Search

Objective: To investigate the epidemiological characteristics of high-risk human papillomavirus (HR-HPV) infection and the genotype distribution of HR-HPV in different regions of China using self-collected vaginal samples. Study Design and Setting: A total of 20,136 women aged 30–59 years were recruited from 13 provinces in China from September 2018 to July 2020. All participants registered, signed electronic informed consent, and filled in individual information voluntarily using an internet-based cervical cancer screening platform, then received a self-sampling kit. The samples were tested for 14 types of HR-HPV using the SeqHPV and BMRT HPV PCR assays. Results: After excluding 33 samples because of labeling errors or insufficient amounts of HPV DNA in specimens, 20,103 women (99.84%) were ultimately analyzed with a mean age of 44.31 ± 7.70 years. The overall prevalence of HR-HPV infection was 13.86%. The vast majority of HR-HPV (77.18%) were still a single type. Among 13 regions, Inner Mongolia had the highest prevalence (21.55%), while the lowest prevalence was in Jilin (9.51%). The following factors were found to be significantly associated with HR-HPV infection: age, sexual behavior, irregular screening, and economic level. The top five most common HR-HPV subtypes were HPV-52 (3.42%), HPV-58 (2.29%), HPV-16 (2.17%), HPV-39 (1.35%), and HPV-51 (1.30%), while HPV18 (0.86%) was the less prevalent. The prevalence of infection with a single type of HR-HPV was 10.70% and the prevalence of infection with multiple types was 3.16%. The prevalence curve of age-specific HR-HPV was V-shaped from 30 years to 59 years, with a lower prevalence observed in women aged 40–44 years (12.35%) and infection subsequently increasing with age. The proportion of women aged 30–34 years with HPV-16 (17%) was much higher than the proportion in other age groups, and the prevalence of HPV-18 (6%) was highest in women aged 45–49 years. The undeveloped regions (according to the GDP) had the highest prevalence of specific combinations of HR-HPV subtypes, of which HPV-16/HPV-18 infections decreased with increasing GDP. Furthermore, a more number of sexual partners and age of first sexual intercourse

Neighborhood aggregation is a key operation in most of the graph neural network-based embedding solutions. Each type of aggregator typically has its best application domain. The single type of aggregator for aggregation adopted by most existing embedding solutions may inevitably result in information loss. To keep the diversity of information during aggregation, it is mandatory to use the most appropriate different aggregators for specific graphs or subgraphs. However, when and what aggregators to be used remain mostly unsolved. To tackle this problem, we introduce a general contrastive learning framework called Cooker, which supports self-supervised adaptive aggregator learning. Specifically, we design three pretext tasks for self-supervised learning and apply multiple aggregators in our model. By doing so, our algorithm can keep the peculiar features of different aggregators in node embeddings and minimize the information loss. Experiment results on node classification and link prediction tasks show that Cooker outperforms the state of the art baselines in all three compared datasets. A set of ablation experiments also demonstrate that the integration of more types of aggregators generally improves the algorithm’s performance and stability.

Ovarian cancer (OC) is the most common gynecological malignant tumor with the highest mortality rate. However, identification of effective immune therapeutic targets and biomarkers are beset by many challenges. CIBERSORT was used to calculate the abundance of 22 immune cell types in 379 OC samples, and indicated that three immune cell types were associated with poor prognoses. Further analysis revealed that 17 hub genes were associated with these three cell types. We screened differentially expressed immune-related prognostic gene associated with clinicopathological factors, which was CST4. We used clinical specimens to detect the expression of CST4, and determined that CST4 was both highly expressed in OC patients and associated with poor prognoses. Our findings indicated that infiltration of immune cells affected the survival of patients with OC, provided therapeutic targets represented by CST4, deepened our understanding of the immune microenvironment of OC, and enhanced the theoretical basis of immunotherapy.

Metastases from colorectal cancer can occur either through the lymphatic or by hematogenous spread. The most common metastatic sites are the lung and liver. Nasopharyngeal metastasis from colorectal cancer has never been previously reported in the literature on the internet databases we can found. In this paper, we present the case of a 79-year-old male suffering from adenocarcinoma of the rectum with distant metastases to the liver, lung, and nasopharynx. Over the previous 7 years, he had received treatment for rectal cancer including radical surgery (miles surgery), chemotherapy, hepatectomy, and pneumonectomy. After local nasopharyngeal radiotherapy, the patient's quality of life significantly declined and they eventually died of dyspnea caused by airway obstruction due to a nasopharyngeal mass after 7 months of palliative treatment involving pain relief from end-stage disease. Nasopharyngeal metastases from colorectal cancer are extremely rare in the clinic. To the best of our knowledge, this is the first case reporting this occurrence which not only extends the disease database but also warns doctors to pay more attention to these clinical scenarios. Strict monitoring of patients with colorectal cancer after primary treatment could lead to the early diagnosis of metastases and give patients better opportunities for treatment and improved prognosis.

