Report of multiple high-grade gliomas in two patients with shared retained ATRX, wild-type IDH, losses of CDKN2A genes and alterations in the PTEN-PI3K axis.

Solitary gliomas have been well described in the literature. Multiple gliomas, however, have not received the same notoriety, and as such further studies may be helpful in elucidating their unique clinicopathologic features and molecular basis. We present two patients, each with multiple high-grade gliomas, and describe their clinicopathologic and molecular characteristics in comparison with those reported in the literature in an attempt to better understand their shared tumorigenic mechanisms.

Gene-nutrient interactions and susceptibility to human obesity.

A large number of genome-wide association studies, transferability studies, and candidate gene studies performed in diverse populations around the world have identified gene variants that are associated with common human obesity. The mounting evidence suggests that these obesity gene variants interact with multiple environmental factors and increase susceptibility to this complex metabolic disease. The objective of this review article is to provide concise and updated information on energy balance, heritability of body weight, origins of gene variants, and gene-nutrient interactions in relation to human obesity.

A global evolutionary and metabolic analysis of human obesity gene risk variants.

It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa).

The Niemann-Pick C1 gene interacts with a high-fat diet to promote weight gain through differential regulation of central energy metabolism pathways.

A genome-wide association study (GWAS) reported that common variation in the human Niemann-Pick C1 gene () is associated with morbid adult obesity. This study was confirmed using our BALB/cJ mouse model, whereby heterozygous mice ( ) with decreased gene dosage were susceptible to weight gain when fed a high-fat diet (HFD) compared with homozygous normal mice ( ) fed the same diet. The objective for our current study was to validate this gene-diet interaction using statistical modeling with fitted growth trajectories, conduct body weight analyses for different measures, and define the physiological basis responsible for weight gain.

Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes.

A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene () polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ethnic groups (non-Hispanic white, Hispanic, and Native American).

The Niemann-Pick C1 and caveolin-1 proteins interact to modulate efflux of low density lipoprotein-derived cholesterol from late endocytic compartments.

The Niemann-Pick C1 (NPC1) protein has a central role in regulating the efflux of lipoprotein-derived cholesterol from late endosomes/lysosomes and transport to other cellular compartments. Since the NPC1 protein has been shown to regulate the transport of cholesterol to cellular compartments enriched with the ubiquitous cholesterol-binding and transport protein caveolin-1, the present study was performed to determine whether the NPC1 and caveolin-1 proteins interact and function to modulate efflux of low density lipoprotein (LDL)-derived cholesterol from endocytic compartments. To perform these studies, normal human fibroblasts were grown in media with lipoprotein-deficient serum (LPDS) or media with LPDS supplemented with purified human LDL.

Curcumin reduces cytotoxicity of 5-Fluorouracil treatment in human breast cancer cells.

Antimetabolites have proven successful as therapeutics for advanced-stage breast cancers, but are often accompanied by severe side effects that can limit treatment regimens. 5-Fluorouracil (5-FU), an antimetabolite that inhibits cell proliferation, has served an important role in standard chemotherapy protocols for a variety of solid tumors. Although reasonable response rates have been reported for 5-FU, continued exploration is necessary to improve clinical outcomes and reduce cytotoxic side effects that are an inherent problem for chemotherapeutic interventions.

Crosstalk between immune cells and adipocytes requires both paracrine factors and cell contact to modify cytokine secretion.

Increased adiposity results in a heightened infiltration of immune cells into fat depots, which in turn generates a pro-inflammatory phenotype in obese individuals. To better understand the causal factors that establish this pro-inflammatory profile, we examined events leading to crosstalk between adipocytes and immune cells. Using isolated spleen-derived immune cells, stimulated with LPS, together with cultured adipocytes, we differentiated the effects of paracrine factors and cell-cell contact on TNFα, IL-6 and MCP-1 secretion levels and secretion profiles.

The genetics of childhood obesity and interaction with dietary macronutrients.

The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene.

SPION-enhanced magnetic resonance imaging of Alzheimer's disease plaques in AβPP/PS-1 transgenic mouse brain.

In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer's disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-β plaques in AD. Here we report studies in AβPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AβPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.

A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD.

Increased CD36 expression signals monocyte activation among patients with type 2 diabetes.

Objective: To explore the hypothesis that CD36, a scavenger receptor and fatty acid translocase, is upregulated in peripheral blood mononuclear cells (PBMCs) among patients with type 2 diabetes and is a biomarker of PBMC activation and inflammation.

Research Design And Methods: We used a cross-sectional observational design to study a multi-racial/ethnic population sample consisting of Caucasians, Hispanics, and Native Americans with type 2 diabetes (n = 33) and nondiabetic control subjects (n = 27). PBMC CD36 mRNA/protein and plasma high sensitivity (hs) C-reactive protein (hsCRP), hs-interleukin-6 (hsIL-6), and adiponectin were measured.

Inhibition of nuclear factor kappaB activation and cyclooxygenase-2 expression by aqueous extracts of Hispanic medicinal herbs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a primary choice of therapy for diseases with a chronic inflammatory component. Unfortunately, long-term NSAID therapy is often accompanied by severe side effects, including cardiovascular and gastrointestinal complications. Because of this, there is critical need for identification of new and safer treatments for chronic inflammation to circumvent these side effects.

A Jurkat transcriptional reporter cell line for high-throughput analysis of the nuclear factor-kappaB signaling pathway.

The transcription factor, Nuclear Factor-kappaB (NF-kappaB), regulates many genes involved in host immunity and cell survival. Unregulated NF-kappaB activity has been linked to many chronic inflammatory diseases and is an important target for the identification of inhibitors to better manage these disorders. We present a novel screening system to identify NF-kappaB inhibitors that combines sensitive fluorescence detection with medium- to high-throughput flow cytometry (HyperCyt).

