Identification of disease-specific genes related to immune infiltration in nonalcoholic steatohepatitis using machine learning algorithms.

To identify disease signature genes associated with immune infiltration in nonalcoholic steatohepatitis (NASH), we downloaded 2 publicly available gene expression profiles, GSE164760 and GSE37031, from the gene expression omnibus database. These profiles represent human NASH and control samples and were used for differential genes (DEGs) expression screening. Two machine learning methods, the Least Absolute Shrinkage and Selection Operator regression model and Support Vector Machine Recursive Feature Elimination, were used to identify candidate disease signature genes. The CIBERSORT deconvolution algorithm was employed to analyze the infiltration of 22 immune cell types in NASH. Additionally, we constructed a NASH cell model using HepG2 cells treated with oleic acid and free fatty acids. The construction of the cell model was verified using oil red O staining, and Western blotting was used to detect the protein expression of the disease signature genes in both control and model groups. As a result, a total of 262 DEGs were identified. These DEGs were primarily associated with metal ion transmembrane transporter activity, sodium ion transmembrane transporter protein activity, calcium ion, and neuroactive ligand-receptor interactions. FOS, IGFBP2, dual-specificity phosphatase 1 (DUSP1), and IKZF3 were identified as disease signature genes of NASH by the least absolute shrinkage and selection operator and Support Vector Machine Recursive Feature Elimination algorithms for DEGs analysis. The receiver operating characteristic curves showed that FOS, IGFBP2, DUSP1, and IKZF3 had good diagnostic value (area under receiver operating characteristic curve > 0.8). These findings were validated in the GSE89632 dataset and through cellular assays. Immunocyte infiltration analysis revealed that NASH was associated with CD8 T cells, CD4 T cells, follicular helper T cells, resting NK cells, eosinophils, regulatory T cells, and γδ T cells. The FOS, IGFBP2, DUSP1, and IKZF3 genes were specifically associated with follicular helper T cells. Lipid droplet aggregation significantly increased in HepG2 cells treated with oleic acid and free fatty acids, indicating successful construction of the cell model. In this model, the expression of FOS, IGFBP2, and DUSP1 was significantly decreased, while that of IKZF3 was significantly elevated (P < .01, P < .001) compared with the control group. Therefore, FOS, IGFBP2, DUSP1, and IKZF3 can be considered as disease signature genes associated with immune infiltration in NASH.

WTAP-mediated N6-methyladenosine modification promotes the inflammation, mitochondrial damage and ferroptosis of kidney tubular epithelial cells in acute kidney injury by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways.

Acute kidney injury (AKI) is a serious complication of sepsis patients, but the pathogenic mechanisms underlying AKI are still largely unclear. In this view, the roles of the key component of N6-methyladenosine (m6A)-wilms tumor 1 associated protein (WTAP) in AKI progression were investigated. AKI mice model was established by using cecal ligation and puncture (CLP). AKI cell model was established by treating HK-2 cells with LPS. Cell apoptosis was analyzed by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining and flow cytometry analysis. Cell viability was analyzed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The concentrations of inflammatory factors were examined with ELISA kits. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and Fe2+ levels were detected with related kits. Gene expression was detected by western blot assay or quantitative real-time polymerase chain reaction (qRT-PCR) assay. The relation between WTAP and lamin B1 (LMNB1) was verified by Methylated RNA Immunoprecipitation (meRIP) assay, RIP assay, dual-luciferase reporter assay and Actinomycin D assay. CLP induced significant pathological changes in kidney tissues in mice and promoted inflammation, mitochondrial damage and ferroptosis. LMNB1 level was induced in HK-2 cells by LPS. LMNB1 knockdown promoted LPS-mediated HK-2 cell viability and inhibited LPS-mediated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis. Then, WTAP was demonstrated to promote LMNB1 expression by m6A Methylation modification. Moreover, WTAP knockdown repressed LPS-treated HK-2 cell apoptosis, inflammation, mitochondrial damage and ferroptosis, while LMNB1 overexpression reversed the effects. Additionally, WTAP affected the pathways of NF-κB and JAK2/STAT3 by LMNB1. WTAP-mediated m6A promoted the inflammation, mitochondrial damage and ferroptosis in LPS-induced HK-2 cells by regulating LMNB1 expression and activating NF-κB and JAK2/STAT3 pathways.

