Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

11 beta-Hydroxysteroid Dehydrogenase Type 1 Deficiency Prevents Memory Deficits with Aging by Switching from Glucocorticoid Receptor to Mineralocorticoid Receptor-Mediated Cognitive Control

Local brain amplification of glucocorticoids (GCs) by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a pivotal role in age-related memory deficits. 11β-HSD1 deficient mice are protected from spatial memory impairments with aging, but the underlying mechanisms are unknown. To determine which brain receptors [high-affinity mineralocorticoid receptors (MRs) or low-affinity glucocorticoid receptors (GRs)] are involved, spatial memory was measured in aged 11β-HSD1(−/−) mice before and during intracerebroventricular infusion (10 d) of spironolactone (MR antagonist) or RU486 (GR antagonist). Aged C57BL/6J control mice showed impaired spatial memory in the Y-maze; this improved with GR blockade, while MR blockade had no effect. In contrast, aged 11β-HSD1(−/−) mice showed intact spatial memory that became impaired with MR blockade, but not GR blockade. Hippocampal MR and GR mRNA expression and plasma corticosterone levels were not significantly altered with spironolactone or RU486 in either genotype. These data support the notion that 11β-HSD1 deficiency in aging mice leads to lower intracellular GC concentrations in brain, particularly in the hippocampus, which activate predominantly MRs to enhance memory, while in aging C57BL/6J controls, the increased intracellular GCs saturate MRs and activate predominantly GRs, thus impairing memory, an effect reversed by GR blockade

Cognitive and disease-modifying effects of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia

Central administration of a cytochrome P450-7 alpha product 7 alpha-hydroxypregnenolone improves spatial memory retention in cognitively impaired aged rats

Pregnenolone ( PREG) and dehydroepiandrosterone ( DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7 alpha-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7 alpha-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7 alpha-hydroxylated metabolite 7 alpha-hydroxyPREG is not known. We investigated this by treating memory- impaired aged rats ( identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7 alpha-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue ( percentage conversion of [C-14]DHEA to [C-14]7 alpha-hydroxyDHEA) was decreased selectively in memory- impaired aged rats compared with both young and memory- intact aged rats. 7 alpha-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory- impaired aged rats for 11 d enhanced spatial memory retention ( after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7 alpha-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory- impaired aged rats may, in part, be overcome by administration of 7 alpha-hydroxyPREG.</p

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

The purpose of this review is to present up-to-date pharmacological, genetic, and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine, and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein, we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this chapter discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general

Diurnal and stress-induced intra-hippocampal corticosterone rise attenuated in 11β-HSD1-deficient mice:a microdialysis study in young and aged mice

11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) locally regenerates active glucocorticoids from their inert forms thereby amplifying intracellular levels within target tissues including the brain. We previously showed greater increases in intra‐hippocampal corticosterone (CORT) levels upon Y‐maze testing in aged wild‐type than in 11β‐HSD1(−/−) mice coinciding with impaired and intact spatial memory, respectively. Here we examined whether ageing influences 11β‐HSD1 regulation of CORT in the dorsal hippocampus under basal conditions during the diurnal cycle and following stress. Intra‐hippocampal CORT levels measured by in vivo microdialysis in freely behaving wild‐type mice displayed a diurnal variation with peak levels in the evening that were significantly elevated with ageing. In contrast, the diurnal rise in intra‐hippocampal CORT levels was greatly diminished in 11β‐HSD1(−/−) mice and there was no rise with ageing; basal intra‐hippocampal CORT levels were similar to wild‐type controls. Furthermore, a short (3 min) swim stress induced a longer lasting increase in intra‐hippocampal CORT levels in wild‐type mice than in 11β‐HSD1(−/−) mice despite no genotypic differences in elevation of plasma CORT. These data indicate that 11β‐HSD1 activity contributes substantially to diurnal and stress‐induced increases in hippocampal CORT levels. This contribution is even greater with ageing. Thus, 11β‐HSD1 inhibition may be an attractive target for treating cognitive impairments associated with stress or ageing

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess

Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role. We previously discovered that Hsd11b2(−/−) mice, lacking 11β-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/−), and Hsd11b2(−/−) littermates from heterozygous (Hsd11b(+/−)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(−/−) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11β-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(−/−) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(−/−) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(−/−) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction