Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Progress in the genetic studies of spermatogenesis abnormalities.

About 15% couples suffer from infertility, half of which are caused by male factors. Male infertility usually manifests as teratozoospermia, oligospermia and/or asthenospermia, of which the most severe form is azoospermia. In this review, we summarize the recent progress in the study of genetic factors involved in nonobstructive azoospermia and teratozoospermia, Recently, with the rapid development of high-throughput chips and sequencing technologies, many genetic factors of spermatogenesis have been discovered and analyzed. For the nonobstructive azoospermia, genome-wide association studies (GWAS) and high-throughput sequencing revealed many risk loci of nonobstructive azoospermia. For the teratozoospermia, the application of whole-exome sequencing (WES) revealed a series of disease-causing genes, greatly enriching our knowledge of teratozoospermia including multiple morphological abnormalities of the flagella (MMAF). The discovery of lots of disease genes helped the characterization of the pathological mechanisms of male infertility. Therefore, a comprehensive and in-depth understanding of genetic factors in spermatogenesis abnormalities will play important roles in the clinical diagnosis, treatment and genetic counseling of male infertility.

Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

[Association of polymorphisms of potassium voltage-gated channel, KQT-like subfamily, member 1 and type 2 diabetes in Jiangsu province, China].

OBJECTIVE: To study the association of polymorphisms in the potassium voltage-gated channel, KQT-like subfamily,member 1(KCNQ1) gene with type 2 diabetes in Chinese population from Jiangsu province. METHODS: Subjects consisting of 2925 cases and 3281 controls were enrolled from a community based cohort study of type 2 diabetes in Wuxi in 2007 and a community based cross-sectional survey on chronic non-communicable disease in Nantong in 2009. Epidemiological questionnaire survey and physical examinations were conducted and 10 h overnight fasting blood samples of 5 ml were drawn for all subjects.Genotypes were determined by TaqMan OpenArray Genotyping System and i-PLEX Sequenom MassARRAY platform. The relationship between KCNQ1 gene polymorphism and risk of type 2 diabetes after adjustment for age,sex and body mass index (BMI) was analyzed. RESULTS: The C allele of rs2237897, rs2237892 and rs2237895 at KCNQ1 increased the risk of type 2 diabetes with adjusted OR (95%CI) value being 1.41(1.30-1.54), 1.35(1.24-1.47), 1.22(1.12-1.33) respectively (all P value < 0.05) under the additive genetic model after adjusted by age,sex and BMI. Stratification analyses in additive genetic model showed that the C allele of rs2237897 increased the risk of type 2 diabetes in subgroups stratified by age ( ≤ 56 years and > 56 years), sex (females and males), BMI (< 24 kg/m(2) and ≥ 24 kg/m(2)) with OR (95%CI) value being 1.39(1.22-1.59), 1.43(1.28-1.60), 1.40(1.26-1.55), 1.44(1.26-1.66), 1.48(1.33-1.66), 1.34(1.17-1.53) respectively (all P value< 0.05). CONCLUSION: Polymorphisms of rs2237897, rs2237892 and rs2237895 in the KCNQ1 gene were associated with occurrence of type 2 diabetes among Jiangsu province population.

Maternal and embryonic signals cause functional differentiation of luminal epithelial cells and receptivity establishment.

Embryo implantation requires temporospatial maternal-embryonic dialog. Using single-cell RNA sequencing for the uterus from 2.5 to 4.5 days post-coitum (DPC) and bulk sequencing for the corresponding embryos of 3.5 and 4.0 DPC pregnant mice, we found that estrogen-responsive luminal epithelial cells (EECs) functionally differentiated into adhesive epithelial cells (AECs) and supporting epithelial cells (SECs), promoted by progesterone. Along with maternal signals, embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, respectively, enhancing the attachment of embryos to the endometrium and furthering embryo development. This differentiation process was largely conserved between humans and mice. Notably, the developmental defects of SOX9-positive human endometrial epithelial cells (similar to mouse EEC) were related to thin endometrium, whereas functional defects of SEC-similar unciliated epithelial cells were related to recurrent implantation failure (RIF). Our findings provide insights into endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is crucial for endometrial receptivity.

[Single nucleotide polymorphism in flanking region of miR-30c influences the maturing process of miR-30c in lung carcinoma].

