The Transcriptional and DNA Binding Activity of Peroxisome Proliferator-activated Receptor α Is Inhibited by Ethanol Metabolism A NOVEL MECHANISM FOR THE DEVELOPMENT OF ETHANOL-INDUCED FATTY LIVER

Fatty acids are ligands for the peroxisome proliferator-activated receptor alpha (PPAR alpha). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPAR alpha. However, ethanol inhibited PPAR alpha activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPAR alpha ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPAR alpha/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPAR alpha exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPAR alpha, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse

Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARgamma was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARgamma-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancr

The Elamite Cylinder Seal Corpus, c.3500 - 1000 BC

The ancient region of Elam (southwestern Iran) has produced a significant assemblage of cylinder seals across a considerable chronological span. Unlike the glyptic material from the related and neighbouring region Mesopotamia, the Elamite cylinder seals have not previously been studied in detailed reference to one another, nor has there been an established paradigm of stylistic development articulated. This study addresses this lacuna by compiling all the published cylinder seals from Elam (as defined here, thus incorporating the historical provinces of Khuzistan, Luristan and Fars), from their earliest appearance (c.3500 BC), throughout the era of their typological dominance (over stamp seals, thus this study departs c.1000 BC). This compilation is presented in the Elamite Cylinder Seal Catalogue (Volume II), and is annotated and described through the annunciation of eighteen chronologically defined developmental styles (with another two non-chronological type classifications and four miscellaneous groups). Through the further analysis of this data, including the newly formulated and articulated styles, several facets and problems of Elamite glyptic material have been addressed (and thus the reliance upon assumed similarity in type and function with the Mesopotamian glyptic material is abandoned). These problems particularly pertain to the function of cylinder seals in Elam and the type and form of the Elamite-Mesopotamian glyptic interaction. In regards to function, a standard administrative function can be discerned, though of varying types and forms across the region and the period of study. Other, non-standard, symbolic glyptic functions can also be demonstrated in the Corpus, including the apparent proliferation of a form known as the ‘votive’ seal, perhaps a specifically Elamite form. The analysis of the style type (whether ‘Elamite’, ‘Mesopotamian Related’ or ‘Shared Elamite-Mesopotamian’), in association with their relative geographical and chronological distribution, has also enabled the discussion of the nature of Elamite-Mesopotamian glyptic interaction, and thereby the constitution of Elamite civilisation (especially in regards to Mesopotamian cultural impact and influence, and thus the testing of several previously presented paradigms [Amiet 1979a; 1979b; Miroschedji 2003])

Susceptibility to glaucoma: differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors

Comparison of gene expression in normal and glaucomatous eyes from Caucasian American and African American donors reveals differences that might reflect different susceptibility to glaucoma

Protein Recognition by Short Peptide Reversible Inhibitors of the Chromatin-Modifying LSD1/CoREST Lysine Demethylase.

The combinatorial assembly of protein complexes is at the heart of chromatin biology. Lysine demethylase LSD1(KDM1A)/CoREST beautifully exemplifies this concept. The active site of the enzyme tightly associates to the N-terminal domain of transcription factors of the SNAIL1 family, which therefore can competitively inhibit the binding of the N-terminal tail of the histone substrate. Our enzymatic, crystallographic, spectroscopic, and computational studies reveal that LSD1/CoREST can bind to a hexapeptide derived from the SNAIL sequence through recognition of a positively charged α-helical turn that forms upon binding to the enzyme. Variations in sequence and length of this six amino acid ligand modulate affinities enabling the same binding site to differentially interact with proteins that exert distinct biological functions. The discovered short peptide inhibitors exhibit antiproliferative activities and lay the foundation for the development of peptidomimetic small molecule inhibitors of LSD1

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients

Gene Expression and Functional Studies of the Optic Nerve Head Astrocyte Transcriptome from Normal African Americans and Caucasian Americans Donors

To determine whether optic nerve head (ONH) astrocytes, a key cellular component of glaucomatous neuropathy, exhibit differential gene expression in primary cultures of astrocytes from normal African American (AA) donors compared to astrocytes from normal Caucasian American (CA) donors.We used oligonucleotide Affymetrix microarray (HG U133A & HG U133A 2.0 chips) to compare gene expression levels in cultured ONH astrocytes from twelve CA and twelve AA normal age matched donor eyes. Chips were normalized with Robust Microarray Analysis (RMA) in R using Bioconductor. Significant differential gene expression levels were detected using mixed effects modeling and Statistical Analysis of Microarray (SAM). Functional analysis and Gene Ontology were used to classify differentially expressed genes. Differential gene expression was validated by quantitative real time RT-PCR. Protein levels were detected by Western blots and ELISA. Cell adhesion and migration assays tested physiological responses. Glutathione (GSH) assay detected levels of intracellular GSH.Multiple analyses selected 87 genes differentially expressed between normal AA and CA (P<0.01). The most relevant genes expressed in AA were categorized by function, including: signal transduction, response to stress, ECM genes, migration and cell adhesion.These data show that normal astrocytes from AA and CA normal donors display distinct expression profiles that impact astrocyte functions in the ONH. Our data suggests that differences in gene expression in ONH astrocytes may be specific to the development and/or progression of glaucoma in AA

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

In Situ XAS Studies of Core-Shell PEM Fuel Cell Catalysts: The Opportunities and Challenges

Core-shell electrocatalysts are of increased interest in PEM fuel cells as a means of improving activity and reducing costs. In situ x-ray absorption spectroscopy (XAS) provides a unique opportunity to provide characterization of the structure of such materials under operating conditions, enabling the effects of the electrochemical environment on the structures to be explored. However, such measurements present numerous challenges in terms of both data collection and analysis. Here we present two case studies that illustrate both the opportunities and challenges; (i) the modification of a Pt catalyst by Ru and the potential dependent formation of a surface alloy and (ii) a Pt shell - Pd core catalyst with varying shell thickness