Circular RNA (circRNA) is a class of non-coding RNA whose functions remain mostly unknown. Recent studies indicate circRNA may be involved in disease pathogenesis, but direct evidence is scarce. Here we characterize the functional role of a novel circRNA, circCCDC66, in colorectal cancer (CRC). RNA-Seq data from matched normal and tumor colon tissue samples identified numerous circRNAs specifically elevated in cancer cells, several of which were verified by quantitative RT-PCR. CircCCDC66 expression was elevated in polyps and colon cancer and was associated with poor prognosis. Gain-of-function and loss-of-function studies in CRC cell-lines demonstrated that circCCDC66 controlled multiple pathological processes, including cell proliferation, migration, invasion, and anchorage-independent growth. In-depth characterization revealed that circCCDC66 exerts its function via regulation of a subset of oncogenes, and knockdown of circCCDC66 inhibited tumor growth and cancer invasion in xenograft and orthotopic mouse models, respectively. Taken together, these findings highlight a novel oncogenic function of circRNA in cancer progression and metastasis.
Efforts to find a better adjuvant in regional anaesthesia are underway since long. Aims and objectives are to compare the efficacy and clinical profile of two α-2 adrenergic agonists, dexmedetomidine and clonidine, in epidural anaesthesia with special emphasis on their sedative properties and an ability to provide smooth intra-operative and post-operative analgesia. A prospective randomized study was carried out which included 50 adult female patients between the ages of 44 and 65 years of (American Society of Anaesthesiologists) ASAI/II grade who underwent vaginal hysterectomies. The patients were randomly allocated into two groups; ropivacaine + dexmedetomidine (RD) and ropivacaine + clonidine (RC), comprising of 25 patients each. Group RD was administered 17 ml of 0.75% epidural ropivacaine and 1.5 μg/kg of dexmedetomidine, while group RC received admixture of 17 ml of 0.75% ropivacaine and 2 μg/kg of clonidine. Onset of analgesia, sensory and motor block levels, sedation, duration of analgesia and side effects were observed. The data obtained was subjected to statistical computation with analysis of variance and chi-square test using statistical package for social science (SPSS) version 10.0 for windows and value of P < 0.05 was considered significant and P < 0.0001 as highly significant. The demographic profile, initial and post-operative block characteristics and cardio-respiratory parameters were comparable and statistically non-significant in both the groups. However, sedation scores with dexmedetomidine were better than clonidine and turned out to be statistically significant (P < 0.05). The side effect profile was also comparable with a little higher incidence of nausea and dry mouth in both the groups which was again a non-significant entity (P > 0.05). Dexmedetomidine is a better neuraxial adjuvant compared to clonidine for providing early onset of sensory analgesia, adequate sedation and a prolonged post-operative analgesia.
The Hedgehog (Hh) pathway is a major regulator of many fundamental processes in vertebrate embryonic development including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. Constitutive activation of the Hh pathway leading to tumorigenesis is seen in basal cell carcinomas and medulloblastoma. A variety of other human cancers, including brain, gastrointestinal, lung, breast and prostate cancers, also demonstrate inappropriate activation of this pathway. Paracrine Hh signaling from the tumor to the surrounding stroma was recently shown to promote tumorigenesis. This pathway has also been shown to regulate proliferation of cancer stem cells and to increase tumor invasiveness. Targeted inhibition of Hh signaling may be effective in the treatment and prevention of many types of human cancers. The discovery and synthesis of specific Hh pathway inhibitors have significant clinical implications in novel cancer therapeutics. Several synthetic Hh antagonists are now available, several of which are undergoing clinical evaluation. The orally available compound, GDC-0449, is the farthest along in clinical development. Initial clinical trials in basal cell carcinoma and treatment of select patients with medulloblastoma have shown good efficacy and safety. We review the molecular basis of Hh signaling, the current understanding of pathway activation in different types of human cancers and we discuss the clinical development of Hh pathway inhibitors in human cancer therapy.
Background Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear. Methods and Results Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as <1%, 1% to <5%, and ≥5%, and 25-year risk estimates were categorized as <8%, 8% to 30%, and ≥30%. During a median follow-up period of 16 years, there were 1621 CVD deaths. The addition of fitness to the traditional risk factor model resulted in reclassification of 10.7% of the men, with significant net reclassification improvement at both 10 years (net reclassification improvement=0.121) and 25 years (net reclassification improvement=0.041) (P<0.001 for both). The integrated discrimination improvement was 0.010 at 10 years (P<0.001), and the relative integrated discrimination improvement was 29%. Similar findings were observed for women at 25 years. Conclusions A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.
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