated with cell survival of a chronically SIV-infected T cell line. Notably, the method can identify not only differentially expressed key hub genes but also non-differentially expressed, critical, ‘hidden’ regulators. Six out of the 13 predicted major hidden key regulators were among the landscape of proteins known to interact with HIV. Several sub-networks were dysregulated upon chronic infection with SIV. Most prominently, factors reported to be engaged in early stages of acute viral infection were affected, e.g. entry, integration and provirus transcription and other cellular responses such as apoptosis and proliferation were modulated. For experimental validation of the gene expression analyses and computational predictions, individual pathways/sub-networks and significantly altered key regulators were investigated further. We showed that the expression of caveolin-1 (Cav-1), the top hub in the affected protein-protein interaction network, was significantly upregulated in chronically SIV-infected CD4+ T cells. Cav-1 is the main determinant of caveolae and a central component of several signal transduction pathways. Furthermore, CD4 downregulation and modulation of the expression of alternate and co-receptors as well as pathways associated with viral integration into the genome were also observed in these cells. Putatively, these modifications interfere with re-infection and the early replication cycle and inhibit cell death provoked by syncytia formation and bystander apoptosis. Conclusions: Thus, by using the novel approach for network analysis, ICF, we predict that in the T cell line chronically infected with SIV, cellular processes that are known to be crucial for early phases of HIV/SIV replication are altered and cellular responses that result in cell death are modulated. These modifications presumably contribute to cell survival despite chronic infection. [ABSTRACT FROM AUTHOR]

Background: Lipid and glucose metabolism abnormalities are associated with nonalcoholic fatty liver disease (NAFLD). The triglyceride–glucose (TyG) index is a recently developed indicator that can identify individuals at risk for NAFLD. However, the applicability of the TyG index for identifying NAFLD in patients with type 2 diabetes mellitus (T2DM) is unclear. The aim of this study was to investigate the ability of the TyG index to identify individuals at risk for NAFLD in the T2DM population. Methods: A total of 2280 participants with T2DM were recruited in this cross-sectional study. The TyG index was calculated, and NAFLD was diagnosed by ultrasonography. Binary logistic regression models were used to evaluate the association of the TyG index, glycemic parameters and lipid parameters with NAFLD. Results: Logistic regression analysis showed that the TyG index was significantly associated with NAFLD in subjects with T2DM, the odds ratio (OR) were 3.27 (95% confidence interval [CI], 2.03–5.27; P < 0.001) for NAFLD in the highest TyG quartile after adjustment for known confounders. In stratified analysis, an elevated TyG index were more remarkably associated with NAFLD in younger patients (< 65 years; OR, 2.35; 95% CI, 1.83–3.02; P < 0.001), females (OR, 2.69; 95% CI, 1.67–4.32; P < 0.001), patients with BMI < 25 kg/m2 (OR, 2.80; 95% CI, 2.01–3.91; P < 0.0001), and with lower high-density lipoprotein cholesterol (< 1 mmol/L; OR, 2.76; 95% CI, 1.98–3.83; P < 0.001). Conclusion: The TyG index is significantly associated with NAFLD and shows superior ability for identify NAFLD risk compared with other lipid and glycemic parameters in T2DM. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer in women worldwide. Toxoplasma gondii (T. gondii) has shown anticancer activity in breast cancer mouse models, and exerted beneficial effect on the survival of breast cancer patients, but the mechanism was unclear. Methods: The effect of tachyzoites of T. gondii (RH and ME49 strains) on human breast cancer cells (MCF-7 and MDA-MB-231 cells) proliferation and migration was assessed using cell growth curve and wound healing assays. Dual RNA-seq was performed for T. gondii-infected and non-infected cells to determine the differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein–Protein Interaction Networks analysis (PPI) were performed to explore the related signaling pathway and hub genes. Hub genes were validated using the Kaplan–Meier plotter database, and Pathogen Host Interaction (PHI-base) database. The results were verified by qRT-PCR. Results: The tachyzoites of T. gondii decreased the expression of Ki67 and increased the expression of E-cadherin, resulting in suppressing the proliferation and migration of infected human breast cancer cells. The inhibitory effect of T. gondii on breast cancer cells showed a significant dose–response relationship. Compared with the control group, 2321 genes were transcriptionally regulated in MCF-7 cells infected with T. gondii, while 169 genes were transcriptionally regulated in infected MDA-MB-231 cells. Among these genes, 698 genes in infected MCF-7 cells and 67 genes in infected MDA-MB-231 cells were validated by the publicly available database. GO and KEGG analyses suggested that several pathways were involved in anticancer function of T. gondii, such as ribosome, interleukin-17 signaling, coronavirus disease pathway, and breast cancer pathway. BRCA1, MYC and IL-6 were identified as the top three hub genes in infected-breast cancer cells based on the connectivity of PPI analysis. In addition, after interacting with breast cancer cells, the expression of ROP16 and ROP18 in T. gondii increased, while the expression of crt, TgIST, GRA15, GRA24 and MIC13 decreased. Conclusions: T. gondii transcriptionally regulates several signaling pathways by altering the hub genes such as BRCA1, MYC and IL-6, which can inhibit the breast tumor growth and migration, hinting at a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are the major cause of death among Malaysians. Reduction of salt intake in populations is one of the most cost-effective strategies in the prevention of CVDs. It is very feasible as it requires low cost for implementation and yet could produce a positive impact on health. Thus, salt reduction initiatives have been initiated since 2010, and two series of strategies have been launched. However, there are issues on its delivery and outreach to the target audience. Further, strategies targeting out of home sectors are yet to be emphasized. Our recent findings on the perceptions, barriers and enablers towards salt reduction among various stakeholders including policy-makers, food industries, food operators, consumers and schools showed that eating outside of the home contributed to high salt intake. Foods sold outside the home generally contain a high amount of salt. Thus, this supplementary document is being proposed to strengthen the Salt Reduction Strategy to Prevent and Control Non-communicable Diseases (NCDs) for Malaysia 2021–2025 by focussing on the strategy for the out-of-home sectors. In this supplementary document, the Monitoring, Awareness and Product (M-A-P) strategies being used by the Ministry of Health (MOH) are adopted with a defined outline of the plan of action and indicators to ensure that targets could be achieved. The strategies will involve inter-sectoral and multi-disciplinary approaches, including monitoring of salt intake and educating consumers, strengthening the current enforcement of legislation on salt/sodium labelling and promoting research on reformulation. Other strategies included in this supplementary document included reformulation through proposing maximum salt targets for 14 food categories. It is hoped that this supplementary document could strengthen the current the Salt Reduction Strategy to Prevent and Control NCDs for Malaysia 2021–2025 particularly, for the out-of-home sector, to achieve a reduction in mean salt intake of the population to 6.0 g per day by 2025. [ABSTRACT FROM AUTHOR]