BackgroundIt is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear.Materials and methodsImmunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer.ResultsZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells.ConclusionThe results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

Background.Human Epididymis Protein 4 (HE4) is a novel serum biomarker for diagnosis of epithelial ovarian cancer (EOC) with high specificity and sensitivity compared with CA125, and the increasing researches have been carried out on its roles in promoting carcinogenesis and chemoresistance in EOC in recent years, however, its underlying molecular mechanisms remain poorly understood. The aim of this study was to elucidate the molecular mechanisms of HE4 stimulation and to identify the key genes and pathways mediating carcinogenesis in EOC using microarray and bioinformatics analysis.Methods. We established a stable HE4-silence ES-2 ovarian cancer cell line labeled as “S”, and its active HE4 protein stimulated cells labeled as “S4”. Human whole genome microarray analysis was used to identify deferentially expressed genes (DEGs) from triplicate samples of S4 and S cells. “clusterProfiler” package in R, DAVID, Metascape, and Gene Set Enrichment Analysis (GSEA) were used to perform gene ontology (GO) and pathway enrichment analysis, and cBioPortal for WFDC2 coexpression analysis. GEO dataset (GSE51088) and quantitative real-time polymerase chain reaction (qRT-PCR) was applied for validation. The protein–protein interaction (PPI) network and modular analyses were performed using Metascape and Cytoscape. Results.In total, 713 DEGs were found (164 up regulated and 549 down regulated) and further analyzed by GO, pathway enrichment and PPI analyses. We found that MAPK pathway accounted for a significant portion of the enriched terms. WFDC2 coexpression analysis revealed ten WFDC2 coexpressed genes (TMEM220A, SEC23A, FRMD6, PMP22, APBB2, DNAJB4, ERLIN1, ZEB1, RAB6B, and PLEKHF1) that were also dramatically changed in S4 cells and validated by dataset GSE51088. Kaplan–Meier survival statistics revealed clinical significance for all of the 10 target genes. Finally, PPI was constructed, sixteen hub genes and eight molecular complex detections (MCODEs) were identified, the seeds of five most significant MCODEs were subjected to GO and KEGG enrichment analysis and their clinical significance was evaluated.Conclusions.By applying microarray and bioinformatics analyses, we identified DEGs and determined a comprehensive gene network of active HE4 stimulation in EOC cells. We offered several possible mechanisms and identified therapeutic and prognostic targets of HE4 in EOC.

Background: Ovarian cancer (OC) is the most lethal malignancy in the female reproductive system. Growing evidences demonstrates that competing endogenous RNA (ceRNA) network play crucial roles in the occurrence and progression of tumors. Therefore, we aimed to explore and identify novel mRNA-miRNA-lncRNA ceRNA networks associated with prognosis of OC. Methods: The differentially expressed gene (DEGs) of four expression profiles datasets (GSE5438, GSE40595, GSE38666 and GSE26712) were collected from Gene Expression Omnibus (GEO) database and analyzed with NetworkAnalyst. Intersection of DEGs were further employed for Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis. Protein-protein interaction (PPI) network and hub genes of DEGs were also identified. The expression levels and survival analysis of the hub genes in OC and their upstream miRNAs and lncRNAs were performed by various bioinformatics databases. More importantly, ceRNA networks were constructed based on mRNA-miRNA-lncRNA in OC. Results: A total of 178 DEGs including 38 upregulated and 140 downregulated genes from intersected DEGs of four expression profiles were identified in OC. Functional enrichment analysis suggested that the commonly DEGs were enriched in regulating enzyme inhibitor activity, glycosaminoglycan and G protein-coupled receptor binding, cell morphogenesis, and involved in pathways including metabolic process, proteoglycans in cancer. Top 10 hub genes with higher connectivity degree were selected for subsequent expression and prognosis analysis. After take expression levels and prognostic roles of hub genes and their upstream miRNAs and lncRNAs in OC into consideration, 2 mRNAs (TACC3 and CXCR4), 2 miRNAs (hsa-miR-425-5p and hsa-miR-146a-5p) and 3 lncRNAs (FUT8-AS1, LINC00665 and LINC01535) were significantly associated with the poor prognosis of OC. The mRNA-miRNA-lncRNA networks (TACC3-hsa-miR-425-5p-FUT8-AS1 and CXCR4-hsa-miR-146a-5p-LINC00665/LINC01535) were eventually constructed in OC based on ceRNA mechanism. Conclusion: We successfully constructed novel ceRNA network associated with the prognosis of ovarian cancer, which may provide a new strategy for early diagnosis and therapeutic intervention of OC.

Background Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It’s of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. Methods The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. Results The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell–cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. Conclusion Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.

