This study aimed to determine the potential mechanisms through which long noncoding (Lnc) RNA cancer susceptibility candidate 15 (CASC15) affects hepatocellular carcinoma (HCC). We retrieved HCC RNA-seq and clinical information from the UCSC Xena database. The differential expression (DE) of CASC15 was detected. Overall survival was analyzed using Kaplan–Meier (K–M) curves. Molecular function and signaling pathways affected by CASC15 were determined using Gene Set Enrichment Analysis. Associations between CASC15 and the HCC microenvironment were investigated using immuno-infiltration assays. A differential CASC15-miRNA-mRNA network and HCC-specific CASC15-miRNA-mRNA ceRNA network were constructed. The overexpression of CASC15 in HCC tissues was associated with histological grade, clinical stage, pathological T stage, poor survival, more complex immune cell components, and 12 immune checkpoints. We identified 27 DE miRNAs and 270 DE mRNAs in the differential CASC15-miRNA-mRNA network, and 10 key genes that were enriched in 12 cancer-related signaling pathways. Extraction of the HCC-specific CASC15-miRNA-mRNA network revealed that IGF1R, MET, and KRAS were associated with HCC progression and occurrence. Our bioinformatic findings confirmed that CASC15 is a promising prognostic biomarker for HCC, and elevated levels in HCC are associated with the tumor microenvironment. We also constructed a disease-specific CASC15-miRNA-mRNA regulatory ceRNA network that provides a new perspective for the precise indexing of patients with elevated levels of CASC15.
Recent data on prevalence, awareness, treatment, and risk factors of diabetes in China is necessary for interventional efforts.
Objective
To estimate trends in prevalence, awareness, treatment, and risk factors of diabetes in China based on national data.
Design, Setting, and Participants
Cross-sectional nationally representative survey data collected in adults aged 18 years or older in mainland China from 170 287 participants in the 2013-2014 years and 173 642 participants in the 2018-2019 years.
Exposures
Fasting plasma glucose and hemoglobin A1clevels were measured for all participants. A 2-hour oral glucose tolerance test was conducted for all participants without diagnosed diabetes.
Main Outcomes and Measures
Primary outcomes were diabetes and prediabetes defined according to American Diabetes Association criteria. Secondary outcomes were awareness, treatment, and control of diabetes and prevalence of risk factors. A hemoglobin A1clevel of less than 7.0% (53 mmol/mol) among treated patients with diabetes was considered adequate glycemic control.
Results
In 2013, the median age was 55.8 years (IQR, 46.4-65.2 years) and the weighted proportion of women was 50.0%; in 2018, the median age was 51.3 years (IQR, 42.1-61.6 years), and the weighted proportion of women was 49.5%. The estimated prevalence of diabetes increased from 10.9% (95% CI, 10.4%-11.5%) in 2013 to 12.4% (95% CI, 11.8%-13.0%) in 2018 (P < .001). The estimated prevalence of prediabetes was 35.7% (95% CI, 34.2%-37.3%) in 2013 and 38.1% (95% CI, 36.4%-39.7%) in 2018 (P = .07). In 2018, among adults with diabetes, 36.7% (95% CI, 34.7%-38.6%) reported being aware of their condition, and 32.9% (95% CI, 30.9%-34.8%) reported being treated; 50.1% (95% CI, 47.5%-52.6%) of patients receiving treatment were controlled adequately. These rates did not change significantly from 2013. From 2013 to 2018, low physical activity, high intake of red meat, overweight, and obesity significantly increased in prevalence.
Conclusions and Relevance
In this survey study, the estimated diabetes prevalence was high and increased from 2013 to 2018. There was no significant improvement in the estimated prevalence of adequate treatment.
Recent studies indicate that cancer-associated fibroblasts (CAFs) are involved in tumor growth, invasion and metastasis, however, the underling mechanisms remain unclear. In the present study, we investigated the role of CAFs on the metastatic potential of lung cancer cells. The stromal fibroblasts we isolated from lung cancer tissues presented CAFs characteristics with high levels of α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Our data showed that the conditioned medium from cultured CAFs (CAF-CM) dramatically enhanced migration and invasion of lung cancer cells. CAF-CM induced epithelial-mesenchymal transition (EMT) by regulating the expression of EMT-associated markers E-cadherin and vimentin, and also modulated metastasis-related genes MMP-2 and VEGF both in vitro and in vivo. Further mechanistic studies demonstrated that CAFs enhanced the metastatic potential of lung cancer cells by secreting IL-6, subsequently activating of JAK2/STAT3 signaling pathway. Additionally, the inhibition of IL-6/STAT3 signaling pathway by IL-6 neutralizing antibody or specific inhibitors of JAK2/STAT3 reversed CAF-CM induced EMT and migration of lung cancer cells. Taken together, these findings revealed a novel mechanism that CAFs induced EMT and promoted metastasis of lung cancer cells through the IL-6/STAT3 signaling pathway.