Expression levels of ADAMTS 5, 9, and 12 in endometrial polyps and their predictive value for the diagnosis and recurrence of endometrial polyps.

PURPOSE: Endometrial polyps (EPs) are common gynecological disorders for which no clear etiology has been found. ADAMTS have been associated with a variety of diseases. This study aimed to investigate the potential correlation between serologic levels of ADAMTS 5, 9, and 12 in patients with EPs. METHODS: A total of 88 patients were categorized into two groups: the EPs group, consisting of recurrent EPs and first occurrence EPs, and a control group. The study compared the general information and serum levels of ADAMTS 5, 9, and 12 between the groups. RESULTS: Regarding the general data, a statistically significant age difference (p < 0.05) was observed, while no significant differences were found in the other variables. After considering age as a confounding factor, the previously observed statistical significance in the differences of ADAMTS5 and 9 between the groups diminished. However, it was found that the concentrations of ADAMTS12 in both the EPs group and the recurrent EPs group were significantly higher compared to the control group and the first occurrence EPs group (p < 0.05). ROC curves were generated to determine the critical values of ADAMTS12 for predicting EPs and recurrent EPs, which were found to be 0.6962 ng/ml (sensitivity: 100 %, specificity: 39.5 %) and 0.8768 ng/ml (sensitivity: 75.0 %, specificity: 76.3 %), respectively. CONCLUSION: Our findings revealed elevated serologic levels of ADAMTS12 in the EPs group, particularly in the recurrent EPs group. Furthermore, ADAMTS-12 was identified as a valuable biomarker for assisting in the diagnosis and prediction of EPs recurrence.

Advances in the ocular complications after hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) has benefited an increasing number of patients with hematological disease in the clinic. It is a curative therapy for malignant and nonmalignant hematological diseases. With the advancement and further clinical application of HSCT in recent years, the life expectancy of patients has increased, but complications have become more common. The occurrence of ocular complications is receiving increasing attention because they can seriously affect the quality of life of patients. Ocular complications require increased attention from clinicians because of their negative impact on patients and increasing incidence. Most of recent reports on posttransplant ocular complications involve ocular manifestations of graft-versus-host disease (GVHD), and a few ocular complications that do not originate from GVHD have also been reported. This review summarizes the diagnosis, scoring criteria, pathophysiology, and clinical manifestations of and common therapies for ocular graft-versus-host disease(oGVHD) after HSCT, and includes a description of some rare cases and novel therapies.

The mir-199b-5p encapsulated in adipocyte-derived exosomes mediates radioresistance of colorectal cancer cells by targeting JAG1.

Radiotherapy is a key treatment option for colorectal cancer, but its efficacy varies among patients. Our previous studies suggested that adipose tissue may confer the radioresistance of several abdominal tumors, such as pancreatic cancer, biliary cancer, and others. In the present work, the effects of adipocytes in regulating the radiosensitivity of colorectal cancer are explored for the first time. It was found that colony formation was increased and radiation-induced apoptosis decreased in colorectal cancer cells HCT8 and HCT116 co-cultured with adipocytes, which verified the mediation of adipocyte-driven radioresistance in colorectal cancer in vitro. Next, the colorectal cancer cells were incubated with adipocyte-derived exosomes, and a perceptible reduction in radiosensitivity was detected. Furthermore, to investigate the possible mechanisms involved, the exosomes were isolated, the encapsulated microRNAs were extracted and analyzed by small RNA sequencing. Based on bioinformatics analysis and qRT-PCR verification, miR-199b-5p was chosen for functional annotation. It was shown that miR-199b-5p expression was significantly upregulated after 6 Gy irradiation, and overexpressed miR-199b-5p significantly suppressed the radiosensitivity of HCT8 and HCT116 cells. In addition, jagged canonical Notch ligand 1(JAG1) was identified as the target gene of miR-199b-5p by using bioinformatics prediction and dual luciferase reporter gene assay. It was demonstrated that JAG1 conferred the radioresistance of colorectal cancer cells both in vivo and in vitro. Taken together, the present study demonstrates that adipocytes trigger the radioresistance of colorectal cancer cells, probably by targeting JAG1 through an adipocyte-derived exosomal miR-199b-5p.

