Pancreatic Cell News Volume 4.25 | Jul 2 2013

Plasmid-Encoded Proinsulin Preserves C-Peptide While Specifically Reducing Proinsulin-Specific CD8⁺ T Cells in Type 1 Diabetes
Researchers hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve ß cell function in type 1 diabetes (T1D) patients through reduction of insulin-specific CD8⁺ T cells. They studied 80 subjects over 18 years of age who were diagnosed with T1D within the past five years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. [Sci Transl Med]
Abstract | Press Release

Ebselen Treatment Prevents Islet Apoptosis, Maintains Intranuclear Pdx-1 and MafA Levels, and Preserves ß-Cell Mass and Function in ZDF Rats
Scientists reported earlier that ß-cell specific overexpression of glutathione peroxidase significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of ß-cell mass and function. Ebselen doubled ß-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of Pdx1 and MafA, two critical insulin transcription factors. [Diabetes] Abstract

Glucokinase Activation Ameliorates ER Stress-Induced Apoptosis in Pancreatic ß Cells
The authors investigated the impact of glucokinase activation by glucokinase activator (GKA) on endoplasmic reticulum (ER) stress in ß cells. GKA administration improved ß-cell apoptosis in Akita mice, a model of ER stress-mediated diabetes. GKA increased the expression of IRS-2 in ß cells, even under ER stress. [Diabetes] Abstract

Plasticity of Schwann Cells and Pericytes in Response to Islet Injury in Mice
Researchers applied three-dimensional histology to perform qualitative and quantitative analyses of the islet Schwann cell network and pericytes in normal, streptozotocin-injected and NOD mouse models. In early/moderate insulitis in the NOD mice, perilesional gliosis occurred at the front of the lymphocytic infiltration with atypical islet Schwann cell morphologies, including excessive branching and perivascular gliosis. [Diabetologia] Abstract

Complex Patterns of Metabolic and Ca²⁺ Entrainment in Pancreatic Islets by Oscillatory Glucose
Glucose-stimulated insulin secretion is pulsatile and driven by intrinsic oscillations in metabolism, electrical activity, and Ca²⁺ in pancreatic islets. Investigators used fluorescence microscopy to demonstrate that glucose oscillations can induce distinct 1:1 and 1:2 entrainment of oscillations in islet Ca²⁺, NAD(P)H, and mitochondrial membrane potential. [Biophys J] Abstract

PANCREATIC CANCER

FOXL1, a Novel Candidate Tumor Suppressor, Inhibits Tumor Aggressiveness and Predicts Outcome in Human Pancreatic Cancer
Investigators report that a higher expression of Forkhead Box L1 (FOXL1) is significantly associated with better clinical outcome in human pancreatic ductal adenocarcinoma. Mechanistic analyses demonstrated that over-expression of FOXL1 induces apoptosis and inhibits proliferation and invasion in pancreatic cancer cells, whereas silencing of FOXL1 by siRNA inhibits apoptosis and enhances tumor cell growth and invasion. [Cancer Res] Abstract

Sensitization of Pancreatic Cancer to Chemoradiation by the Chk1 Inhibitor, MK8776
Scientists tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)- proficient and deficient pancreatic cancer cells and assessed Rad51 focus formation. They found that MK8776 significantly sensitized HRR- proficient but not deficient pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. [Clin Cancer Res] Abstract

Gossypol and an HMT G9a Inhibitor Act in Synergy to Induce Cell Death in Pancreatic Cancer Cells
To understand the mechanism of genetic selectivity, investigators used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. [Cell Death Dis] Full Article

Metformin Inhibits Pancreatic Cancer Cell and Tumor Growth and Downregulates Sp Transcription Factors
Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and researchers hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. [Carcinogenesis] Abstract

Comparative Benefits of Nab-Paclitaxel Over Gemcitabine or Polysorbate-Based Docetaxel in Experimental Pancreatic Cancer
Researchers evaluated nab-paclitaxel effects compared with gemcitabine or docetaxel. Net tumor growth inhibition after gemcitabine, docetaxel or nab-paclitaxel was 67%, 31% and 72%, which corresponded with intratumoral proliferative and apoptotic indices. [Carcinogenesis] Abstract

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Atu027 Update: Progression into Phase IIa
Silence announced that the Data Safety Monitoring Board has unanimously recommended the continuation of the Phase Ib/IIa study of Atu027. The Phase Ib/IIa study uses Atu027 in combination with gemcitabine, a chemotherapy agent in patients with advanced pancreatic cancer qualifying for first-line-treatment. [Silence Therapeutics plc] Press Release

Islet Sciences Chief Scientific Officer Receives $1.27 Million in Grant from JDRF to Create Innovative Diabetes Treatments
Islet Sciences, Inc., announced that Dr. Jonathan Lakey, Associate Professor of Surgery and Biomedical Engineering at the University of California Irvine and Chief Scientific Officer and Chairman of the Scientific Advisory Board of Islet Sciences, has received $1.27 million in grant funding from the JDRF to develop innovative methods to treat and possibly cure type 1 diabetes. [Islet Sciences, Inc.] Press Release

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