CD4/CD8 Ratio Recovered as a Predictor of Decreased Liver Damage in Adults Infected With HIV: 16-Year Observational Cohort Study.

BACKGROUND: As the life expectancy of individuals infected with HIV continues to increase, vigilant monitoring of non-AIDS-related events becomes imperative, particularly those pertaining to liver diseases. In comparison to the general population, patients infected with HIV experience a higher frequency of liver-related deaths. The CD4/CD8 ratio is emerging as a potential biomarker for non-AIDS-related events. However, few existing studies have been specially designed to explore the relationship between the CD4/CD8 ratio and specific types of non-AIDS-related events, notably liver damage. OBJECTIVE: This study aimed to investigate the potential association between the CD4/CD8 ratio and the development of liver damage in a sizable cohort of patients infected with HIV receiving antiretroviral treatment (ART). Additionally, the study sought to assess the effectiveness of 3 antiretroviral drugs in recovering the CD4/CD8 ratio and reducing the occurrence of liver damage in this population. METHODS: We conducted an observational cohort study among adults infected with HIV receiving ART from 2004 to 2020 in Guangxi, China. Propensity score matching, multivariable Cox proportional hazard, and Fine-Gray competing risk regression models were used to determine the relationship between the CD4/CD8 ratio recovered and liver damage. RESULTS: The incidence of liver damage was 20.12% among 2440 eligible individuals during a median follow-up period of 4 person-years. Patients whose CD4/CD8 ratio did not recover to 1.0 exhibited a higher incidence of liver damage compared to patients with a CD4/CD8 ratio recovered (adjusted hazard ratio 7.90, 95% CI 4.39-14.21; P<.001; subdistribution hazard ratio 6.80, 95% CI 3.83-12.11; P<.001), findings consistent with the propensity score matching analysis (adjusted hazard ratio 6.94, 95% CI 3.41-14.12; P<.001; subdistribution hazard ratio 5.67, 95% CI 2.74-11.73; P<.001). The Efavirenz-based regimen exhibited the shortest time for CD4/CD8 ratio recovery (median 71, IQR 49-88 months) and demonstrated a lower prevalence of liver damage (4.18/100 person-years). CONCLUSIONS: Recovery of the CD4/CD8 ratio was associated with a decreased risk of liver damage in patients infected with HIV receiving ART, adding evidence for considering the CD4/CD8 ratio as a potential marker for identifying individuals at risk of non-AIDS-related diseases. An efavirenz-based regimen emerged as a recommended choice for recovering the CD4/CD8 ratio and mitigating the risk of liver damage.

Trends and associated factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area: an 11-year cross-sectional study (2010-2020).

BACKGROUND: Data on recent human immunodeficiency virus (HIV), hepatitis C virus (HCV) and syphilis prevalence among drug users in the Southwest China are sparse despite the high burden of drug use. This study aims at assessing the prevalence trends and related factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area. METHODS: A continuous cross-sectional survey was conducted among drug users from 2010 to 2020 in the China-Vietnam border area. Chi-square trend tests were used to assess the trend of HIV, HCV and syphilis prevalence and the proportion for drug type used by drug users. Multivariate logistic regression was used to identify associated factors of HIV, HCV and syphilis infection in different drug users. RESULTS: In this study, a total of 28,951 drug users were included, of which 27,893 (96.45%) male, 15,660 (54.09%) aged 13-34 years, 24,543 (84.77%) heroin-only users, 2062 (7.12%) synthetic drug-only (SD-only) users and 2346 (8.10%) poly-drug users. From 2010 to 2020, the proportion of heroin-only users decreased from 87.79% to 75.46%, whereas SD-only users and poly-drug users increased from 5.16% to 16.03%, and from 7.05% to 8.52%, respectively. The prevalence of HIV, HCV, and syphilis during the study period declined from 12.76%, 60.37% and 5.72% to 4.35%, 53.29% and 4.53%, respectively, among heroin-only users and declined from 18.30%, 66.67% and 15.69% to 6.95%, 27.81% and 5.35%, respectively, among poly-drug users; however, the prevalence of HIV and HCV among SD-only users increased from 0.89% and 8.93% to 2.84% and 18.75%, respectively. Having ever injected drugs and needle sharing were common associated factors for both HIV and HCV infection among poly-drug users and heroin-only users. Aged ≥ 35 years old was an associated factor for HIV, HCV and syphilis infection among the SD-only users. Female drug users were at high risk of contracting syphilis among three different drug users. CONCLUSIONS: The prevalence of HIV, HCV and syphilis among heroin-only users and poly-drug users decreased during the study period. However, the prevalence of HIV and HCV among SD-only users increased. Comprehensive intervention strategies, particularly focusing on the SD-only users are needed in order to bring down the disease burden in this population in the China-Vietnam border areas.

lncRNA CDKN2A-AS1 facilitates tumorigenesis and progression of epithelial ovarian cancer via modulating the SOSTDC1-mediated BMP-SMAD signaling pathway.

