Association between interpregnancy interval and gestational diabetes mellitus: A cohort study of the National Vital Statistics System 2020.

OBJECTIVE: To assess the association between interpregnancy interval (IPI) and gestational diabetes mellitus (GDM). METHODS: Data of this retrospective cohort study were obtained from the National Vital Statistics System (NVSS) 2020. The participants were divided into different groups according to different IPI (<6, 6-11, 12-17, 18-23, 24-59 (reference), 60-119, ≥120 months). Multivariate logistic models were constructed to evaluate the association between IPI and GDM. Subgroup analysis was further performed. RESULTS: A total of 1 515 263 women were included, with 123 951 (8.18%) having GDM. Compared with the 24-59 months group, the <6 months (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.46-0.90, P = 0.009), 12-17 months (OR 0.96, 95% CI 0.94-0.98, P < 0.001), and 18-23 months (OR 0.94, 95% CI 0.93-0.96, P < 0.001) groups had a significantly lower risk of GDM, while the 60-119 months (OR 1.13, 95% CI 1.11-1.15, P < 0.001) and ≥120 months (OR 1.18, 95% CI 1.15-1.21, P < 0.001) groups had a significantly higher risk of GDM. No significant difference was observed in the risk of GDM between the 6-11 and 24-59 months groups (P = 0.542). The PI-GDM association varied across different groups of age, pre-pregnancy body mass index, pre-pregnancy smoking status, history of cesarean section, history of preterm birth, prior terminations, and parity. CONCLUSION: An IPI of 18-23 months may be a better interval than 24-59 months in managing the risk of GDM.

CircCCNB1 Knockdown Blocks the Progression of Cervical Cancer by Acting as Competing Endogenous RNA in the miR-370-3p/SOX4 Pathway.

OBJECTIVE: Cervical cancer is one of the leading causes of cancer-related death in women, which has been shown to be associated with the deregulation of circular RNAs (circRNAs). The aim of this study was to determine the role of circRNA cyclin B1 (circCCNB1) in cervical cancer. METHODS: The expression of circCCNB1, microRNA-370-3p (miR-370-3p), and SRY-box transcription factor 4 (SOX4) mRNA was detected by quantitative real-time PCR (qPCR). Functional experiments, including colony formation assay, EdU assay, transwell assay and flow cytometry assay, were performed. Lactate production and glucose uptake were examined to assess glycolysis metabolism. The protein levels of glycolysis-related markers and SOX4 were detected by western blot. The interaction between miR-370-3p and circCCNB1 or SOX4 was verified by dual-luciferase reporter, RIP, and pull-down assay. Xenograft assay was performed to monitor the role of circCCNB1 in animal models. RESULTS: CircCCNB1 was highly expressed in cervical cancer tissues and cells (squamous cell carcinoma and adenocarcinoma cells). The knockdown of circCCNB1 inhibited cell proliferation, migration, invasion and glycolysis metabolism, and induced cell apoptosis. CircCCNB1 functioned as miR-370-3p sponge to suppress miR-370-3p expression and function. Moreover, circCCNB1 inhibited the expression of miR-370-3p to increase the expression of SOX4. MiR-370-3p inhibition reversed the effects of circCCNB1 knockdown and thus promoted cell proliferation, migration, invasion and glycolysis. SOX4 overexpression reversed the effects of miR-370-3p restoration and thus promoted cell proliferation, migration, invasion and glycolysis. CONCLUSION: CircCCNB1 knockdown blocks cervical cancer development by targeting the miR-370-3p/SOX4 pathway.

Trends in surgical approaches and adnexal surgeries during hysterectomies for benign diseases between 2015-2021.