Background: Significant lower genital tract (LGT) dysbiosis and an associated lower rate of clinical pregnancy after in vitro fertilization–frozen embryo transfer (IVF-FET) among polycystic ovary syndrome (PCOS) patients have been previously reported by our group. We aimed to assess whether transvaginal Lactobacillus supplementation can reverse LGT dysbiosis and further improve perinatal outcomes in PCOS patients after IVF-FET. Methods/design: This is a protocol for a multicenter, open-label, randomized controlled trial in China. Women diagnosed with PCOS who are undergoing IVF-FET treatment will be recruited. Allocation to the intervention/control arms at a ratio of 1:1 will be executed by an electronic randomization system. Participants in the intervention arm will receive the live Lactobacillus capsule vaginally for 10 consecutive days before embryo transfer, while those in the control arm will receive standard individualized care. The primary outcomes will be the clinical pregnancy rate, implantation rate, and live birth rate. 16S rRNA sequencing and liquid chromatography–mass spectrometry will be conducted to evaluate the LGT microbiome and systemic metabonomics before and after the intervention. A sample of 260 participants will provide 95% power to detect a 20% increase in the rate of clinical pregnancy (α = 0.025, one-tailed test, 15% dropout rate). A total of 300 participants will be recruited. Discussion: This is the first large and multicenter randomized controlled trial aimed at assessing the efficacy of transvaginal Lactobacillus supplementation on restoring the LGT microbiome and improving perinatal outcomes in PCOS patients after IVF-FET. This pragmatic trial is promising for increasing the rates of clinical pregnancy and live birth in PCOS patients after IVF-FET. Ethics and dissemination: Ethical review approval was obtained from the Medical Research Ethics Committees of the International Peace Maternity and Child Health Hospital of Shanghai Jiao Tong University (15 October 2020, GKLW 2020-29). To maximize dissemination, these findings will be reported in open access publications in journals with high impact, and oral and poster conference presentations will be performed. Trial registration: ChiCTR ChiCTR2000036460. Registered on 13 September 2020, https://www.chictr.org.cn/showproj.html?proj=59549. [ABSTRACT FROM AUTHOR]

Background: The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear.Methods: We detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus.Results: We observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time.Conclusions: miRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) have significant tumor regulatory functions, and CAFs-derived exosomes (CAFs-Exo) released from CAFs play an important role in the progression of oral squamous cell carcinoma (OSCC). However, a lack of comprehensive molecular biological analysis leaves the regulatory mechanisms of CAFs-Exo in OSCC unclear. Methods: We used platelet derived growth factor-BB (PDGF-BB) to induce the transformation of human oral mucosa fibroblast (hOMF) into CAFs, and extracted exosomes from the supernatant of CAFs and hOMF. We validated the effect of CAFs-Exo on tumor progression by exosomes co-culture with Cal-27 and tumor-forming in nude mice. The cellular and exosomal transcriptomes were sequenced, and immune regulatory genes were screened and validated using mRNA-miRNA interaction network analysis in combination with publicly available databases. Results: The results showed that CAFs-Exo had a stronger ability to promote OSCC proliferation and was associated with immunosuppression. We discovered that the presence of immune-related genes in CAFs-Exo may regulate the expression of PIGR, CD81, UACA, and PTTG1IP in Cal-27 by analyzing CAFs-Exo sequencing data and publicly available TCGA data. This may account for the ability of CAFs-Exo to exert immunomodulation and promote OSCC proliferation. Conclusions: CAFs-Exo was found to be involved in tumor immune regulation through hsa-miR-139-5p, ACTR2 and EIF6, while PIGR, CD81, UACA and PTTG1IP may be potentially effective targets for the treatment of OSCC in the future. [ABSTRACT FROM AUTHOR]

Background: High salt intake is a major cause of hypertension and cardiovascular diseases. The out-of-home sectors have been identified as one of the contributors of high salt intake in the population. The National Salt Reduction Policy of Malaysia was initiated in 2015; however, out-of-home sectors are yet to be emphasized and perception by policy-makers and the food industries towards salt reduction are yet unknown. This study aimed to determine the perceptions, barriers and enablers towards salt reduction in the out-of-home sector in Malaysia, as well as among policy-makers and the food industries. Methods: This is a qualitative study via semi-structured in-depth interviews (IDI) and focus group discussions (FGD) involving several stakeholders consisting of policy-makers from five ministries, five nongovernment organizations (NGOs) and food science/food technology researchers from five regions (West, North, East, and South Peninsular and East Malaysia/Borneo), as well as the food industries. The IDI and FGD sessions were recorded, transcribed verbatim and analysed thematically using Nvivo software version 12. Results: All participants agreed that salt intake in Malaysia is high and leads to hypertension and cardiovascular diseases. Lack of awareness, poor eating culture and behaviour and frequent eating out were among the causes of high salt intake. Awareness campaigns and education, sodium content labelling and product reformulation were strategies that have been implemented by the government; whilst for the food industries, some of them have tried to reduce salt and labelled the sodium content on their food products. However, there were several barriers including perceived poor consumer acceptance, lack of knowledge and resources, and challenges in reformulation, as well as unavailability of guidelines and salt targets. Hence, several enablers have been suggested, which include prioritizing the salt reduction strategy, creating more awareness, collaboration and engagement, research and technology particularly for reformulation and shelf-life stability, incentives and salt tax. Conclusions: Salt reduction efforts of the out-of-home sector in Malaysia could be achieved through several measures or enablers that can overcome the barriers currently faced by stakeholders, especially policy-makers, food industries and the consumers themselves. This study will benefit the policy-makers to improve the salt reduction policy of out-of-home sectors and highlight the concerns among the food industries on the policy. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T (CAR-T) cells are genetically modified T cells with redirected specificity and potent T-cell-mediated cytotoxicity toward malignant cells. Despite several CAR-T products being approved and commercialized in the USA, Europe, and China, CAR-T products still require additional optimization to ensure reproducible and cost-effective manufacture. Here, we investigated the critical parameters in the CD3+ T-cell isolation process that significantly impacted CAR-T manufacturing's success. Methods: CAR-T cells were prepared from cryopreserved peripheral blood mononuclear cells (PBMC). The thawed PBMC was rested overnight before the CD3+ T cell isolation process using CTS™ Dynabeads™ CD3/CD28. Different isolation media, cell-bead co-incubation time, and cell density were examined in this study. Activated CD3+ T cells were transduced with a gamma retroviral vector carrying the CD19 or BCMA CAR sequence. The CAR-T cells proliferated in a culture medium supplemented with interleukin 2 (IL-2). Results: CD14+ monocytes hindered T-cell isolation when X-VIVO 15 basic medium was used as the selection buffer. The activation of T cells was blocked because monocytes actively engulfed CD3/28 beads. In contrast, when DPBS was the selection medium, the T-cell isolation and activation were no longer blocked, even in patients whose PBMC contained abnormally high CD14+ monocytes and a low level of CD3+ T cells. Conclusions: In this study, we discovered that selecting CD3+ T-cell isolation media is critical for improving T-cell activation, transduction, and CAR-T proliferation. Using DPBS as a CD3+ T cell isolation buffer significantly improved the success rate and shortened the duration of CAR-T production. The optimized process has been successfully applied in our ongoing clinical trials. Trial registration NCT03798509: Human CD19 Targeted T Cells Injection Therapy for Relapsed and Refractory CD19-positive Leukemia. Date of registration: January 10, 2019. NCT03720457: Human CD19 Targeted T Cells Injection (CD19 CAR-T) Therapy for Relapsed and Refractory CD19-positive Lymphoma. Date of registration: October 25, 2018. NCT04003168: Human BCMA Targeted T Cells Injection Therapy for BCMA-positive Relapsed/Refractory Multiple Myeloma. Date of registration: July 1, 2019 [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety are common among pregnant women. Internet-delivered psychological therapies such as cognitive behavioral therapy (iCBT) have been developed to increase accessibility and address common help-seeking barriers, especially during pandemic period. The objective of this trial is to evaluate the short-term and long-term effects of iCBT on reducing depressive symptoms among pregnant women during the COVID-19 pandemic with the overall goal of preventing depression recurrence in the first 12 months postpartum.Methods: A multi-site randomized controlled trial will be conducted where 300 pregnant women early in their third trimester will be screened for depression symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during a routine obstetrical visit. Eligible and consenting women with a score greater than 9 will be randomly allocated (1:1) to either intervention group or control group. ICBT involving the completion of 7 weekly online modules will be delivered via a well-designed perinatal mental healthcare app. The primary objective is to evaluate the effect of iCBT on reducing depression symptoms among pregnant Chinese women starting from their third trimester. The secondary objectives are to examine the effect of iCBT on anxiety, sleep quality, social support, parenting stress, co-parenting relationship, and infant development.Discussion: This multi-center randomized controlled trial has been planned in accordance with best practices in behavioral trial design. The internet-based intervention addressed the needs of pregnant women during a major pandemic where face-to-face therapy is not preferable. The trial has a relatively large sample size with sufficient power to evaluate the efficacy of iCBT intervention for the primary and secondary outcomes. One year follow-up evaluation in the study is designed to determine the longer-term effect of the intervention on both maternal and infant outcomes. Although a limitation is the assessment of depression and anxiety using self-report measures, these easily incorporated and maternal-preferred assessments allow for real-life scalability if the intervention is proven to be effective.Ethics and Dissemination: Ethics was approved by the institutional review board of International Peace Maternity and Child Health Hospital (GKLW2020-25). Dissemination of results will be published in peer-reviewed academic journals and presented at scientific conferences.Trial Status: The first patient was enrolled on 19 August 2020. To date, 203 participants have met eligibility requirements and been randomized to either the intervention group or control group. Data collection aims to be complete in September 2022. Date and version identifier: 2020715-version1.0.Trial Registration: ChiCTR2000033433. Registered 31 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=54482 . [ABSTRACT FROM AUTHOR]

