Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma.

Mice in which lung epithelial cells can be induced to express an oncogenic Kras(G12D) develop lung adenocarcinomas in a manner analogous to humans. A myriad of genetic changes accompany lung adenocarcinomas, many of which are poorly understood. To get a comprehensive understanding of both the transcriptional and post-transcriptional changes that accompany lung adenocarcinomas, we took an omics approach in profiling both the coding genes and the non-coding small RNAs in an induced mouse model of lung adenocarcinoma. RNAseq transcriptome analysis of Kras(G12D) tumors from F1 hybrid mice revealed features specific to tumor samples. This includes the repression of a network of GTPase-related genes (Prkg1, Gnao1 and Rgs9) in tumor samples and an enrichment of Apobec1-mediated cytosine to uridine RNA editing. Furthermore, analysis of known single-nucleotide polymorphisms revealed not only a change in expression of Cd22 but also that its expression became allele specific in tumors. The most salient finding, however, came from small RNA sequencing of the tumor samples, which revealed that a cluster of ∼53 microRNAs and mRNAs at the Dlk1-Dio3 locus on mouse chromosome 12qF1 was markedly and consistently increased in tumors. Activation of this locus occurred specifically in sorted tumor-originating cancer cells. Interestingly, the 12qF1 RNAs were repressed in cultured Kras(G12D) tumor cells but reactivated when transplanted in vivo. These microRNAs have been implicated in stem cell pleuripotency and proteins targeted by these microRNAs are involved in key pathways in cancer as well as embryogenesis. Taken together, our results strongly imply that these microRNAs represent key targets in unraveling the mechanism of lung oncogenesis.

Substance abuse, traumatic brain injury and neuropsychological outcome.

The neuropsychological performance of 119 patients with severe closed traumatic brain injury (TBI) who had received toxicology screens at the time of trauma centre admission was examined. Three groups were created: normal screen, positive alcohol screen, or positive abused drugs screen (with or without the presence of alcohol). The admitting Glasgow Coma Scale (GCS) score was significantly lower in the positive alcohol screen group than the normal screen group, while the three groups did not differ in length of post-traumatic amnesia (PTA) or years of education. Neuropsychological assessment was conducted during inpatient rehabilitation, following resolution of PTA. Normal screen patients obtained significantly better scores than the abused-drugs patients on the Full Scale IQ (FIQ) and Verbal IQ (VIQ) indices of the Wechsler Adult Intelligence Scale-Revised and the Verbal Memory, General Memory, Attention-Concentration, and Delayed Recall indices of the Wechsler Memory Scale-Revised. Normal screen patients also scored significantly higher than positive alcohol screen patients on FIQ and VIQ indices and all five indices from the Wechsler Memory Scale-Revised. These data suggest the existence of an additive effect of substance abuse on neuropsychological outcome in TBI. Findings have potential implications for both acute management and rehabilitation of TBI.

Substance abuse as a factor in the causality, severity, and recurrence rate of traumatic brain injury.

The effects of substance abuse on the cause, severity, and recurrence of traumatic brain injury in 322 admissions to a large rehabilitation inpatient facility are explored. Study patients tended to be young and predominantly male. Few had completed high school and a significant minority had a history of cerebral dysfunction. Patients tended to have moderate to severe closed head injuries. Motor vehicle crashes were the most common cause of injury, but patients reporting drug or drug and alcohol abuse were more likely to sustain violent injuries (e.g., gunshot wounds).