Edited by Xiao-Fan WangMutations in the genes encoding nuclear factor (erythroidderived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found to cause esophageal hyperproliferation and hyperkeratosis in mice. However, the underlying mechanism is unclear. In this study, we aimed to understand the molecular mechanisms of esophageal hyperproliferation in mice due to hyperactive Nrf2. Esophageal tissues were obtained from genetically modified mice that differed in the status of the Nrf2 gene and genes in the same pathway (Nrf2 ؊/؊ , Keap1 ؊/؊ , K5Cre;Pkm2 fl/fl ;Keap1 ؊/؊ , and WT) and analyzed for metabolomic profiles, Nrf2 ChIP-seq, and gene expression. We found that hyperactive Nrf2 causes metabolic reprogramming and up-regulation of metabolic genes in the mouse esophagus. One of the glycolysis genes encoding pyruvate kinase M2 (Pkm2) was not only differentially up-regulated, but also glycosylated and oligomerized, resulting in increased ATP biosynthesis. However, constitutive knockout of Pkm2 failed to inhibit this esophageal phenotype in vivo, and this failure may have been due to compensation by Pkm1 up-regulation. Transient inhibition of NRF2 or glycolysis inhibited the growth of human ESCC cells in which NRF2 is hyperactive in vitro. In summary, hyperactive Nrf2 causes metabolic reprogramming in the mouse esophagus through its transcriptional regulation of metabolic genes. Blocking glycolysis transiently inhibits cell proliferation and may therefore have therapeutically beneficial effects on NRF2 high ESCC in humans.Esophageal cancer affects 16,940 adults in the United States, and the 5-year survival rate is 18% (1). There are mainly two histological types of esophageal cancer, squamous cell carcinoma (ESCC) 4 and adenocarcinoma, each having a distinct etiology. Low income, moderate/heavy alcohol intake, tobacco use, and infrequent consumption of raw fruits and vegetables account for almost all cases of ESCC (2). With the recent technological advances in NextGen sequencing, human ESCC samples from North and South America, China, Japan, Vietnam, and Malawi have been sequenced. Among many gene mutations, nuclear factor (erythroid-derived 2)-like 2 (NRF2 or NFE2L2) mutations are commonly seen with a frequency over 5%, even up to ϳ20% in certain reports. Mutations in other genes of the NRF2 signaling pathway, Kelch-like ECH associated protein 1 (KEAP1) and cullin 3 (CUL3), are relatively less common. NRF2 mutations are mostly located in the DLG and ETGE motifs (KEAP1-binding domain) and the DNA-binding domain, whereas KEAP1 mutations tend to be scattered across the whole gene. NRF2 mutations and KEAP1 mutations tend to be mutually exclusive (3,4).As a major cellular defense mechanism, the NRF2 signaling pathway is known to regulate expression of enzymes involved in detoxification and ant...
PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Background Outcome prediction for patients with sepsis may be conductive to early aggressive interventions. Numerous biomarkers and multiple scoring systems have been utilized in predicting outcomes, however, these tools were either expensive or inconvenient. We performed a meta-analysis to evaluate the prognostic role of red blood cell distribution width (RDW) in patients with sepsis. Methods The online databases of Embase, Web of science, Pubmed, Corchrane library, Chinese Wanfang database, CNKI database were systematically searched from the inception dates to June, 24th, 2020, using the keywords red cell distribution width and sepsis. The odds ratio (OR) or Hazards ratio (HR) with corresponding 95% confidence intervals (95%CI) were pooled to evaluate the association between baseline RDW and sepsis. A random-effects model was used to pool the data, and statistical heterogeneity between studies was evaluated using the I2 statistic. Sensitivity and subgroup analyses were performed to detect the publication bias and origin of heterogeneity. Results Eleven studies with 17,961 patients with sepsis were included in the meta-analysis. The pooled analyses indicated that increased baseline RDW was associated with mortality (HR = 1.14, 95%CI 1.09–1.20, Z = 5.78, P < 0.001) with significant heterogeneity (I2 = 80%, Pheterogeneity < 0.001). Similar results were found in the subgroup analysis stratified by site of infection, comorbidity, Newcastle-Ottawa Scale (NOS) score, study design, patients’ country. The predefined subgroup analysis showed that NOS score may be the origin of heterogeneity. Conclusions For patients with sepsis, baseline RDW may be a useful predictor of mortality, patients with increased RDW are more likely to have higher mortality.
High-throughput sequencing measurements of the vaginal microbiome have yielded intriguing potential relationships between the vaginal microbiome and preterm birth (PTB; live birth prior to 37 weeks of gestation). However, results across studies have been inconsistent. Here we perform an integrated analysis of previously published datasets from 12 cohorts of pregnant women whose vaginal microbiomes were measured by 16S rRNA gene sequencing. Of 1926 women included in our analysis, 568 went on to deliver prematurely. Substantial variation between these datasets existed in their definition of preterm birth, characteristics of the study populations, and sequencing methodology. Nevertheless, a small group of taxa comprised a vast majority of the measured microbiome in all cohorts. We trained machine learning (ML) models to predict PTB from the composition of the vaginal microbiome, finding low to modest predictive accuracy (0.28-0.79). Predictive accuracy was typically lower when ML models trained in one dataset predicted PTB in another dataset. Earlier preterm birth (<32 weeks, <34 weeks) was more predictable from the vaginal microbiome than late preterm birth (34 - 37 weeks), both within and across datasets. Integrated differential abundance analysis revealed a highly significant negative association between L. crispatus and PTB that was consistent across almost all studies. The presence of the majority (18 out of 25) of genera was associated with a higher risk of PTB, with L. iners, Prevotella, and Gardnerella showing particularly consistent and significant associations. Some example discrepancies between studies could be attributed to specific methodological differences, but not most study-to-study variations in the relationship between the vaginal microbiome and preterm birth. We believe future studies of the vaginal microbiome and PTB will benefit from a focus on earlier preterm births, and improved reporting of specific patient metadata shown to influence the vaginal microbiome and/or birth outcomes.
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