Ovarian cancer (OC) is the fifth most common female malignant tumor and the leading cause of cancer-related death in women worldwide. Epithelial ovarian cancer (EOC) is the predominant type of OC. Investigating the mechanism underlying tumorigenesis and progression of EOC is urgent. Our previous research has shown that long non-coding RNAs (lncRNAs) CDKN2A-AS1 is upregulated in EOC tissues and cells. Furthermore, we have predicted that CDKN2A-AS1 is associated with the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is negatively regulated by the sclerostin domain containing 1 (SOSTDC1). Therefore, we conjecture that the CDKN2A-AS1 regulate BMP-SMAD signaling pathway via interacting with SOSTDC1, which need more investigation. Moreover, the functions of the BMP-SMAD signaling pathway and the SOSTDC1 on EOC are still unclear. Herein, we unearthed that CDKN2A-AS1, BMP2/4/7, SMAD1/5/9 and phosphorylation of SMAD1/5/9 (p-SMAD1/5/9) were upregulated in EOC tissues and cells, whereas SOSTDC1 was downregulated in EOC tissues and cells. We firstly demonstrated that CDKN2A-AS1 bound directly with the SOSTDC1. CDKN2A-AS1 downregulated the expression of SOSTDC1, but upregulated the expression of BMP2/4/7, SMAD1/5/9, and p-SMAD1/5/9. CDKN2A-AS1 promoted the proliferation, migration, invasion of EOC cells and tumor growth in vivo, whereas SOSTDC1 inhibited the proliferation, migration, invasion of EOC cells. Knockdown SOSTDC1 rescued the inhibitory effect of si-lncRNA CDKN2A-AS1 on the EOC cells proliferation, migration and invasion. These results demonstrated that CDKN2A-AS1activated the BMP-SMAD signaling pathway by directly bind with SOSTDC1 to promote EOC tumor growth. CDKN2A-AS1/SOSTDC1 axis may provide a novel therapeutic strategy for EOC treatment.

Microarray profiling and co-expression network analysis of lncRNAs and mRNAs in ovarian cancer.

Dysregulated long noncoding RNAs (lncRNAs) are involved in the pathogenesis and development of human diseases, such as epithelial ovarian cancer (EOC). In this study, we identified EOC-related lncRNAs and performed lncRNA and mRNA microarray analyses using IOSE80, a normal ovary cell line, and two ovarian carcinoma cell lines (SKOV3 and SKOV3/DDP) to investigate the potential roles of lncRNAs in EOC. lncRNA-HEIH expression in EOC tissues and cell lines was measured by quantitative real-time polymerase chain reaction (qPCR). In addition, we generated a lncRNA-mRNA co-expression network in order to identify lncRNA-expression trends and potential lncRNA target genes. Cell viability, migration, and invasion were determined by Cell Counting Kit-8, transwell assay, and wound-healing assay, respectively, and apoptosis was analyzed by flow cytometry. We identified 3527 differentially expressed lncRNAs upon comparison of the lncRNA profiles from IOSE80 with those of SKOV3 cell lines, with 11 differentially expressed lncRNAs confirmed by qPCR. Both pathway and gene ontology analyses demonstrated the involvement of lncRNAs, especially HEIH and LINC-PINT, in multiple biological processes. Furthermore, in vitro knockdown experiments confirmed that suppression of HEIH expression inhibited EOC cell proliferation. Our findings provide a foundation for further research into the role of these lncRNAs in EOC carcinogenesis and progression.

12-HETE facilitates cell survival by activating the integrin-linked kinase/NF-κB pathway in ovarian cancer.

