Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex

<p>Abstract</p> <p>Background</p> <p>The β-amyloid precursor protein (APP) and the related β-amyloid precursor-like proteins (APLPs) undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer's disease, the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase-generated APP intracellular domain (AICD) functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial.</p> <p>Results</p> <p>To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators, we performed DNA microarray transcriptome profiling of prefrontal cortex of adult wild-type (WT), APP knockout (APP^-/-), APLP2 knockout (APLP2^-/-) and APPsα knockin mice (APP^α/α) expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included neurogenesis, transcription, and kinase activity. Comparative analysis of transcriptome changes between mutant and wild-type mice, followed by qPCR validation, identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity-related genes that were both down-regulated in knockout cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including <it>Bace1</it>, <it>Kai1</it>, <it>Gsk3b</it>, <it>p53</it>, <it>Tip60</it>, and <it>Vglut2</it>. Only <it>Egfr </it>was slightly up-regulated in APLP2^-/-mice. Comparison of APP^-/-and APP^α/αwith wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2^-/-on different genetic backgrounds revealed that background-related transcriptome changes may dominate over changes due to the knockout of a single gene.</p> <p>Conclusion</p> <p>Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.</p

The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Comprehensive molecular characterization of the hippo signaling pathway in cancer

Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era

Estimating renal function in morbidly obese patients

BackgroundThis paper aims to evaluate, in a clinical context, current creatinine-based formulas commonly used to calculate renal function in morbidly obese patients.MethodsA retrospective analysis was performed of the estimates of renal function of 63 obese or morbidly obese patients undergoing gastric bypass surgery. Each patient's glomerular filtration rate (GFR) was calculated using five methods, both before and after surgery, and these approximations were then compared.ResultsPrior to surgery, the values offered by the five formulas for the renal function of this population ranged widely, by over a factor of 2. After surgery, the three weight-based GFR estimation methods indicated that a significant change in GFR had occurred, but the two non-weight-based formulas showed no significant change in estimated GFR.ConclusionsAt baseline and after significant weight loss, creatinine-based formulas differ twofold in their estimates of renal function of the morbidly obese. An accurate method for calculating these patients' renal function is required to improve patient safety with drug dosing as well as to ensure early detection of renal failure.Alex Lovell, Philip Game, Gary Wittert, Campbell Thompso

Increased postprandial energy expenditure may explain superior long term weight loss after Roux-en-Y gastric bypass compared to vertical banded gastroplasty

BACKGROUND AND AIMS: Gastric bypass results in greater weight loss than Vertical banded gastroplasty (VBG), but the underlying mechanisms remain unclear. In addition to effects on energy intake the two bariatric techniques may differentially influence energy expenditure (EE). Gastric bypass in rats increases postprandial EE enough to result in elevated EE over 24 hours. This study aimed to investigate alterations in postprandial EE after gastric bypass and VBG in humans. METHODS: Fourteen women from a randomized clinical trial between gastric bypass (n = 7) and VBG (n = 7) were included. Nine years postoperatively and at weight stability patients were assessed for body composition and calorie intake. EE was measured using indirect calorimetry in a respiratory chamber over 24 hours and focused on the periods surrounding meals and sleep. Blood samples were analysed for postprandial gut hormone responses. RESULTS: Groups did not differ regarding body composition or food intake either preoperatively or at study visit. Gastric bypass patients had higher EE postprandially (p = 0.018) and over 24 hours (p = 0.048) compared to VBG patients. Postprandial peptide YY (PYY) and glucagon like peptide 1 (GLP-1) levels were higher after gastric bypass (both p<0.001). CONCLUSIONS: Gastric bypass patients have greater meal induced EE and total 24 hours EE compared to VBG patients when assessed 9 years postoperatively. Postprandial satiety gut hormone responses were exaggerated after gastric bypass compared to VBG. Long-term weight loss maintenance may require significant changes in several physiological mechanisms which will be important to understand if non-surgical approaches are to mimic the effects of bariatric surgery

Paediatric Body Composition Measurement Techniques in Morbidly Obese Patients

Obesity is associated with adverse health outcomes both in paediatric and in adult age. There is a need to adopt consistent methods of measuring body composition in order to detect modifiable risk factors and consequences. Nutritional assessment based on body composition in early age can guide optimal nutrition and nutritional management during growth. On the other hand, body composition is a predictor of clinical outcome as well as a useful task either in prevention or in treatment at single and population level.Aim of this chapter is to review the currently available methods for body composition assessment with particular attention to methods useful and available for overweight and obese subjects. Obesity is challenging the body composition measurements due to altered body hydration, difficult to partitioning fat mass (FM) and fat free mass (FFM) and because several methods have less accuracy and precision in this population. Measurements for quantifying total body and regional adiposity and for mapping adipose tissue distribution to evaluate metabolic risk factors both in children and in adults are discussed.We summarised the advantages and disadvantages of the body composition measurement methods discussed in this chapter having the opportunity that measurements chosen will provide a simple framework to aid decision-making in day-by-day clinical practice