OBJECTIVE: To investigate the effect of a common polymorphism rs928508(A/G) in flanking region of miR-30c on the expression of pri, pre and mature miR-30c, and discuss the effect of this polymorphism on the maturing process of miR-30c in lung carcinoma. METHODS: The pGL3-promoter-miR-30c-A and pGL3-promoter-miR-30c-G luciferase plasmids were created containing A or G allele of miR-30c flanking region. Taqman assay was used to genotype rs928508 polymorphism in 50 lung cancer tissues. RT-PCR was performed to determine the expression of pri-miR-30c, pre-miR-30c, mature miR-30c and miR-30c host gene NFYC in the 50 lung cancer tissues. RESULTS: The luciferase expression level of the pGL3-promoter-miR-30c-A construct group was not significantly different compared with that in the the pGL3-promoter-miR-30c-G construct group (A549 cells, P = 0.758; 293A cells, P = 0.554; CHO cells, P = 0.175). The results demonstrated that rs928508(A/G) variant had no effect on the transcriptional regulation of pri-miR-30c. In the genotype-phenotype collection analysis of the 50 lung cancer tissues, the expression of pre-miR-30c and mature miR-30c for rs928508 AG/GG genotypes showed significantly lower levels compared with those in the AA genotype (P = 0.009, P = 0.011). However, the expression of pri-miR-30c showed no significant difference between AG/GG genotypes and AA genotype. Similarly, the expression of host NFYC gene was correlated with pri-miR-30c, showed no significant difference between AG/GG genotypes and AA genotype. CONCLUSION: The rs928508(A/G) polymorphism in flanking region of miR-30c could influence the processing from pri-miR-30c to mature miR-30c, but does not influence the transcription of pri-miR-30c.

[Random forest analysis of high dimensional case and control study of lung cancer].

OBJECTIVE: To investigate the performance of random forest method as a SNP screening procedure in high dimensional case-control data of lung cancer. METHODS: This study included 500 lung cancer patients and 517 controls. A total of 5 ml venous blood sample was collected from each participant. The genotypes were classified by GoldenGate platform, and 399 SNPs were selected. The random forest method was first applied to reduce the dimension, and then the traditional logistic regression method was used to analyze the variables and the genetic susceptibility between lung cancer and multiple SNPs was analyzed by AUC (areas under receiver operation characteristics (ROC) curves). RESULTS: Fifty important variables, whose average importance scores were highest and whose error rates were lowest, were selected by random forest method. The importance scores of environmental variables (smoking, age and gender) were all listed at top 20, which were respectively 4.05, 3.12 and 1.16. After adjusting 3 environmental variables and false discovery rate (FDR), 6 SNPs were still significantly associated with lung cancer (FDR-P < 0.05). However, if traditional logistic regression analysis were directly applied, no significant SNPs were found. The likelihood testing result of AUC of the 2 ROC (one curve only included environmental variables and the other curve included environmental variables and SNPs) were 0.6491 ± 0.0172 and 0.6811 ± 0.0166 respectively; showed statistical significance of the association between the 6 SNPs and lung cancer (χ² = 43.82, P = 3.6×10⁻¹¹). CONCLUSION: Random forest analysis could first remove the turbulent SNPs and then make the analysis by logistic regression method. This could improve the testing efficacy, which is significantly better than single logistic regression analysis.

The role of PTEN in primary sensory neurons in processing itch and thermal information in mice.

PTEN is known as a tumor suppressor and plays essential roles in brain development. Here, we report that PTEN in primary sensory neurons is involved in processing itch and thermal information in adult mice. Deletion of PTEN in the dorsal root ganglia (DRG) is achieved in adult Drg11-CreER: PTENflox/flox (PTEN CKO) mice with oral administration of tamoxifen, and CKO mice develop pathological itch and elevated itch responses on exposure to various pruritogens. PTEN deletion leads to ectopic expression of TRPV1 and MrgprA3 in IB4+ non-peptidergic DRG neurons, and the TRPV1 is responsive to capsaicin. Importantly, the elevated itch responses are no longer present in Drg11-CreER: PTENflox/flox: TRPV1flox/flox (PTEN: TRPV1 dCKO) mice. In addition, thermal stimulation is enhanced in PTEN CKO mice but blunted in dCKO mice. PTEN-involved regulation of itch-related gene expression in DRG neurons provides insights for understanding molecular mechanism of itch and thermal sensation at the spinal level.

[The relationship between gene polymorphism of telomerase reverse transcriptase and susceptibility to hepatocellular carcinoma].