BACKGROUND: The dysfunction of cell apoptosis is an important event in the progression of cancer, and the growth of cancer cells is negatively regulated by cell apoptosis. In different types of cancers, inhibition of cellular apoptosis is often observed in the cancerous tissue, and increased resistance to apoptosis is a hallmark of cancer. Although previous studies have shown that 12-lipoxygenase (12-LOX)/12-hydroxyeicosatetraenoic acid (12-HETE) is activated and upregulated in different types of cancers, the consequences of 12-LOX/12-HETE upregulation and its precise roles in the survival of ovarian carcinoma cells are still unknown. METHODS: MTT assays, caspase activity assays, lactate dehydrogenase (LDH) assays, and Western blot analysis were the methods used in this study. RESULTS: In our study, we found that 12-HETE, a major metabolic product of arachidonic acid using 12-LOX catalysis, inhibited cell apoptosis in a dose-dependent manner and that the effects of 12-HETE on cell apoptosis were mediated by the integrin-linked kinase (ILK) pathway. Moreover, the downstream target of 12-HETE-activated ILK was nuclear factor kappa-B (NF-κB) in ovarian carcinoma. The inhibitory effects of 12-HETE on cell apoptosis were attenuated by the inhibition of the NF-κB pathway. CONCLUSION: These results indicate that 12-HETE participates in the inhibition of cell apoptosis by activating the ILK/NF-κB pathway, implying an important underlying mechanism that promotes the survival of ovarian cancer cells.

Effect of integrin­linked kinase gene silencing on microRNA expression in ovarian cancer.

Integrin­linked kinase (ILK) is overexpressed in ovarian cancer (OC), and ILK gene silencing results in apoptosis in OC cells. In the present study, the mechanism by which ILK induces apoptosis was explored from the perspective of microRNA (miRNA) expression. Alterations in the global miRNA expression profile were detected using a miRNA microarray after OC cells were transduced with an ILK small hairpin RNA lentivirus. ILK silencing led to a significant upregulation of 14 miRNAs by at least 1.5­fold. These findings were validated by reverse transcription­quantitative polymerase chain reaction. A pathway analysis of experimentally validated target genes revealed the inhibition of multiple cancer­associated signaling pathways and the wnt signaling pathway. Compared with cells transfected with scrambled RNA, the ILK­silenced cells had remarkably lower expression of wnt ligands (wnt3a, wnt4 and wnt5a) and downstream ß­catenin. ILK silencing led to apoptosis of OC cells and impaired the migratory ability. Taken together, the present results suggested that miRNA­mediated wnt pathway alterations are involved in the anti­apoptotic role of ILK in OC. It was also indicated that ILK silencing reduced the ability of OC cells to adhere to fibronectin, which may lead to unstable focal contact. Consistently, the phosphorylation levels of focal adhesion kinase and RAC­α serine/threonine protein kinase were downregulated. The present work demonstrated the first global miRNA expression profile of OC cells when ILK was inhibited, and this expression profile may provide a basis for the development of biomarkers and therapeutic targets for OC.

Associations between antioxidant vitamins and the risk of invasive cervical cancer in Chinese women: A case-control study.

Previous studies on the associations between dietary antioxidant vitamins and the risk of cervical cancer remain inconsistent, and little evidence is available for serum antioxidant vitamins, which provide more accurate measurements of these nutrients. We conducted a case-control study of 458 incident cases with invasive cervical cancer and 742 controls to assess the effects of diet or serum antioxidant vitamins. Higher serum antioxidant vitamins were associated with a lower risk of cervical cancer after adjusting for potential confounders. The odds ratios (ORs) for the highest (vs. lowest) quartile were 0.66 (95% confidence interval [CI] = 0.46-0.93; P = 0.024) for α-carotene, 0.63 (95% CI = 0.45-0.90; P = 0.006) for ß-carotene, 0.53 (95% CI = 0.37-0.74; P < 0.001) for vitamin E, and 0.48 (95% CI = 0.33-0.69; P < 0.001) for vitamin C. Dietary intakes of vitamins E and C were inversely associated with the risk of cervical cancer. Risk of cervical cancer from serum antioxidant vitamins was more evident in passive smokers than non-passive smokers. These findings indicated that antioxidant vitamins (mainly α-carotene, ß-carotene, and vitamins E and C) might be beneficial in reducing the risk of invasive cervical cancer in Chinese women, especially in passive smokers.

RNAi-mediated knockdown of the CLN3 gene inhibits proliferation and promotes apoptosis in drug-resistant ovarian cancer cells.