Background: Fertility awareness and menses prediction are important for improving fecundability and health management. Previous studies have used physiological parameters, such as basal body temperature (BBT) and heart rate (HR), to predict the fertile window and menses. However, their accuracy is far from satisfactory. Additionally, few researchers have examined irregular menstruators. Thus, we aimed to develop fertile window and menstruation prediction algorithms for both regular and irregular menstruators. Methods: This was a prospective observational cohort study conducted at the International Peace Maternity and Child Health Hospital in Shanghai, China. Participants were recruited from August 2020 to November 2020 and followed up for at least four menstrual cycles. Participants used an ear thermometer to assess BBT and wore the Huawei Band 5 to record HR. Ovarian ultrasound and serum hormone levels were used to determine the ovulation day. Menstruation was self-reported by women. We used linear mixed models to assess changes in physiological parameters and developed probability function estimation models to predict the fertile window and menses with machine learning. Results: We included data from 305 and 77 qualified cycles with confirmed ovulations from 89 regular menstruators and 25 irregular menstruators, respectively. For regular menstruators, BBT and HR were significantly higher during fertile phase than follicular phase and peaked in the luteal phase (all P < 0.001). The physiological parameters of irregular menstruators followed a similar trend. Based on BBT and HR, we developed algorithms that predicted the fertile window with an accuracy of 87.46%, sensitivity of 69.30%, specificity of 92.00%, and AUC of 0.8993 and menses with an accuracy of 89.60%, sensitivity of 70.70%, and specificity of 94.30%, and AUC of 0.7849 among regular menstruators. For irregular menstruators, the accuracy, sensitivity, specificity and AUC were 72.51%, 21.00%, 82.90%, and 0.5808 respectively, for fertile window prediction and 75.90%, 36.30%, 84.40%, and 0.6759 for menses prediction. Conclusions: By combining BBT and HR recorded by the Huawei Band 5, our algorithms achieved relatively ideal performance for predicting the fertile window and menses among regular menstruators. For irregular menstruators, the algorithms showed potential feasibility but still need further investigation. Trial registration: ChiCTR2000036556. Registered 24 August 2020. [ABSTRACT FROM AUTHOR]

Background: Overweight and obesity in children and adults is a major public health concern. Emerging evidence suggests dietary sodium intake may be associated with obesity. This systematic review and meta-analysis will aim to (i) assess the relation between dietary sodium intake and measures of adiposity in children and adults and (ii) examine the relation between sodium intake and sugar-sweetened beverage (SSB) consumption, which is a known risk factor for obesity. Methods/design: An electronic search will be conducted using Medline Complete, CINAHL, Scopus, Embase and Cochrane central register of controlled trials (CENTRAL). The search strategy will identify published peer-reviewed articles that report on dietary sodium and either a marker of adiposity or SSB consumption. Only human studies (ages >1 year) in English will be included, and no limits will be placed on publication date. No restrictions will be placed on the method of sodium intake assessment. Cross-sectional, prospective studies, and randomised controlled trials with a duration of ≥3 months will be included. Studies with participants with renal disease, cancer, type 1 diabetes or heart failure or who are pregnant will be excluded. To assess the quality of studies, the Cochrane's Collaboration tool for assessing risk of bias in randomised trials will be used for randomised controlled trials (RCTs), and the modified Newcastle-Ottawa Scale will be used for cross-sectional and prospective studies. Meta-analysis will be used to assess the relation of sodium intake with two primary outcomes: (i) BMI and body weight in adults and BMI z-score in children and (ii) weight category (i.e. healthy weight vs. overweight/obese). For any outcomes in which meta-analysis is not possible, we will present data as a systematic review. Findings will be grouped and reported separately for children and adolescents (ages 1-17 years) and adults (ages >18 years). Discussion: This review and meta-analysis will provide insight into the relation between dietary sodium intake and overweight and obesity. This information can be used to inform public health policies which target population sodium consumption. Systematic review registration: Prospero CRD42015016440 [ABSTRACT FROM AUTHOR]

Background: Sodium intake in China is extremely high and eating in restaurants is increasingly popular. Little research has explored the sodium level of restaurant dishes. The present study aims to assess the content and sources of sodium in Chinese restaurants.Methods: Cross-sectional data were obtained from the baseline survey of the Restaurant-based Intervention Study (RIS) in 2019. A total of 8131 best-selling restaurant dishes with detailed recipes from 192 restaurants in China were included. Sodium content per 100 g and per serving were calculated according to the Chinese Food Composition Table. The proportion of restaurant dishes exceeding the daily sodium reference intake level in a single serving and the major sources of sodium were determined.Results: Median sodium content in restaurant dishes were 487.3 mg per 100 g, 3.4 mg per kcal, and 2543.7 mg per serving. For a single serving, 74.9% of the dishes exceeded the Chinese adults' daily adequate intake for sodium (AI, 1500 mg per day), and 62.6% of dishes exceeded the proposed intake for preventing non-communicable chronic diseases (PI, 2000 mg per day). Cooking salt was the leading source of sodium in Chinese restaurant dishes (45.8%), followed by monosodium glutamate (17.5%), food ingredients (17.1%), soy sauce (9.4%), and other condiments/seasonings (10.2%). More types of salted condiments/seasonings use were related to higher sodium level.Conclusions: The sodium levels in Chinese restaurant dishes are extremely high and variable. In addition to cooking salt, other salted condiments/seasonings also contribute a large proportion of sodium. Coordinated sodium reduction initiatives targeting the main sources of sodium in restaurant dishes are urgently needed. [ABSTRACT FROM AUTHOR]