OBJECTIVE: To explore the correlation between single-nucleotide polymorphisms (SNPs) of telomerase reverse transcriptase (TERT) rs2736098 and rs2736100 and the susceptibility to hepatocellular carcinoma (HCC). METHODS: This case-control study design included 1300 diagnosed HCC patients with HBsAg positive and 1344 HBsAg positive people as control-group.rs2736098 and rs2736100 on TERT were selected as research sites, whose polymorphisms were detected by TaqMan allelic discrimination assay. The OR values (95%CI) were calculated by logistic regression to compare the correlation between different genotype and susceptibility to HCC. RESULTS: The distribution frequencies of three genotypes as GG, AG and AA on rs2736098 were separately 39.3% (500/1273), 44.2% (563/1273) and 16.5% (210/1273) in case group; while respectively 39.6% (526/1328), 45.5% (604/1328) and 14.9% (198/1328) in control group. The distribution frequencies of three genotypes as AA, AC and CC on rs2736100 were separately 33.7% (428/1269), 49.9% (633/1269) and 16.4% (208/1269) in case group; while respectively 34.0% (449/1322), 49.2% (651/1322) and 16.8% (222/1322) in control group. The multi-variates logistic regression analysis showed that there was no significant difference between rs2736098 mutated A carriers and genotype GG carriers in the susceptibility to HCC after adjusting by age, sex, smoking and drinking factors (rs2736098, AA + AG vs GG: adjusted OR = 1.00 (95%CI: 0.86 - 1.18)); and there was no significant different between rs2736100 mutated C carriers and genotype AA carriers in the susceptibility to HCC either (AC + CC vs AA: adjusted OR = 1.03 (95%CI: 0.87 - 1.22)). CONCLUSION: The polymorphisms of rs2736098 and rs2736100 on TERT may not play a landmark role in susceptibility to HCC among Chinese population.

[Relationship between genetic polymorphism of promoter region let-7 and genetic susceptibility to hepatocellular carcinoma].

OBJECTIVE: The purpose of this study was to discuss the relationship between genetic polymorphism of promoter region let-7 and genetic susceptibility to hepatocellular carcinoma (HCC) in Chinese population. METHODS: In this case-control study, 1300 cases of HBV positive patients were recruited in case group and another 1344 cases of persistent chronic HBV carriers were selected as control. 5 ml of blood sample was collected from each subject, from which the DNA was extracted; and rs10877887 and rs13293512 in promoter region let-7 were selected as the study sites. The polymorphism was detected by TaqMan allelic discrimination assay and the OR value (95%CI) was evaluated by Logistic Regression Method to analyze the relationship between susceptibility to HCC and different genotypes. RESULTS: The frequencies of genotype TT, CT and CC in site rs10877887 were 43.0% (542/1261), 44.7% (564/1261) and 12.3% (155/1261) respectively in case group; while separately 44.0% (581/1319), 44.4% (585/1319) and 11.6% (153/1319)in control group. The frequencies of genotype TT, CT and CC in site rs13293512 were 32.0% (406/1270), 48.1% (611/1270) and 19.9% (253/1270) respectively in case group; while separately 33.1% (427/1291), 49.4% (638/1291) and 17.5% (226/1291) in control group. The results of multifactor logistic regression analysis showed no statistical significance in the relationship between different genotype TT, mutated genotype C in site rs10877887 and susceptibility to HCC (CC + CT vs TT, adjusted OR = 1.05, 95%CI: 0.90 - 1.23); and either no statistical significance in the relationship between different genotype TT, mutated genotype C in site rs13293512 and susceptibility to HCC (CC + CT vs TT, adjusted OR = 1.06, 95%CI: 0.89 - 1.25). The united-analysis of the two sites showed the frequencies of 0, 1, 2 and 3-4 mutated-genotype C were 13.3% (164/1235), 36.2% (447/1235), 33.0% (408/1235) and 17.5% (216/1235) respectively in case group; and separately 14.2% (181/1269), 37.0% (469/1269), 33.1% (420/1269) and 15.7% (199/1269) in control group. The susceptibility to HCC in 1,2,3-4 mutated-genotype C carriers were 1.05 (0.81 - 1.34), 1.07 (0.83 - 1.38) and 1.22 (0.91 - 1.62) times of the non-mutated genotype subjects; but there was no statistical significance (Wald χ(2) = 1.79, P = 0.181). CONCLUSION: The polymorphism of study sites rs10877887 and rs13293512 may not be the biomarker of susceptibility to HCC in Chinese.

[Relationship between genetic polymorphism in microRNAs precursor and genetic predisposition of hepatocellular carcinoma].