Animal models of chemotherapy-induced peripheral neuropathy for hematological malignancies: A review.

Chemotherapy is one of the main treatments for hematologic malignancies. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxic reactions in chemotherapy, and the occurrence of CIPN affects patients' quality of life and can cause interruption of chemotherapy in severe cases, thus reducing the efficacy of chemotherapy. We currently summarize the existing CIPN animal models, including the characteristics of several common animal models such as bortezomib-induced peripheral neuropathy, vincristine-induced peripheral neuropathy, and oxaliplatin-induced peripheral neuropathy. It was found that CIPN may lead to behavioral, histopathological, and neurophysiological changes inducing peripheral neuropathy. However, the mechanism of CIPN has not been fully elucidated, especially the prevention and treatment protocols need to be improved. Therefore, this review article summarizes the progress of research on CIPN animal models and the possible mechanisms and treatment of CIPN.

Benzo(a)pyrene regulates chaperone-mediated autophagy via heat shock protein 90.

AIMS: Some studies have shown that the Benzo(a)pyrene (BaP) exposure induced oxidative damage, DNA damage and autophagy, but the molecular mechanism is not clear. Heat shock protein 90 (HSP90) is regarded as an important target in cancer therapy and a key factor in autophagy. Therefore, this study aims to clarify the new mechanism of BaP regulating CMA through HSP90. MAIN METHODS: C57BL mice were fed with BaP at a dose of 25.3 mg/kg. A549 cells were treated with different concerntrations of BaP, and MTT assay was used to observe the effect of BaP on the proliferation of A549 cells. DNA damage was detected by alkaline comet assay. Focus experiment for detection of γ-H2AX by immunofluorescence. The mRNA expression of HSP90, HSC70 and Lamp-2a was detected by qPCR. The protein expressions of HSP90, HSC70 and Lamp-2a were detected by Western blot. Next, we knocked down HSP90 expression by the HSP90 Inhibitor, NVP-AUY 922, exposed or HSP90α shRNA lentivirus transduction in A549 cells. KEY FINDINGS: In these studies, we first found that heat shock protein 90 (HSP90), heat shock cognate 70 (HSC70) and lysosomal-associated membrane protein type 2 receptor (Lamp-2a) expressions of C57BL mice lung tissue and A549 cells exposed to BaP were significant increase, as well as BaP induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by comet assay and γ-H2AX foci analysis in A549 cells. Our results demonstrated BaP induced CMA and caused DNA damage. Next, we knocked down HSP90 expression by the HSP90 Inhibitor, NVP-AUY 922, exposed or HSP90α shRNA lentivirus transduction in A549 cells. HSC70 and Lamp-2a expressions of these cells exposed to BaP were not significant increase, which showed that BaP inducted CMA was mediated by HSP90. Further, HSP90α shRNA prevented BaP induced of BaP which suggested BaP regulated CMA and caused DNA damage by HSP90. Our results elucidated a new mechanism of BaP regulated CMA through HSP90. SIGNIFICANCE: BaP regulated CMA through HSP90. HSP90 is involved in the regulation of gene instability induced by DNA damage by BaP, which promotes CMA. Our study also revealed that BaP regulates CMA through HSP90. This study fills the gap of the effect of BaP on autophagy and its mechanism, which will lead to a more comprehensive understanding of the action mechanism of BaP.

Interaction between AhR and HIF-1 signaling pathways mediated by ARNT/HIF-1ß.

BACKGROUND: The main causes of lung cancer are smoking, environmental pollution and genetic susceptibility. It is an indisputable fact that PAHs are related to lung cancer, and benzo(a) pyrene is a representative of PAHs. The purpose of the current investigation was to investigate the interaction between AhR and HIF-1 signaling pathways in A549 cells, which provide some experimental basis for scientists to find drugs that block AhR and HIF-1 signaling pathway to prevent and treat cancer. METHODS: This project adopts the CYP1A1 signaling pathways and the expression of CYP1B1 is expressed as a measure of AhR strength index. The expression of VEGF and CAIX volume as a measure of the strength of the signal path HIF-1 indicators. Through the construction of plasmid vector, fluorescence resonance energy transfer, real-time quantitative PCR, western blotting and immunoprecipitation, the interaction between AhR signaling pathway and HIF-1 signaling pathway was observed. RESULTS: BaP can enhance the binding ability of HIF-1α protein to HIF-1ß/ARNT in a dose-dependent manner without CoCl2. However, the binding ability of AhR protein to HIF-1ß/ARNT is inhibited by HIF-1α signaling pathway in a dose-dependent manner with CoCl2. CONCLUSION: It is shown that activation of the AhR signaling pathway does not inhibit the HIF-1α signaling pathway, but activation of the HIF-1α signaling pathway inhibits the AhR signaling pathway.

Molecular mechanism of benzo [a] pyrene regulating lipid metabolism via aryl hydrocarbon receptor.

BACKGROUND: Benzo [a] pyrene (BaP), a potent carcinogen, has been proved that it has toxicological effects via activation the aryl hydrocarbon receptor (AhR) pathway. AhR can participate in regulating lipogenesis and lipolysis. This topic will verify whether BaP regulates lipid metabolism via AhR. METHODS: (1) C57BL/6 mice were gavaged with BaP for 12 weeks to detect serum lipids, glucose tolerance, and insulin resistance. Morphological changes in white adipose tissue (WAT) were detected by Hematoxylin and Eosin staining. The mRNA expression levels of adipogenesis-related factors included recombinant human CCAAT/enhancer binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid binding protein 4 (FABP4) and inflammatory factors included nuclear factor kappa-B (NF-κB), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α) were detected using PCR. (2) Neutral lipid content changes in differentiated 3 T3-L1 adipocytes treated with BaP with and w/o AhR inhibitor were detected by Oil red staining. The protein expression levels of adipogenesis- and decomposition-related factors included PPARγ coactivator-1 alpha (PGC-1α), and peroxisome proliferation-activated receptor alpha (PPARα) were detected using western blotting. The mRNA expression levels of inflammatory factors were detected using PCR. RESULTS: (1) BaP inhibited body weight gain, decreased lipid content, increased lipid levels, and decreased glucose tolerance and insulin tolerance in mice; (2) BaP reduced the expressions of C/EBPα, PPARγ, FABP4, PGC-1α, and PPARα and increased the expressions of NF-κB, MCP-1, and TNF-α by activating AhR. CONCLUSION: BaP inhibit fat synthesis and oxidation while inducing inflammation by activating AhR, leading to WAT dysfunction and causing metabolic complications.

Association of Thiamine Intake with Human Papillomavirus (HPV) Infection in American Women: A Secondary Data Analysis Based on the National Health and Nutrition Examination Survey from 2003 to 2016.

BACKGROUND Studies have shown that thiamine intake is associated with cervical cancer, but the relationship between thiamine and HPV infection remains unclear. In the present study, we used the National Health and Nutrition Examination Survey (NHANES) database to investigate whether HPV infection was associated with thiamine intake. MATERIAL AND METHODS A total of 13 471 women ages 18-59 years were selected from the NHANES database from 2003 to 2016. Using thiamine intake as the independent variable, HPV infection as the dependent variable, and sociodemographic data and other data as the covariates, we analyzed the relationship between thiamine and HPV infection by conducting a weighted logistic regression model in a cross-sectional research design. RESULTS The two-piecewise linear model indicated the inflection point of thiamine intake was 2.07 mg. On the left side of the inflection point, the difference in the thiamine intake of log2 conversion was related to the difference of 0.82 in HPV infection, which means that the increase of every 1 unit increase in thiamine intake is associated with the decrease of the HPV infection by 18%. On the right side of the inflection point, we did not observe a correlation between HPV infection and thiamine intake. CONCLUSIONS Thiamine intake is negatively correlated with HPV infection. Intake of an appropriate amount of thiamine can prevent HPV infection. The best preventive effect can be achieved when the intake is about 2 mg, and excessive intake will not increase the preventive effect.

