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Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy with a complex tumor ecosystem. How the interplay between tumor cells, EBV, and the microenvironment contributes to NPC progression and immune evasion remains unclear. Here we performed single-cell RNA sequencing on ~104,000 cells from 19 EBV(+) NPCs and 7 nonmalignant nasopharyngeal biopsies, simultaneously profiling the transcriptomes of malignant cells, EBV, stromal and immune cells. Overall, we identified global upregulation of interferon responses in the multicellular ecosystem of NPC. Notably, an epithelial–immune dual feature of malignant cells was discovered and associated with poor prognosis. Functional experiments revealed that tumor cells with this dual feature exhibited a higher capacity for tumorigenesis. Further characterization of the cellular components of the tumor microenvironment (TME) and their interactions with tumor cells revealed that the dual feature of tumor cells was positively correlated with the expression of co-inhibitory receptors on CD8(+) tumor-infiltrating T cells. In addition, tumor cells with the dual feature were found to repress IFN-γ production by T cells, demonstrating their capacity for immune suppression. Our results provide new insights into the multicellular ecosystem of NPC and offer important clinical implications.

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4+ and CD8+ T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Regulatory T cells (Tregs) represent an important contributor to cancer immune escape, but the molecular mechanism responsible for Treg expansion in tumors is heterogeneous and unclear. Here, we investigated the role of S1P1, a receptor of the bioactive lipid sphingosine 1-phosphate (S1P), in regulating the crosstalk between tumor cells and tumor-associated Tregs in bladder cancer (BC). We found that the frequency of CD4+Foxp3+ Tregs was increased in circulating and tumor-infiltrating lymphocytes from BC patients. S1P1 expression was upregulated in BC tissues compared with tumor-adjacent tissues and was positively correlated with the density of tumor-infiltrated Foxp3+ Tregs. Both S1P1 and Treg predicted poor overall survival in BC patients. The in vitro data paralleled the in vivo data and suggested that the activation or overexpression of S1P1 in BC cells promoted the generation of BC-induced (i)Tregs from CD4+CD25−cells, and the generation of these cells was reversed by treatment with anti-IL-10 or anti-TGF-β. Moreover, S1P1 promoted Treg migration mediated by BC cells. Mechanistically, S1P1 activated the TGF-β signaling pathway, leading to the secretion of TGF-β and IL-10 from BC cells. In total, our findings suggest that S1P1 induces tumor-derived Treg expansion in a cell-specific manner and serves as a potent prognostic biomarker and therapeutic target in BC.

The expansion of myeloid‐derived suppressor cells (MDSCs) correlates with tumorigenesis in colorectal cancer (CRC). Here, we found a significant association between CD33(+) MDSC number and Yes‐associated protein 1 (YAP1) and phosphatase and tensin homologue (PTEN) levels in CRC patients (P < 0·05). Moreover, the CD33(+) MDSCs, YAP1 and PTEN were identified as predictors for the prognosis of CRC patients (P < 0·05). Notably, CD33(+) MDSCs were an independent survival predictor for CRC patients through a Cox model analysis. In vitro data determined that the expression levels of YAP1 and PTEN in CRC‐derived cell lines were associated with CRC‐derived MDSC induction, and the blockade of YAP1 and PTEN decreased CRC‐derived MDSC induction. A mechanistic analysis revealed that YAP1 promoted CRC‐derived MDSC induction by suppressing PTEN expression to up‐regulate COX‐2, P‐AKT and P‐p65 in CRC‐derived cells, leading to secretion of the cytokine granulocyte–macrophage colony‐stimulating factor. Our findings establish a novel mechanism of pro‐tumorigenic MDSC induction mediated by ectopic YAP1 and PTEN expression in CRC.

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4

Yeast Cia2p is a component of the cytosolic Fe/S protein assembly (CIA) machinery. Initial studies of the CIA machinery were performed in yeast, but the precise role of Cia2p in this eukaryote is still unknown. We report that CIA2 deficiency results in impaired oxidative stress response, as evidenced by increased sensitivity to the oxidant cumene hydroperoxide (CHP), impaired activities of superoxide dismutases and aconitase and decreased replicative lifespan in the mutants. Moreover, intracellular reactive oxygen species levels were significantly increased in CIA2-deficient cells after treatment with CHP. We also show that CIA2-deficient cells display an increased resistance to tunicamycin-induced endoplasmic reticulum (ER) stress, as evidenced by the upregulated splicing of the mRNA of HAC1, which encodes a functional transcription factor that regulates the transcription of unfolded protein response (UPR) target genes, suggesting enhanced intracellular UPR activity. Furthermore, the transcription of several canonical UPR target genes is strongly induced in CIA2-deficient cells as compared with wild-type controls. Taken together, these results suggest the involvement of Cia2p in oxidative and ER stress responses in yeast.