Background: The diagnosis and management of cervical cancer in pregnant women is a grim fact due to inadequate cervical cancer screening in China. Based on a muti-center collected data from 2009-2017, we aimed to estimate the epidemiology, management, and maternal and infant outcomes of cervical cancer during pregnancy in China. Methods: One hundred and five cases of cervical cancer in pregnancy were collected in 22 central hospitals from 15 provinces during Jan, 2009 to Nov,2017 initiated by Chinese Society for Colposcopy and Cervical Pathology (CSCCP) in China. We requested a listing of individual records of cancer cases, including age, the tumor clinical feature (based on FIGO staging and histopathology), the management of cancer (during pregnancy or postpartum), the obstetrical indicators as gestational age [GA] at diagnosis and delivery, delivery mode, birthweight, 5-minute Apgar scores, and neonatal outcome), and the maternal outcome. We also compared the management of patients who terminated pregnancy (P-tp) and the patients who continued pregnancy (P-cp) and the oncologic and obstetric outcome in China. Findings: A total of 105 women diagnosed with cervical cancer in pregnancy were identified from 45 652 patients of cervical cancer (0.23%, 105/45 652) and 525 000 pregnant women (0.020%, 105/525 000) during the study period. The mean age was 33±5 years old (range, 17-45 years old). 98 (93.3%) of 105 patients diagnosed with cervical cancer during pregnancy were stage IB1 and above at the time of diagnosis. 86 (81.90%) of 105 patients presented at the clinic with vaginal hemorrhage during pregnancy. 76 (72.38%) of 105 patients had never been screened for more than five years by their pregnancies. In all, P-tp group(n= 67) were more likely to be diagnosed earlier in pregnancy compared with P-cp group (n=38) (14.8 vs 30.8 weeks, p

Background: Ovarian cancer is one of the common malignant tumors in gynecology. Although the treatment strategy for ovarian cancer has been greatly improved in recent years, due to the metastasis, recurrence and drug resistance, the 5-year overall survival rate of patients is still less than 47%. However, at present, there is no specific markers for clinical application. The purpose of this study is to verify the expression and clinical significance of KIF23 in ovarian cancer and identify potential targets for the clinical treatment of ovarian cancer. Methods: The expression of KIF23 in ovarian cancer tissues and its relationship between survival prognosis and clinical pathological parameters were analyzed in Oncomine, GEO, and TCGA databases. KIF23 expression was analyzed by Kaplan-Meier plotter database and its relationship with chemo-resistance was studied. The molecular mechanism involved in KIF23 was analyzed from the perspective of gene mutation, copy number variation and other genomics. Finally, immunohistochemistry experiment was used to verify the expression of KIF2, and its relationship between the clinical pathological parameters and prognosis of ovarian cancer patients was analyzed by single factor and multivariate Cox regression models. Results: Bioinformatic and experimental results have demonstrated that KIF23 is highly expressed in ovarian cancer, and its high expression is positively correlated with poor prognosis. Overexpression of KIF23 can cause chemotherapy resistance in ovarian cancer and affect the overall survival of patients. Genomics analysis showed that KIF23 expression was associated with mutations such as FLG2 and TTN, and it was significantly enriched in tumor signaling pathways such as DNA replication and cell cycle. Conclusions: KIF23 can not only be used as a biomarker of poor prognosis in patients with various stages of ovarian cancer, but also be used as a molecular targeted drug and an independent prognostic biomarker for the treatment of ovarian cancer patients.

The purpose of this study is to explore the expression and clinical significance of KIF23 in ovarian cancer (OV) and identify potential targets for clinical treatment. Oncomine, GEO, and TCGA databases were used to analysis the expression of KIF23 in OV. The prognostic value of KIF23 gene was analyzed by the Kaplan-Meier plotter database. The molecular mechanism of KIF23 activity was analyzed from the perspective of immunology, gene mutation, copy number variation (CNV). Finally, immunohistochemistry was conducted to validate the expression of KIF23, univariable and multivariate cox analysis were used to determine its relationship with clinical characteristics and OV prognosis. It showed that highly expressed KIF23 is an adverse independent prognostic biomarker for OV patients. Genomics analysis showed that KIF23 expression was associated with mutations such as FLG2 and TTN, and was significantly enriched in DNA replication and the cell cycle tumor-related signaling pathways. Immunology analysis showed that KIF23 is closely related to the immune infiltration. KIF23 can not only performed as a prognosis signature in OV but also as a target of immune molecular therapeutics.

Heart failure (HF) is a major cardiovascular disease worldwide, and the early detection and diagnosis remain challenges. Recently, heart rhythm complexity analysis, derived from non-linear heart rate variability (HRV) analysis, has been proposed as a non-invasive method to detect diseases and predict outcomes. In this study, we aimed to investigate the diagnostic value of heart rhythm complexity in HF patients. We prospectively analyzed 55 patients with symptomatic HF with impaired left ventricular ejection fraction and 97 participants without HF symptoms and normal LVEF as controls. Traditional linear HRV parameters and heart rhythm complexity including detrended fluctuation analysis (DFA) and multiscale entropy (MSE) were analyzed. The traditional linear HRV, MSE parameters and DFAα1 were significantly lower in HF patients compared with controls. In regression analysis, DFAα1 and MSE scale 5 remained significant predictors after adjusting for multiple clinical variables. Among all HRV parameters, MSE scale 5 had the greatest power to differentiate the HF patients from the controls in receiver operating characteristic curve analysis (area under the curve: 0.844). In conclusion, heart rhythm complexity appears to be a promising tool for the detection and diagnosis of HF.

