Pancreatic Cell News Volume 8.08 | Feb 28 2017

TOP STORY

Autoimmunity against a Defective Ribosomal Insulin Gene Product in Type 1 Diabetes

Researchers describe an alternative open reading frame within human insulin mRNA encoding a highly immunogenic polypeptide that is targeted by T cells in type 1 diabetes (T1D) patients. They showed that cytotoxic T cells directed against the N-terminal peptide of this nonconventional product are present in the circulation of individuals diagnosed with T1D, and they provide direct evidence that such CD8⁺ T cells are capable of killing human beta cells and thereby may be diabetogenic. [Nat Med] Abstract | Press Release

(Ranked by impact factor of the journal)

DIABETES & PANCREATITIS

Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to Reverse Diabetes

In mice, a four-day fasting mimicking diet (FMD) induced a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restored insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduced PKA and mTOR activity and induced Sox2 and Ngn3 expression and insulin production. [Cell] Full Article | Press Release | Graphical Abstract | Video

Glucagon-Like Peptide-1 Protects Pancreatic Beta-Cells from Death by Increasing Autophagic Flux and Restoring Lysosomal Function

Researchers report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity increases LC3 II, a marker of autophagy. Co-treatment with the glucagon-like peptide-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. [Diabetes] Abstract

Interferon Alpha Impairs Insulin Production in Human Beta Cells via Endoplasmic Reticulum Stress

Researchers exposed human islets and human EndoC-βH1 cells to interferon alpha (IFNα) and tested for endoplasmic reticulum stress markers, glucose stimulated insulin secretion and insulin content. IFNα decreased the expression of both proinsulin convertase 1 and proinsulin convertase 2, suggesting an altered functional state of the beta cells characterized by a slower proinsulin-insulin conversion. [J Autoimmun] Abstract

Calcium Pre-Conditioning Substitution Enhances Viability and Glucose Sensitivity of Pancreatic Beta-Cells Encapsulated Using Polyelectrolyte Multilayer Coating Method

Scientists used 3D-concave agarose micro-wells to culture robust pancreatic MIN-6 cell spheroids within 24 hours that were shown to exhibit cell-cell contact and uniform size. Novel polyelectrolyte multilayer coated cells were shown to secret significantly different amounts of insulin in response to changes in glucose concentration. [Sci Rep] Full Article

Cytoprotective Effect of Kaempferol against Palmitic Acid-Induced Pancreatic β-Cell Death through Modulation of Autophagy via AMPK/mTOR Signaling Pathway

Investigators determined the cytoprotective effect of kaempferol on pancreatic β-cells undergoing apoptosis in palmitic acid (PA)-stressed condition. The data showed that kaempferol treatment increased cell viability and anti-apoptotic activity in PA-stressed RIN-5F cells and murine pancreatic islets. [Mol Cell Endocrinol] Abstract

PANCREATIC CANCER

Mutant Kras- and p16-Regulated NOX4 Activation Overcomes Metabolic Checkpoints in Development of Pancreatic Ductal Adenocarcinoma

The authors discovered that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyze the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 required catalytic subunit p22^phox, which was upregulated following Kras activation. Both alterations were also detectable in pancreatic ductal adenocarcinoma cell lines and patient specimens. [Nat Commun] Full Article

Distinct Populations of Inflammatory Fibroblasts and Myofibroblasts in Pancreatic Cancer

Scientists identified a cancer-associated fibroblast (CAF) subpopulation with elevated expression of α-smooth muscle actin located immediately adjacent to neoplastic cells in mouse and human pancreatic ductal adenocarcinoma (PDA) tissue. They recapitulated this finding in co-cultures of murine pancreatic stellate cells and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. [J Exp Med] Full Article | Press Release | Video

Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers

By performing a genome-wide gene expression analysis of in vivo-derived bulk tumor cells and residual cancer cells lacking the expression of mutant KRAS or c-MYC, investigators identified an increase in autocrine IGF1/AKT signaling as a common survival mechanism in dormant cancer cells. [Cell Rep] Full Article | Graphical Abstract

Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression

Investigators showed that extracellular acidic pH triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets, along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. [Cell Rep] Full Article | Graphical Abstract

Inhibition of Group 1 p21-Activated Kinases Suppresses Pancreatic Stellate Cell Activation and Increases Survival of Mice with Pancreatic Cancer

Investigators examined the role of p21-activated kinase 1 (PAK1) in pancreatic stellate cells (PSCs) and in the interaction of PSCs with pancreatic cancer cells. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. [Int J Cancer] Abstract | Press Release

Genomics of Islet (Dys)function and Type 2 Diabetes

Researchers discuss how genome-wide association studies and recent developments in islet (epi)genome and transcriptome profiling are providing novel insights into the genetic, environmental, and cellular contributions to islet (dys)function and type 2 diabetes mellitus pathogenesis. [Trends Genet] Abstract

Early Detection of Pancreatic Cancer: Where Are We Now and Where Are We Going?

The authors summarize recent advances in effective screening for early diagnosis of pancreatic cancer using imaging modalities and novel molecular biomarkers discovered from various “omics” studies including genomics, epigenomics, non-coding RNA, metabonomics, liquid biopsy and microbiomes, and their use in body fluids. [Int J Cancer] Abstract

Visit our reviews page to see a complete list of reviews in the pancreatic cell research field.

