Despite the success of immune checkpoint blockade against melanoma, many "cold" tumors like prostate cancer remain unresponsive. We found that hypoxic zones were prevalent across preclinical prostate cancer and resisted T cell infiltration even in the context of CTLA-4 and PD-1 blockade. We demonstrated that the hypoxia-activated prodrug TH-302 reduces or eliminates hypoxia in these tumors. Combination therapy with this hypoxia-prodrug and checkpoint blockade cooperated to cure more than 80% of tumors in the transgenic adenocarcinoma of the mouse prostate-derived (TRAMP-derived) TRAMP-C2 model. Immunofluorescence imaging showed that TH-302 drives an influx of T cells into hypoxic zones, which were expanded by checkpoint blockade. Further, combination therapy reduced myeloid-derived suppressor cell density by more than 50%, and durably reduced the capacity of the tumor to replenish the granulocytic subset. Spontaneous prostate tumors in TRAMP transgenic mice, which completely resist checkpoint blockade, showed minimal adenocarcinoma tumor burden at 36 weeks of age and no evidence of neuroendocrine tumors with combination therapy. Survival of Pb-Cre4, Ptenpc-/-Smad4pc-/- mice with aggressive prostate adenocarcinoma was also significantly extended by this combination of hypoxia-prodrug and checkpoint blockade. Hypoxia disruption and T cell checkpoint blockade may sensitize some of the most therapeutically resistant cancers to immunotherapy.

Objective: Circular RNAs (circRNAs) are a significant class of molecules involved in a wide range of diverse biological functions that are abnormally expressed in many types of diseases. The present study aimed to determine the circRNAs specifically expressed in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients to identify their possible molecular mechanisms. Methods: To identify the circRNAs specifically expressed in RA, we started by sequencing the of PBMCs circRNA and microRNAs (miRNAs) from a RA group (n = 3) and a control group (n = 3). We constructed a network of differentially expressed circRNAs and miRNAs. Then, we selected differentially expressed circRNAs in PBMCs from 10 RA patients relative to 10 age-and sex-matched controls using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Spearman's correlation test was used to evaluate the correlation of circRNAs with biochemical measurements. Results: A total of 165 circRNAs and 63 miRNAs were differently expressed between RA patients and healthy people according to RNA-seq, including 109 circRNAs that were significantly up-regulated and 56 circRNAs that were down-regulated among the RA patients. RT-qPCR validation demonstrated that the expression levels of hsa circ 0001200, hsa circ 0001566, hsa circ 0003972, and hsa circ 0008360 were consistent with the results from the sequencing analysis. Then, we found that there were significant correlations between the circRNAs and disease severity. Conclusion: Generally, these results suggest that expression of hsa circ 0001200, hsa circ 0001566, hsa circ 0003972, and hsa circ 0008360 in PBMCs from RA patients may serve as potential biomarkers for the diagnosis of RA, and these circRNAs may influence the occurrence and development of RA.

Despite evidence of a relationship among obstructive sleep apnea (OSA), metabolic dysregulation, and diabetes, it is uncertain whether OSA treatment can improve metabolic parameters. We sought to determine effects of long-term continuous positive airway pressure (CPAP) treatment on glycemic control and diabetes risk in patients with cardiovascular disease (CVD) and OSA. RESEARCH DESIGN AND METHODSBlood, medical history, and personal data were collected in a substudy of 888 participants in the Sleep Apnea cardioVascular Endpoints (SAVE) trial in which patients with OSA and stable CVD were randomized to receive CPAP plus usual care, or usual care alone. Serum glucose and glycated hemoglobin A 1c (HbA 1c ) were measured at baseline, 6 months, and 2 and 4 years and incident diabetes diagnoses recorded. RESULTSMedian follow-up was 4.3 years. In those with preexisting diabetes (n 5 274), there was no significant difference between the CPAP and usual care groups in serum glucose, HbA 1c , or antidiabetic medications during follow-up. There were also no significant between-group differences in participants with prediabetes (n 5 452) or new diagnoses of diabetes. Interaction testing suggested that women with diabetes did poorly in the usual care group, while their counterparts on CPAP therapy remained stable. CONCLUSIONSAmong patients with established CVD and OSA, we found no evidence that CPAP therapy over several years affects glycemic control in those with diabetes or prediabetes or diabetes risk over standard-of-care treatment. The potential differential effect according to sex deserves further investigation.Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper-airway collapse during sleep that causes intermittent hypoxemia, sleep fragmentation, and daytime sleepiness. The standard therapy for OSA is continuous positive airway pressure (CPAP) to prevent airway obstruction (1).OSA is common in the population and strongly associated with obesity (2). Prospective cohort studies have found associations between moderate to severe OSA and

The progression of colorectal cancer (CRC) is a multistep process and metastatic CRC is always incurable; consequently, CRC is the leading cause of cancer-related deaths. There is therefore an urgent need for identifying useful biomarkers with enough sensitivity and specificity to detect this disease at early stages, which will significantly reduce the mortality for this malignancy. In this study, we performed an integrating analysis of different RNA-Seq data sets to find new candidate biomarkers for diagnosis, prognosis and as therapeutic targets for this malignancy, as well as to elucidate the molecular mechanisms of CRC carcinogenesis. We identified 883 differentially expressed genes (DEGs) across the studies between CRC and normal control (NC) tissues by combining five RNA-Seq data sets. Gene function analysis revealed high correlation with carcinogenesis. The top 10 most significantly DEGs were further evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in both rectal cancer (RC) and colon cancer (CC), and the results matched well with integrating data, suggesting that the method of integrating analysis of different RNA-seq data sets is acceptable. Therefore, integrating analysis of different RNA-seq data sets may be a useful way to overcome the limitation of small sample size in a single RNA-seq study. In addition, our study showed that some genes, such as SIM2, ADAMTS6, FOXD4L4 and DNAH5, may have an important role in the development of CRC, which could be applied for diagnosis, prognosis and as therapy for this malignancy. Our findings would also help to understand the pathology of CRC.

Wheat powdery mildew, caused by the biotrophic fungus Blumeria graminis f. sp. tritici (Bgt), is a serious disease of wheat worldwide that can cause significant yield losses. Growing resistant cultivars is the most cost-effective and eco-soundly strategy to manage the disease. Therefore, a high breeding priority is to identify genes that can be readily used either singly or in combination for effective resistance to powdery mildew and also in combination with genes for resistance to other diseases. Yunnan Province, with complex and diverse ecological environments and climates, is one of the main wheat growing regions in China. This region provides initial inoculum for starting epidemics of wheat powdery mildew in the region and other regions and thus, plays a key role in the regional and large-scale epidemics of the disease throughout China. The objectives of this study were to evaluate seedling resistance of 69 main wheat cultivars to powdery mildew and to determine the presence of resistance genes Pm3, Pm8, Pm13, Pm16, and Pm21in these cultivars using gene specific DNA markers. Evaluation of 69 wheat cultivars with six Bgt isolates showed that only four cultivars were resistant to all tested isolates, indicating that the overall level of powdery mildew resistance of Yunnan wheat cultivars is inadequate. The molecular marker results showed that 27 cultivars likely have at least one of these genes. Six cultivars were found likely to have Pm3,18 likely to have Pm8,5 likely to have Pm16,and 3 likely to have Pm21. No cultivar was found to carry Pm13. The information on the presence of the Pmresistance genes in Yunnan wheat cultivars can be used in future wheat disease breeding programs. In particular, cultivars carrying Pm21, which is effective against all Bgtraces in China, should be pyramided with other effective genes to developing new cultivars with durable resistance to powdery mildew.