OBJECTIVE: To investigate the relationship between genetic polymorphism in microRNAs (miRNAs) precursor and genetic predisposition of hepatocellular carcinoma (HCC) in Chinese population. METHODS: A case-control study including 963 HCC cases and 829 HBsAg positive controls and 852 HBsAg negative controls was conducted. hsa-mir-146a rs2910164 C→G and hsa-mir-196-a2 rs11614913 T→C were selected, where the genotypes were determined by the primer introduced restriction analysis-PCR (PIRA-PCR) assay. Odd ratios (ORs) and 95% confidence intervals (CIs) were evaluated by logistic regression analysis to investigate the relationship between onset risk of HCC and different genotypes. RESULTS: The genotype frequencies of CC, CG and GG at rs2910164 gene locus were separately 34.5% (319/925), 48.6% (450/925) and 16.9% (156/925) in cases; 36.4% (274/753), 45.0% (339/753) and 18.6% (140/753) in HBsAg positive controls; and 36.1% (303/840), 46.0% (386/840) and 18.0% (151/840) in HBsAg negative controls. The genotype frequencies of TT, CT and CC at rs11614913 were respectively 29.7% (277/934), 48.1% (449/934) and 22.3% (208/934) in cases; 30.3% (238/785), 51.0% (400/785) and 18.7% (147/785) in HBsAg positive controls; and 28.6% (239/837), 49.8% (417/837) and 21.6% (181/837) in HBsAg negative controls. No significant relationships were observed between these two single nucleotide polymorphisms (SNPs) and onset risk of HCC after adjusting the factors as age, gender, smoking and drinking status in comparison with HBsAg positive controls: hsa-mir-146a rs2910164 (CG + GG vs CC): adjusting OR = 1.10, 95%CI: 0.90 - 1.36; hsa-mir-196-a2 rs11614913 (CC + CT vs TT): adjusting OR = 1.01, 95%CI: 0.81 - 1.25; as well as in comparison with HBsAg negative controls: hsa-mir-146a rs2910164 (CG + GG vs CC): adjusting OR = 1.06, 95%CI: 0.87 - 1.29; hsa-mir-196-a2 rs11614913 (CC + CT vs TT): adjusting OR = 0.94, 95%CI: 0.76 - 1.16. As well, no significant relationships were observed between these two SNPs and onset risk of HCC in the subgroups stratified by age, gender, smoking and drinking status. CONCLUSION: hsa-mir-146a rs2910164 C→G and hsa-mir-196-a2 rs11614913 T→C may not play an important role in the HCC predisposition among Chinese populations.

Plasma Vitamin D Levels And Vitamin D Receptor Polymorphisms Are Associated with Survival of Non-small Cell Lung Cancer.

OBJECTIVE: Vitamin D and its receptor (VDR) involve in multiple cellular processes and play an important role in the initiation and progression of malignancy. Thus we hypothesized that plasma vitamin D levels and single nucleotide polymorphisms (SNPs) in VDR may be of prognostic significance in non-small cell lung cancer (NSCLC). METHODS: We examined plasma 25-hydroxyvitamin D [25(OH)D] levels in 87 patients diagnosed with NSCLC using enzyme-linked immunosorbent assay (ELISA) and genotyped seven potentially functional SNPs in VDR in 568 NSCLC patients on Illumina Golden Gate platform. RESULTS: Patients with higher plasma 25(OH)D levels had worse survival than patients with lower ones (P for trend = 0.048). The SNPs of rs1544410 and rs739837 were independently associated with NSCLC survival (adjusted HR = 1.61, 95% CIs = 1.06-2.45 for rs739837 AA vs AC/CC and adjusted HR = 1.51, 95% CIs = 1.06-2.16 for rs1544410 AG/AA vs GG). A joint effect was observed between rs1544410 and rs739837 and the risk of death elevated as the number of unfavourable genotypes patients carried increased (P for trend = 0.003). There were no significant associations between VDR polymorphisms and plasma 25(OH)D levels. CONCLUSION: Our findings indicate that plasma 25(OH)D levels and genetic variants of VDR may serve as prognostic markers for NSCLC in this Chinese population.

Diagnostic and Predictive Values of Strain Ratios in the Regions of Interests in Reference Tissue for Breast Tumor.

