Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

BACKGROUND. MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. RESULTS. We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a) represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b) the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c) the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d) the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC) and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX), VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1, ERBB4, and (SLC12A1, TCF21) respectively. We also found strong anti-correlation between VEGFA and the miR-200 family of microRNA: miR-200a*, 200b, 200c and miR-141. Several identified microRNA/mRNA pairs were validated on an independent set of matched ccRCC/normal samples. The regulation of SEMA6A by miR-141 was verified by a transfection assay. CONCLUSIONS. We describe a simple and reliable method to identify direct gene targets of microRNA in any cancer. The constraints we impose (strong dysregulation signature for microRNA and mRNA levels between tumor/normal samples, evolutionary conservation of seed sequence and strong anti-correlation of expression levels) remove spurious matches and identify a subset of robust, tissue specific, functional mRNA targets of dysregulated microRNA.Cancer Institute of New Jersy; New Jersey Commission for Cacner Research; Lineberger Comprehensive Cancer Center Tissue Procurement and Genomics Core Facility; Crawford Fun

Hibernus++: a self-calibrating and adaptive system for transiently-powered embedded devices

Energy harvesters are being used to power autonomous systems, but their output power is variable and intermittent. To sustain computation, these systems integrate batteries or supercapacitors to smooth out rapid changes in harvester output. Energy storage devices require time for charging and increase the size, mass and cost of systems. The field of transient computing moves away from this approach, by powering the system directly from the harvester output. To prevent an application from having to restart computation after a power outage, approaches such as Hibernus allow these systems to hibernate when supply failure is imminent. When the supply reaches the operating threshold, the last saved state is restored and the operation is continued from the point it was interrupted. This work proposes Hibernus++ to intelligently adapt the hibernate and restore thresholds in response to source dynamics and system load properties. Specifically, capabilities are built into the system to autonomously characterize the hardware platform and its performance during hibernation in order to set the hibernation threshold at a point which minimizes wasted energy and maximizes computation time. Similarly, the system auto-calibrates the restore threshold depending on the balance of energy supply and consumption in order to maximize computation time. Hibernus++ is validated both theoretically and experimentally on microcontroller hardware using both synthesized and real energy harvesters. Results show that Hibernus++ provides an average 16% reduction in energy consumption and an improvement of 17% in application execution time over stateof- the-art approaches

Effect of a gum-based thickener on the safety of swallowing in patients with poststroke oropharyngeal dysphagia

Altres ajuts: This work has been supported by Danone Nutricia Research, Fundació Salut del Consorci Sanitari del Maresme, Furega (Fundació per a la Recerca en Gastroenterologia) and Centro de Investigación en Red en Enfermedades Hepáticas y Digestivas (CIBERehd).Background: Increasing viscosity with thickening agents is a valid therapeutic strategy for oropharyngeal dysphagia (OD). To assess the therapeutic effect of a xanthan gum-based thickener (Nutilis Clear) at six viscosities compared with thin liquid in poststroke OD (PSOD) patients. Methods: A total of 120 patients with PSOD were studied in this controlled, multiple-dose, fixed-order, and single-blind study using videofluoroscopy (VFSS). A series of boluses of 10 mL thin liquid and 2000, 1400, 800, 450, 250, and 150 mPa s viscosities were given in duplicate, interrupted in case of aspiration. We assessed the safety and efficacy of swallow and the kinematics of the swallow response. Key Results: A total of 41.2% patients had safe swallow at thin liquid which significantly increased for all viscosities from 71.9% at 150 mPa s to 95.6% at 1400 mPa s (P <.001). PAS score (3.7 ± 2.3) at thin liquid was also reduced by increasing bolus viscosity (P <.001). The prevalence of patients with aspiration at thin liquid was 17.5% and decreased at all viscosities (P <.01), except at 150 mPa s. Increasing viscosity shortened time to laryngeal vestibule closure (LVC) at all viscosities (P <.01) and reduced bolus velocity at ≥450 mPa s (P <.05). The prevalence of patients with pharyngeal residue at each viscosity 37.7%-44.7% was similar to that at thin liquid (41.2%). Conclusions and Inferences: The prevalence of unsafe swallow with thin liquids is very high in PSOD. Increasing shear bolus viscosity with this xanthan gum-based thickener significantly increased the safety of swallow in patients with PSOD in a viscosity-dependent manner without increasing the prevalence of pharyngeal residue

Histomorphological evaluation, cell proliferation and endothelial immunostaining in oral and maxillofacial myofibroblastic lesions

Myofibroblasts (MF) are mesenchymal cells with features of both fibroblasts and smooth muscle cells. Although these are usually reactive cells, they can lead to myofibroblastic tumors that may share clinical and histomorphological characteristics but with different prognosis. The aim of this study is to perform a histomorphological evaluation as well as to compare and evaluate two different cell proliferation immunomarkers and two endothelial markers in a group of oral and maxillofacial myofibroblastic lesions (MFL). Cross-sectional and retrospective study. Demographic, clinical, histomorphological and immunohistochemical characteristics of 39 cases of MFL were analyzed. Immunohistochemical reactions were performed with the Ki67, MCM2, CD34 and CD105 antibodies. Kruskal-Wallis test and Spearman correlation analysis were used. Four cases of nodular fasciitis (NF), 18 myofibromas (My), 6 desmoplastic fibromas (DF), 7 inflammatory myofibroblastic tumors (IMT) and 4 myofibroblastic sarcomas (MFS) were studied. There were twenty women (51.2%); the median age was 13 [Q1-Q3: 8-24] years and most cases occurred in the mandible (48.7%). A statistically significant difference with MCM2 immunostaining (p=0.0221) was observed between the MFL; furthermore, a correlation between CD34 and CD105 immunostaining in NF (p <0.0001) and IMT (p=0.0408), between MCM2 and CD34 in IMT (p=0.0362) and between MCM2 and CD105 in MFS (p <0001) were found. MCM2 immunostaining could assess more clearly the cell growth fraction in MFL. The correlation between MCM2 and CD34 in IMT and between MCM2 and CD105 in MFS are indicative of the high activity of these lesions. These results emphasize the importance of the studied immunohistochemistry markers as possible tools for a better characterization of some of the MFL

Guatemala's Pacific cetaceans: :Fifty years of history

Cetaceans have been studied in Guatemala since 1960s, but only a few scientific works based on the collected cetacean data were published. We reviewed literatures about cetaceans in Guatemala for the past fifty years to gain the biological knowledge for conservation and management plans. A total of 1,014 sighting records (1979- 2011), 62 tuna fishery by-catch events (1961-1985) and 16 stranding records (1975, 2007-2012) were obtained and analyzed with bathymetric maps and plot against maps with different anthropogenic pressures in the area. Nineteen species belonging to five different families of cetaceans, such as Balaenopteridae, Delphinidae, Ziphiidae, Kogiidae, and Physeteridae, were identified. Data sampling areas have been changed during 1961-2012. We identified several species-specific-spatial-distribution patterns. Species occurrence was higher in areas with complex topography. Although, all by-catch events were recorded offshore, species with coastal distribution occurred in areas with higher anthropogenic risk. Stranding events were reported for eight species, and occurred mainly in the department of Escuintla from 2007. Due to the great diversity in spatial-distribution patterns of cetacean in Guatemala, behavior and habitat use of cetaceans in the areas, combined with different anthropogenic risks, an integrative approach should be considered when conservation and management plans are implemented in Guatemala