Background: Hysterectomy is a widely used surgical approach for benign gynecological conditions, although recently there have been differences in the surgical route selected in different regions. Aims: To estimate recent temporal trends, this study collected data on surgical approaches and adnexal surgeries during hysterectomies for benign diseases at a single institute from 2015 to 2021. Materials and methods: We retrospectively analyzed data from Xiangyang No.1 People's Hospital, Hubei University of Medicine in Xiangyang, China, and identified 1828 women who underwent hysterectomies for benign gynecologic conditions performed with or without bilateral salpingectomy (BS) or bilateral salpingo-oophorectomy (BSO) between January 2015 and December 2021. Results: There was an upward trend in the performance of hysterectomy and hysterectomy with BS, and there was a difference in the trends of concomitant adnexal surgery between AH, TLH, and VH, especially in TLH with BS. Patient characteristics data demonstrated that the most frequent indication for hysterectomy was leiomyoma, especially in women aged 45 to 65. Compared to AH, TLH, and VH, the operative bleeding, duration of surgery, and length of hospital stays of patients undergoing TLH with BS and BSO was the lowest. The surgical approach to benign diseases has changed dramatically due to a growing proportion of patients choosing minimally invasive procedures. The laparoscopic approach is becoming popular due to its capacity to decrease intraoperative blood loss and reduce hospitalization. Conclusions: We should put more emphasis on surgical training for the TLH approach and help gynecologic surgeons provide the proposed added benefit of BS to their patients.

Resistant-Associated Substitutions Do Not Affect HCV RNA and HCV Core Antigen Clearance During Direct-Acting Antiviral Agent Treatment in a Real-World Setting.

Background: Since oral direct-acting antiviral agents (DAAs) became available, the global hepatitis C treatment situation has undergone tremendous changes. However there are still many issues worthy of attention in treatment. Methods: We selected 53 HCV-infected patients who were treated and followed up in the Peking University First Hospital from December 2017 to January 2021 to detect the RASs in HCV. Pearson correlation analysis was used to analyze HCV RNA and HCV cAg, the Fisher exact test and chi-square test was used to compare the effects of RASs on the rate of decline of HCV RNA and HCV core antigen (cAg) during DAA treatment. Results: The RASs and its prevalence on the NS3 are mainly Y56F 2.56% (1/39), Q80K 23.08% (9/39), S122G 71.79% (28/39), and V170I 38.46% (15/39). On the NS5A were R30Q 10.53% (4/38), P32A 5.26% (2/38), P58S 2.63% (1/39), and Y93H 21.05% (8/38). On NS5B were C316N 71.05% (27/38), C451H 2.63% (1/38), and I585C 2.63% (1/38). There was no significant correlation between the RASs (Y93H, V179I, Q80K, S122G, C316N) and HCV genotype (p > 0.05). The baseline serum HCV RNA and HCV cAg had a significant medium-degree correlation (r = 0.601, p = 0.002). After 1 week of DAA treatment was weak correlation (r = 0.413, p = 0.032). Q80K, S122G, V170I, Y93H, and C316N had no effect on the clearance of HCV RNA and HCV cAg within the first week of DAA treatment (p>0.05). Conclusion: The HCV genotype may have a limited impact on the presence of the five RASs (Y93H, V179I, Q80K, S122G, and C316N) as shown in this study. HCV RNA and HCV cAg have a correlation, especially at baseline is the highest; the appearance of some RASs has no effect on DAA treatment in most chronic hepatitis C patients.

Circ_FOXP1 promotes the growth and survival of high glucose-treated human trophoblast cells through the regulation of miR-508-3p/SMAD family member 2 pathway.

Gestational diabetes mellitus (GDM) is a health risk for pregnant women and infants. Emerging evidence suggests that the deregulation of circular RNAs (circRNAs) is associated with the progression of this disorder. The objective of this study was to investigate the role of circ_FOXP1 in GDM. Cell models of GDM were established by treating human trophoblast cells with high glucose (HG). The expression of circ_FOXP1, miR-508-3p and SMAD family member 2 (SMAD2) mRNA was detected by quantitative real-time PCR (qPCR). Cell proliferation was assessed by EdU assay and MTT assay, and cell cycle and cell apoptosis were determined by flow cytometry assay. The protein levels of proliferation- and apoptosis-related markers and SMAD2 were measured by western blot. The relationship between miR-508-3p and circ_FOXP1 or SMAD2 was validated by dual-luciferase reporter assay or pull-down assay. The expression of circ_FOXP1 was downregulated in HG-treated HTR-8/SVneo cells. Circ_FOXP1 overexpression promoted HG-inhibited HTR-8/SVneo cell proliferation and suppressed HG-induced HTR-8/SVneo cell cycle arrest and apoptosis. Circ_FOXP1 positively regulated the expression of SMAD2 by targeting miR-508-3p. MiR-508-3p was overexpressed in HG-treated HTR-8/SVneo cells, and its overexpression reversed the effects of circ_FOXP1 overexpression. MiR-508-3p inhibition also alleviated HG-induced HTR-8/SVneo cell injuries, while the knockdown of SMAD2 abolished these effects. Collectively, circ_FOXP1 promotes the growth and survival of HG-treated human trophoblast cells through the miR-508-3p/SMAD2 pathway, hinting that circ_FOXP1 was involved in GDM progression.