Relationship between Methylation of FHIT and CDH13 Gene Promoter Region and Liver Cancer.

In order to demonstrate the relationship between methylation of fragile histidine triad (FHIT) and T-cadherin/H-cadherin (CDH13) genes and liver cancer, the methylation status of FHIT and CDH13 was detected in healthy individuals and in Mongolian and Han patients with liver cancer. The phenol-chloroform method was used to extract genomic DNA. The methylation specific polymerase chain reaction method was applied to detect the methylation status of FHIT and CDH13. The relationship between smoking and alcohol consumption and gene (FHIT and CDH13) methylation was analyzed. There was significant difference in methylation rate of FHIT (72.67%, 34.67%) and CDH13 (72.0%, 28.0%) between liver cancer patients and healthy individuals of Mongolian descent (P<0.05), as well as that of FHIT (68%, 30.67%) and CDH13 (64%, 26%) between liver cancer patients and healthy individuals of Han individuals (P<0.05). There was also a relationship between smoking and drinking and the methylation of FHIT and CDH13 (P<0.05). Thus, the methylation of FHIT and CDH13 had a relationship with liver cancer incidence. Smoking and alcohol ingestion may promote the methylation of FHIT and CDH13.

A preliminary study to quantitatively evaluate the development of maturation degree for fetal lung based on transfer learning deep model from ultrasound images.

PURPOSE: The evaluation of fetal lung maturity is critical for clinical practice since the lung immaturity is an important cause of neonatal morbidity and mortality. For the evaluation of the development of fetal lung maturation degree, our study established a deep model from ultrasound images of four-cardiac-chamber view plane. METHODS: A two-stage transfer learning approach is proposed for the purpose of the study. A specific U-net structure is designed for the applied deep model. In the first stage, the model is to first learn the recognition of fetal lung region in the ultrasound images. It is hypothesized in our study that the development of fetal lung maturation degree is generally proportional to the gestational age. Then, in the second stage, the pretrained deep model is trained to accurately estimate the gestational age from the fetal lung region of ultrasound images. RESULTS: Totally 332 patients were included in our study, while the first 206 patients were used for training and the subsequent 126 patients were used for the independent testing. The testing results of the established deep model have the imprecision as 1.56 ± 2.17 weeks on the gestational age estimation. Its correlation coefficient with the ground truth of gestational age achieves 0.7624 (95% CI 0.6779 to 0.8270, P value < 0.00001). CONCLUSION: The hypothesis that the development of fetal lung maturation degree can be represented by the texture information from ultrasound images has been preliminarily validated. The fetal lung maturation degree can be considered as being represented by the deep model's output denoted by the estimated gestational age.

Association of Menstrual Extension and Surgery Effectiveness with Ultrasound Parameters of Cesarean Section Scar Diverticulum in Patients Undergoing Transvaginal Uterine Diverticulum Repair.

The association of residual myometrium thickness (RMT) and scar defect depth (D) with menstrual abnormalities and the effectiveness of vaginal repair remain to be determined in patients with cesarean section scar diverticulum (CSD). To assess the value of ultrasound to predict vaginal repair effectiveness. This was a retrospective study of patients with CSD treated with vaginal repair between 01/2014 and 02/2016 at Shanghai First Maternity and Infant Hospital (Tongji University). Transvaginal ultrasound was performed before and 3 months after surgical repair. RMT, D, scar defect length (L), and scar defect width (W) were measured. Width (W), D, and L increased along the duration of menstrual period (P < 0.05). When the menstrual extension time was ≥15 days, RMT/D and RMT/(RMT + D) were smaller than in patients with period <15 days (P < 0.05). L was the most positively correlated ultrasonic parameter with menstrual prolongation (r = 0.492). RMT/D and RMT/(RMT + D) were negatively correlated with prolonged menstruation (r = -0.304 and -0.305, respectively). RMT/D and RMT/(RMT + D) were associated with the disappearance of CSD after vaginal repair (P < 0.05). The cutoff value of RMT/(RMT + D) was 0.496, with sensitivity of 53.0% and specificity of 61.4%. L of CSD is closely correlated with menstrual extension but has no relationship with the effectiveness of surgery. RMT/(RMT + D) is correlated with menstrual extension time ≥15 days and the effectiveness of vaginal repair.

