Quantitative techniques in 18FDG PET scanning in oncology

The clinical applications of 18F-fluoro-2-deoxyglucose (18FDG) positron emission tomography (PET) in oncology are becoming established. While simple static scanning techniques are used for the majority of routine clinical examinations, increasing use of PET in clinical trials to monitor treatment response with 18FDG and novel tracers reflecting different pharmacodynamic end points, often necessitates a more complex and quantitative analysis of radiopharmaceutical kinetics. A wide range of PET analysis techniques exist, ranging from simple visual analysis and semiquantitative methods to full dynamic studies with kinetic analysis. These methods are discussed, focusing particularly on the available methodologies that can be utilised in clinical trials

Characterization of High-Fat, Diet-Induced, Non-alcoholic Steatohepatitis with Fibrosis in Rats

An ideal animal model is necessary for a clear understanding of the etiology, pathogenesis, and mechanisms of human non-alcoholic steatohepatitis (NASH) and for facilitating the design of effective therapy for this condition. We aimed to establish a rat model of NASH with fibrosis by using a high-fat diet (HFD). Male Sprague–Dawley (SD) rats were fed a HFD consisting of 88 g normal diet, 10 g lard oil, and 2 g cholesterol. Control rats were fed normal diet. Rats were killed at 4, 8, 12, 16, 24, 36, and 48 weeks after HFD exposure. Body weight, liver weight, and epididymal fat weight were measured. Serum levels of fasting glucose, triglyceride, cholesterol, alanine aminotransferase (ALT), free fatty acids (FFA), insulin, and tumor necrosis factor-alpha (TNF-α) were determined. Hepatic histology was examined by H&E stain. Hepatic fibrosis was assessed by VG stain and immunohistochemical staining for transforming growth factor beta 1 (TGF-β1), and alpha-smooth-muscle actin (α-SMA). The liver weight and liver index increased from week 4, when hepatic steatosis was also observed. By week 8, the body weight and epididymal fat weight started increasing, which was associated with increased serum levels of FFA, cholesterol, and TNF-α, as well as development of simple fatty liver. The serum ALT level increased from week 12. Steatohepatitis occurred from weeks 12 through 48. Apparent hepatic perisinosodial fibrosis did not occur until week 24, and progressed from week 36 to 48 with insulin resistance. Therefore, this novel model may be potentially useful in NASH study

Insulin-Stimulated Degradation of Apolipoprotein B100: Roles of Class II Phosphatidylinositol-3-Kinase and Autophagy

Both in humans and animal models, an acute increase in plasma insulin levels, typically following meals, leads to transient depression of hepatic secretion of very low density lipoproteins (VLDL). One contributing mechanism for the decrease in VLDL secretion is enhanced degradation of apolipoprotein B100 (apoB100), which is required for VLDL formation. Unlike the degradation of nascent apoB100, which occurs in the endoplasmic reticulum (ER), insulin-stimulated apoB100 degradation occurs post-ER and is inhibited by pan-phosphatidylinositol (PI)3-kinase inhibitors. It is unclear, however, which of the three classes of PI3-kinases is required for insulin-stimulated apoB100 degradation, as well as the proteolytic machinery underlying this response. Class III PI3-kinase is not activated by insulin, but the other two classes are. By using a class I-specific inhibitor and siRNA to the major class II isoform in liver, we now show that it is class II PI3-kinase that is required for insulin-stimulated apoB100 degradation in primary mouse hepatocytes. Because the insulin-stimulated process resembles other examples of apoB100 post-ER proteolysis mediated by autophagy, we hypothesized that the effects of insulin in autophagy-deficient mouse primary hepatocytes would be attenuated. Indeed, apoB100 degradation in response to insulin was significantly impaired in two types of autophagy-deficient hepatocytes. Together, our data demonstrate that insulin-stimulated apoB100 degradation in the liver requires both class II PI3-kinase activity and autophagy. © 2013 Andreo et al

A new synaptic player leading to autism risk: Met receptor tyrosine kinase

The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD

Kidney transplantation in childhood: mental health and quality of life of children and caregivers

Our objective was to assess the mental health and health-related quality of life (HRQOL) in children and their parents after renal transplantation (TX) compared to healthy controls and children with acute lymphoblastic leukemia (ALL) and to identify possible health status variables associated with impaired mental health and HRQOL. Thirty-eight TX children with a median age of 13 (range 3–19) years were investigated. Mental health was assessed by the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and the Strength and Difficulties Questionnaire (SDQ-20). Each mother’s own mental health and QOL were assessed by the General Health Questionnaire (GHQ-30) and the Quality of Life Scale (QOLS). Forty children with ALL [median age 11 (8.5–15.4) years] and 42 healthy children [median age 11 (8.9– 15) years] served as controls. Treadmill exercise results from 22 of the 38 patients were included in the analysis. TX children showed significantly higher levels of mental health problems and lower HRQOL at 2 to 16 years after transplantation compared to both control groups. Body mass index and maximal oxygen uptake (n = 22/38) were significant predictors of child mental health (SDQ) and child QOL (PedsQL), respectively. Based on these results, we suggest that rehabilitation after TX should include a focus on physical activity and QOL to reduce interconnected physical and psychological morbidity in kidney TX children

Transcriptome Analysis Reveals Strain-Specific and Conserved Stemness Genes in Schmidtea mediterranea

The planarian Schmidtea mediterranea is a powerful model organism for studying stem cell biology due to its extraordinary regenerative ability mediated by neoblasts, a population of adult somatic stem cells. Elucidation of the S. mediterranea transcriptome and the dynamics of transcript expression will increase our understanding of the gene regulatory programs that regulate stem cell function and differentiation. Here, we have used RNA-Seq to characterize the S. mediterranea transcriptome in sexual and asexual animals and in purified neoblast and differentiated cell populations. Our analysis identified many uncharacterized genes, transcripts, and alternatively spliced isoforms that are differentially expressed in a strain or cell type-specific manner. Transcriptome profiling of purified neoblasts and differentiated cells identified neoblast-enriched transcripts, many of which likely play important roles in regeneration and stem cell function. Strikingly, many of the neoblast-enriched genes are orthologs of genes whose expression is enriched in human embryonic stem cells, suggesting that a core set of genes that regulate stem cell function are conserved across metazoan species

Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

The Role Of Condition-Specific Preference-Based Measures In Health Technology Assessment

A condition-specific preference-based measure (CSPBM) is a measure of health related quality of life (HRQoL) that is specific to a certain condition or disease and that can be used to obtain the quality adjustment weight of the quality adjusted life year (QALY) for use in economic models. This article provides an overview of the role of CSPBMs, the development of CSPBMs, and presents a description of existing CSPBMs in the literature. The article also provides an overview of the psychometric properties of CSPBMs in comparison to generic preference-based measures (generic PBMs), and considers the advantages and disadvantages of CSPBMs in comparison to generic PBMs. CSPBMs typically include dimensions that are important for that condition but may not be important across all patient groups. There are a large number of CSPBMs across a wide range of conditions, and these vary from covering a wide range of dimensions to more symptomatic or uni-dimensional measures. Psychometric evidence is limited but suggests that CSPBMs offer an advantage in more accurate measurement of milder health states. The mean change and standard deviation can differ for CSPBMs and generic PBMs, and this may impact on incremental cost-effectiveness ratios. CSPBMs have a useful role in HTA where a generic PBM is not appropriate, sensitive or responsive. However due to issues of comparability across different patient groups and interventions, their usage in health technology assessment is often limited to conditions where it is inappropriate to use a generic PBM or sensitivity analyses