Dose-response relationship between qAnti-HBc and liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase based on liver biopsy.

The proportion of chronic hepatitis B (CHB) patients with normal or mildly elevated alanine transaminase (NMALT) levels who have moderate to severe inflammation was not rare. However, we lacked appropriate biomarkers to evaluate liver inflammation in these populations. We aimed to explore the relationship between quantitative hepatitis B core antibody (qAnti-HBc) and hepatic histological inflammation. This multicenter cohort study enrolled participants from 34 Chinese hospitals including 1376 treatment-naive CHB patients with liver biopsy (934 with NMALT entered treatment-naive cohort; 423 with secondary liver biopsy entered treatment cohort). Using unadjusted and multivariate-adjusted generalized linear models, generalized additive models with smooth curve fitting, we evaluated the associations between qAnti-HBc and liver inflammation in these patients. In the treatment-naive patients, qAnti-HBc was positively associated with liver inflammation (histology activity index [HAI] evaluated by Ishak scoring system; fully adjusted model: ß = 0.48, 95% confidence interval [CI] [0.30-0.66], p < 0.001). For per-SD increase in qAnti-HBc, the risk of moderate to severe inflammation (HAI ≥ 5) increased by 56% (odds ratio [OR] = 1.56, 95% CI [1.28-1.91], p < 0.001). The curve fitting indicated a significant "threshold effect" (inflection point was 4.5 log10  IU/ml, p < 0.001). Subgroup analyses and interactions were not significant (all p > 0.05). In the treatment patients, there was no significant correlation between qAnti-HBc and liver inflammation, whether based on unadjusted, minimally adjusted, or fully adjusted models (all p > 0.100). Paired analyses showed a significant correlation between decreasing in qAnti-HBc and alleviation of liver inflammation. qAnti-HBc was positively correlated with liver inflammation in treatment-naive CHB patients with NMALT. The cutoff value of qAnti-HBc for the diagnosis of moderate to severe inflammation was 4.5 log10  IU/ml. Decreasing in qAnti-HBc was positively correlated with liver inflammation relieving.

Evaluation of the association of a variant in PNPLA3 and TM6SF2 with fibrosis progression in patients with chronic hepatitis C infection after eradication: A retrospective study.

The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24 weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI] = 1.096-5.794, p = 0.03). The G and GG alleles were predictive of advanced fibrosis (OR = 1.98, 95% CI = 1.021-4.196, p = 0.015; OR = 3.12, 95% CI = 1.572-6.536, p = 0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI = 1.081-6.29, p = 0.033). T and TT alleles were predictive of advanced fibrosis (OR = 2.3, 95% CI = 1.005-5.98, p = 0.007; OR = 3.05, 95% CI = 1.32-6.87, p = 0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI = 0.707-2.959, p = 0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR = 2.47, 95% CI = 1.125-5.89, p = 0.003). The GG alleles were predictive of fibrosis progression (OR = 2.95, 95% CI = 1.35-6.35, p = 0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI = 1.006-5.373, p = 0.045; 95% CI = 1.18-5.75, p = 0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR = 2.218, 95% CI = 1.095-5.631, p = 0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR = 2.558, 95% CI = 1.252-5.15, p = 0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI = 1.013-5.592, p = 0.038; 95% CI = 1.25-5.956, p = 0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI = 1.02-2.575, p = 0.017; and HR2.109, 95% CI = 1.36-3.271, p = 0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR = 1.322, 95% CI = 1.003-1.857, p = 0.045; and HR = 1.855, 95% CI = 1.35-2.765, p = 0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.

High levels of soluble programmed death-1 are associated with virological response in chronic hepatitis B patients after antiviral treatment.