Ketamine delays progression of oxidative and damaged cataract through regulating HMGB-1/NF-κB in lens epithelial cells.

OBJECTIVE: Lens epithelial cell (LEC) membrane damage is one of the pathogenesis of cataract. High mobility group box-1 (HMGB-1) and nuclear factor-κB (NF-κB) play vital roles in a variety of diseases, such as inflammation. Ketamine has numerous pharmacological effects that can inhibit inflammation. However, its role in cataract rats LECs has not yet been elucidated. MATERIALS AND METHODS: LECs were isolated from SD rats and cultured in vitro. The cells were randomly divided into three groups, including the control group, cataract model group induced by H2O2, and ketamine group treated by 10 mM ketamine under H2O2 environment. LECs proliferation was assessed by MTT assay. LECs apoptosis was evaluated by Caspase-3 activity detection. NF-κB mRNA and protein expressions were tested by real-time PCR and Western blot. HMGB-1 expressions in cells and supernatant were detected by real-time PCR and ELISA. TNF-α and IL-1ß secretions were detected by ELISA. RESULTS: In H2O2 model group, the LECs proliferation was significantly inhibited, the caspase-3 activity significantly increased, HMGB-1 mRNA and secretion significantly enhanced, NF-κB mRNA and protein levels significantly elevated, compared to the Control group (p < .05). While the TNF-α and IL-1ß secretions significantly up-regulated in H2O2 model group compared to the Control group (p < .05). Ketamine significantly promoted the LECs proliferation, significantly reduced the caspase-3 activity, and significantly declined the HMGB expression compared to H2O2 model group (p < .05). The NF-κB mRNA and protein levels were significantly decreased, TNF-α and IL-1ß secretions were significantly decreased in the Ketamine group compared with the model group (p < .05). CONCLUSIONS: Ketamine delays the progression of oxidative and damaged cataract by regulating HMGB-1/NF-κB expression, inhibiting TNF-α, IL-1ß, and apoptosis, and promoting cell proliferation.

Identification and characterization of Clonorchis sinensis cathepsin B proteases in the pathogenesis of clonorchiasis.

BACKGROUND: Human clonorchiasis is a prevailing food-borne disease caused by Clonorchis sinensis infection. Functional characterizations of key molecules from C. sinensis could facilitate the intervention of C. sinensis associated diseases. METHODS: In this study, immunolocalization of C. sinensis cathepsin B proteases (CsCBs) in C. sinensis worms was investigated. Four CsCBs were expressed in Pichia pastoris yeast cells. Purified yCsCBs were measured for enzymatic and hydrolase activities in the presence of various host proteins. Cell proliferation, wound-healing and transwell assays were performed to show the effect of CsCBs on human cells. RESULTS: CsCBs were localized in the excretory vesicle, oral sucker and intestinal tract of C. sinensis. Recombinant yCsCBs from yeast showed active enzymatic activity at pH 5.0-5.5 and at 37-42 °C. yCsCBs can degrade various host proteins including human serum albumin, human fibronectin, human hemoglobin and human IgG. CsCBs were detected in liver tissues of mice and cancer patients afflicted with clonorchiasis. Various bioassays collectively demonstrated that CsCBs could promote cell proliferation, migration and invasion of human cancer cells. CONCLUSION: Our results demonstrated that CsCBs can degrade various human proteins and we proved that the secreted CsCBs are involved in the pathogenesis of clonorchiasis.

Association of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region.

