High throughput gene expression profiling has showed great promise in providing insight into molecular mechanisms. Metastasis-related mRNAs may potentially enrich genes with the ability to predict cancer recurrence，therefore we attempted to build a recurrence-associated gene signature to improve prognostic prediction of colorectal cancer (CRC). We identified 2848 differentially expressed mRNAs by analyzing CRC tissues with or without metastasis. For the selection of prognostic genes, a LASSO Cox regression model was employed. Using this method, a 13-mRNA signature was identified and then validated in two independent Gene Expression Omnibus (GEO) cohorts. This classifier could successfully discriminate the high-risk patients in discovery cohort (HR = 5.27, 95%CI= 2.30-12.08, P < 0.0001). Analysis in two independent cohorts yielded consistent results (GSE14333: HR=4.55, 95%CI=2.18 – 9.508, P<0.0001) (GSE33113: HR=3.26, 95%CI=2.16 – 9.16, P=0.0176). Further analysis revealed that the prognostic value of this signature was independent of tumor stage, postoperative chemotherapy and somatic mutation. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of this signature was 0.8861 and 0.8157 in the discovery and validation cohort, respectively. A nomogram was constructed for clinicians, which did well in the calibration plots. Furthermore, this 13-mRNA signature outperformed other known gene signatures, including oncotypeDX colon cancer assay. Single-sample gene-set enrichment analysis (ssGSEA) revealed that a group of pathways related to drug resistance, cancer metastasis and stemness were significantly enriched in the high-risk patients. In conclusion, this 13-mRNA signature may be a useful tool for prognostic evaluation and will facilitate personalized management of CRC patients.
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
Probiotics can colonize both the human and animal bodies and consist of active microorganisms that are beneficial to health. The use of probiotics has been shown to alleviate certain neurological diseases and disturbances in gut microbiota resulting from chronic ethanol exposure. Research indicates that probiotics can influence the nervous system via the microbial-gut-brain axis, wherein extracellular vesicles secreted by the gut microbiota play a significant role in this process. In this study, we first established a 30-day ethanol exposure and probiotic gavage mouse model, both of which influenced behavior and the composition of gut microbiota. We then extracted gut microbiota-derived extracellular vesicles from the feces of these model mice and injected them into new mice via the tail vein to assess the role of each set of extracellular vesicles. The results indicated that the extracellular vesicles derived from the intestinal microbiota in the ethanol group induced anxiety-like behavior and hippocampal neuroinflammation in the recipient mice. In contrast, the extracellular vesicles secreted by the gut microbiota from the probiotic group mitigated the anxiety-like behavior and neuroinflammation induced by ethanol-influenced extracellular vesicles. Our study demonstrates that extracellular vesicles secreted by the gut microbiota can influence the nervous system via the microbial-gut-brain axis. Furthermore, we found that the extracellular vesicles secreted by the gut microbiota from the probiotic group exert a beneficial therapeutic effect on anxiety and hippocampal neuroinflammation.
Erythrodermic psoriasis (EP) is a severe form of psoriasis that affects multiple organs, including the cardiovascular system. However, few studies have focused on this condition.This study is aimed to assess the prevalence and factors associated with heart failure in EP patient, and to the measure the serum concentrations of fibroblast growth factor 23 (FGF23), a potential predictor of chronic heart failure.We retrospectively studied patients with EP hospitalized at Peking Union Medical College Hospital between January 2005 to October 2021. The prevalence of heart failure and associated factors was measured. In addition, peripheral blood samples were collected from 17 patients and matched with samples from eight healthy controls, and their serum concentrations of FGF23 were measured by ELISA.We studied 225 patients with EP, with a male: female ratio of 2.7:1 and a mean age of 47.6 ± 16.7 years. Twenty-five (11.1%) participants were diagnosed with heart failure during their hospital stay. The patients with EP and heart failure were older (58.2 years vs. 46.2 years, p = 0.001); had a higher prevalence of a history of coronary heart disease (32.0% vs. 21.5%, p < 0.001), fever (48.0% vs. 23.0%, p = 0.007), infection (56.0% vs. 35.5%, p = 0.046); higher hsCRP concentration (43.2 mg/L vs. 8.2 mg/L, p = 0.005); and higher prevalence of anemia (60.0% vs. 22.0%, p < 0.001), hypoalbuminemia (64.0% vs. 42.0%, p = 0.037), and hyperlipidemia (40.0% vs. 20.0%, p = 0.023) than those without heart failure. The serum FGF23 concentration was significantly higher in patients with EP than controls (493.1 pg/ml vs. 277.8 pg/ml, p = 0.027), and was significantly lower after treatment (395.7 pg/ml vs. 463.1 pg/ml, p = 0.022).Clinicians should be aware of the risk of heart failure in patients with EP, and especially those of advanced age and with a history of coronary heart disease, severe systemic symptoms, high concentrations of inflammatory biomarkers, and poor nutritional status.