Transforming growth factor-β, a cell secretion factor of the TGF-β superfamily, is involved in the regulation of cell proliferation, differentiation, cytoskeleton formation, migration, invasion and other biological behaviors. Autophagy and mitophagy play an important role in tumor progression by regulating self-digestion, and degradation and reuse of cells and mitochondria. In this study, changes in autophagy and mitophagy processes in ovarian cancer cells under TGF-β1 treatment were detected via Western blot and immunofluorescence, as well as the role of fucosylation modification. Changes in mitochondrial membrane potential in response to TGF-β1 and fucosylation were detected via immunofluorescence. The effects of TGF-β1 and its fucosylation on autophagic flux were further determined by transient transfection of cells with Ad-mRFP-GFP-LC3 adenovirus. TGF-β1 clearly promoted autophagy and mitophagy in ovarian cancer cells. TGF-β1 fucosylation stimulated these regulatory effects on ovarian cancer cells via modulation of PI3K/Akt and Ras-Raf-MEK-ERK pathways through TAK1. Our collective data support the physiological significance of TGF-β1 and provide a novel direction for targeted therapy for ovarian cancer.

Ming-Jun Zheng,1,2,* Jing Wang,1,2,* Hui-Min Wang,1,2 Ling-Ling Gao,1,2 Xiao Li,1,2 Wen-Chao Zhang,1,2 Rui Gou,1,2 Qian Guo,1,2 Xin Nie,1,2 Juan-Juan Liu,1,2 Bei Lin1,2 1Department of Gynaecology and Obstetrics, Shengjing Hospital Affiliated to China Medical University, Heping District, Shenyang 110004, Liaoning, China; 2Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China *These authors contributed equally to this work Aim: The aim of this study was to explore the expression of peroxiredoxin1 (PRDX1) in epithelial ovarian cancer, analyze the relationship between PRDX1 and clinicopathologic parameters of patients with ovarian cancer, including their prognosis, and describe changes and the mechanisms involved in malignant biologic behavior of ovarian cancer cells when PRDX1 expression is inhibited.Methods: The expression of PRDX1 was detected immunohistochemically in 15 samples of normal ovarian tissue, 21 benign, 11 borderline, and 101 malignant epithelial ovarian tumors. Changes in ovarian cancer cell proliferation, invasion, and metastasis before and after inhibiting PRDX1 expression were assessed by cell function assay. Additionally, gene set enrichment analysis (GSEA) of PRDX1 was performed by the Cancer Genome Atlas database. A protein–protein interaction network was then constructed and a pathway function analysis of the genes in the network was conducted.Results: PRDX1 expression was mainly localized to the cytoplasm, as well as the nucleus of cells. The expression rate of PRDX1 in epithelial ovarian malignant tissues (96.04%) was significantly higher than that in borderline (72.72%) and benign (57.14%) epithelial ovarian tumors, and normal ovarian tissue (20%; all P

Several transition metal complexes of triaminoguanidine (TAG) nitrate, TAG-Ni, TAG-Co, graphene oxide (GO)/TAG-Ni (GT-Ni), GO/TAG-Co (GT-Co), and GO/ TAG-Cu (GT-Cu) were prepared using GO as a stabilizer. It has been shown that these complexes are promising energetic catalysts for decomposition of ammonium perchlorate (AP), which was uniformly coated with the mentioned catalysts. The decomposition kinetic parameters and mechanisms of the complexes have been studied by means of differential scanning calorimetry/thermogravimetric techniques. Results show that the presence of GO in such hybrid catalysts is able to stabilize AP before its decomposition, but the strong catalytic effects occur on HClO4 as the intermediate of the initial decomposition of AP. In the cases of TAG-Co, GT-Co, and GT-Cu, they would make the two-step decomposition of AP into a single step. The heat releases have been greatly increased as well because of a more complete decomposition. More importantly, the thermolysis mechanism of AP c...

Hirschsprung’s disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10−5, OR = 1.37, 95% CI: 1.17–1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10−5, OR = 1.42, 95% CI: 1.20–1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10−6). NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors.

Herein we combine the enzyme-nanoprobe induced biomineralization of cupric subcarbonate with a sensitive copper chromogenic reaction to develop an ultrasensitive colorimetric immunosensing method. The nanoprobe was prepared through the surface assembly of signal antibody and high-content urease on the nanocarrier of gold nanoparticle (Au NP). Upon sandwich immunoreaction at a magnetic bead (MB)-based immunosensing platform, the analyte of carcinoembryonic antigen and the Au NP/urease nanoprobe were quantitatively captured onto the MB surface successively to form an immunocomplex. The enzyme reaction of the nanoprobe resulted in the catalyzed hydrolysis of the urea substrate to produce large amounts of OH− and HCO3−. These ions were further combined with added Cu2+ to form the biomineralization of cupric subcarbonate rapidly on the immunocomplex. Based on the acid-release of Cu2+ from the biomineralized products for the chromogenic reaction, a red complex was obtained and employed for the ultrasensitive colorimetric signal transduction. Under the optimum conditions, a linear range over five orders of magnitude was obtained with a low detection limit of 0.45 pg/mL. In addition, this method features low cost, rapid and convenient operation as well as satisfactory reproducibility, stability and accuracy. It thus owns great potentials for practical applications.

