Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.
The Ontario Cancer Registry (OCR) and the Surveillance, Epidemiology and End Results (SEER) databases were used to describe temporal trends in the incidence and survival of squamous cancers of the upper aerodigestive tract (UADT) in Ontario and the US between 1984 and 2001. Between the 1984-86 and 1999-01 periods, the age-adjusted incidence rate of all first primary cancers of the UADT decreased from 11.6 (11.2-12.0) to 8.8 (8.5-9.1) in Ontario and 13.0 (12.7-13.3) to 10.2 (10.0-10.4) in the US. Significant decreases in incidence were observed in many UADT sites but there was no significant change in the incidence of cancer of the oropharynx in either the US or Canada. Over the same period, the 5-year relative survival for all UADT cancers increased from 49.2% (47.2-51.2%) to 57.1%(55.0-59.1%) in Ontario and from 48.1% (46.9-49.3%) to 52.4% (51.2-53.6%) in the US. This significant improvement in the outcome of UADT cancer was largely due to a dramatic increase in the 5-year relative survival for cancers of the oropharynx from 31.1% (27.1-35.1%) to 53.6% (49.3-57.9%) in Ontario and from 35.3% (32.9-37.8%) to 51.0% (48.7-53.3%) in the US. Smaller increases in survival were observed in cancers of the oral cavity, nasopharynx, and hypopharynx, but there was no evidence of any increase in survival for cancer of the larynx. These results are consistent with the hypothesis that there has been a major change in the etiology of cancer of the oropharynx in Canada and the US and a concomitant change in its response to therapy. '
UICCKey words: head and neck cancer; cancer of the oropharynx; incidence; etiology; relative survival Cancer of the UADT remains a significant problem in North America. 1 Until recently, the use of tobacco and alcohol were considered to be the principal causes of UADT cancers in the developed countries. 2 The decline in smoking rates in recent decades has been associated with a reduction in the overall incidence of cancer of the UADT in the US. However, the incidence of cancer of the oropharynx has not decreased in parallel with that of other UADT cancers. 3,4 This has led to the hypothesis that a real decrease in the incidence of smoking-related cancers of the oropharynx may have been obscured by a simultaneous increase in the incidence of a new variant of the disease caused by human papilloma virus (HPV). [3][4][5][6][7][8][9] In a previous population-based study of UADT cancer over the period from 1982from to 1994 showed that the incidence of UADT cancers in Ontario, Canada was remarkably similar to that in the US. Smoking rates have been decreasing in Canada 11 as they have in the US, 3 but it is not yet known whether this has resulted in a decrease in the incidence of UADT cancer in Canada. The first objective of this study was to compare trends in the incidence of UADT cancers in Ontario and the US to determine: (a) whether the overall incidence of UADT cancer in Ontario has decreased as it has in the US; and (b) whether the temporal trend in the incidence of oropharyngeal cancer in Ontar...
Small RNA RNA-seq for microRNAs (miRNAs) is a rapidly developing field where opportunities still exist to create better bioinformatics tools to process these large datasets and generate new, useful analyses. We built miRge to be a fast, smart small RNA-seq solution to process samples in a highly multiplexed fashion. miRge employs a Bayesian alignment approach, whereby reads are sequentially aligned against customized mature miRNA, hairpin miRNA, noncoding RNA and mRNA sequence libraries. miRNAs are summarized at the level of raw reads in addition to reads per million (RPM). Reads for all other RNA species (tRNA, rRNA, snoRNA, mRNA) are provided, which is useful for identifying potential contaminants and optimizing small RNA purification strategies. miRge was designed to optimally identify miRNA isomiRs and employs an entropy based statistical measurement to identify differential production of isomiRs. This allowed us to identify decreasing entropy in isomiRs as stem cells mature into retinal pigment epithelial cells. Conversely, we show that pancreatic tumor miRNAs have similar entropy to matched normal pancreatic tissues. In a head-to-head comparison with other miRNA analysis tools (miRExpress 2.0, sRNAbench, omiRAs, miRDeep2, Chimira, UEA small RNA Workbench), miRge was faster (4 to 32-fold) and was among the top-two methods in maximally aligning miRNAs reads per sample. Moreover, miRge has no inherent limits to its multiplexing. miRge was capable of simultaneously analyzing 100 small RNA-Seq samples in 52 minutes, providing an integrated analysis of miRNA expression across all samples. As miRge was designed for analysis of single as well as multiple samples, miRge is an ideal tool for high and low-throughput users. miRge is freely available at http://atlas.pathology.jhu.edu/baras/miRge.html.
The mechanisms restricting regeneration and maintaining cell identity following injury are poorly characterized in higher vertebrates. Upon β-cell loss, 1–2% of the glucagon-producing α-cells spontaneously engage in insulin production in mice. Here we explore the mechanisms inhibiting α-cell plasticity. We show that the adaptive α-cell identity changes are constrained by intra-islet Insulin- and Smoothened-mediated signaling, among others. The combination of β-cell loss, or insulin signaling inhibition, with Smoothened inactivation in α- or δ-cells, stimulates insulin production in more α-cells. These findings suggest that removing constitutive “brake signals” is crucial for neutralizing the refractoriness to adaptive cell-fate changes. It appears that cell identity maintenance is an
active
process mediated by repressive signals, released by neighbor cells, curbing an intrinsic trend of differentiated cells to change.
Collectively, our data demonstrate that the antitumor effects of abemaciclib in preclinical ES models are multifaceted and include cell-cycle inhibition, DNA demethylation, and immunogenic changes.
Using only a few key covariates, aggregated global trauma data can be used to adequately perform international trauma center benchmarking. The creation of the ITDB is feasible and recommended as it may be a pivotal step towards improving global trauma outcomes.
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