Syros’ Drug Discovery Research in Immuno-Oncology Highlighted at UCSD Moores Cancer Center Symposium

Syros Pharmaceuticals announced that its collaborator, Andrew Lowy, M.D., Professor of Surgery and Chief of the Division of Surgical Oncology at the University of California San Diego (UCSD) Moores Cancer Center, presented Syros’ drug discovery research in immuno-oncology. As part of a research collaboration in pancreatic cancer with the Lowy laboratory at the Moores Cancer Center, Syros scientists discovered alterations in regulatory regions of the genome in tumor-associated macrophages in a subset of patient tissues. [Press release from Syros Pharmaceuticals discussing research presented at the 13^th UCSD Moores Cancer Center Industry/Academia Translational Oncology Symposium, San Diego] Press Release

Beyond Type 1 Provides Grant to ViaCyte to Support Research and Development of Cell Replacement Therapies for Type 1 Diabetes

ViaCyte, Inc. and Beyond Type 1 announced a grant from Beyond Type 1 to support ViaCyte’s efforts to develop a functional cure for type 1 and other insulin-requiring diabetes. The company’s pluripotent stem cell-derived islet cell replacement therapy, the PEC-Direct^™ product candidate, has the potential to be a breakthrough treatment for high-risk type 1 diabetes. [ViaCyte, Inc.] Press Release

MabVax Therapeutics Announces FDA Authorization to Proceed with MVT-1075 in a Phase I Clinical Trial for the Treatment of Pancreatic Cancer

MabVax Therapeutics Holdings, Inc. announced that it has received notice from the U.S. Food and Drug Administration (FDA) authorizing the initiation a Phase I clinical trial with MVT-1075 as a therapeutic treatment for pancreatic cancer. MabVax plans to initiate the Phase I clinical trial in patients with recurrent pancreatic cancer and other CA19-9 positive malignancies the first half in 2017. [MabVax Therapeutics Holdings, Inc.] Press Release

Enrollment Completed in Ligand’s Phase II Trial of LGD-6972 in Type 2 Diabetes

Ligand Pharmaceuticals Incorporated announced the completion of enrollment in the company’s Phase II clinical trial with its novel, small-molecule glucagon receptor antagonist LGD-6972 for the treatment of type 2 diabetes mellitus (T2DM). This randomized, double-blind, placebo-controlled study is evaluating the safety and efficacy of LGD-6972 as an adjunct to diet and exercise in subjects with T2DM whose blood glucose levels are inadequately controlled with metformin. [Ligand Pharmaceuticals Incorporated] Press Release

FDA Approves Once-Daily QTERN^® (Dapagliflozin and Saxagliptin) Tablets for Adults with Type-2 Diabetes

AstraZeneca announced that the US Food and Drug Administration (FDA) has approved once-daily QTERN^® for the treatment of type-2 diabetes. [AstraZeneca] Press Release

Trina Health of Missouri Opens State’s First Artificial Pancreas Treatment Clinic

Animo Health, Inc., d/b/a Trina Health of Missouri, opened its inaugural Trina Health Artificial Pancreas Treatment^® (APT) Clinic. It is the first of many clinics that Animo Health plans to open throughout the state that feature the Trina Health APT – the only patented, FDA approved, and clinically proven treatment that can slow, halt, and/or reverse, in most cases, the chronic complications in Type I and II diabetes. [Animo Health, Inc. (Business Wire, Inc.)] Press Release

Trump’s 2018 Budget Will Squeeze Civilian Science Agencies

The chunk of the federal budget that includes most of the U.S. government’s spending on basic science would shrink by 10.5% in 2018 under a plan outlined by President Donald Trump and administration officials. [ScienceInsider] Editorial

Departing Senior NSF Manager Offers Hopeful Assessment of Agency’s Future

The top aide to National Science Foundation (NSF) Director France Córdova has returned to his university after failing to win confirmation as deputy NSF director. But engineer Richard Buckius says his departure, less than a week after President Donald Trump took office, was long in the cards and not a political statement. In fact, Buckius predicts that NSF and academic research will do fine under the new Trump administration. [ScienceInsider] Editorial

UK Scientists Welcome Changes to Controversial Research Reforms

Amendments aim to protect autonomy and the independence of research funders from political interference. [Nature News] Editorial

NEW American Hepato-Pancreato-Biliary Association 2017 Annual Meeting
March 29-April 2, 2017
Miami, United States

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Associate – Human Pancreatic Stem Cells (Nestlé)

NEW Postdoctoral Fellowship – Beta Cell Regeneration (Helmholtz Zentrum München)

Senior Scientist – Pancreatic Cell Research (STEMCELL Technologies Inc.)

Lecturer/Senior Lecturer – Pancreatic Cancer (Queen Mary University of London)

Postdoctoral Fellows – Cancer Epigenetics (Baylor Scott & White Research Institute)

Postdoctoral Fellow/ Research Scientist – Diabetes Research (Novo Nordisk)

Postdoctoral Position – Pancreatic Cancer (Cold Spring Harbor Laboratory)

Postdoctoral Fellow – Islet Function/Regeneration (Toronto General Research Institute)

Postdoctoral Fellow – Pancreatic Beta Cell Biology and Regeneration (Icahn School of Medicine at Mount Sinai)

Postdoctoral Associate – Pancreatic Cancer (University of Miami)

Postdoctoral Research Fellow – Pancreatic Cancer (Fred Hutchinson Cancer Research Center)

Postdoctoral Fellow – Oncogenic Signaling Pathways of Colorectal/Pancreatic Cancer (German Cancer Research Center)

Postdoctoral Position – Pancreatic Cancer (University of Liege)

Principle Scientist – Translational Development (Celgene Corporation)

Assistant Professor – Molecular Therapeutics (Dartmouth College/Geisel School of Medicine)

Vice President – Pancreatic Cancer Disease Lead (Celgene Corporation)

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