Hirschsprung disease (HSCR) is a severe multifactorial genetic disorder. Microarray studies indicated GAL, GAP43 and NRSN1 might contribute to the altered risk in HSCR. Thus, we focused on genetic variations in GAL, GAP43 and NRSN1, and the gene-gene interactions involved in HSCR susceptibility. We recruited a strategy combining case-control study and MassArray system with interaction network analysis. For GAL, GAP43 and NRSN1, a total of 18 polymorphisms were assessed in 104 subjects with sporadic HSCR and 151 controls of Han Chinese origin. We found statistically significant differences between HSCR and control groups at 5 genetic variants. For each gene, the haplotypes combining all polymorphisms were the most significant. Based on SNPsyn, MDR and GeneMANIA analyses, we observed significant gene-gene interactions among GAL, GAP43, NRSN1 and our previous identified RELN, GABRG2 and PTCH1. Our study for the first time indicates that genetic variants within GAL, GAP43 and NRSN1 and related gene-gene interaction networks might be involved in the altered susceptibility to HSCR in the Han Chinese population, which might shed more light on HSCR pathogenesis.

Ovarian cancer (OC) is one of the most common gynecologic malignancies with poor survival rate, and Iberin is a member of isothiocyanate family with anti-tumor activity. However, the role of Iberin in OC development has not been reported yet. In this study, A2780 and OVCAR-3 cells were treated with gradient concentrations of Iberin to investigate the effect of Iberin on OC in vitro. Meanwhile, the in vivo tumorgenesis experiment was performed using female BALB/c nude mice treated with Iberin. Iberin inhibited cell proliferation, induced G2 cell cycle arrest and promoted cell apoptosis in OC cells. Besides, Iberin reduced GSH/GSSG level, enhanced ROS accumulation, and activated MAPK signaling in OC cells. More interestingly, ROS scavenger (NAC) compensated the anti-proliferative and pro-apoptotic effects of Iberin on OC cells, suggesting the involvement of ROS in the regulation of Iberin on OC cell growth. Notably, Iberin induced down-regulation of glutathione peroxidase-1 (GPX1), and over-expression of GPX1 reversed Iberin-mediated alterations in the proliferation, apoptosis and ROS accumulation of OC cells. The in vivo tumorgenesis study further evidenced the protection of Iberin against OC development. Besides, Iberin displayed a synergistic effect on the enhancement of chemo-sensitivity in OC cells. In summary, our study demonstrates the anti-tumor effect of Iberin on OC and its potential as a therapeutic agent against OC in the future.

As a tumor-associated carbohydrate antigen, elevated expression of Lewis y promotes the malignant behaviors of tumor cells. Although our preliminary study showed that the increased expression of Lewis y antigen decreased the expression of cell cycle inhibitor protein p27, the relevant mechanism remains unclear. Autophagy and the ubiquitin-proteasome system are two main ways of intracellular protein degradation, whose abnormal activities are closely associated with progression of malignant tumors. In our present study, we constructed two stable transfected cell lines with high expression of Lewis y antigen, named CAOV3-FUT1 and SKOV3-FUT1. We showed that the proportion of cells at S phase was significantly increased after FUT1 transfection, whereas p27 protein was obviously decreased. The autophagy activity, the levels of ubiquitination, and chymotrypsin-like protease activity were increased remarkably in the transfected cells. Interestingly, Lewis y antigen promoted the degradation of p27 by increasing ubiquitin-proteasome activity. In the vivo studies, Lewis y antigen improved the tumorigenic ability of ovarian cancer cells in nude mice and reduced the expression of p27. These findings suggested that Lewis y antigen activated both the autophagy and ubiquitin-proteasome activity and promoted the degradation of p27 through the ubiquitin-proteasome pathway.

MUC1 is a type I transmembrane glycoprotein and is overexpressed in various epithelial tumor tissues. Some researchers have demonstrated that the glycosylation status of MUC1 can affect MUC1-mediated tumor growth and cell differentiation. In our previous study, we proved that the abilities of cell proliferation, adhesion, invasion and metastasis, and drug resistance were enhanced in ovarian cancer cells stably expressing Lewis(y). Therefore, we hypothesized that Lewis(y) antigen may play a central role in regulating MUC1 expression, and MUC1-mediated cell growth and differentiation may be closely associated with Lewis(y) antigen. This study aimed to examine the correlation between MUC1 expression and Lewis(y) antigen levels in ovarian cancer cell lines and tissue samples. A series of techniques, including RT-qPCR, western blot anlaysis, immunoprecipitation, immunohistochemistry and double-labeling immunofluorescence were applied to detect the expression of Lewis(y) and MUC1. In malignant epithelial ovarian tumors, the positive expression rates of Lewis(y) antigen and MUC1 were 88.33 and 86.67%, respectively, which were markedly higher than those in borderline (60.00 and 53.33%, P0.05). The expression levels of Lewis(y) and MUC1 correlated with the clinical FIGO stage (P