BACKGROUND: Soluble programmed cell death protein-1 (sPD-1) plays an important role in chronic hepatitis B virus (HBV) infection by counteracting the inhibitory effect of programmed death ligand-1 (PD-L1) on immune cells. Here, we investigated the ability of sPD-1 to predict the virological response (VR) in chronic hepatitis B (CHB) patients undergoing Nucleos(t)ide analogue (NA) therapy. METHODS: CHB patients [hepatitis B surface antigen (HBsAg) positive ≥6 months] who initiated NA therapy in March 2007 at Peking University First Hospital (China) were enrolled in this study. Eighty-nine CHB patients were followed-up every 12 weeks for 96 weeks. RESULTS: Serum sPD-1 levels at baseline were negatively correlated with hepatitis B surface antigen (HBsAg) and HBV DNA. Immune-active CHB patients exhibited higher serum sPD-1 levels at baseline. Patients with VR during the antiviral treatment exhibited higher sPD-1 levels and lower HBsAg levels at baseline. Receiver operating characteristic (ROC) curves were generated to determine the predictive value of sPD-1 and HBsAg for VR in patients who received first-line therapy (entecavir, ETV). The area under ROC (AUROC) values of sPD-1 and HBsAg at baseline were 0.850 (95%CI:0.729-0.971, P = 0.0005) and 0.785 (95%CI: 0.642-0.929, P = 0.005), respectively, and the optimal cut-off values were 459.46 pg/mL and 14,710 IU/mL, respectively. The combination of sPD-1 and HBsAg exhibited a higher AUROC value (0.870,95% CI: 0.748-0.983, P = 0.001) than did sPD-1 or HBsAg alone. In patients administered second-line therapy (lamivudine, LAM/adefovir divipoxil, ADV), baseline sPD-1 levels above 677.2 pg/mL were significantly associated with higher incidence of VR after 96 weeks of antiviral therapy. It is 7.956 times the level of ≤677.2 pg/mL. CONCLUSIONS: By combining sPD-1 and HBsAg, we obtained a biomarker significantly associated with VR in CHB patients. The sPD-1 levels could be used to screen out patients with poor prognosis of antiviral therapy.

Soluble programmed death-1 is predictive of hepatitis B surface antigen loss in chronic hepatitis B patients after antiviral treatment.

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss, a functional cure in patients with chronic hepatitis B (CHB) undergoing antiviral therapy, might be an ideal endpoint of antiviral treatment in clinical practice. The factors that contribute to the functional cure remain unclear, and the predictors of functional cure are worth exploring. The concentration and kinetics of soluble programmed death-1 (sPD-1) in patients with CHB may play an important role in elucidating the immune response associated with functional cure after nucleos(t)ide analogs therapy. AIM: To investigate the factors associated with HBsAg loss and explore the influence of sPD-1 Levels. METHODS: This study analyzed the data and samples from patients with CHB who underwent antiviral treatment in a non-interventional observational study conducted at Peking University First Hospital in Beijing (between 2007 and 2019). All patients were followed up: Serum samples were collected every 3 mo during the first year of antiviral treatment and every 6 mo thereafter. Patients with positive hepatitis B e antigen levels at baseline and with available sequential samples who achieved HBsAg loss during antiviral treatment served as the case group. This case group (n = 11) was further matched to 44 positive hepatitis B e anti patients without HBsAg loss as controls. The Spearman's rank correlation test and receiver operating characteristic curves analysis were performed. RESULTS: The sPD-1 Levels were higher in patients with HBsAg loss than in those without HBsAg loss from baseline to month 96, and the differences were significant between the groups at baseline (P = 0.0136), months 6 (P = 0.0003), 12 (P < 0.0001), 24 (P = 0.0007), 48 (P < 0.0001), and 96 (P = 0.0142). After 6 mo of antiviral treatment, the sPD-1 levels were positively correlated with alanine transaminase (ALT) levels (r = 0.5103, P = 0.0017), and the sPD-1 levels showed apparent correlation with ALT (r = 0.6883, P = 0.0192) and HBV DNA (r = 0.5601, P = 0.0703) levels in patients with HBsAg loss. After 12 mo of antiviral treatment, the sPD-1 levels also showed apparent correlation with ALT (r = 0.8134, P = 0.0042) and HBV DNA (r = 0.6832, P = 0.0205) levels in patients with HBsAg loss. The sPD-1 levels were negatively correlated with HBsAg levels in all patients after 12 mo of antiviral treatment, especially at 24 (r = -0.356, P = 0.0497) and 48 (r = -0.4783, P = 0.0037) mo. After 6 mo of antiviral treatment, the AUC of sPD-1 for HBsAg loss was 0.898 (P = 0.000), whereas that of HBsAg was 0.617 (P = 0.419). The cut-off value of sPD-1 was set at 2.34 log pg/mL; the sensitivity and specificity were 100% and 66.7%, respectively. CONCLUSION: The sPD-1 levels at 6 mo can predict HBsAg loss after 144 mo of antiviral treatment.

Direct antiviral agent treatment leads to rapid and significant fibrosis regression after HCV eradication.

Limited data are currently available regarding fibrosis progression after hepatitis C virus (HCV) eradication. The goal of the present study was to evaluate the effects of HCV eradication on liver stiffness measurements (LSMs), aspartate aminotransferase/platelet ratio index (APRI) scores, fibrosis-4(FIB-4) scores, chitinase-3-like protein 1 (CHI3L1) levels and Golgi protein 73 (GP73) levels in patients with chronic hepatitis C (CHC). One hundred and two patients who received direct antiviral agents (DAAs) therapy at Peking University First Hospital participated in the present study. Clinical information and serum samples were collected at baseline, at the end of treatment (EOT), and at the weeks 12, 24 and 48 after treatment (W12, W24 and W48, respectively). Of the 102 patients, 51 had mild-to-moderate fibrosis (F1/F2), and 51 had advanced fibrosis (F3/F4). The LSMs improved for all patients at the EOT, with observed changes of 2.85 kPa, and the decrease continued to W12. However, a more pronounced improvement was noted for the advanced fibrosis (F3/F4) patients, with a change of 3.6 kPa from baseline to the EOT. Significant decreases between the baseline and EOT measurements were observed in the APRI and FIB-4 scores [0.64 (0.39-1.21) vs. 0.35 (0.26-0.52), p<0.001; 2.53 (1.30-3.91) vs. 1.87 (0.89-2.5), p<0.001], after which the values decreased until W12, with no significant difference observed. Serum CHI3L1 and GP73 levels were profoundly decreased at the EOT compared with those at baseline [134.07 (154.49) vs. 103.75 (98.04), p=0.025; 98.24 (64.76) vs. 88.91 (50.89), p=0.002]. DAA treatments could significantly improve liver fibrosis of CHC patients as evidenced by decreased liver stiffness, APRI scores and FIB-4 scores. Improvements in liver fibrosis markers (especially serum CHI3L1 and GP73) were prominent in patients with advanced fibrosis, indicating that serum CHI3L1 and GP73 could be noninvasive markers for monitoring fibrosis in CHC patients. Significance Statement The prospective cohort evaluated the effect of direct antiviral agents (DAAs) on fibrosis regression after hepatitis C virus (HCV) eradication of Chinese people in the real-world study. This study highlighted that rapid and significant fibrosis regression rather than reduction in inflammation was achieved with DAA treatment, and this regression could be detected as early as the end of treatment. We found the serum CHI3L1 and GP73 levels can be used to monitor changes in fibrosis in CHC patients.

Genome-wide association study identifies new loci associated with risk of HBV infection and disease progression.

BACKGROUND: Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. METHODS: Collected samples from different outcomes of HBV infection and performed genotyping by Affymetrix 500 k SNP Array. GCTA tool, PLINK, and Bonferroni method were applied for analysis of genotyping and disease progression. ANOVA was used to evaluate the significance of the association between biomarkers and genotypes in healthy controls. PoMo, FST, Vcftools and Rehh package were used for building the racial tree and population analysis. FST statistics accesses 0.15 was used as a threshold to detect the signature of selection. RESULTS: There are 1031 participants passed quality control from 1104 participants, including 275 HBV clearance, 92 asymptomatic persistence infection (ASPI), 93 chronic hepatitis B (CHB), 188 HBV-related decompensated cirrhosis (DC), 214 HBV-related hepatocellular carcinoma (HCC) and 169 healthy controls (HC). In the case-control study, one novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2, P = 1.57 × 10-6) and HCC (SNP: rs2833856, Gene: EVA1C, P = 1.62 × 10-6; SNP: rs4661093, Gene: ETV3, P = 2.26 × 10-6). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1, P = 1.85 × 10-6), and three MHC loci (HLA-DRB1, HLA-DPB1, HLA-DPA2) showed significant increased progressive risk from ASPI to CHB. Underlying the evolutionary study of HBV-related genes in public database, the derived allele of two HBV clearance related loci, rs3077 and rs9277542, are under strong selection in European population. CONCLUSIONS: In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Two SNPs that show selective significance (HLA-DPA1, HLA-DPB1) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.