Development of a Mammalian suspension culture for expression of active recombinant human urokinase-type plasminogen activator.

The development of specific catalytic inhibitors for the serine protease urokinase-type plasminogen activator (uPA) has been hindered due to difficulties in producing sufficient amounts of active recombinant uPA that is catalytically equivalent to native uPA. The purpose of this study was to develop an efficient system for the expression of recombinant human uPA that exhibits comparable proteolytic activity to that of the native protein. Since post-translational modifications (e.

Substituted trans-stilbenes can inhibit or enhance the TPA-induced up-regulation of activator protein-1.

Background: The activator protein-1 (AP-1) family of transcription factors contributes to regulation of numerous genes involved in proliferation, apoptosis, and tumorigenesis. A wide array of stimuli can activate AP-1, including pro-inflammatory cytokines, growth factors, tumor promoters and stress. Numerous plant polyphenols have been shown to inhibit the activation of AP-1, which often is ascribed to the anti-oxidant properties of these natural products.

Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes.

Background: Adipocytes express inflammatory mediators that contribute to the low-level, chronic inflammation found in obese subjects and have been linked to the onset of cardiovascular disorders and insulin resistance associated with type 2 diabetes mellitus. A reduction in inflammatory gene expression in adipocytes would be expected to reverse this low-level, inflammatory state and improve cardiovascular function and insulin sensitivity. The natural products, curcumin and resveratrol, are established anti-inflammatory compounds that mediate their effects by inhibiting activation of NF-kappaB signaling.

Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy.

Background: A major portion of available fatty acids for adipocyte uptake is derived from lipoprotein lipase (LPL)-mediated hydrolysis of circulating lipoprotein particles. In vivo studies aimed at identifying the precise role of adipocyte-derived LPL in fat storage function of adipose tissue have been unable to provide conclusive evidence due to compensatory mechanisms that activate endogenous fatty acid synthesis. To address this gap in knowledge, we have measured the effect of reducing adipocyte LPL expression on intracellular lipid accumulation using a well-established cultured model of adipocyte differentiation.

Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB.

The transcription factor nuclear factor kappaB (NF-kappaB), which regulates expression of numerous antiinflammatory genes as well as genes that promote development of the prosurvival, antiapoptotic state is up-regulated in many cancer cells. The natural product resveratrol, a polyphenolic trans-stilbene, has numerous biological activities and is a known inhibitor of activation of NF-kappaB, which may account for some of its biological activities. Resveratrol exhibits activity against a wide variety of cancer cells and has demonstrated activity as a cancer chemopreventive against all stages, i.

Syndecan-1 mediates internalization of apoE-VLDL through a low density lipoprotein receptor-related protein (LRP)-independent, non-clathrin-mediated pathway.

Background: Triacylglyerol-rich very low density lipoprotein (VLDL) particles are the primary carriers of fatty acids in the circulation and as such serve as a rich energy source for peripheral tissues. Receptor-mediated uptake of these particles is dependent upon prior association with apolipoprotein E (apoE-VLDL) and is brought about by cell surface heparan sulfate proteoglycans (HSPG) in some cell types and by the low density lipoprotein receptor-related protein (LRP) in others. Although LRP's role in apoE-VLDL uptake has been well studied, the identity of the HSPG family member that mediates apoE-VLDL uptake has not been established.

TPA-induced up-regulation of activator protein-1 can be inhibited or enhanced by analogs of the natural product curcumin.

The activator protein-1 (AP-1) family of transcription factors, including the most common member c-Jun-c-Fos, participates in regulation of expression of numerous genes involved in proliferation, apoptosis, and tumorigenesis in response to a wide array of stimuli including pro-inflammatory cytokines, growth factors, stress, and tumor promoters. A number of plant polyphenols including curcumin, a yellow compound in the spice turmeric, have been shown to inhibit the activation of AP-1. Curcumin is a polyphenolic dienone that is potentially reactive as a Michael acceptor and also is a strong anti-oxidant.

Protease nexin-1 expression is altered in human breast cancer.

Background: Urokinase-type Plasminogen Activator (uPA), a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility. In more advanced breast cancers, uPA activity is significantly up regulated and serves as a prognostic indicator of poor patient outcome. Classically, regulation of uPA activity, especially in breast cancers, is thought to be mediated by Type 1 Plasminogen Activator Inhibitor (PAI-1).

Cell surface heparan sulfate proteoglycans contribute to intracellular lipid accumulation in adipocytes.

Background: Transport of fatty acids within the cytosol of adipocytes and their subsequent assimilation into lipid droplets has been thoroughly investigated; however, the mechanism by which fatty acids are transported across the plasma membrane from the extracellular environment remains unclear. Since triacylglycerol-rich lipoproteins represent an abundant source of fatty acids for adipocyte utilization, we have investigated the expression levels of cell surface lipoprotein receptors and their functional contributions toward intracellular lipid accumulation; these include very low density lipoprotein receptor (VLDL-R), low density lipoprotein receptor-related protein (LRP), and heparan sulfate proteoglycans (HSPG).

Results: We found that expression of these three lipoprotein receptors increased 5-fold, 2-fold, and 2.

Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells.

Podocalyxin (PC) is the major sialoglycoprotein expressed on the apical membrane of the podocyte. Previously it was shown that PC is connected to actin through the PC/NHERF2/ezrin complex, and this connection is disrupted in the nephrotic syndrome. For assessing whether expression of PC affects the organization of the actin cytoskeleton, MDCK cell lines stably expressing either full-length PC or a PC mutant lacking the NHERF binding site was established.