Pancreatic Cell News Volume 9.26 | Jul 3 2018

TOP STORY

Inhibition of SNAT5 Induces Incretin Responsive State from Incretin Unresponsive State in Pancreatic β-Cells: Study of β-Cell Spheroid Clusters as a Model

Glutamate production by glucose through the malate-aspartate shuttle and cAMP signaling, both of which are critical for incretin-induced insulin secretion (IIIS), were enhanced in K20-spheroid clusters (SC). SC formed from β-cells deficient for aspartate aminotransferase 1, a critical enzyme in the malate-aspartate shuttle, exhibited reduced IIIS. [Diabetes] Abstract

(Ranked by impact factor of the journal)

DIABETES & PANCREATITIS

Pseudotime Ordering of Single Human β-Cells Reveals States of Insulin Production and Unfolded Protein Response

Scientists reported the pseudotime ordering of single non-diabetic human β-cells detected by large-scale RNA sequencing. They identified major states with low unfolded protein response (UPR) and low insulin gene expression, low UPR and high insulin gene expression or high UPR and low insulin gene expression. The latter state was enriched for proliferating cells. [Diabetes] Abstract

ZBED6 Negatively Regulates Insulin Production, Neuronal Differentiation, and Cell Aggregation in MIN6 Cells

The authors identified >4000 putative zinc finger BED domain containing protein 6 (ZBED6)-binding sites in the MIN6 genome, with an enrichment of ZBED6 sites at upregulated genes, such as the β-cell transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and Nk6 homeobox 1. [FASEB J] Abstract

Expression Characteristics of Long Noncoding RNA uc.322 and Its Effects on Pancreatic Islet Function

Long noncoding RNA (lncRNA) uc.322 was highly expressed in pancreatic tissue. Upregulation of lncRNA uc.322 expression increased the insulin transcription factors pancreatic and duodenal homeobox 1 and Forkhead box O1 expression, promoted insulin secretion in the extracellular fluid of Min6 cells, and increased the adenosine triphosphate concentration. [J Cell Biochem] Abstract

Pro-Inflammatory Cytokines Attenuate Glucose-Stimulated Insulin Secretion from INS-1E Insulinoma Cells by Restricting Mitochondrial Pyruvate Oxidation Capacity – Novel Mechanistic Insight from Real-Time Analysis of Oxidative Phosphorylation

Investigators showed that 24-hour exposure to cytokines dampened both glucose- and pyruvate-stimulated insulin secretion, but did not affect KCl-induced insulin release. Mirroring secretory defects, glucose- and pyruvate-stimulated mitochondrial respiration were lowered after cytokine exposure. [PLoS One] Full Article

PANCREATIC CANCER

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

The authors showed that metformin inhibited pancreatic stellate cells (PSCs) proliferation and decreased the production of extracellular matrix proteins by activation of adenosine monophosphate-activated protein kinase phosphorylation. Silencing of organic cation transporter member 1 (OCT1) expression resulted in a reduction in the effects of metformin on PSCs activity. [Cell Physiol Biochem] Full Article

Melatonin Synergizes with Sorafenib to Suppress Pancreatic Cancer via Melatonin Receptor and PDGFR-β/STAT3 Pathway

Melatonin synergized with sorafenib to suppress the growth of pancreatic ductal adenocarcinoma (PDAC) both in vitro and in vivo. The effect was due to increased apoptosis rate of PDAC cells that was accompanied by mitochondria dysfunction. The enhanced anticancer efficacy by the co-treatment could be explained by blockade of PDGFR-β/STAT3 signaling pathway and melatonin receptor-mediated STAT3. [Cell Physiol Biochem] Full Article

Preclinical Efficacy of Anti-RON Antibody-Drug Conjugate Zt/g4-MMAE for Targeted Therapy of Pancreatic Cancer Overexpressing RON Receptor Tyrosine Kinase

In vitro, Zt/g4-MMAE rapidly induced RON internalization, resulting in cell cycle arrest followed by massive cell death. The maximal effect was seen in pancreatic cancer cells with more than 10 000 receptor molecules per cell. Zt/g4-MMAE also synergized in vitro with chemotherapeutics including gemcitabine, 5-fluorouracil, and oxaliplatin to further reduce pancreatic ductal adenocarcinoma cell viability. [Mol Pharm] Abstract | Graphical Abstract

Clinical Implications of Lysyl Oxidase-Like Protein 2 Expression in Pancreatic Cancer

Higher lysyl oxidase-like protein 2 (LOXL2) expression was observed in cell lines from mesenchymal type pancreatic cancer (PC) than in those from epithelial type PC. According to the multivariate analysis, high LOXL2 expression was a significant independent prognostic factor for patients with PC. LOX inhibition significantly decreased PC cell proliferation, migration, and invasion in vitro. [Sci Rep] Full Article

The Effect of GPRC5a on the Proliferation, Migration Ability, Chemotherapy Resistance, and Phosphorylation of GSK-3β in Pancreatic Cancer

Investigators showed that G-protein-coupled receptor family C, member 5, group A (GPRC5a) was upregulated in pancreatic cancer (PaCa) tissues and various PaCa cell lines. Knockout of GPRC5a reduced the proliferation and migration ability of PaCa cell lines and suppressed the chemotherapy drug resistance of gemcitabine, oxaliplatin, and fluorouracil in PaCa cells. [Int J Mol Sci] Full Article

E-Cadherin Is Downregulated by Microenvironmental Changes in Pancreatic Cancer and Induces EMT

In pancreatic cancer cells under hypoxic, serum-starved and TGF-β-induced microenvironments, E-cadherin protein and mRNA levels were significantly decreased, while vimentin protein and mRNA expression levels were significantly increased. Researchers also showed that the protein level of E-cadherin in pancreatic cancer tissues was positively correlated with overall survival. [Oncol Rep] Abstract

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Use of Nano Engineered Approaches to Overcome the Stromal Barrier in Pancreatic Cancer

The authors provide a short overview of the role of the stroma in chemotherapy resistance, including the use of nanocarriers to negate this barrier. They provide a perspective and guidance towards the implementation of nanotherapeutic approaches to improve therapeutic delivery and efficacy of pancreatic ductal adenocarcinoma management. [Adv Drug Deliv Rev] Abstract | Graphical Abstract

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Kadimastem and the Australian Foundation for Diabetes Research (AFDR) Selected to Receive a Bi-National Grant from the Australian Government and the Israel Innovation Authority to Explore a Combined Diabetes Solution

Kadimastem announced the approval of the Australian Government and the Israel Innovation Authority, to receive a joint research grant as part of a bi-national program to examine and develop the company’s technology for the treatment of diabetes, together with a dedicated medical device developed by the AFDR. [Kadimastem – Stem Cell to Cure Diseases] Press Release

Poxel Announces Completion of Patient Enrollment for TIMES 1 Trial in the Phase III Registration Program for Imeglimin, an Investigational Therapeutic Agent for Type 2 Diabetes, in Japan

Referred to as TIMES (Trials of IMeglimin for Efficacy and Safety), the imeglimin Phase III registration program in Japan includes three pivotal trials to evaluate the efficacy and safety of imeglimin in approximately 1,100 patients. The TIMES 1 trial is a multicenter, double-blind, placebo-controlled, randomized, monotherapy study in over 200 Japanese patients with type 2 diabetes. [Poxel SA] Press Release

NOXXON Provides Update on Patient Recruitment in Ongoing NOX-A12 Pancreatic and Colorectal Cancer Trial

NOXXON Pharma N.V. announced that patient recruitment is almost complete in its ongoing clinical trial testing NOX-A12 alone and subsequently in combination with Merck & Co./MSD’s Keytruda^® in metastatic, microsatellite stable pancreatic and colorectal cancer patients. [NOXXON Pharma] Press Release

PanCAN’s Research Grants Program Funds Nine New Projects

The Pancreatic Cancer Action Network (PanCAN) announces the funding of nine new, innovative pancreatic cancer research projects through its Research Grants Program. Since 2003, PanCAN and its charitable donors have invested more than $48 million to help advance the field of pancreatic cancer research, a significant portion through research grants. [Pancreatic Cancer Action Network] Press Release

LGBTQ Scientists Are Still Left Out

People who identify as LGBTQ are leaking out of the scientific pipeline in similar ways to women and those from minority ethnic groups. But many initiatives to increase diversity do not support them. Including LGBTQ people in diversity initiatives would foster their representation, and it could bring in perspectives that improve science itself. [Nature News] Editorial

Europe’s Biggest Research Fund Cracks Down on ‘Ethics Dumping’

Ethics dumping — doing research deemed unethical in a scientist’s home country in a foreign setting with laxer ethical rules — will be rooted out in research funded by the European Union, officials announced. [Nature News] Editorial

U.S. Lawmakers Want NIH and CDC Foundations to Say More about Donors

A key congressional spending panel has fired a shot across the bow of two federally chartered medical foundations, warning that the way they disclose information about donors may not pass muster. [ScienceInsider] Editorial

NEW Keystone Symposia: Cellular Plasticity: Reprogramming, Regeneration and Metaplasia
January 27-31, 2019
Keystone, Colorado, United States

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NEW Lecturer/ Professor/ Clinical Academic – Diabetes (University of Exeter)

Postdoctoral Research Fellow – Drivers of Pancreatic Cancer Metastasis (The Moffitt Cancer Center)

Postdoctoral Associate – Type 1 Diabetes Research (University of Florida)

Postdoctoral Fellow – Cellular Biology of Pancreatic Cancer (The Francis Crick Institute)

Assistant or Associate Professor (Tenure Track) – Immunopathology of Metabolic Diseases)

Postdoctoral Research Scientist – Metabolic Homeostasis Research (London Institute of Medical Sciences)

Postdoctoral Position – Human Pluripotent Stem Cell-Based Cell Therapy in Type 1 Diabetes (University of Copenhagen)

Postdoctoral Positions – Translational Diabetes Research (Partner of German Center for Diabetes Research)

Postdoctoral Scholars – Structural Biology (The University of Chicago)

EBPOD Fellowship – Pancreatic Cancer Analysis (European Molecular Biology Laboratory)

Postdoctoral Positions – Immunology of Diabetes (Cochin Institute)

Postdoctoral Fellow – Molecular Medicine (City of Hope)

Doctoral Thesis Position – Diabetes Research (Universite Libre de Bruxelles)

Pioneer Award Postdoctoral Fellowships – Pancreatic Cancer (University of Miami Miller School of Medicine)

Postdoctoral Position – Inflammation and Metabolism (Sanford Burnham Prebys Medical Discovery Institute)

Postdoctoral Fellow – Epigenetic Regulation of Pancreatic Beta-Cell Mass (City of Hope)

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