PURPOSE: To explore associations of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region. MATERIALS AND METHODS: CYP2E1 and NAT2 polymorphisms were detected by PCR-RFLP in 930 lung cancer patients and 1000 controls. RESULTS: (1) Disequilibrium of the distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations (p=0.031). (2) Lung cancer risk was higher in individuals with c1, D allele of CYP2E1 RsaI/PstI, DraI polymorphisms and slow acetylation of NAT2 (c1 compared with c2, OR=1.382, 95%CI: 1.178- 1.587, p=0.003; D compared with C, OR=1.241, 95%CI: 1.053-1.419, P<0.001; slow acetylation compared with rapid acetylation, OR=1.359, 95%CI:1.042-1.768, p=0.056) (3) Compared with c2/c2 and rapid acetylation, c1/c1 together with slow acetylation synergetically increased risk of lung cancer 2.83 fold. (4) Smokers with CYP2E1 c1/c1, DD, and NAT2 slow acetylation have 2.365, 1.916, 1.841 fold lung cancer risk than others with c2/c2, CC and NAT2 rapid acetylation, respectively. (5) Han smokers with NAT2 slow acetylation have 1.974 fold lung cancer risk than others with rapid acetylation. CONCLUSIONS: Disequilibrium distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations. Besides, Han smokers with NAT2 slow acetylation may have higher lung cancer risk compared with rapid acetylation couterparts. CYP2E1 c1/ c1, DD and NAT2 slow acetylation, especially combined with smoking, contributes to the development of lung cancer. CYP2E1 c1/c1 or DD genotype and NAT2 slow acetylation have strong synergistic action in increasing lung cancer risk.

Association between +936 C>T gene polymorphism of vascular endothelial growth factor and lung cancer: a meta-analysis.

BACKGROUND: +936C>T polymorphism of vascular endothelial growth factor (VEGF) is one of the most investigated polymorphisms, it has been suggested that it plays a vital role in tumorigenesis. Intensive studies centering on the association between VEGF +936C>T polymorphism and lung cancer risk or lung cancer patients' overall survival were conducted in recent years, but with inconclusive and ambiguous results. OBJECTIVE AND METHODS: We investigated whether VEGF +936C>T polymorphism influences lung cancer risk and lung cancer patients' overall survival (OS) using pooled odds ratios (ORs) and hazard ratios (HRs) with their corresponding 95% confidence intervals (CI) under different genetic models. RESULTS: A total of 12 eligible studies were included. In the overall analysis, we didn't find any statistical evidence that +936C>T polymorphism was related to the risk of lung cancer in any genetic model. However, increased lung cancer risk was detected in adenocarcinoma subgroup (OR=1.532, 95%CI: 1.016-2.312, P=0.042). For an aggregate result of survival analysis, +936C>T polymorphism was linked to an unfavorable OS (HR=2.248, 95%CI: 1.257-4.017, P=0.006) under homozygous model (TT/CC).

Characterization of the secreted cathepsin B cysteine proteases family of the carcinogenic liver fluke Clonorchis sinensis.

Clonorchis sinensis excretory/secretory products (ESP) have gained high attentions because of their potential to be vaccine candidates and drug targets in C. sinensis prevention. In this study, we extensively profiled the characteristics of four C. sinensis cathepsin B cysteine proteases (CsCB1, CsCB2, CsCB3, and CsCB4). Bioinformatics analysis showed all CsCBs contained signal peptides at the N-terminal. Functional domains and residues were found in CsCB sequences. We expressed four CsCBs and profiled immune responses followed by vaccine trials. Recombinant CsCBs could induce high IgG titers, indicating high immunogenicity of CsCB family. Additionally, ELISA results showed that both IgG1 and IgG2a levels apparently increased post-immunization with all four CsCBs, showing that combined Th1/Th2 immune responses were triggered by CsCB family. Both Real-time polymerase chain reaction (RT-PCR) and Western blotting confirmed that four CsCBs have distinct expression patterns in C. sinensis life stages. More importantly, we validated our hypothesis that CsCBs were C. sinensis excretory/secretory products. CsCBs could be recognized by C. sinensis-infected sera throughout the infection period, indicating that secreted CsCBs are immune triggers during C. sinensis infection. The protective effect was assessed by comparing the worm burden and egg per gram (EPG) between CsCB group and control group, showing that worm burden (P < 0.01) and EPG (P < 0.01) in CsCB2 and CsCB3 groups were significantly lower than in control group. In conclusion, we profiled secreted cathepsin B cysteine proteases family for the first time and demonstrated that all CsCB family were C. sinensis excretory/secretory products that may regulate host immune responses.