Background: In Mozambique, HIV infection disproportionately affects young adults, particularly women. Despite awareness and knowledge of HIV transmission, many university students have not received HIV testing and continue to engage in high-risk sexual behaviors, including inconsistent condom use. Further understanding of patterns of engagement with HIV prevention and testing is key to reducing HIV transmission in this at-risk population.Methods: This study used a sequential mixed methods approach to examine patterns of engagement and perceptions of HIV prevention and testing services among higher education students in Mozambique. Survey data were collected from a representative sample of 501 students from Universidade Eduardo Mondlane (UEM) in Maputo, Mozambique to assess the primary outcomes of 1) HIV testing within the last 12 months; and 2) condom use during last sexual encounter. We employed univariate and multivariate regression models. The survey was followed by qualitative interviews with 70 survey participants which were analyzed using an inductive, content-focused analysis to further explain and contextualize survey findings.Results: Over 85% of students reported to be sexually active, among these 74% reported condom use during their last sexual encounter, and 64.2% reported an HIV test within the past 12 months. Females were more likely to have had HIV testing in the past 12 months in comparison to their male peers (aOR 1.82, 95% CI 1.11, 2.99), but were half as likely to have used a condom with their last sexual encounter (aOR 0.52, 95% CI 0.33, 0.83), when controlling for other factors. Qualitative data suggests that these discrepancies may be explained by differential perceptions in risk and trust/mistrust, with women being more concerned about infidelity by their male partner(s) and assuming more responsibility for knowing their own serostatus. Women were also subject to negative stereotypes for possessing condoms in comparison to men, which could explain lower propensity for use.Conclusion: Given gendered differences in uptake of condom use and HIV testing, and perceived HIV risk, interventions tailored specifically to male and female students may impact engagement with HIV prevention and testing and empower informed choices about sexual behaviors. [ABSTRACT FROM AUTHOR]

Background: Sodium is an essential mineral needed by the human body that must be obtained from food. An excess intake, however, can lead to many diseases. As food is the main source of sodium, this study aims to provide information on high sodium food consumption patterns in the Malaysian adult population.Methods: The Malaysian Community Salt Study (MyCoSS) was a nationwide cross-sectional study, conducted between October 2017 and March 2018. A multistage complex sample was applied to select a nationally representative sample of respondents aged 18 years and above. Face to face interview by a validated Food Frequency Questionnaire (FFQ) comprising 104 food items was used to gain information on high sodium food consumption patterns.Results: A total of 1047 respondents were involved in this study, with 1032 (98.6%) answering the FFQ. From the number, 54.1% exceed the recommendation of sodium intake <2000mg/day by FFQ assessment. The results also demonstrated that fried vegetables (86.4%) were the most common high sodium food consumed, followed by bread (85.9%) and omelet (80.3%). In urban areas, bread was the most common while fried vegetables took the lead in rural areas. By sex, bread was most commonly eaten by males and fried vegetables by females. The results also found that kolok mee/kampua mee contributed the highest sodium, 256.5mg/day in 9.0% adult population, followed by soy sauce 248.1mg/day in 33.2% adult population, and curry noodles 164.2mg/day in 18.5% adult population.Conclusion: Fried vegetables, bread, and soy sauce were the main source of sodium consumption among adult. Reducing the amount of sodium added to these foods should be the top priority to reduce population sodium intake and thereby prevent sodium-related diseases in Malaysia. [ABSTRACT FROM AUTHOR]

Background: Hypertension is one of the most common risk factors for cardiovascular disease and leading cause of mortality globally. The aims of this study were to assess the prevalence of hypertension and its associated risk factors among Malaysian population using data from the Malaysian Community Salt Study (MyCoSS).Methods: This study was a cross-sectional study using multi-stage stratified sampling method. Data collection was carried out via face-to-face interview at the respondent's home from October 2017 until March 2018. A total of 1047 respondents aged 18 years and above completed the questionnaires and blood pressure measurement. A person who reported diagnosis of hypertension by a physician and had systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on three readings was categorised as hypertensive. Risk factors of hypertension were analysed using multiple logistic regression.Results: The prevalence of hypertension in the present study was 49.39% (95% CI 44.27-54.51). There was no statistically significant difference in gender. Age, household income, BMI, and diabetes were significantly associated with hypertension. Hypertension found had inverse association with the level of education. Age was the strongest predictor of hypertension (35-44 years old; OR=2.39, 95% CI=1.39-4.09, 45-54 years old; OR=5.50, 95% CI=3.23-9.38, 55-64 years old OR=13.56, 95% CI=7.77-23.64 and 65 years old and above; OR=25.28, 95% CI=13.33-48.66). Those who had higher BMI more likely to be hypertensive as compared to respondents with normal weight (overweight, OR=1.84; 95% CI=1.18-2.86; obese, OR=4.29% CI=2.56-7.29).Conclusion: The findings showed that hypertension is prevalent among adults in Malaysia. Those with older age, higher BMI, and diabetes are more likely to have hypertension. Efforts regarding lifestyle modification and education could be important in hypertension management and prevention. [ABSTRACT FROM AUTHOR]

Background: High blood pressure or hypertension has become one of the main health problems, worldwide. A number of studies have proven that an increased intake of salt was related to an increased prevalence of cardiovascular diseases. Of late, its relationship with high salt intake has received a lot of attention. Studies in Malaysia have shown both rising hypertension over time as well as high salt consumption. Actions to reduce salt intake are essential to reduce hypertension and its disease burden. As such, we carried out a study to determine associations between knowledge, attitude and behaviour towards salt intake and hypertension among the Malaysian population.Methods: Data obtained from the Malaysian Community Salt Survey (MyCoSS) was used partially for this study. The survey used a cross-sectional two-stage sampling design to select a nationally representative sample of Malaysian adults aged 18 years and above living in non-institutional living quarters (LQ). Face-to-face interviews were done by trained research assistants (RA) to obtain information on sociodemography, medical report, as well as knowledge, attitude and behaviour of the respondents towards salt intake and blood pressure.Results: Majority of the respondents have been diagnosed with hypertension (61.4%) as well as knowledge of the effects of high salt intake on blood pressure (58.8%). More than half of the respondents (53.3%) said they controlled their salt intake on a regular basis. Those who knew that a high salt diet could contribute to a serious health problem (OR=0.23) as well as those who controlled their salt intake (OR=0.44) were significantly less likely to have hypertension.Conclusion: Awareness of the effects of sodium on human health, as well as the behaviour of controlling salt intake, is essential towards lowering the prevalence of hypertension among Malaysians. [ABSTRACT FROM AUTHOR]

Background: High sodium intake was an established risk factor for stroke and cardiovascular diseases. The objective of this study was to investigate factors associated with high sodium intake based on 24-h urinary sodium excretion from the MyCoSS study.Methods: The cross-sectional survey was conducted among adults aged 18 years and above in Malaysia. A multi-stage stratified sampling was used to represent nationally. Twenty-four-hour urine was collected from a total of 900 respondents. Indirect ion-selective electrode (ISE) method was used to measure sodium intake. Descriptive and logistic regression analysis was applied to determine factors associated with high sodium intake based on 24-h urinary sodium excretion.Results: A total of 798 respondents (76% response rate) completed the 24-h urine collection process. Logistic regression revealed that high sodium intake associated with obese [aOR 2.611 (95% CI 1.519, 4.488)], male [aOR 2.436 (95% CI 1.473, 4.030)], having a waist circumference of > 90cm for adult males [aOR 2.260 ( 95% CI 1.020, 5.009) and >80cm for adult females [aOR 1.210 (95% CI 0.556, 2.631)], being a young adult [aOR 1.977 (95% CI 1.094, 3.574)], and living in urban areas [aOR 1.701 (95% CI 1.094, 2.645)].Conclusion: Adults who are obese, have a large waist circumference, of male gender, living in urban areas, and belonging to the young adult age group were found to have higher sodium intake than other demographic groups. Hence, reduction of salt consumption among these high-risk groups should be emphasised to reduce the risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Background: Excessive intake of sodium is a major public health concern. Information on knowledge, perception, and practice (KPP) related to sodium intake in Malaysia is important for the development of an effective salt reduction strategy. This study aimed to investigate the KPP related to sodium intake among Malaysian adults and to determine associations between KPP and dietary sodium intake.Methods: Data were obtained from Malaysian Community Salt Survey (MyCoSS) which is a nationally representative survey with proportionate stratified cluster sampling design. A pre-tested face-to-face questionnaire was used to collect information on socio-demographic background, and questions from the World Health Organization/Pan American Health Organization were adapted to assess the KPP related to sodium intake. Dietary sodium intake was determined using single 24-h urinary sodium excretion. Respondents were categorized into two categories: normal dietary sodium intake (< 2000 mg) and excessive dietary sodium intake (≥ 2000 mg). Out of 1440 respondents that were selected to participate, 1047 respondents completed the questionnaire and 798 of them provided valid urine samples. Factors associated with excessive dietary sodium intake were analyzed using complex sample logistic regression analysis.Results: Majority of the respondents knew that excessive sodium intake could cause health problems (86.2%) and more than half of them (61.8%) perceived that they consume just the right amount of sodium. Overall, complex sample logistic regression analysis revealed that excessive dietary sodium intake was not significantly associated with KPP related to sodium intake among respondents (P > 0.05).Conclusion: The absence of significant associations between KPP and excessive dietary sodium intake suggests that salt reduction strategies should focus on sodium reduction education includes measuring actual dietary sodium intake and educating the public about the source of sodium. In addition, the relationship between the authority and food industry in food reformulation needs to be strengthened for effective dietary sodium reduction in Malaysia. [ABSTRACT FROM AUTHOR]

Background: Kindlin Family Members have been reported to be aberrantly expressed in various human cancer types and involved in tumorigenesis, tumor progression, and chemoresistance. However, their roles in non-small cell lung cancer (NSCLC) remain poorly elucidated. Methods: We analyzed the prognostic value and immune infiltration of Kindlins in NSCLC through Oncomine, GEPIA, UALCAN, CCLE, Kaplan‑Meier plotter, cBioPortal, TIMER, GeneMANIA, STRING, and DAVID database. Additionally, the mRNA expression levels of Kindlins were verified in 30 paired NSCLC tissues and NSCLC cell lines by real-time PCR. Results: The expression level of FERMT1 was remarkably increased in NSCLC tissues and NSCLC cell lines, while FERMT2 and FERMT3 were reduced. Kindlins expressions were associated with individual cancer stages and nodal metastasis. We also found that higher expression level of FERMT1 was obviously correlated with worse overall survival (OS) in patients with NSCLC, while higher FERMT2 was strongly associated with better overall survival (OS) and first progression (FP). Additionally, the expression of FERMT2 and FERMT3 were obviously correlated with the immune infiltration of diverse immune cells. Functional enrichment analysis has shown that Kindlins may be significantly correlated with intracellular signal transduction, ATP binding and the PI3K-Akt signaling pathway in NSCLC. Conclusions: The research provides a new perspective on the distinct roles of Kindlins in NSCLC and likely has important implications for future novel biomarkers and therapeutic targets in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Previous studies have focused on pregnancy outcomes after frozen embryo transfer (FET) performed using different endometrial preparation protocols. Few studies have evaluated the effect of endometrial preparation on pregnancy-related complications. This study was designed to explore the association between different endometrial preparation protocols and adverse obstetric and perinatal complications after FET.Methods: We retrospectively included all FET cycles (n = 12,950) in our hospital between 2010 and 2017, and categorized them into three groups, natural cycles (NC), hormone replacement therapy (HRT) and ovarian stimulation (OS) protocols. Pregnancy-related complications and subsequent neonatal outcomes were compared among groups.Results: Among all 12,950 FET cycles, the live birth rate was slightly lower for HRT cycles than for NC (HRT vs. NC: 28.15% vs. 31.16%, p < 0.001). The pregnancy loss rate was significantly higher in OS or HRT cycles than in NC (HRT vs. NC: 17.14% vs. 10.89%, p < 0.001; OS vs. NC: 16.44% vs. 10.89%, p = 0.001). Among 3864 women with live birth, preparing the endometrium using OS or HRT protocols increased the risk of preeclampsia, and intrahepatic cholestasis of pregnancy (ICP) in both singleton and multiple deliveries. Additionally, OS and HRT protocols increased the risk of low birth weight (LBW) and small for gestational age (SGA) in both singletons and multiples after FET.Conclusion: Compared with HRT or OS protocols, preparing the endometrium with NC was associated with the decreased risk of pregnancy-related complications, as well as the decreased risk of LBW and SGA after FET. [ABSTRACT FROM AUTHOR]