Molecular Epidemiology and Clinical Features Analysis of Respiratory Adenovirus Infections Reveals Correlations between Genotype, Inflammatory Biomarkers, and Disease Severity.

BACKGROUND: Human adenoviruses (HAdVs) are commonly causing respiratory disease. We molecularly genotyped HAdV circulating in Chinese hospitalized children with respiratory infections and summarized the clinical profiles and common inflammatory biomarkers, so as to better determine their associations with disease severity. METHOD: Children with respiratory single HAdV infection cases that occurred from December 2017 to March 2019 were enrolled for a cross-sectional study. Clinical/laboratory features based on the genotypes of respiratory HAdV infection were reviewed for comparative analysis. RESULTS: A total of 84 patients were enrolled, and HAdV types were identified from 82 patients. Species B (HAdV-7, 44%; HAdV-3, 43%, and HAdV-14, 5%) was the most common, followed by C (HAdV-2, 4% and HAdV-1, 1%) and E (HAdV-4, 1%). Severe HAdV infection and HAdV-7 infection groups were associated with significantly longer duration of fever and hospitalized days, higher morbidity of tachypnea/dyspnea, more pleural effusion, more respiratory rales, more frequently required mechanical ventilation, and significantly higher fatality rate. The elevated procalcitonin (PCT) and C-reactive protein (CRP) levels were significantly associated with severe HAdV infection. CONCLUSIONS: HAdV-7 and HAdV-3 were the most common types among children with respiratory adenovirus infection; vaccines against these two genotypes are in urgent need. PCT and CRP are significantly associated with the severity of HAdV infection.

Decrease in Chitinase 3-Like Protein 1 Levels Reflects Improvement in Liver Fibrosis after HCV Eradication.

AIM: The success of direct-acting antivirals (DAAs) against hepatitis C virus is a major breakthrough in hepatology. Previous studies have shown that chitinase 3-like protein 1 (CHI3L1) was a marker for staging of liver fibrosis caused by HCV. In this investigation, we used CHI3L1 as a surrogate marker to compare dynamic hepatic fibrosis variations following the elimination of HCV among cases receiving sofosbuvir (SOF)-based regimens and pegylated interferon/ribavirin (PR) treatments. METHODS: The study enrolled 105 patients, including 46 SOF-based regimens treated patients, 34 PR-experienced patients, and 25 untreated patients. Serum samples and clinical data were obtained at the baseline, the end of treatment, and at weeks 24 and 48 after treatments. RESULTS: First, we found that serum level of CHI3L1 correlated moderately but significantly with LSM (r = 0.615, P < 0.001) at the baseline, and diagnosed liver cirrhosis at baseline with high accuracy (AUC = 0.939) by ROC analysis. So we explored CHI3L1 as a sensitive biomarker to monitor the regression of liver fibrosis after HCV eradication. We found that the serum CHI3L1 level of CHC cases receiving SOF-based regimen treatments was markedly reduced immediately after treatment compared with that at the baseline (123.79 (118.55) vs. 118.20 (103.68), P = 0.001). For cases undergoing PR treatment, the serum CHI3L1 decreased significantly at week 24 posttreatment compared with that at the baseline (69.98 (51.44) vs 89.15 (110.59), P = 0.016). For the untreated cirrhotic patients, CHI3L1 levels increased at week 96 follow-up compared with that at the baseline (194.73 (172.46) vs. 89.50 (242.97), P = 0.048), reflecting continued worsening of liver fibrosis. CONCLUSION: CHI3L1 is suggested to be the sensitive marker to monitor fibrosis variations in weeks during treatments and after achieving SVR. It has the potential to allow the identification of early treatment failure for a timely switch to alternative treatment and to allow monitoring progression of fibrosis as a risk factor for liver cirrhosis.

New Gene Variants Associated with the Risk of Chronic HBV Infection.