Aims: Hypoxia inducible factor-1α (HIF-1α) plays important roles in response to hypoxia. In this study, the effects of adenovirus mediated transgenic HIF-1α on cardiac function in acute myocardial infarction (AMI) models was investigated. Methods and Results: Ad-HIF-1α (adenovirus vector containing HIF-1α gene) or Rz-HIF-1α group (adenovirus vector containing HIF-1α ribozyme gene) were transfected into myocardial cells respectively. It was discovered that the expression of HIF-1α and VEGF increased at first, reached the peak at 7d (7th day) and decreased gradually from then on. At 56d (56 day), HIF-1α protein was undetectable, and VEGF protein was hardly expressed as well. Meanwhile, the amount of apoptotic cells was the largest in Rz-HIF-1α group, while the one was rather small in Ad-HIF-1α group. Conclusions: In summary, in animal models of myocardial infarction , this adenovirus mediated medical treatment using Ad-HIF-1α gene injection could reverse both the damage to cardiac function and myocardial cell apoptosis under the hypoxia induction. Significance and Impact of the Study: These results may provide an experimental and theoretical proof of adenovirus mediated transgenic HIF-1α in clinical application of myocardial infarction.

It describes a new kind of Time shift TV architecture which is based on metadata and has very good manipulation for users. On current HuDong digital TV environment, it can transfer broadcast model into on-demand model by seamless switch technique. The architecture will satisfy effectively the individuation requirement on on-demand TV and help Radio Film and Television operators to improve their competition on alluring customer.

The mobile communication network planning and optimization of high-precision in high-density urban areas dependent on the wave propagation model, and precise three-dimensional model of high density building group is the foundation to achieve an accurate forecast. With the help of telecommunications project financing of Wuhan Telecom, from the point of achieving high accuracy wave propagation prediction, we build a highly efficient large-scale high-density complex 3D graphics engine based on OpenGL. With the two-dimensional electronic map data, default height of buildings and reasonable organizations structure of map data, it realizes the three-dimensional display and roam of buildings in Wuhan City, which may be helpful to the design and realization of the three-dimensional GIS.

SUMMARY 1 The present study was conducted to investigate whether hydroxysafflor yellow A (HSYA) has a protective effect against heart injury after ischaemia–reperfusion and to determine the possible mechanism involved. 2 Hearts isolated from male Sprague-Dawley rats were perfused on a Langendorff apparatus and subjected to 30 min global ischaemia, followed by 120 min reperfusion. Infarct size and the level of lactate dehydrogenase (LDH) in the coronary effluent were determined. In mitochondria from isolated perfused hearts, Ca2+-induced swelling was observed. In isolated ventricular myocytes, depolarization of the mitochondrial membrane was determined by tetramethyl-rhodamine ethyl ester (TMRE) fluorescence. Furthermore, levels of phosphorylated endothelial nitric oxide synthase (eNOS) protein were measured by western blot. 3 Pretreatment with HSYA for 5 min before ischaemia reduced infarct size and the release of LDH. Administration of 20 µmol/L atractyloside, an opener of the mitochondrial permeability transition pore, and 10 µmol/L NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, attenuated the protective effects of HSYA. In mitochondria isolated from hearts pretreated with 0.1 mmol/L HSYA for 5 min, a significant inhibition of Ca2+-induced swelling was observed and this inhibition was attenuated by l-NAME. In isolated ventricular myocytes, pretreatment with HSYA prevented ischaemia-induced cell death and depolarization of the mitochondrial membrane, whereas atractyloside or l-NAME attenuated the effects of HSYA. Levels of phosphorylated eNOS protein were significantly enhanced in the HSYA-treated group. 4 The findings of the present study indicate that HSYA protects the myocardium against ischaemia–reperfusion injury by inhibiting mitochondrial permeability transition pore opening. The effect of HSYA on mitochondrial permeability transition pore opening may be mediated through enhanced nitric oxide production by eNOS activation.