Background: Alfalfa is a high-quality forage cultivated widely in northern China. Recently, the failure of alfalfa plants to survive the winter has caused substantial economic losses. Water management has attracted considerable attention as a method for the potential improvement of winter survival. The aim of this study was to determine whether and how changes in the water regime affect the freezing tolerance of alfalfa. Results: The alfalfa variety WL353LH was cultivated under water regimes of 80 and 25% of water-holding capacity, and all the plants were subjected to low temperatures at 4/0 °C (light/dark) and then − 2/− 6 °C (light/dark). The semi-lethal temperatures were lower for water-stressed than well-watered alfalfa. The pool sizes of total soluble sugars, total amino acids, and proline changed substantially under water-deficit and low-temperature conditions. Metabolomics analyses revealed 72 subclasses of differential metabolites, among which lipid and lipid-like molecules (e.g., fatty acids, unsaturated fatty acids, and glycerophospholipids) and amino acids, peptides, and analogues (e.g., proline betaine) were upregulated under water-deficit conditions. Some carbohydrates (e.g., D-maltose and raffinose) and flavonoids were also upregulated at low temperatures. Finally, Kyoto Encyclopedia of Genes and Genomes analyses revealed 18 significantly enriched pathways involved in the biosynthesis and metabolism of carbohydrates, unsaturated fatty acids, amino acids, and glycerophospholipids. Conclusions: Water deficit significantly enhanced the alfalfa' freezing tolerance, and this was correlated with increased soluble sugar, amino acid, and lipid and lipid-like molecule contents. These substances are involved in osmotic regulation, cryoprotection, and the synthesis, fluidity, and stability of the cellular membrane. Our study provides a reference for improving alfalfa' winter survival through water management. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL)-37 has emerged as a novel anti-inflammatory cytokine that play an immunosuppressive role in regulating inflammatory response. This study aimed to measure IL-37 levels in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with systemic juvenile idiopathic arthritis (sJIA), and to establish the correlation between IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines.Methods: The mRNA levels of IL-37 in PBMCs and plasma IL-37 concentrations in 46 sJIA patients and 30 age- and sex-matched healthy controls were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The correlations between plasma IL-37 levels and disease activity, laboratory parameters and inflammatory cytokines in sJIA were analyzed by Spearman correlation test. PBMCs from the sJIA patients were stimulated with recombinant human IL-37 (rhIL-37) protein, expressions of IL-1β, IL-6, TNF-α and IL-17 were detected by RT-PCR and ELISA.Results: Plasma levels of IL-37 and relative IL-37 mRNA expression were significantly elevated in sJIA patients, especially in active sJIA patients, when compared with the healthy controls (P < 0.001). Furthermore, patients with active disease showed higher IL-37 mRNAs and plasma protein levels than those with inactive disease as well as healthy controls. Plasma IL-37 levels were correlated with disease activity and inflammatory cytokines (IL-6, TNF-α, IL-17 and GM-CSF) in sJIA patients. The productions of inflammatory cytokines such as IL-6, TNF-α, IL-17 in PBMCs from sJIA patients were obviously decreased after recombinant IL-37 stimulation, whereas the production of IL-1β was not changed.Conclusions: Our results demonstrate that levels of IL-37 were higher in sJIA patients, which were correlated with disease activity and sJIA related inflammatory cytokines. In addition, rhIL-37 down-regulates the expressions of inflammatory cytokines form PBMCs in sJIA patients, suggesting that IL-37 may have the potential role as a natural inhibitor for the pathogenesis and therapy of sJIA. [ABSTRACT FROM AUTHOR]

Background: Salinity is an important abiotic stress that influences the physiological and metabolic activity, reproduction, growth and development of marine fish. It has been suggested that half-smooth tongue sole (Cynoglossus semilaevis), a euryhaline fish species, uses a large amount of energy to maintain osmotic pressure balance when exposed to fluctuations in salinity. To delineate the molecular response of C. semilaevis to different levels of salinity, we performed RNA-seq analysis of the liver to identify the genes and molecular and biological processes involved in responding to salinity changes. Results: The present study yielded 330.4 million clean reads, of which 83.9% were successfully mapped to the reference genome of C. semilaevis. One hundred twenty-eight differentially expressed genes (DEGs), including 43 up-regulated genes and 85 down-regulated genes, were identified. These DEGs were highly represented in metabolic pathways, steroid biosynthesis, terpenoid backbone biosynthesis, butanoate metabolism, glycerolipid metabolism and the 2-oxocarboxylic acid metabolism pathway. In addition, genes involved in metabolism, osmoregulation and ion transport, signal transduction, immune response and stress response, and cytoskeleton remodeling were affected during acclimation to low salinity. Genes acat2, fdps, hmgcr, hmgcs1, mvk, pmvk, ebp, lss, dhcr7, and dhcr24 were up-regulated and abat, ddc, acy1 were down-regulated in metabolic pathways. Genes aqp10 and slc6a6 were down-regulated in osmoregulation and ion transport. Genes abat, fdps, hmgcs1, mvk, pmvk and dhcr7 were first reported to be associated with salinity adaptation in teleosts. Conclusions: Our results revealed that metabolic pathways, especially lipid metabolism were important for salinity adaptation. The candidate genes identified from this study provide a basis for further studies to investigate the molecular mechanism of salinity adaptation and transcriptional plasticity in marine fish. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS), whose etiology remains uncertain, is a highly heterogenous and genetically complex endocrine disorder. The aim of this study was to identify differentially expressed genes (DEGs) in granulosa cells (GCs) from PCOS patients and make epigenetic insights into the pathogenesis of PCOS. Results: Included in this study were 110 women with PCOS and 119 women with normal ovulatory cycles undergoing in vitro fertilization acting as the control group. RNA-seq identified 92 DEGs unique to PCOS GCs in comparison with the control group. Bioinformatic analysis indicated that synthesis of lipids and steroids was activated in PCOS GCs. 5-Methylcytosine analysis demonstrated that there was an approximate 25% reduction in global DNA methylation of GCs in PCOS women (4.44 ± 0.65%) compared with the controls (6.07 ± 0.72%; P < 0.05). Using MassArray EpiTYPER quantitative DNA methylation analysis, we also found hypomethylation of several gene promoters related to lipid and steroid synthesis, which might result in the aberrant expression of these genes. Conclusions: Our results suggest that hypomethylated genes related to the synthesis of lipid and steroid may dysregulate expression of these genes and promote synthesis of steroid hormones including androgen, which could partially explain mechanisms of hyperandrogenism in PCOS. [ABSTRACT FROM AUTHOR]

Background: Motor imagery (MI) induced EEG patterns are widely used as control signals for brain-computer interfaces (BCIs). Kinetic and kinematic factors have been proved to be able to change EEG patterns during motor execution and motor imagery. However, to our knowledge, there is still no literature reporting an effective online MI-BCI using kinetic factor regulated EEG oscillations. This study proposed a novel MI-BCI paradigm in which users can online output multiple commands by imagining clenching their right hand with different force loads.Methods: Eleven subjects participated in this study. During the experiment, they were asked to imagine clenching their right hands with two different force loads (30% maximum voluntary contraction (MVC) and 10% MVC). Multi-Common spatial patterns (Multi-CSPs) and support vector machines (SVMs) were used to build the classifier for recognizing three commands corresponding to high load MI, low load MI and relaxed status respectively. EMG were monitored to avoid voluntary muscle activities during the BCI operation. The event-related spectral perturbation (ERSP) method was used to analyse EEG variation during multiple load MI tasks.Results: All subjects were able to drive BCI systems using motor imagery of different force loads in online experiments. We achieved an average online accuracy of 70.9%, with the highest accuracy of 83.3%, which was much higher than the chance level (33%). The event-related desynchronization (ERD) phenomenon during high load tasks was significantly higher than it was during low load tasks both in terms of intensity at electrode positions C3 (p < 0.05) and spatial distribution.Conclusions: This paper demonstrated the feasibility of the proposed MI-BCI paradigm based on multi-force loads on the same limb through online studies. This paradigm could not only enlarge the command set of MI-BCI, but also provide a promising approach to rehabilitate patients with motor disabilities. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that turning is associated with more instability than straight walking and instability increases with turning angles. However, the precise relationship of changes in stability with the curvature and step length of turning is not clear. The traditional center of mass (COM)-center of pressure (COP) inclination angle requires the use of force plates. A COM-foot contact point (FCP) inclination angle derived from kinematic data is proposed in this study as a measure of the stability of turning.Methods: In order to generate different degrees of stability, we designed an experiment of walking with different curvatures and step lengths. Simultaneously, a novel method was proposed to calculate the COM-FCP inclination angles of different walking trajectories with different step lengths for 10 healthy subjects. The COM-FCP inclination angle, the COM acceleration, the step width and the COM-ankle inclination angles were statistically analyzed.Results: The statistical results showed that the mediolateral (ML) COM-FCP inclination angles increased significantly as the curvature of the walking trajectories or the step length in circular walking increased. Changes in the ML COM acceleration, the step width and the ML COM-ankle inclination angle verified the feasibility and reliability of the proposed method. Additionally, the ML COM-FCP inclination angle was more sensitive to the ML stability than the ML COM-ankle inclination angle.Conclusions: The work suggests that it is more difficult to keep balance when walking in a circular trajectory with a larger curvature or in a larger step length. Essentially, turning with a larger angle in one step leads to a lower ML stability. A novel COM-FCP inclination angle was validated to indicate ML stability. This method can be applied to complicated walking tasks, where the force plate is not applicable, and it accounts for the variability of the base of support (BOS) compared to the COM-ankle inclination angle. [ABSTRACT FROM AUTHOR]