PURPOSE: To investigate the diagnostic and predictive value of strain ratios in the regions of interests (ROIs) in reference tissue for breast tumor. PATIENTS AND METHODS: A total of 707 lesions in 665 consecutive patients were examined with B-mode Breast Imaging-Reporting and Data System (BI-RADS) and Ultrasonic elastography (UE). Elasticity score (ES) and strain ratio (SR) in each lesion were calculated. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of BI-RADS, ES, SR1, SR2, BI-RADS combined with ES (BI-RADS+ES), BI-RADS combined with SR1 (BI-RADS+SR1), and BI-RADS combined with SR2 (BI-RADS+SR2). The sensitivity, specificity, and areas under the ROC curves (Az) were obtained. Scatter plots were generated to demonstrate the correlation between SR1 and SR2. Kruskal-Walls H-test, Mann-Whitney U-test and one-way ANOVA were performed to evaluate SRs and tumor-related variables. Multiple linear regression analysis was carried out to determine variables independently associated with SRs. RESULTS: BI-RADS had high sensitivity and low specificity in the diagnosis of breast tumor. The specificity of BI-BADS combined with ES or SR was even higher. The Az value of BI-RADS+ES or BI-RADS+SRs was higher than that of BI-RADS (P < 0.001). The Az value of ES was higher than those of SR1 and SR2 (P < 0.001), and those of SR1 and SR2 were similar. SR1 and SR2 were highly positively correlated. There was no statistical difference between Az values of BI-RADS+ES, BI-RADS+SR1, and BI-RADS+SR2. Indistinct margin, high histologic grade, histological type, and negative human epidermal growth factor receptor (Her-2) were associated with SR1 and SR2. Progesterone receptor (PR) status and molecular subtype were associated with SR2. Histologic grade and tumor margin were significantly associated with SR1, and tumor margin was associated with SR2. CONCLUSION: SRs in different ROIs in the reference tissue at the same depth showed no different diagnostic value for breast tumor. Both SR1 and SR2 could be useful in assessing the biological characteristics of invasive breast carcinoma.

Cholesterol metabolic enzyme Ggpps regulates epicardium development and ventricular wall architecture integrity in mice.

During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underlying mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact, which makes epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

Dietary habits and risk of hepatocellular carcinoma among hepatitis B surface antigen carriers: A prospective cohort study in China.

OBJECTIVE: In this prospective cohort study, we aimed to evaluate the association between dietary habits and the risk of developing hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg)-positive carriers in Qidong, an hepatitis B virus (HBV)-epidemic area in China. METHODS: A total of 3199 HBsAg carriers aged 30-70 years in a prospective cohort in Qidong, China from 2007 to 2011 were included in the study. At baseline, all participants self-reported their dietary habits in a questionnaire interview. A follow-up check-up was performed every 6 months to identify HCC cases until November 2017. Cox's regression analysis and an interaction analysis were performed to estimate the relative risks of HCC in terms of baseline diet. RESULTS: Among 3199 HBsAg-positive participants, 270 developed HCC (143.86/100 000 person-years [PYs]). Compared with participants who rarely consume garlic, the risk of HCC in those who consumed it ≥ once per week decreased along with the increase in frequency (HR = 1.00, 0.90 and 0.62 in those who consumed it rarely vs those who consumed it 1-6 times per week and ≥ 7 times per week, respectively). This study found a synergistic effect between garlic and tea consumption on the risk of HCC (P = 0.039 for a multiplicative interaction). CONCLUSIONS: HBsAg carriers should improve their diet. Regular consumption of garlic and tea drinking may reduce the HCC incidence in HBsAg carriers.

Promoter polymorphisms of IL2, IL4, and risk of gastric cancer in a high-risk Chinese population.

Interleukin 2 (IL2) is a typical Th1 cytokine, and interleukin 4 (IL4) is an inducible Th2 cytokine. These cytokines are critical mediators of the Th1/Th2 balance and apoptosis potential and involved in the process of inflammation-mediated carcinogenesis in human organs, including the gastrointestinal tract. Therefore, we tested the hypothesis that functional variants in IL2 and IL4 were associated with risk of gastric cancer by genotyping two promoter polymorphisms in IL2 G-330T (rs2069762) and IL4 T-168C (rs2070874) in a case-control study of 1045 patients with incident gastric cancer and 1100 cancer-free controls in a high-risk Han Chinese population. We found that, compared with the IL4 -168TT genotype, heterozygous -168TC and combined -168TC/CC genotypes were associated with a significantly decreased gastric cancer risk [adjusted odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.98 for -168TC; OR = 0.83, 95% CI = 0.69-1.00 for -168TC/CC, respectively]. Furthermore, this significant protective effect was more evident for gastric cardia cancer patients (adjusted OR = 0.73, 95% CI = 0.56-0.95 for -168TC/CC vs. -168TT). For IL2 G-330T, subjects carrying GT/TT genotypes also had a significantly reduced risk of gastric cardia cancer (adjusted OR = 0.68, 95% CI = 0.46-0.99), compared with those carrying the GG genotype. Our results indicate that IL4 T-168C and IL2 G-330T promoter polymorphisms may contribute to the etiology of gastric cardia cancer in Chinese populations.