Susceptibility of lung cancer with polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 genotypes in the population of Inner Mongolia region.

BACKGROUND: To study the relationship of susceptibility to lung cancer with the gene polymorphisms of CYP1A1, GSTM1, GSTM3, GSTT1, GSTP1 and smoking status in Han and Mongolian populations of Inner Mongolia, an autonomous region of China. MATERIALS AND METHODS: PCR-RFLP, allele-specific and multiplex PCR were employed to identify the genotypes of CYP1A1, GSTM1, GSTM3, GSTT1 and GSTP1 in a case-control study of 322 lung cancer patients diagnosed by bronchoscopy and 456 controls free of malignancy. RESULTS: There is a significant difference in genotypic frequency of GSTT1 of healthy Mongolian and Han subjects. A statistically prominent association was found between CYP1A1 Msp1 (vt/vt) (OR=4.055, 95%CI:2.107-7.578, p=0.000), GSTM1 (-) (OR=2.290, 95%CI:1.467-3.573, p=0.000) and lung cancer in Mongolians. Similarly, in the Han population, CYP1A1 Msp1 (vt/vt) (OR=3.194, 95%CI:1.893-5.390, p=0.000) and GSTM1 (-) (OR=1.884, 95%CI:1.284-2.762, p=0.001) carriers also had an elevated risk of lung cancer. The smokers were more susceptible to lung cancer 2.144 fold and 1.631 fold than non-smokers in Mongolian and Han populations, respectively. The smokers who carried with CYP1A1 Msp1 (wt/vt+vt/vt), exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) respectively were found all to have a high risk of lung cancer. CONCLUSIONS: CYP1A1 Msp1 (vt/ vt) and GSTM1 (-) are risk factors of lung cancer in Han and Mongolian population in the Inner Mongolia region. The smokers with CYP1A1 Msp1 (wt/vt+vt/vt), CYP1A1 exon7 (Val/Val+Ile /Val), GSTM1 (-), GSTM3 (AB+BB), and GSTT1 (-) genotypes, respectively, are at elevated risk of lung cancer.

The carcinogenic liver fluke, Clonorchis sinensis: new assembly, reannotation and analysis of the genome and characterization of tissue transcriptomes.

Clonorchis sinensis (C. sinensis), an important food-borne parasite that inhabits the intrahepatic bile duct and causes clonorchiasis, is of interest to both the public health field and the scientific research community. To learn more about the migration, parasitism and pathogenesis of C. sinensis at the molecular level, the present study developed an upgraded genomic assembly and annotation by sequencing paired-end and mate-paired libraries. We also performed transcriptome sequence analyses on multiple C. sinensis tissues (sucker, muscle, ovary and testis). Genes encoding molecules involved in responses to stimuli and muscle-related development were abundantly expressed in the oral sucker. Compared with other species, genes encoding molecules that facilitate the recognition and transport of cholesterol were observed in high copy numbers in the genome and were highly expressed in the oral sucker. Genes encoding transporters for fatty acids, glucose, amino acids and oxygen were also highly expressed, along with other molecules involved in metabolizing these substrates. All genes involved in energy metabolism pathways, including the ß-oxidation of fatty acids, the citrate cycle, oxidative phosphorylation, and fumarate reduction, were expressed in the adults. Finally, we also provide valuable insights into the mechanism underlying the process of pathogenesis by characterizing the secretome of C. sinensis. The characterization and elaborate analysis of the upgraded genome and the tissue transcriptomes not only form a detailed and fundamental C. sinensis resource but also provide novel insights into the physiology and pathogenesis of C. sinensis. We anticipate that this work will aid the development of innovative strategies for the prevention and control of clonorchiasis.