High throughput gene expression profiling has showed great promise in providing insight into molecular mechanisms. Metastasis-related mRNAs may potentially enrich genes with the ability to predict cancer recurrence，therefore we attempted to build a recurrence-associated gene signature to improve prognostic prediction of colorectal cancer (CRC). We identified 2848 differentially expressed mRNAs by analyzing CRC tissues with or without metastasis. For the selection of prognostic genes, a LASSO Cox regression model was employed. Using this method, a 13-mRNA signature was identified and then validated in two independent Gene Expression Omnibus (GEO) cohorts. This classifier could successfully discriminate the high-risk patients in discovery cohort (HR = 5.27, 95%CI= 2.30-12.08, P < 0.0001). Analysis in two independent cohorts yielded consistent results (GSE14333: HR=4.55, 95%CI=2.18 – 9.508, P<0.0001) (GSE33113: HR=3.26, 95%CI=2.16 – 9.16, P=0.0176). Further analysis revealed that the prognostic value of this signature was independent of tumor stage, postoperative chemotherapy and somatic mutation. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of this signature was 0.8861 and 0.8157 in the discovery and validation cohort, respectively. A nomogram was constructed for clinicians, which did well in the calibration plots. Furthermore, this 13-mRNA signature outperformed other known gene signatures, including oncotypeDX colon cancer assay. Single-sample gene-set enrichment analysis (ssGSEA) revealed that a group of pathways related to drug resistance, cancer metastasis and stemness were significantly enriched in the high-risk patients. In conclusion, this 13-mRNA signature may be a useful tool for prognostic evaluation and will facilitate personalized management of CRC patients.
Objective
To investigate the relationship between genetic variants in the Toll-like receptor (TLR) pathway genes and susceptibility of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC).
Methods
The data of whole genome association studies of the high-risk population of GC and ESCC in China were analyzed by adaptive rank-truncated product (ARTP) method in pathway and gene level. The associations between single nucleotide polymorphism (SNP) and susceptibility of GC and ESCC were analyzed with additive model of unconditional Logistic regressions. PLINK 1.07 and SPSS 19.0 software were performed for statistical analyses, and ARTP package in R3.0.2 was used for pathway and gene level analysis.
Results
In gene-level analyses, eight genes were found to be associated with susceptibility of GC (P <0.05) and six genes were associated with susceptibility of ESCC (P <0.05). In single SNP-level analyses, 21 SNPs were statistically correlated with susceptibility of GC (P <0.01), and 11 SNPs were statistically correlated with susceptibility of ESCC (P <0.01).
Conclusions
Some genetic variants in TLR pathway are associated with risk of GC and ESCC. The potential molecular mechanisms need further investigation.