Some patients with chronic hepatitis B virus (HBV) infection failed to clear HBV, even persistently continue to produce antibodies to HBV. Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV. The first stage involved genome wide exome sequencing of 101 cases (HBsAg plus anti-HBs positive) compared with 102 control patients (anti-HBs positive, HBsAg negative). Over 80% of individual sequences displayed 20 × sequence coverage. Adapters, uncertain bases > 10% or low-quality base calls (> 50%) were filtered and compared to the human reference genome hg19. In the second stage, 579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage. Although there were no significant associated gene variants in the first stage, two significant gene associations were discovered when the two stages were assessed in a combined analysis. One association showed rs506121-"T" allele [within the dedicator of cytokinesis 8 (DOCK8) gene] was higher in chronic HBV infection group than that in clearance group (P = 0.002, OR = 0.77, 95% CI [0.65, 0.91]). The second association involved rs2071676-A allele within the Carbonic anhydrase (CA9) gene that was significantly elevated in chronic HBV infection group compared to the clearance group (P = 0.0003, OR = 1.35, 95% CI [1.15, 1.58]). Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.

Aspirin inhibits endometrial fibrosis by suppressing the TGF­ß1­Smad2/Smad3 pathway in intrauterine adhesions.

Intrauterine adhesions (IUAs) represent one of the most common diseases in women of reproductive age. Patients with moderate­to­severe IUA can experience a decrease in normal menstrual patterns, amenorrhea and even infertility. At present, the first­line treatment strategies for IUAs in the clinical practice are hysteroscopic transuterine resection of adhesion and postoperative adjuvant therapy, including oestrogen. However, a high recurrence rate of IUAs remains. In recent years, studies have demonstrated that aspirin combined with oestrogen may significantly prevent the postoperative disease recurrence rate, improve endometrial receptivity and improve the conception rate by increasing endometrial blood supply and angiogenesis more effectively. The TGF­ß1­Smad2/Smad3 pathway is one of the important mechanisms involved in endometrial fibrosis. However, whether aspirin can inhibit endometrial fibrosis through the TGF­ß1­Smad2/Smad3 pathway to prevent postoperative re­adhesion remains to be elucidated. The results of the present study suggested that aspirin inhibits endometrial fibrosis by suppressing the TGF­ß1­Smad2/Smad3 pathway, which may provide new hypotheses for the mechanism of action of aspirin in the treatment of IUAs.

Hepatitis B virus pregenomic RNA status can reveal the long-term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues.

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long-time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment-naïve and had begun a 7-year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real-time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg-negative rates also increased. After 48 weeks' NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA-positive. After 7 years of treatment, more HBV pgRNA-negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA-positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA-positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75-31.08). The median time to HBeAg clearance in the HBV pgRNA-positive patients was longer than that of the HBV pgRNA-negative patients (152 weeks vs 72 weeks). The HBV pgRNA-positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33-144.67 vs 48 weeks, 95% CI: 34.80-61.20). The HBV pgRNA status after NA treatment can predict the long-term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA-positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.

ERG the modulates Warburg effect and tumor progression in cervical cancer.

Altered aerobic glycolysis is an important feature of cancer cell energy metabolism, known as the Warburg effect. Cervical cancer is one of the most common causes of cancer death in females. However, the roles of aerobic glycolysis in the development of cervical cancer are still poorly defined. Here, we identified a transcription factor (TF), ETS-related gene (ERG), as a new regulator of cancer progression and the glycolysis process in cervical cancer. In this study, we found that ectopic expression of ERG enhanced the capacity of aerobic glycolysis and increased glucose uptake, lactate production, and ATP generation. ERG overexpression increased and ERG knockdown decreased the anchorage independent cell growth and cell invasion in cervical cancer cells. Mechanistically, we propose that ERG regulates the expression of hexokinase 2 (HK2) and phosphoglycerate kinase 1 (PGK1) in the glycolytic pathway by directly binding to their promoters. A gain-of-function study showed that the knockdown or overexpression of HK2 and PGK1 abolished the increased or decreased aerobic glycolysis and cervical cancer progression induced by stable ectopic expression or depletion of ERG, respectively. Taken together, our findings suggest that ERG plays a potential role in the progression of cervical cancer, and could serve as a novel biomarker and potential therapeutic target in cervical cancer.

Tumor-suppressive miR-3650 inhibits tumor metastasis by directly targeting NFASC in hepatocellular carcinoma.