CLN3 is a recently identified anti-apoptotic gene, which has been demonstrated to be highly expressed in a diverse range of cancer cell lines, including ovarian cancer. In the present study, RNA interference, mediated by a lentivirus expressing CLN3 short hairpin RNA (shRNA) was utilized to knockdown the expression of CLN3 in the A2780 human ovarian cancer cell line, and its cisplatin­resistant and carboplatin­resistant sublines, A2780/DDP and A2780/CBP cells. It was revealed that the mRNA and protein expression levels of CLN3 were significantly reduced in the CLN3­specific shRNA­transduced cells, compared with the untransduced and control shRNA­transduced cells. In addition, specific knockdown of CLN3 in these cells inhibited cell proliferation and led to cell cycle arrest at the G0/G1 phase, with eventual apoptosis. CLN3 knockdown caused increases in the levels of Bax, FAX, cleaved­caspase 3, cleaved­caspase 8 and cleaved­RARP, but decreased the level of Bcl­2. Finally, it was observed that CLN3 depletion markedly reduced the half maximum inhibitory concentration in the A2780/DDP and A2780/CBP cells. Taken together, these data suggested that CLN3 is involved in tumorigenesis and drug resistance in ovarian cancer, and may serve as a promising therapeutic target for its treatment.

Polymorphism in PHD1 gene and risk of non-small cell lung cancer in a Chinese population.

Hypoxia is a common phenomenon in the development of solid tumors, and hypoxia inducible factor 1 (HIF-1) plays a central role in coordinating the cellular response to hypoxia and in oxygen homeostasis. The prolyl hydrolase 1 (PHD1) is a key adjustment factor that mediates the HIF-1 degradation and relates with the process of tumorigenesis. Thus, polymorphism in PHD1 may affect cellular response to hypoxic conditions and associate with cancer susceptibility. We conducted a case-control study with 406 non-small cell lung cancer cases and 812 healthy controls matched on age and sex to examine the effect of rs10680577 polymorphism within the PHD1 promoter on non-small cell lung cancer (NSCLC) risk in a Chinese population. The genotype of rs10680577 polymorphism was detected by non-denaturing polyacrylamide gel electrophoresis. The ins/del genotype of rs10680577 was associated with significantly increased non-small cell lung cancer risk (ins/del vs. ins/ins: OR = 1.35, 95 % confidence interval (CI) 1.05-1.74, P = 0.020; ins/del vs. ins/ins + del/del: OR = 1.34, 95 % CI = 1.04-1.72, P = 0.022). In addition, the association was more pronounced in the group of >60 years of age. rs10680577 polymorphism is associated with the risk of non-small cell lung cancer in a Chinese population. This is the first time to show that PHD1 rs10680577 is associated NSCLC risk.

Revealing the architecture of genetic and epigenetic regulation: a maximum likelihood model.

Gene expression is modulated by multiple mechanisms, including genetic and/or epigenetic regulation, and associated with the processes of cellular differentiation and morphogenesis. Single nucleotide polymorphisms (SNPs) and DNA methylation play important roles in regulating gene expression. In this study, we focused on revealing the relationship between SNPs, DNA methylation and gene expression in two human populations genome-wide through proposing four regulation patterns and developed maximum likelihood estimate models. Using simulated data with different correlation coefficients between any two traits, the power of our approach showed a favourable performance and relative stability. In all, 6733 SNP-CpG-gene pairs including 957 genes were obtained in Northern European ancestry (CEU) population. As the results showed, SNPs and DNA methylation had approximately the same effect on expression regulation of 49% genes, which was termed cooperative/antagonistic regulation pattern. Less than 30% of genes are controlled only by one of the factors (SNP/DNA methylation). The others showed SNPs that affect methylation have no consequent effects or crosstalk regulation on gene expression. Similar result was shown in Yourba (YRI) population. Specific genes were inferred using the different mechanisms of gene regulation involved in complex diseases by combining literature. This approach provides a method to comprehensively assess regulation patterns of gene expression in the whole genome.

Small metal soft tissue foreign body extraction by using 3D CT guidance: a reliable method.