Aim Cervical cancer is a common malignant carcinoma of the gynecological tract with high morbidity and mortality. Therefore, it is crucial to elucidate the pathogenesis, prevention, diagnosis and prognosis of cervical cancer by searching for the involved key genes. Method In this study, the alternative splicing (AS) events of 253 patients with cervical cancer were analyzed, and 41,766 AS events were detected in 9961 genes. Univariate analysis was performed to screen prognostic AS events. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify the pathways in which these AS events were involved. Results We found that exon skip (ES) is the main AS event in patients with cervical cancer. There was pronounced consistency between the genes involved in overall survival and those involved in recurrence. At the same time, we found that a gene may exhibit several different types of AS events, and these different AS events may be related to prognosis. Four characteristic genes, HSPA14, SDHAF2, CAMKK2 and TM9SF1, that can be used as prognostic markers for cervical cancer were selected. Conclusion: The importance of AS events in the development of cervical cancer and prediction of prognosis was revealed by a large amount of data at the whole genome level, which may provide a potential target for cervical cancer treatment. We also provide a new method for exploring the pathogenesis of cervical cancer to determine clinical treatment and prognosis more accurately.

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.

Purpose Ovarian cancer is one of the most common malignant tumors of the female reproductive system, which seriously threatens the health of patients. It is of great significance to identify biomarkers to improve the clinical status of ovarian cancer patients. Methods Methylation, RNA- sequencing, Copy number variation (CNV), mutation and clinical characteristics of ovarian cancer and control samples were downloaded from The Cancer Genome Atlas database (TCGA). The “iClusterPlus”. R package was used to cluster the molecular subtypes. The copy number variation of the entire lncRNA genome was analyzed using GISTIC. The prognosis-associated lncRNA related to CNV was screened as potential targets for ovarian cancer. Results Six molecular subtypes were identified based on multi-omics analysis and DElncRNAs are significantly enriched in specific molecular subtypes. The deletion or amplification of lncRNA copy number affects the occurrence and development of ovarian cancer to some extent. Three prognostic-associated lncRNA including LOC101927151, LINC00861 and LEMD1-AS1 were selected. These lncRNAs can be used as biomarkers to predict survival in patients with ovarian cancer. The accuracy of results were verified using the Gene Expression Omnibus (GEO) dataset. Conclusion Based on genome-wide copy number variation, prognostic-associated lncRNAs were identified as new biomolecular markers for ovarian cancer.

Background Abnormal activation of the classic Wnt signaling pathway is closely related to the occurrence of epithelial cancers. B-cell lymphoma 9 (BCL9), a transcription factor, is a novel oncogene discovered in the classic Wnt pathway and promotes the occurrence and development of various tumors. Ovarian cancer is the gynecological malignant tumor with the highest mortality because it is difficult to diagnose early, and easy to relapse and metastasis. The expression and role of BCL9 in epithelial ovarian cancer (EOC) have not been studied. Thus, in this research, we aimed to investigate the expression and clinical significance of BCL9 in EOC tissues and its effect on the malignant biological behavior of human ovarian cancer cells. Methods We detect the expression of BCL9 in ovarian epithelial tumor tissues and normal ovarian tissues using immunohistochemistry and analyzed the relationship between it and clinicopathological parameters and patient prognosis. The expression of proteins was detected by Western blot. The MTT assay, flow cytometry, the scratch assay, and the transwell assay were used to detect cell proliferation, apoptosis, migration, and invasion, respectively. A total of 374 ovarian cancer tissue samples were collected using TCGA database. A gene set enrichment analysis of BCL9 was performed. Results BCL9 was overexpressed in EOC tissues. The level of BCL9 expression was correlated with the 5-year progression-free survival rate and overall survival rate in ovarian cancer patients and independently predicted the risk of ovarian cancer recurrence. Low BCL9 expression inhibited proliferation, invasion and migration of EOC cells, decreased MMP2 and MMP9 expression of ES-2 cell line, increased the BAX/BCL2 ratio and promoted apoptosis of EOC cells. Conclusion BCL9 is overexpressed in epithelial ovarian tumors, resulting in a poor prognosis for ovarian cancer patients. Low BCL9 expression can promote ovarian cancer cell apoptosis, inhibit proliferation and migration. BCL9 promotes the development of ovarian cancer.