Abstract Tumor evolution is a key feature intrinsic to tumor biology and contributes to intratumor heterogeneity, escape of immune surveillance, treatment failure, and patients’ prognosis. The evolutionary process of tumor is driven by selecting favorable phenotypes in terms of their fitness and survival in a tumor ecosystem. While genomic alterations provide rich materials for tumor evolution, only a few can induce a recognizable phenotypic change with even fewer for a fitness advantage. Thus, transcriptomics, a major molecular feature reflecting functional activities, will be informative in modeling tumor heterogeneity and crucial in understanding tumor evolution. Here, we aim to study tumor clonal evolution by single-cell transcriptomic profiling of hepatocellular carcinoma and intrahepatic cholangiocarcinoma from 37 patients participating the immune checkpoint inhibition trials. By analyzing core biopsies before or after treatment, we determined the single-cell atlas of liver tumors and confidently separated malignant cells and non-malignant cells by inferring chromosomal copy number variations. We developed a consensus clustering model based on machine learning algorithms and statistical methods to identify functional clones from malignant cells within each tumor. We further determined the clonal relationship by constructing the phylogenetic tree of the clones from all tumors. The clonal relationship within each tumor was independently assessed by manifold based single-cell trajectory and RNA-velocity based cell lineage. The analyses revealed a tumor branching evolutionary architecture of the clones. Noticeably, tumor branching evolution was associated with patient outcomes, which was also validated by using bulk transcriptomic data from 765 liver tumors. We found tumors in the poor prognosis branch were enriched in the pathways of hypoxia, epithelial-mesenchymal transition and angiogenesis. Remarkably, the functional role of the clones within a tumor varied, indicating a cooperative tumor cell community. We found a polarization of immune landscape associated with tumor branching evolution driven by tumor cell-specific cytokines. Our results offer insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers for tumor evolution in response to immunotherapy. Citation Format: Lichun Ma, Limin Wang, Ching-Wen Chang, Sophia Franck, Dana Dominguez, Marshonna Forgues, Julian Candia, Maria O. Hernandez, Michael Kelly, Yongmei Zhao, Bao Tran, Jonathan M. Hernandez, Jeremy L. Davis, David E. Kleiner, Bradford J. Wood, Tim F. Greten, Xin Wei Wang. Understanding tumor clonal evolution by single-cell transcriptomic analysis in liver cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR04.
Abstract Background: Cytotoxic T lymphocytes (CTLs) is the mainstay to kill cancer cells. Little was known about its impact in osteosarcoma. This study aimed the reveal its functional and prognostic role in osteosarcoma. Methods: The gene expression data from 88 osteosarcoma patients in the TARGET programs were downloaded, and the clinical characteristics of these patients including overall survival and vital status were also collected. The ssGSEA was applied to generate the CTL score for each sample based on CTL signature, and osteosarcoma cases were divided to the high and low CTL score cohorts. Differentially expressed genes (DEGs) between the two groups were identified, and an optimal CTL-related risk model was generated by LASSO Cox regression analyses. CIBERSORT was used to evaluate the amounts of 22 tumor infiltrating immune cells in the microenvironment. Results: CTL score can predict OS in osteosarcoma patients. GSEA indicated several pro-inflammatory pathways with significant enrichment in the high-CTL infiltration cluster. The proportion of γδ T cells, and M1 macrophages were notably higher in high CTL score subgroup, while the naïve B cells, resting NK cells, and M0 macrophages were significantly lower. Furthermore, DEGs between the two groups were applied to univariate and LASSO Cox regression analysis to build a six-gene risk model. Kaplan-Meier analysis and ROC curves further confirmed the predictive values of the risk model. Conclusions: CTLs were predictive of overall survival in osteosarcoma and can reflect anti-cancer inflammatory state. The predictive capability of the six-gene risk model is high.
Caged dynamics is the precursor of β-relaxation and is part of the complex relaxation dynamics of metallic glasses. However, limited by the lack of suitable experimental instruments, the pressure dependence of the caged dynamics of glass-forming (GF) liquids and its underlying mechanism is still open to date. An unusual caged dynamics manifests a sudden drop near 0.1 ps in the partial non-Gaussian parameter of Al atoms in La-Al GF liquid. The present work investigates the caged dynamics of the model La80Al20GF liquid with strong atomic interactions under different pressures by molecular dynamics simulations. It is found that pressurization makes the atomic vibration frequency be fast and the vibrational amplitude tend to be consistent. In addition, the dominant polyhedra are transformed from the stable icosahedral-like polyhedra to the unstable ones that are compatible with crystal symmetry, which promotes the rearrangement of atoms. These in turn cause the central Al atoms to be less hindered by the surrounding atoms, enhancing the cage-breaking motion and weakening the unusual caged dynamics. These findings may provide new insights into the caged dynamics under pressure from the perspective of microstructure and vibrational behaviors.
Abstract Background Perinatal hypoxia-ischemia (HI) remains the primary cause of acute neonatal brain injury, leading to a high mortality rate and long-term neurological deficits, such as cerebral palsy of children. In this study we performed investigations of systemic inflammatory cytokines from peripheral blood and T lymphocytes and CD11b+ cells from spleen tissue at acute stage after self-recovery neonatal HI brain injury in rats. Methods HI was induced in 4-day old rat and specimen was collected up to 14 days natural resuscitation to investigate expression of immune associated with cell-markers, CD3, CD4, CD8 and CD11b, and multiple inflammation cytokines (IL-1β, IL-6, TNF-α, L-8 and IL-10). We assessed quantity changes of T cell populations and CD11b from the spleen by flow cytometry. We measured cytokines concentration from peripheral blood by ELISA after recovery HI rats. Results At 14d after recovery HI rats, FACS analysis showed a marked decrease in the number of CD3, CD4 and CD8 (p<0.001), CD11b+ cells was no relative increase of (p = 0.14). IL-1β, IL-6 and TNF-α was higher than control group in peripheral blood (p=0.0012, 0.001 and 0.003 respectively) and IL-8 and IL-10 were lower than control group (p=0.0042 and 0.018 respectively). CONCLUSIONS/SIGNIFICANCE Our findings demonstrate inhibition of systemic immune responses is changes in self-recovery stage after hypoxic ischemic neonatal. The short term immune inhibition observed is of general importance for future studies of the immune response after hypoxic-ischemia as most previous studies have focused on the first few days after damage, while the effects of the late immunocompromise may be remain existed.
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