Key words:
Stomach neoplasms; Esophageal neoplasms; Carcinoma, squamous cell; Variation (genetics); GWAS; Single nucleotide polymorphisms; Toll-like receptor pathway
Abstract Continuous stimulation of inflammation is harmful to tissues of an organism. Inflammatory mediators not only have an effect on metabolic and inflammatory bone diseases but also have an adverse effect on certain genetic and periodontal diseases associated with bone destruction. Inflammatory factors promote vascular calcification in various diseases. Vascular calcification is a pathological process similar to bone development, and vascular diseases play an important role in the loss of bone homeostasis. The NLRP3 inflammasome is an essential component of the natural immune system. It can recognize pathogen-related molecular patterns or host-derived dangerous signaling molecules, recruit, and activate the pro-inflammatory protease caspase-1. Activated caspase-1 cleaves the precursors of IL-1β and IL-18 to produce corresponding mature cytokines or recognizes and cleaves GSDMD to mediate cell pyroptosis. In this review, we discuss the role of NLRP3 inflammasome in bone diseases and vascular calcification caused by sterile or non-sterile inflammation and explore potential treatments to prevent bone loss.
Conventional antitumor chemotherapeutics generally have shortcomings in terms of dissolubility, selectivity and drug action time, and it has been difficult to achieve high antitumor efficacy with single-drug therapy. At present, combination therapy with two or more drugs is widely used in the treatment of cancer, but a shortcoming is that the drugs do not reach the target at the same time, resulting in a reduction in efficacy. Therefore, it is necessary to design a carrier that can release two drugs at the same site. We designed an injectable pH-responsive OE peptide hydrogel as a carrier material for the antitumor drugs gemcitabine (GEM) and paclitaxel (PTX) that can release drugs at the tumor site simultaneously to achieve the antitumor effect. After determining the optimal gelation concentration of the OE polypeptide, we conducted an in vitro release study to prove its pH sensitivity. The release of PTX from the OE hydrogel in the medium at pH 5.8 and pH 7.4 was 96.90% and 38.98% in 7 days. The release of GEM from the OE hydrogel in media with pH of 5.8 and 7.4 was 99.99% and 99.63% in 3 days. Transmission electron microscopy (TEM) and circular dichroism (CD) experiments were used to observe the microstructure of the peptides. The circular dichroism of OE showed a single negative peak shape when under neutral conditions, indicating a β-folded structure, while under acidic conditions, it presented characteristics of a random coil. Rheological experiments were used to investigate the mechanical strength of this peptide hydrogel. Furthermore, the treatment effect of the drug-loaded peptide hydrogel was demonstrated through in vitro and in vivo experiments. The results show that the peptide hydrogels have different structures at different pH values and are highly sensitive to pH. They can reach the tumor site by injection and are induced by the tumor microenvironment to release antitumor drugs slowly and continuously. This biologically functional material has a promising future in drug delivery for combination drugs.
High throughput gene expression profiling has showed great promise in providing insight into molecular mechanisms. Metastasis-related mRNAs may potentially enrich genes with the ability to predict cancer recurrence，therefore we attempted to build a recurrence-associated gene signature to improve prognostic prediction of colorectal cancer (CRC). We identified 2848 differentially expressed mRNAs by analyzing CRC tissues with or without metastasis. For the selection of prognostic genes, a LASSO Cox regression model was employed. Using this method, a 13-mRNA signature was identified and then validated in two independent Gene Expression Omnibus (GEO) cohorts. This classifier could successfully discriminate the high-risk patients in discovery cohort (HR = 5.27, 95%CI= 2.30-12.08, P < 0.0001). Analysis in two independent cohorts yielded consistent results (GSE14333: HR=4.55, 95%CI=2.18 – 9.508, P<0.0001) (GSE33113: HR=3.26, 95%CI=2.16 – 9.16, P=0.0176). Further analysis revealed that the prognostic value of this signature was independent of tumor stage, postoperative chemotherapy and somatic mutation. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of this signature was 0.8861 and 0.8157 in the discovery and validation cohort, respectively. A nomogram was constructed for clinicians, which did well in the calibration plots. Furthermore, this 13-mRNA signature outperformed other known gene signatures, including oncotypeDX colon cancer assay. Single-sample gene-set enrichment analysis (ssGSEA) revealed that a group of pathways related to drug resistance, cancer metastasis and stemness were significantly enriched in the high-risk patients. In conclusion, this 13-mRNA signature may be a useful tool for prognostic evaluation and will facilitate personalized management of CRC patients.
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