Pancreatic Cell News Volume 10.19 | May 21 2019

TOP STORY

Toll-Like Receptors TLR2 and TLR4 Block the Replication of Pancreatic β Cells in Diet-Induced Obesity

Researchers showed that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of β cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of β cells, but not that of α cells, leading to enlarged β cell area and hyperinsulinemia in diet-induced obesity. [Nat Immunol] Abstract | Press Release

(Ranked by impact factor of the journal)

DIABETES & PANCREATITIS

Cellular Stressors May Alter Islet Hormone Cell Proportions by Moderation of Alternative Splicing Patterns

The authors assessed the effects of aspects of the diabetic microenvironment on hormone staining, total gene expression, splicing regulation and the alternative splicing patterns of key genes in EndoC-βH1 human beta cells. Genes encoding islet hormones, differentiation markers and cell stress markers were dysregulated in stressed EndoC-βH1 cells, as were some serine arginine rich splicing factor splicing activator and heterogeneous ribonucleoprotein particle inhibitor genes. [Hum Mol Genet] Full Article | Press Release

Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like Peptide-1 in Pancreatic Islets

In α-cells treated with eplerenone added on aldosterone (E+A), interleukin-6 (IL-6) and glucagon-like peptide-1 (GLP-1) concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased mineralocorticoid receptor (MR) and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA. [J Clin Med] Full Article

PANCREATIC CANCER

Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy

ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and type I interferon signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. [Cancer Res] Abstract

Knockdown of Hypoxia-Inducible Factor-1 Alpha by Tumor Targeted Delivery of CRISPR/Cas9 System Suppressed the Metastasis of Pancreatic Cancer

A tumor targeted lipid-based CRISPR/Cas9 delivery system was developed to suppress hypoxia-inducible factor-1α (HIF-1α). Plasmids encoding Cas9 and HIF-1α-targeting sgRNA were successfully constructed and coencapsulated in R8-dGR peptide modified cationic liposome with PTX. R8-dGR-Lip exhibited enhanced BxPC-3 cell targeting and deep penetration into tumor spheroids. [J Control Release] Abstract | Graphical Abstract

Preclinical Validation of 3-Phosphoinositide-Dependent Protein Kinase 1 Inhibition in Pancreatic Cancer

Scientists report the role and mechanism of action of 3-phosphoinositide-dependent protein kinase 1 (PDK1), a protein kinase of the AGC family, in pancreatic ductal adenocarcinoma. Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumor growth in a xenograft model. [J Exp Clin Cancer Res] Full Article

The LIM Protein Ajuba/SP1 Complex Forms a Feed Forward Loop to Induce SP1 Target Genes and Promote Pancreatic Cancer Cell Proliferation

Mechanistically, Ajuba bound to the C-terminus of SP1 and functioned as a co-activator to enhance SP1 gene expression and promote cell proliferation; the promoter of Ajuba contained functional SP1 responsive elements and Ajuba itself was a target gene of SP1. [J Exp Clin Cancer Res] Full Article

IQGAP1 Promotes Pancreatic Cancer Progression and Epithelial-Mesenchymal Transition (EMT) through Wnt/β-Catenin Signaling

Investigators found that IQ motif-containing GTPase-activating protein 1 (IQGAP1) expression was an independent prognostic factor for pancreatic ductal adenocarcinoma. IQGAP1 upregulation significantly promoted cell proliferation, migration, invasion and EMT, whereas IQGAP1 downregulation impaired its oncogenic functions. [Sci Rep] Full Article

Loss of Disabled-2 Expression in Pancreatic Cancer Progression

Downregulation of disabled-2 (Dab2) expression in pancreatic cancer cell lines was found to trigger induction of genes characteristic of EMT and the cancer stem cell phenotype, while overexpression of Dab2 in the Panc1 cell line blocked the process of TGFβ-stimulated EMT. In addition, selective inhibition of the TGFβRI/RII receptors was found to reverse genes altered by Dab2 downregulation. [Sci Rep] Full Article

FoxM1 Induced Paclitaxel Resistance via Activation of FoxM1/PHB1/RAF-MEK-ERK Pathway and Enhancement of ABCA2 Transporter

FoxM1 contributed to the prohibitin1 (PHB1)/C-RAF interaction and phosphorylation of ERK1/2 kinases, thus promoting paclitaxel resistance. Notably, FoxM1 conferred tumor cell resistance to paclitaxel, but knocking down PHB1 could sensitize pancreatic cancer cells to it. [Mol Ther Oncolytics] Abstract | Full Article

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β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity

The authors focus on evidence of islet plasticity in humans-from the normal state, progressing to insulin resistance to overt type 2 diabetes-to explain the seemingly contradictory results from different cross-sectional studies in the literature. [Diabetes] Abstract

