Epigenetic regulation of CD271, a potential cancer stem cell marker associated with chemoresistance and metastatic capacity.

Cancer stem cells (CSCs) are considered to be the cause of tumor initiation, metastasis and recurrence. Additionally, CSCs are responsible for the failure of chemotherapy and radiotherapy. The isolation and identification of CSCs is crucial for facilitating the monitoring, therapy or prevention of cancer. We aimed to identify esophageal squamous cell carcinoma (ESCC) stem-like cells, the epigenetic mechanism and identify novel biomarkers for targeting ESCC CSCs. Sixty-three paired ESCC tissues and adjacent non-cancerous tissues were included in this study. CD271, which was identified as the CSC marker for melanoma, was assessed using quantitative PCR (qPCR). Using flow cytometry, we isolated CD271+ cells comprising 7.5% of cancer cells from the KYSE70 cell line. Sphere formation and anchorage-independent growth were analyzed in CD271+ and CD271- cancer cells, respectively. qPCR was used to detect stem-related genes and CCK-8 was performed to analyze the sensitivity to chemotherapy in the two groups. Bisulfite genomic sequencing was used to analyze the methylation status. CD271 expression was significantly higher in ESCC tissues than in adjacent non-cancerous tissues. Compared with CD271- cancer cells, CD271+ cancer cells showed a higher ability of sphere and colony formation, a high level expression of stem-related gene, and resistance to chemotherapy. The expression of CD271 was induced by a demethylation agent. In conclusion, CD271+ ESCC cells possess stem-like properties. CD271 can potentially act as a prognostic marker for ESCC, whose expression is regulated epigenetically

Report drawn up on behalf of the Committee on Economic and Monetary Affairs on the possible loan from the OPEC countries to the Federal Republic of Germany and to France. EP Working Documents 1982-83, Document 1-284/82, 4 June 1982

Abstract Background Hand, foot, and mouth disease (HFMD) has become an emerging infectious disease in China in the last decade. There has been evidence that meteorological factors can influence the HFMD incidence, and understanding the mechanisms can help prevent and control HFMD. Methods HFMD incidence data and meteorological data in Minhang District, Shanghai were obtained for the period between 2009 and 2015. Distributed lag non-linear models (DLNMs) were utilized to investigate the impact of meteorological factors on HFMD incidence after adjusting for potential confounders of long time trend, weekdays and holidays. Results There was a non-linear relationship between temperature and HFMD incidence, the RR of 5th percentile compared to the median is 0.836 (95% CI: 0.671–1.042) and the RR of 95th percentile is 2.225 (95% CI: 1.774–2.792), and the effect of temperature varied across age groups. HFMD incidence increased with increasing average relative humidity (%) (RR = 1.009, 95% CI: 1.005–1.015) and wind speed (m/s) (RR = 1.197, 95% CI: 1.118–1.282), and with decreasing daily rainfall (mm) (RR = 0.992, 95% CI: 0.987–0.997) and sunshine hours (h) (RR = 0.966, 95% CI: 0.951–0.980). Conclusions There were significant relationships between meteorological factors and childhood HFMD incidence in Minhang District, Shanghai. This information can help local health agencies develop strategies for the control and prevention of HFMD under specific climatic conditions

The GECAM Real-Time Burst Alert System

Gravitational Wave High-energy Electromagnetic Counterpart All-sky Monitor (GECAM), consisting of two micro-satellites, is designed to detect gamma-ray bursts associated with gravitational-wave events. Here, we introduce the real-time burst alert system of GECAM, with the adoption of the BeiDou-3 short message communication service. We present the post-trigger operations, the detailed ground-based analysis, and the performance of the system. In the first year of the in-flight operation, GECAM was triggered by 42 GRBs. GECAM real-time burst alert system has the ability to distribute the alert within $\sim$1 minute after being triggered, which enables timely follow-up observations.Comment: 17 pages, 10 figures; Accepted for publication in RA

Metabolomics combined with transcriptomics analyses of mechanism regulating testa pigmentation in peanut

Peanut testa (seed coat) contains large amounts of flavonoids that significantly influence seed color, taste, and nutritional qualities. There are various colors of peanut testa, however, their precise flavonoid components and regulatory mechanism of pigmentation remain unclear. In this study, a total of 133 flavonoids were identified and absolutely quantified in the seed coat of four peanut cultivars with different testa color using a widely targeted metabolomic approach. Black peanut skin had more types and substantial higher levels of cyanidin-based anthocyanins, which possibly contribute to its testa coloration. Procyanidins and flavan-3-ols were the major co-pigmented flavonoids in the red, spot and black peanuts, while flavanols were the most abundant constitutes in white cultivar. Although the concentrations as well as composition characteristics varied, the content ratios of procyanidins to flavan-3-ols were similar in all samples except for white peanut. Furthermore, MYB-like transcription factors, anthocyanidin reductases (ANR), and UDP-glycosyltransferases (UGT) were found to be candidate genes involved in testa pigmentation via RNA-seq and weighted gene co-expression network analysis. It is proposed that UGTs and ANR compete for the substrate cyanidin and the prevalence of UGTs activities over ANR one will determine the color pattern of peanut testa. Our results provide a comprehensive report examining the absolute abundance of flavonoid profiles in peanut seed coat, and the finding are expected to be useful for further understanding of regulation mechanisms of seed coat pigmentation in peanut and other crops