Background: The combination of dendritic cells (DCs) and cytokine-induced killer cells (CIKs) can induce the anti-tumor immune response and radiotherapy may promote the activity. We aimed to explore the feasibility of DCs/CIKs combined with thoracic radiotherapy (TRT) for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC).Method: In this study, patients with unresectable stage III/IV NSCLC and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 and previously receiving two or more cycles of platinum-based doublet chemotherapy without disease progression received TRT plus DCs/CIKs or TRT alone until disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS). In treatment group, patients received four-cycle autologous DCs/CIKs infusion starting from the 6(th) fraction of irradiation.Results: From Jan 13, 2012 to June 30, 2014, 82 patients were enrolled, with 21 patients in treatment group and 61 in control group. The mPFS in treatment group was longer than that in control group (330 days vs 233 days, hazard ratio 0.51, 95 % CI 0.27-1.0, P < 0.05), and the objective response rate (ORR) of treatment group (47.6 %) was significantly higher that of control group (24.6 %, P < 0.05). There was no significant difference in disease control rate (DCR) and median overall survival (mOS) between two groups (P > 0.05). The side effects in treatment group were mild and there was no treatment-related deaths.Conclusion: The combination of DCs/CIKs with TRT could be a feasible regimen in treating locally advanced or metastatic NSCLC patients. Further investigation of the regimen is warranted. [ABSTRACT FROM AUTHOR]

Background: A number of studies have been done on movement imagination of motor sequences with a single limb. However, brain oscillatory patterns induced by movement imagination of motor sequences involving multiple limbs have not been reported in recent years. The goal of the present study was to verify the feasibility of application of motor sequences involving multiple limbs to brain-computer interface (BCI) systems based on motor imagery (MI). The changes of EEG patterns and the inter-influence between movements associated with the imagination of motor sequences were also investigated.Methods: The experiment, where 12 healthy subjects participated, involved one motor sequence with a single limb and three kinds of motor sequences with two or three limbs. The activity involved mental simulation, imagining playing drums with two conditions (60 and 30 beats per minute for the first and second conditions, respectively).Results: Movement imagination of different limbs in the sequence contributed to time-variant event-related desynchronization (ERD) patterns within both mu and beta rhythms, which was more obvious for the second condition compared with the first condition. The ERD values of left/right hand imagery with prior hand imagery were significantly larger than those with prior foot imagery, while the phase locking values (PLVs) between central electrodes and the mesial frontocentral electrode of non-initial movement were significantly larger than those of the initial movement during imagination of motor sequences for both conditions. Classification results showed that the power spectral density (PSD) based method outperformed the multi-class common spatial patterns (multi-CSP) based method: The highest accuracies were 82.86 % and 91.43 %, and the mean values were 65 % and 74.14 % for the first and second conditions, respectively.Conclusions: This work implies that motor sequences involving multiple limbs can be utilized to build a multimodal classification paradigm in MI-based BCI systems, and that prior movement imagination can result in the changes of neural activities in motor areas during subsequent movement imagination in the process of limb switching. [ABSTRACT FROM AUTHOR]

Background: Panax notoginseng (Burk.) F.H. Chen is one ofthe most highly valued medicinal plants in the world. The major bioactive molecules are triterpene saponins, which are also known as ginsenosides. However, its large genome size has hindered the assembly of a draft genome by whole genome sequencing. Hence, genomic and transcriptomic details about P. notoginseng, especially its biosynthetic pathways and gene expression in different parts ofthe plant, have remained largely unknown until now. Results: In this study, RNA sequencing of three different P. notoginseng tissues was performed using next generation DNA sequencing. After assembling the high quality sequencing reads into 107,340 unigenes, biochemical pathways were predicted and 9,908 unigenes were assigned to 135 KEGG pathways. Among them, 270 unigenes were identified to be involved in triterpene saponin biosynthesis. In addition, 350 and 342 unigenes were predicted to encode cytochrome P450s and glycosyltransferases, respectively, based on the annotation results, some of which encode enzymes responsible for the conversion of the triterpene saponin backbone into different ginsenosides. In particular, one unigene predominately expressed in the root was annotated as CYP716A53v2, which probably participates in the formation of protopanaxatriol from protopanaxadiol in P. notoginseng. The differential expression of this gene was further confirmed by real-time PCR. Conclusions: We have established a global transcriptome dataset for P. notoginseng and provided additional genetic information for further genome-wide research and analyses. Candidate genes involved in ginsenoside biosynthesis, including putative cytochrome P450s and glycosyltransferases were obtained. The transcriptomes in different plant tissues also provide invaluable resources for future study ofthe differences in physiological processes and secondary metabolites in different parts of P. notoginseng. [ABSTRACT FROM AUTHOR]

Background: Panax notoginseng (Burk.) F.H. Chen is one of the most highly valued medicinal plants in the world. The major bioactive molecules are triterpene saponins, which are also known as ginsenosides. However, its large genome size has hindered the assembly of a draft genome by whole genome sequencing. Hence, genomic and transcriptomic details about P. notoginseng, especially its biosynthetic pathways and gene expression in different parts of the plant, have remained largely unknown until now. Results: In this study, RNA sequencing of three different P. notoginseng tissues was performed using next generation DNA sequencing. After assembling the high quality sequencing reads into 107,340 unigenes, biochemical pathways were predicted and 9,908 unigenes were assigned to 135 KEGG pathways. Among them, 270 unigenes were identified to be involved in triterpene saponin biosynthesis. In addition, 350 and 342 unigenes were predicted to encode cytochrome P450s and glycosyltransferases, respectively, based on the annotation results, some of which encode enzymes responsible for the conversion of the triterpene saponin backbone into different ginsenosides. In particular, one unigene predominately expressed in the root was annotated as CYP716A53v2, which probably participates in the formation of protopanaxatriol from protopanaxadiol in P. notoginseng. The differential expression of this gene was further confirmed by real-time PCR. Conclusions: We have established a global transcriptome dataset for P. notoginseng and provided additional genetic information for further genome-wide research and analyses. Candidate genes involved in ginsenoside biosynthesis, including putative cytochrome P450s and glycosyltransferases were obtained. The transcriptomes in different plant tissues also provide invaluable resources for future study of the differences in physiological processes and secondary metabolites in different parts of P. notoginseng. [ABSTRACT FROM AUTHOR]

Background: The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown.Methods: The relationship between SOX9 expression and T, N, M classification was assessed using the χ2 test and Spearman's analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/β-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect β-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines.Results: We found that SOX9 overexpression correlates with the T, N and M stage significantly (p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/β-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of β-catenin and increase the phosphorylation of GSK3β at Ser9. Further, inhibition of β-catenin suppressed the metastasis-promoting effects of SOX9 overexpression.Conclusions: This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