In recent years, a growing body of evidence has provided support for the important role of microRNAs (miRNAs) in the progression of human cancers. A recent study showed that a novel miRNA miR-3650 expression was significantly decreased in hepatocellular carcinoma (HCC). However, the precise role of miR-3650 in HCC have remained poorly understood. In this study, we found that miR-3650 expression was frequently decreased in HCC tissues. Low expression of miR-3650 is positively associated with tumor metastasis and poor survival of HCC patients. Forced expression of miR-3650 significantly inhibited the migration and epithelial-mesenchymal transition (EMT) of HCC cells. Through bioinformatic analysis and luciferase assays, we confirmed that neurofascin (NFASC) is a directly target mRNA of miR-3650. Rescue experiment demonstrated that NAFSC overexpression could partially counteracted the inhibitory effect of miR-3650 in HCC metastasis and EMT. In conclusion, our findings are the first time to demonstrate that reduced expression of miR-3650 in HCC was correlated with tumor metastasis and poor survival. MiR-3650 repressed HCC migration and EMT by directly targeting NFASC. Our findings suggested that miR-3650 may serve as a potential prognostic marker and promising application in HCC therapy.

Serum hepatitis B virus RNA is a predictor of HBeAg seroconversion and virological response with entecavir treatment in chronic hepatitis B patients.

BACKGROUND: Characteristics of alterations of serum hepatitis B virus (HBV) RNA in different chronic hepatitis B (CHB) patients still cannot be fully explained. Whether HBV RNA can predict HBeAg seroconversion is still controversial. AIM: To investigate whether HBV RNA can predict virological response or HBeAg seroconversion during entecavir (ETV) treatment when HBV DNA is undetectable. METHODS: The present study evaluated 61 individuals who were diagnosed and treated with long-term ETV monotherapy at the Department of Infectious Diseases of Peking University First Hospital (China) from September 2006 to December 2007. Finally, 30 treatment-naive individuals were included. Serum HBV RNA were extracted from 140 µL serum samples at two time points. Then they were reverse transcribed to cDNA with the HBV-specific primer. The product was quantified by real-time quantitative PCR (RT-PCR) using TAMARA probes. Statistical analyses were performed with IBM SPSS 20.0. RESULTS: Level of serum HBV RNA at baseline was 4.15 ± 0.90 log10 copies/mL. HBV RNA levels showed no significant difference between the virological response (VR) and partial VR (PVR) groups at baseline (P = 0.940). Serum HBV RNA significantly decreased among patients who achieved a VR during ETV therapy (P < 0.001). The levels of HBV RNA in both HBeAg-positive patients with seroconversion group and those with no seroconversion increased after 24 wk of treatment. Overall, HBV RNA significantly but mildly correlated to HBsAg (r = 0.265, P = 0.041), and HBV RNA was not correlated to HBV DNA (r = 0.242, P = 0.062). Furthermore, serum HBV RNA was an independent indicator for predicting HBeAg seroconversion and virological response. HBeAg seroconversion was more likely in CHB patients with HBV RNA levels below 4.12 log10 copies/mL before treatment. CONLUSION: The level of serum HBV RNA could predict HBeAg seroconversion and PVR during treatment. In the PVR group, the level of serum HBV RNA tends to be increasing.

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer.

Aberrant methylation of DNA sequences plays a criticle role in finding novel aberrantly methylated genes and pathways in thyroid cancer (THCA). This study aimed to integrate three cohorts profile datasets to find novel aberrantly methylated genes and pathways in THCA. Data of gene expression profiling microarrays (GSE33630 and GSE65144) and gene methylation profiling microarrays (GSE51090) were downloaded from the Gene Expression Omnibus database. Aberrantly methylated and differentially expressed genes were sorted and pathways were analyzed. Functional and enrichment analyses of selected genes were performed using the String database. A protein-protein interaction network was constructed using the Cytoscape software, and module analysis was performed using Molecular Complex detection. In total, we identified 12 hypomethylation/high-expression genes and 30 hypermethylation/low-expression genes at the screening step and, finally, found 6 mostly changed hub genes including PPARGC1A, CREBBP, EP300, CD44, SPP1, and MMP9. Pathway analysis showed that aberrantly methylated differentially expressed genes were mainly associated with the thyroid hormone signaling pathway, AMP-activated protein kinase (AMPK) signaling pathway, and cell cycle process in THCA. After validation in the Cancer Genome Atlas database, the methylation and expression status of hub genes was significantly altered and the same with our results. Taken together, we identified novel aberrantly methylated genes and pathways in THCA, which could improve our understanding of the cause and underlying molecular events, and these candidate genes could serve as aberrant methylation-based biomarkers for precise diagnosis and treatment of THCA.