MicroRNA Regulation of Human Herpesvirus Latency

Herpesviruses are ubiquitous human pathogens. After productive (lytic) infection, all human herpesviruses are able to establish life-long latent infection and reactivate from it. Latent infection entails suppression of viral replication, maintenance of the viral genome in infected cells, and the ability to reactivate. Most human herpesviruses encode microRNAs (miRNAs) that regulate these processes during latency. Meanwhile, cellular miRNAs are hijacked by herpesviruses to participate in these processes. The viral or cellular miRNAs either directly target viral transcripts or indirectly affect viral infection through host pathways. These findings shed light on the molecular determinants that control the lytic-latent switch and may lead to novel therapeutics targeting latent infection. We discuss the multiple mechanisms by which miRNAs regulate herpesvirus latency, focusing on the patterns in these mechanisms

Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies

Cancer immunotherapy strategies based on chimeric antigen receptor (CAR) transduced T cells or antibodies against immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), achieved significant successes from bench to clinic in the past 2 years. CARs are artificial engineered receptors that can specifically target tumor cell surface antigen, activate T cell and further enhance T cell function, independent of major histocompatibility complex. CAR T cells have shown promising outcomes in cancers, especially in hematologic malignancies. CTLA-4 and PD-1 are two important immune checkpoints negatively regulating T cell activation. Clinical benefits of CTLA-4/PD-1 antibodies are significant in melanoma and other solid tumors. PD-1 is predicted to have fewer side effects and greater antitumor activity than CTLA-4. In this review, we will summarize current immunotherapies based on CAR T cells and PD-1

Potential anticancer activity of curcumin analogs containing sulfone on human cancer cells

Three curcumin analogs(S1-S3) containing sulfone were investigated for their effects on human prostate cancer PC-3, colon cancer HT-29, lung cancer H1299 and pancreatic cancer BxPC-3 cells. The three compounds were approximately 16-to 96-fold more active than curcumin in these cell lines as determined by the MTT assay. The effects of these compounds on cell growth were further studied in prostate cancer PC-3 cells in both two dimensional (2D) and three dimensional (3D) cultures. S1-S3strongly inhibited the growth and induced cell death in PC-3 cells, and the effects of these compounds were associated with suppression of nuclear factor kappa B (NF-κB) transcriptional activity. Moreover, treatment of PC-3 cells with all three compounds caused a decrease in the level of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) (Tyr705),but not p-STAT3(Ser727). Only S1and S2decreased the presence of phosphorylated Akt (p-Akt) in PC-3 cells. These curcumin analogs warrant further in vivo studies for anticancer activities in suitable animal models

Dynamic changes in CD45RA−Foxp3high regulatory T-cells in chronic hepatitis C patients during antiviral therapy

Objectives: CD4+Foxp3+ regulatory T-cells (Treg) are known to accumulate under certain pathological conditions. This study was conducted to evaluate the characteristics of and dynamic changes in Treg cells in chronic hepatitis C (CHC) patients during antiviral therapy. Methods: One hundred and forty-five subjects were enrolled in this study, including 105 CHC patients and 40 healthy donors. The phenotypes and functions of Treg cells were analyzed by flow cytometry. Results: A significant elevation in Treg cells was observed in the peripheral blood of CHC patients compared with healthy donors. Interestingly, compared with non-suppressive Treg (non-Treg) and resting Treg (rTreg) cells, activated Treg (aTreg) cells expressed higher levels of ectonucleotidase, CD39, and CD73. After treatment with interferon alpha (IFN-α) and ribavirin (RBV) in vitro, the frequencies of total Treg cells and aTreg cells in peripheral blood mononuclear cells (PBMC), as well as the levels of transforming growth factor beta (TGF-β) secreted by aTreg and non-Treg cells, were significantly decreased. Importantly, it was found that levels of aTreg cells in patients with a sustained virological response (SVR) were lower than in relapsed patients, suggesting that a high frequency of aTreg cells might be associated with a poor clinical outcome in HCV infection. Conclusion: These results demonstrate a decreasing trend in aTreg cells, which express higher levels of CD39, CD73, and TGF-β, in SVR patients during antiviral therapy

Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis

Chimeric antigen receptor (CAR) modified T cells targeted CD19 showed promising clinical outcomes in treatment of B cell malignances such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) and other indolent lymphomas. However, the clinical benefit varies tremendously among different trials. This meta-analysis investigated the efficacy (response rates and survival time) of CD19-CAR T cells in refractory B cell malignances in Phase I clinical trials. We searched publications between 1991 and 2014 from PubMed and Web of Science. Pooled response rates were calculated using random-effects models. Heterogeneity was investigated by subgroup analysis and meta-regression. Fourteen clinical trials including 119 patients were eligible for response rate evaluation, 62 patients in 12 clinical trials were eligible for progression-free survival analysis. The overall pooled response rate of CD19-CAR T cells was 73% (95% confidence interval [CI]: 46-94%). Significant heterogeneity across estimates of response rates was observed (p < 0.001, I2=88.3%). ALL patients have higher response rate (93%, 95% CI: 65-100%) than CLL (62%, 95% CI: 27-93%) and lymphoma patients (36%, 95% CI: 1-83%). Meta-regression analysis identified lymphodepletion and no IL-2 administrated T cells as two key factors associated with better clinical response. Lymphodepletion and higher infused CAR T cell number were associated with better prognosis. In conclusion, this meta-analysis showed a high clinical response rate of CD19-CAR T cell-based immunotherapy in treatment of refractory B cell malignancies. Lymphodepletion and increasing number of infused CD19-CAR T cells have positive correlations with the clinical efficiency, on the contrary, IL-2 administration to T cells is not recommended