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

Background and Purpose: Turning while walking has a frequent occurrence in daily life. Evaluation of its dynamic stability will facilitate fall prevention and rehabilitation scheme. This knowledge is so limited that we set it as the first aim of this study. Another aim was to investigate spatiotemporal parameters during turning.Methods: Fifteen healthy young adults were instructed to perform straight walking, 45° step turn to the left and 45° spin turn to the right at natural speed. Dynamic stability was measured by margin of stability (MoS) in anterior, posterior, left and right direction at each data point where significant differences were detected using 95% bootstrap confidence band. Common spatiotemporal parameters were computed in each condition subdivided into approach, turn and depart phases.Results: Results showed that minimum anterior MoS appeared at middle of swing while minimum lateral MoS at contralateral heel strike in all conditions. Posterior MoS decreased before middle of turn phase in spin whereas after middle of turn phase in step. Lateral MoS and stride width declined in turn phase of spin while in depart of step. Spin had a long step and stride length. Long swing phases were observed in turns.Conclusions: These data help explain that people are most likely to fall forward at middle of swing and to fall toward the back and the support side at heel strike. Our findings demonstrate that instability mainly exist in turn phase of spin and depart phase of step turn. [ABSTRACT FROM AUTHOR]

Genome-scale CRISPR-Cas9 Knockout Screening was applied to investigate novel targets in imatinib-resistant gastrointestinal stromal tumor (GIST). 20 genes and 2 miRNAs have been selected by total reads of sgRNA and sgRNA diversity, which has been further validated in imatinib-resistant GIST cells by CCK8 and qPCR analysis. Our study has finally revealed 9 genes (DBP, NR3C1, TCF12, TP53, ZNF12, SOCS6, ZFP36, ACYP1, and DRD1) involved in imatinib-resistant GIST-T1 cells. TP53 and SOCS6 may be the most promising candidate genes for imatinib-resistance due to the possible signaling pathway, such as apoptosis pathway and Wnt signaling pathway, JAK-STAT signaling pathway. It is necessary to perform more studies to discover novel targets in imatinib-resistant GIST, including DBP, NR3C1, TCF12, ZNF12, ZFP36, ACYP1 and DRD1. [ABSTRACT FROM AUTHOR]

Background: Few studies have explored the association between a previous caesarean section (CS) and adverse perinatal outcomes in a subsequent pregnancy, especially in women who underwent a non-indicated CS in their first delivery. We designed this study to compare the perinatal outcomes of a subsequent pregnancy in women who underwent spontaneous vaginal delivery (SVD) or CS in their first delivery.Methods: This retrospective cohort study included women who underwent singleton deliveries at the International Peace Maternity and Child Health Hospital from January 2013 to December 2016. Data on the perinatal outcomes of all the women were extracted from the medical records. Multivariate logistic regression was conducted to assessed the association between CS in the first delivery and adverse perinatal outcomes in the subsequent pregnancy.Results: CS delivery in the subsequent pregnancy was more likely for women who underwent CS in their first birth than for women with previous SVD (97.3% versus 13.2%). CS in the first birth was also associated with a significantly increased risk of adverse outcomes in the subsequent pregnancy, especially in women who underwent a non-indicated CS. Adverse perinatal outcomes included pregnancy-induced hypertension [adjusted odds ratio (OR), 95% confidence interval (CI): 2.20, 1.59-3.05], gestational diabetes mellitus (1.82, 1.57-2.11), gestational anaemia (1.27, 1.05-1.55), placenta previa (3.18, 2.15-4.71), placenta accreta (2.75, 1.75-4.31), and polyhydramnios (2.60, 1.57-4.31) in the mother and preterm delivery (1.37, 1.06-1.78), low birth weight (3.78, 2.07-6.90), macrosomia (5.04, 3.95-6.44), and neonatal jaundice (1.72, 1.39-2.14) in the baby.Conclusions: CS in the first delivery markedly increases the risk of repeated CS and maternal-fetal complications in the subsequent pregnancy, especially in women with a non-indicated CS. [ABSTRACT FROM AUTHOR]

Background: Our previous study indicated that emergency contraception, including levonorgestrel and progesterone, could lead to ectopic pregnancy following contraception failure. However, our understanding of the effects of levonorgestrel and progesterone on oviductal physiology is limited. Methods: The receptivity of the fallopian tubal epithelium after levonorgestrel and progesterone treatment was examined through western blots for receptivity markers and JAr-spheroid-fallopian tubal epithelial cell attachment assays. The ciliary beat frequency was analyzed using an inverted bright-field microscope. Furthermore, an in vivo animal model of embryo-tubal transplantation was also studied to determine the effects of levonorgestrel- and progesterone-induced ciliary beat reduction. Results: Our results showed that levonorgestrel and progesterone did not change the levels of fallopian tubal epithelial cell receptive markers, including LIF, STAT3, IGFBP1, ITGB3, MUC1, and ACVR1B, or affect JAr-spheroid implantation. However, levonorgestrel and progesterone reduced the ciliary beat frequency in fallopian tubes in a dose-dependent manner. An in vivo model also showed that levonorgestrel and progesterone could lead to embryo retention in the oviducts. Conclusions: These findings show that levonorgestrel and progesterone can reduce the ciliary beat frequency without altering receptivity, indicating a possible mechanism for progesterone- or levonorgestrel-induced tubal pregnancy. [ABSTRACT FROM AUTHOR]

Background: Despite limited information on neonatal safety, the transfer of frozen-thawed cleavage-stage embryos with blastomere loss is common in women undergoing in vitro fertilization. We aimed to evaluate the pregnancy outcomes and safety of frozen-thawed cleavage-stage embryos with blastomere loss.Methods: This prospective, multicenter, cohort study included all frozen-thawed cleavage-stage embryo transfer (FET) cycles between 2002 and 2012. Pregnancy outcomes and subsequent neonatal outcomes were compared between FET cycles with intact embryos and those with blastomere loss.Results: A total of 12,105 FET cycles were included in the analysis (2259 cycles in the blastomere loss group and 9846 cycles in the intact embryo group). The blastomere loss group showed significantly poorer outcomes with respect to implantation, pregnancy, and live birth rates than the intact embryo group. However, following embryo implantation, the two groups were similar with respect to live birth rates per clinical pregnancy. Among multiple pregnancies (4229 neonates), neonates from the blastomere loss group were at an increased risk of being small for gestational age (aOR = 1.50, 95% CI 1.00-2.25) compared to those from the intact group. A similar trend was observed among singletons (aOR = 1.84, 95% CI 0.99-3.37). No associations were found between blastomere loss and the subsequent occurrence of congenital anomalies or neonatal mortality. However, neonates from the blastomere loss group were at an increased risk of transient tachypnea of the newborn (aOR = 5.21, 95% CI 2.42-11.22).Conclusions: The transfer of embryos with blastomere loss is associated with reduced conception rates. Once the damaged embryos have implanted, pregnancies appear to have the same probability of progressing to live birth but with an increased risk of small for gestational age neonates and transient tachypnea of the newborn.Study Registration: This study was retrospectively registered at Chinese Clinical Trial Registry. Registration number: ChiCTR-OOC-16007753 . Registration date: 13 January 2016. [ABSTRACT FROM AUTHOR]

Background: The existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism. Results: We found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation gene Fyn showed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells. Conclusion: We provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development. [ABSTRACT FROM AUTHOR]