OBJECTIVE: To introduce a useful and accurate technique for the locating and removal of small metal foreign bodies in the soft tissues. METHODS: Eight patients presented with suspected small metal foreign bodies retained in the soft tissues of various body districts. Under local anesthesia, 3-6 pieces of 5 ml syringe needles or 1 ml syringe needles were induced through three different planes around the entry point of the foreign bodies. Using these finders, the small metal FBs were confirmed under 3D CT guidance. Based on the CT findings, the soft tissues were dissected along the path of the closest needle and the FBs were easily found and removed according to the relation with the closest needle finder. RESULTS: Eight metal foreign bodies (3 slices, 3 nails, 1 fish hook, 1 needlepoint) were successfully removed under 3D CT guidance in all patients. The procedures took between 35 min and 50 min and the operation times took between 15 min and 25 min. No complications arose after the treatment. CONCLUSION: 3D CT-guided technique is a good alternative for the removal of small metal foreign body retained in the soft tissues as it is relatively accurate, reliable, quick, carries a low risk of complications and can be a first-choice procedure for the extraction of small metal foreign body.

Association of homocysteine, asymmetric dimethylarginine, and nitric oxide with preeclampsia.

PURPOSE: Endothelial dysfunction underlies the pathogenesis of preeclampsia, but its mechanism has not yet been completely understood. In this study we have aimed to measure homocysteine (Hcy), asymmetric dimethylarginine (ADMA), and nitric oxide (NO) levels as endothelial dysfunction markers in preeclamptic women. METHODS: Control-case study with 62 preeclamptic patients and 30 controls without pregnancy complications was conducted. Plasma total Hcy, determined by capillary column gas chromatography/mass spectrometry (GC/MS), was correlated with serum ADMA (determined by liquid chromatography/tandem mass spectrometry using (13)C(6)-L: -arginine as the internal standard) and NO (analyzed by GC/MS). RESULTS: There was a highly significant increase in the plasma concentration of homocysteine (P < 0.001) and ADMA (P < 0.001) and a highly significant decrease in the plasma concentration of nitric oxide (P < 0.001) among the preeclamptic patients. The differences were more significant between mild and severe preeclampsia, with and without eclampsia, with and without HELLP (hemolysis, elevated serum level of liver enzymes, and low platelets). In the combined patients and control groups a highly significant positive correlation was found between the plasma concentrations of homocysteine and ADMA (r = 0.853, P < 0.001). In addition, significant negative correlations were detected between the plasma concentrations of nitric oxide and the plasma concentration of homocysteine (r = -0.870, P < 0.001) and ADMA (r = -0.895, P < 0.001). These significant correlations were found to persist, even when they were restricted to the preeclamptic patients. CONCLUSIONS: The homocysteine-ADMA-NO may be at least partly responsible for etiology in preeclampsia and could be regarded as markers for the severity of the disease. Therefore, L: -arginine may represent a novel therapy for the treatment of preeclampsia.

[Study of teratogenicity of hyperglycemia on neural tube defects and antagonistic effect of taurine].

OBJECTIVE: To explore the molecular mechanism of neural tube defects (NTDs) caused by hyperglycemia and thiadiazole and the antagonistic effect of taurine. METHODS: The pregnant mice were divided into hyperglycemia groups, thiadiazole group, taurine groups and control groups. The mRNA and the protein of Pax3 or Cx43 gene were detected respectively by reverse transcription-polymerase chain reaction assay and immunohistochemical method. RESULTS: As compared with mice treated by thiadiazole-stomach-perfusing, NTDs were significantly increased from mice treated with glucose-injection when blood glucose levels were >or= 13.4 mmol/L. Elevated glucose and thiadiazole could cause changes in Pax3 and Cx43 expression. Hyperglycemia had stronger developmental toxicity on mice embryos. Expression of Pax3 (mRNA 0.97 +/- 0.20, protein 0.11 +/- 0.02) in hyperglycemia group was significantly decreased, while expression of Cx43 (mRNA 7.05 +/- 1.63, protein 0.94 +/- 0.05) was significantly increased, and the relationship of dose-effect was demonstrated. In the thiadiazole group, the expression of Cx43 (mRNA 6.96 +/- 0.73, protein 0.92 +/- 0.12) was significantly stronger than control groups, but there were no significant differences in expression of Pax3 between thiadiazole and its control groups. Both of their teratogenicity could be antagonized by taurine. CONCLUSIONS: This study suggests that congenital malformation associated with diabetic pregnancy is caused by disruption of regulatory genes, Pax3 and Cx43 expression in embryo in response to elevated glucose. Thiadiazole can only disturb the regulation of Cx43 gene causing NTDs. Taurine can correct the disruption caused by the two teratogens.