Previously, we reported that the expression of human epididymis protein (HE4) was correlated with the expression of RAB23 in ovarian cancer cells. Rab23 is a member of the Ras-related small GTPase superfamily, which plays a key role in the Sonic Hedgehog (Shh) signaling pathway. However, the function of Rab23 in ovarian cancer remains unclear. In this study, we explored the location and expression of Rab23 in ovarian cancer tissues and cells (CaoV3 and A2780), and further investigated the function and potential mechanism of Rab23 in malignant biological behaviors including the epithelial-mesenchymal transition (EMT) process in ovarian cancer for the first time. Rab23 is highly expressed in ovarian cancer tissues and associated with advanced stage, and shortened overall survival time of ovarian cancer patients. We are the first to report that human epididymis protein (HE4) can regulate the expression of the Rab23 protein, and that knockdown of RAB23 decreases the proliferation, invasion, and migration abilities as well as inhibits the epithelial-mesenchymal transition (EMT) process in ovarian cancer cells. Furthermore, downregulation of Rab23 significantly inhibited Shh-Gli1 and PI3K-AKT signaling pathways. Collectively, our results indicate that Rab23 plays a critical role in the malignant biological behavior of ovarian cancer and may serve as a potential biomarker and therapeutic target for ovarian cancer.

CD147 is a highly glycosylated transmembrane protein expressed on the surface of tumor cells. In the present study, the expression and clinical significance of the Lewis y antigen and CD147 in epithelial ovarian cancer (EOC) were analyzed, and the function and correlation in between the expression of Lewis y and CD147 were evaluated using immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis, immunocytochemical staining, immunoprecipitation and western blotting. The results showed that the expression of CD147 was higher in EOC tissues and correlated with a higher tumor burden. Lewis y and CD147 exhibited similar expression patterns and their expression was positively correlated. The results of the immunofluorescence and immunoprecipitation experiments showed that Lewis y and CD147 colocalized in the cell membrane and cytoplasm. Lewis y antigen, but not Lewis x or sialyl Lewis x, was predominantly expressed in the highly glycosylated form of CD147. These changes occurred at the post-transcriptional level. As an important component of CD147, Lewis y promoted CD147-mediated cell adhesion and the expression of matrix metalloproteinase 2. In conclusion, Lewis y antigen and CD147 were significantly upregulated in ovarian tumors, and the altered expression of Lewis y may cause changes in CD147. The two molecules are associated with carcinogenesis and the development of ovarian cancer, and Lewis y antigen is a component of the CD147 structure.

The objective of this study is to compare the efficacy of ethanol extracts from different parts of Sophora viciifolia. The content of polyphenols, flavonoids, alkaloids, and antioxidant capacity, antimicrobial activity were investigated, and individual polyphenols and alkaloids were analyzed and quantified by ultra-high performance liquid chromatography (UPLC). The microdilution method was used to determine the antimicrobial activity of extracts from S. viciifolia on six strains. The results for extracts from the different parts (flowers, leaves, and fruit) were compared in varying concentrations to determine whether one extract source is superior to another. Testing verified that extracts from the different parts of S. viciifolia did vary, as expected. For example, extract from the leaves had the best antimicrobial activity against pathogenic Candida albicans, but all extracts had good antimicrobial activity against the six tested strains. These results reveal that the active substances in S. viciifolia are abundant and have good antioxidant and antimicrobial activities, which can provide theoretical support for the subsequent development and utilization of S. viciifolia extracts.

Background Asian citrus psyllid (ACP) is the primary vector responsible for the transmission of the phloem-limited bacteria Candidatus Liberibacter spp., associated with huanglongbing (HLB), which causes great loss to the citrus industry. Although the roles of leaf color and volatile compounds in the orientation of ACP have been proven, the quantification of color and allelochemicals in the host plant are kept unclear, especially in wild citrus germplasms. Results Chongyi wild mandarin significantly attracted more ACP than wild Hong Kong kumquat, ‘Gannan zao’ navel orange and orange jasmine did in the four-choice and olfactometer assays. The color parameters of the tender leaves from Chongyi wild mandarin and ‘Gannan zao’ were similar. The yellow color in both of them was less saturated than that of the other two plants species, but Chongyi wild mandarin had significant lower carotenoid content (P < 0.05). Notably metabolic profiling differences were observed among the healthy tender shoots from the four tested plants via UPLC-QQQ-MS and GC-MS analyses. Comparing with the other three plant species, 66 and 50 metabolites with significantly different contents in Chongyi wild mandarin were selected as UPLC-identified and GC-identified metabolites of interest (P < 0.05), respectively. Flavonoids accounted for a large group of secondary metabolites of interest, which may function as stimulants or repellents of ACP. Higher content of salicylic acid o-hexoside and lower content of (+)-jasmonic acid in Chongyi wild mandarin may lead to higher amount of methyl salicylate (an ACP attractant) and lower amount of trans-ocimene (an attractant to herbivores’ natural enemies) as well as the suppression of JA-mediated wounding response. This kind of synergistic or antagonistic effect among the metabolites differentially accumulated in Chongyi wild mandarin made it a more attractive host plant to ACP. Conclusions Less saturated yellow color, high amount of attractants, low amount of repellents and insensitivity of JA-mediated wounding response are the four possible reasons why Chongyi wild mandarin attracted more ACP. This work may shed light on the olfactory and visual response of ACP to wild citrus germplasm hosts, and suggest the feasibility of developing ACP attractants or repellents patterned on potential metabolites. Electronic supplementary material The online version of this article (10.1186/s12870-019-1818-7) contains supplementary material, which is available to authorized users.