Multifunctional necklace-like Cu@cross-linked poly(vinyl alcohol) microcables with fluorescent property and their manipulation by an external magnet.

Unique magnetite-nanoparticles-attached necklace-like Cu@cross-linked poly(vinyl alcohol) (PVA) microcables with multi-functionalities can be synthesized by in situ loading the magnetite nanoparticles in the network structure of a cross-linked PVA sheath using a modified polyol method; the superparamagnetic and green fluorescent properties of the cables enable this type of magnetic functionalized microcables to be manipulated and detected easily for device fabrication.

Combining previously published studies with current data in Bayesian logistic regression model: an example for identifying susceptibility genes related to lung cancer in humans.

A general analysis method is proposed that utilizes meta-analysis to incorporate similar studies in addition to our current investigation in order to obtain informative prior effect parameters in a logistic regression model. It is common in epidemiological studies that data from similar previous studies are available. The case of gene susceptibility association with increased lung cancer frequency was used to demonstrate this methodology. Results of Markov chain Monte Carlo (MCMC) iterations provided a more precise estimation of the regression coefficient in a logistic model with informative prior distribution compared to the noninformative prior distribution model. In situations where similar historical data are available, it is proposed to include as much relevant information as previously published results in the analysis of current data.

Potentially functional polymorphisms of the vascular endothelial growth factor gene and risk of gastric cancer.

Vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, plays an important role in the development of different kind of tumors, including gastric cancer (GC). The aim of this study is to test the hypothesis that genetic variants of VEGF are associated with risk of GC. We genotyped four potentially functional polymorphisms (-2578C > A, -1498T > C, -634G > C, and +936C > T) of the VEGF gene in a population-based case-control study of 540 GC cases and 561 frequency-matched cancer-free controls in a high risk Chinese population. We found that none of the four polymorphisms or their haplotypes achieved significant difference in their distributions between GC cases and controls. Multiple logistic regression analyses revealed that GC risk was not significantly associated with the variant genotypes of the four VEGF polymorphisms as compared with their wild-type genotypes. In conclusion, our data did not support a significant association between VEGF SNPs and the risk of GC.

The prognostic role of HBV infection in chronic lymphocytic leukemia.

PURPOSE: We attempt to assess the impact of hepatis-B virus (HBV) status on the prognosis of chronic lymphocytic leukemia (CLL) using a Chinese case cohort. METHODS: Five hundred and one consecutive newly diagnosed subjects with CLL were enrolled in this case cohort. HBV infection was defined as hepatitis B surface antigen (HBsAg) positive or hepatitis-B core antibody (HBcAb) positive. Univariate and stepwise multivariate Cox regression analyses were used to screen the prognostic risk factors associated with the end point of time-to-treatment (TTT) or overall survival (OS). Bootstrap re-sampling method was used to evaluate the model's internal validity. The discriminative ability of the models was evaluated using time-dependent receiver-operator characteristic (ROC) curves and corresponding areas under the curve (AUC). RESULTS: One hundred and twenty-one subjects (24%) among 501 patients were HBV positive. HBV infection was an independent predictor for the prognosis of TTT (HR = 1.37; 95% CI 1.04-1.80) or OS (HR =2.85; 95% CI 1.80-4.52). The AUCs for HBV infection were 0.62 (95% CI 0.58-0.66) for TTT and 0.69 (95% CI 0.66-0.72) for OS, respectively. When we combined HBV infection with the traditional clinical and biological factors, significant improvements for model's discrimination were observed for TTT [AUC: 0.81 (95% CI: 0.77-0.85) vs. 0.78 (95% CI: 0.74-0.82), P < 0.001] and OS [AUC: 0.81 (95% CI 0.76-0.86) vs. 0.76 (95% CI 0.71-0.82), P < 0.001). Further bootstrap re-sampling method revealed good internal consistence for the final optimal models (Average AUC: 0.78 for TTT and 0.79 for OS based on 1000 bootstraps). CONCLUSIONS: Our results indicated that HBV infection should be served as an important risk predictor for prognosis of CLL (TTT and OS).