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AzurRx BioPharma Presents Positive Secondary Endpoint Data in Its Phase II MS1819-SD Chronic Pancreatitis Study

AzurRx BioPharma, Inc. released new data for its lead development candidate MS1819-SD. The presentation entitled “Results from a Phase II Study of MS1819, a Recombinant Lipase for the Treatment of Exocrine Pancreatic Insufficiency in Patients with Chronic Pancreatitis” was delivered by Dr. Nam Q. Nguyen, et al. [Press release from AzurRx BioPharma, Inc. discussing research presented at the 2019 Digestive Disease Week (DDW) Conference, San Diego] Press Release

EastGate Biotech Announces Preparation to Initiate Phase III Clinical Trials on Insugin, Its Liquid Insulin Mouth Rinse for Type 2 Diabetes Patients

Eastgate Biotech Corp. announced its plans to take the next steps to initiate Phase III of its innovative liquid insulin mouth rinse solution, Insugin, for Type 2 diabetes patients in Pakistan. The Phase III study will be a multicenter, randomized, double-blind, placebo-controlled, parallel group study. [Eastgate Biotech Corp.] Press Release

Oramed Completes Patient Recruitment of Phase IIb HbA1c Trial for Oral Insulin Capsule ORMD-0801

Oramed Pharmaceuticals Inc. announced that it has completed enrollment for its 90-day dose-ranging Phase IIb clinical study of its oral insulin capsule main cohort. Close to 300 patients have now been enrolled. 70% of these patients have completed treatment in the study. [Oramed Pharmaceuticals Inc.] Press Release

PharmaCyte Biotech Proceeding with GMP Production of Pancreatic Cancer Product after Successful Changes to Manufacturing Process

PharmaCyte Biotech, Inc. announced that it has made further important progress in optimizing the complete manufacturing process, including significant improvement of the growth characteristics of the cells from PharmaCyte’s Master Cell Bank after encapsulation. These encapsulated cells will be used, in combination with low doses of the cancer prodrug ifosfamide, for the treatment of locally advanced, non-metastatic, inoperable pancreatic cancer. [PharmaCyte Biotech, Inc.] Press Release

Pershing Square Sohn Prize Awards $4.2M to Seven “Next Generation” Innovators in Cancer Research

The Pershing Square Sohn Cancer Research Alliance announced the seven winners of the 2019 Pershing Square Sohn Prize for Young Investigators in Cancer Research, awarded annually to talented New York City-area cancer research scientists and physician-scientists. The Prize, totaling $4.2 million in funding awarded, emboldens early-career investigators to pursue research projects at a stage when traditional funding is lacking. [Pershing Square Sohn Cancer Research Alliance] Press Release

National Cancer Institute Will Stop Funding Nanotechnology Centers

The end to funding represents a “natural transition” from putting dedicated support into an emerging field to becoming a more mature research field that fits in with other cancer fields, says Piotr Grodzinski of the National Cancer Institute’s Nanodelivery Systems and Devices Branch, which oversees the Centers of Cancer Nanotechnology Excellence, to Science. [The Scientist] Editorial

Indonesia Tops Open-Access Publishing Charts

European funders have been leading a charge under ‘Plan S’ to make more of the scientific literature free to read. Yet the nations that publish the highest proportion of their research papers open access aren’t in Europe, according to a preliminary analysis shared with Nature. [Nature News] Editorial

NEW Keystone Symposia: Tumor Metabolism
March 8-12, 2020
Banff, Alberta, Canada

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NEW Postdoctoral Research Scientist – Regeneration of Insulin-Producing β-Cells (MRC London Institute of Medical Sciences)

Postdoctoral Position – Lung and Pancreatic Cancers (University of California, San Francisco)

Professor – Diabetes Research (University of Tennessee Health Science Center)

Postdoctoral Researcher – Islet Biology (University of Wisconsin-Madison)

Postdoctoral Fellowship – Pancreatic Cancer (Oregon Health and Science University)

Postdoctoral Fellowship – Regenerative Medicine (Cornell University)

Postdoctoral Research Position – Molecular Biology and Cancer Research (Augusta University)

Postdoctoral Research Affiliate – Pancreatic Cancer Research (Roswell Park)

Postdoctoral Research Fellow – Type 2 Diabetes and Obesity (Harvard Medical School/Boston Children’s Hospital)

Postdoctoral Fellowship – Regenerative Medicine and Metabolic Biology (Indiana Biosciences Research Institute)

Research Positions – Pancreatic Beta-Cells (Université de Montréal)

Postdoctoral Fellow – Neuroscience and Diabetes (The Child Health Institute of New Jersey)

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