Table S1. The correlation coefficient of seven GC-identified metabolites with some UPLC-identified metabolites.. (DOCX 18 kb)

Figure S1-S4. (DOCX 990 kb)

Intestinal villus atrophy is a major complication of total parenteral nutrition (TPN). Our previous study revealed that TPN-induced villus atrophy is accompanied by elevated expression of CUGBP, Elav-like family member 1 (CELF1); however, its mechanism of action has not been fully understood. Herein, we report a pivotal role of CELF1/p53 axis, which induces a sustained antiproliferative signal, leading to suppressed proliferation of intestinal epithelial cells (IECs). By using a rat model of TPN, we found synchronous upregulation of CELF1 and p53 in jejunum mucosa, accompanied by a 51% decrease in crypt cell proliferation rate. By using HCT-116 cells as an IEC model in vitro, we found that the expression of CELF1 altered dynamically in parallel to proliferation rate, suggesting a self-adaptive expression pattern in IECs in vitro. Furthermore, ectopic overexpression of CELF1 elicited a significant antiproliferative effect in HCT-116, Caco-2, and IEC-6 cells, whereas knockdown of CELF1 elicited a significant proproliferative effect. Moreover, cell-cycle assay revealed that ectopic overexpression of CELF1 induced sustained G2 arrest and G1 arrest in HCT-116 and IEC-6 cells, respectively, which could be abolished by p53 silencing. Mechanistically, polysomal profiling and nascent protein analysis revealed that regulation of p53 by CELF1 was mediated through accelerating its protein translation in polysomes. Taken together, our findings revealed a sustained suppression of IEC proliferation evoked by CELF1/p53 axis, which may be a potential therapeutic target for the treatment of TPN-induced villus atrophy.-Yan, J.-K., Zhang, T., Dai, L.-N., Gu, B.-L., Zhu, J., Yan, W.-H., Cai, W., Wang, Y. CELF1/p53 axis: a sustained antiproliferative signal leading to villus atrophy under total parenteral nutrition.

Background and Aims: Elevated intestinal permeability of lipopolysaccharide (LPS) is a major complication for patients with parenteral nutrition (PN), but the pathogenesis is poorly understood. Intestinal P-glycoprotein (P-gp) is one of the efflux transporters that contribute to restricting the permeability of lipopolysaccharide via transcellular route. P-gp expression may be regulated by PN ingredients, and thus this study sought to investigate the effect of PN on the expression of P-gp and to elucidate the underlying mechanism in vitro. Methods: Caco-2 cells were treated with PN ingredients. Changes in P-gp expression and function were determined and the role of ERK-FOXO 3a pathway was studied. Transport studies of FITC-lipopolysaccharide (FITC-LPS) across Caco-2 cell monolayers were also performed. Results: Among PN ingredients, soybean oil-based lipid emulsion (SOLE) exhibited significant inhibitory effect on P-gp expression and function. This regulation was mediated via activation of ERK pathway with subsequent nuclear exclusion of FOXO 3a. Importantly, P-gp participated in antagonizing the permeation of FITC-LPS (apical to basolateral) across Caco-2 cell monolayers. SOLE significantly increased the permeability of FITC-LPS (apical to basolateral), which was associated with impaired P-gp function. Conclusions: The expression and function of intestinal P-gp is suppressed by SOLE in vitro.

Currently, there are emerging multiple studies on human epididymis protein 4 (HE4) in ovarian cancer. HE4 possesses higher sensitivity and specificity than CA125 in the confirmative early diagnosis for ovarian cancer. Although much attention has been given to explore its clinical application, research of the basic mechanisms of HE4 in ovarian cancer are still unclear. In the present study, we provide fundamental data to identify full-scale differentially expressed genes (DEGs) in response to HE4 by use of human whole-genome microarrays in human epithelial ovarian cancer cell line ES-2 following overexpression and silencing of HE4. We found that a total of 717 genes were upregulated and 898 genes were downregulated in the HE4-overexpressing cells vs. the HE4-Mock cells, and 166 genes were upregulated and 285 were downregulated in the HE4-silenced cells vs. the HE4-Mock cells. An overlap of 16 genes consistently upregulated and 8 genes downregulated in response to HE4 were noted. These DEGs were involved in MAPK, steroid biosynthesis, cell cycle, the p53 hypoxia pathway, and focal adhesion pathways. Interaction network analysis predicted that the genes participated in the regulatory connection. Highly differential expression of the FOXA2, SERPIND1, BDKRD1 and IL1A genes was verified by quantitative real-time PCR in 4 cell line samples. Finally, SERPIND1 (HCII) was validated at the protein level by immunohistochemistry in 107 paraffin-embedded ovarian tissues. We found that SERPIND1 may act as a potential oncogene in the development of ovarian cancer. The present study displayed the most fundamental and full-scale data to show DEGs in response to HE4. These identified genes may provide a theoretical basis for investigations of the underlying molecular mechanism of HE4 in ovarian cancer.