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Pancreatic Neoplasms: HELP
Articles by Paola Fogar
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, P. Fogar wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma. 2019

Obazee, O / Archibugi, L / Andriulli, A / Soucek, P / Małecka-Panas, E / Ivanauskas, A / Johnson, T / Gazouli, M / Pausch, T / Lawlor, R T / Cavestro, G M / Milanetto, A C / Di Leo, M / Pasquali, C / Hegyi, P / Szentesi, A / Radu, C E / Gheorghe, C / Theodoropoulos, G E / Bergmann, F / Brenner, H / Vodickova, L / Katzke, V / Campa, D / Strobel, O / Kaiser, J / Pezzilli, R / Federici, F / Mohelnikova-Duchonova, B / Boggi, U / Lemstrova, R / Johansen, J S / Bojesen, S E / Chen, I / Jensen, B V / Capurso, G / Pazienza, V / Dervenis, C / Sperti, C / Mambrini, A / Hackert, T / Kaaks, R / Basso, D / Talar-Wojnarowska, R / Maiello, E / Izbicki, J R / Cuk, K / Saum, K U / Cantore, M / Kupcinskas, J / Palmieri, O / Delle Fave, G / Landi, S / Salvia, R / Fogar, P / Vashist, Y K / Scarpa, A / Vodicka, P / Tjaden, C / Iskierka-Jazdzewska, E / Canzian, F. ·Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, Pancreatic Disorders Clinic, S. Andrea Hospital, University of Sapienza, Rome, Italy. · Pancreatico/Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Milan, Italy. · Division of Gastroenterology and Research Laboratory, Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Laboratory of Pharmacogenomics, Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Plzen, Czech Republic. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School National and Kapodistrian University of Athens, Athens, Greece. · Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Germany. · ARC-Net, Applied Research on Cancer Centre, University of Verona, Verona, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy. · Institute for Translational Medicine and 1st Department of Medicine, University of Pécs, Pécs, Hungary. · Fundeni Clinical Institute, Bucharest, Romania. · First Propaedeutic Surgical Department, "Hippocratio" General Hospital Athens Medical School, National and Kapodistrian University of Athens, Athens, Greece. · Pathologisches Institut der Universität Heidelberg, Heidelberg, Germany. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague and Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic. · Dipartimento di Biologia, Università di Pisa, Pisa, Italy. · Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Massa Carrara Oncological, Azienda USL Toscana Nord Ovest, Carrara, Italy. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic. · Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy. · Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Surgery, Konstantopouleion General Hospital of Athens, Athens, Greece. · Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Section for Visceral Surgery, Department of Surgery, Kantonsspital Aarau AG, Aarau, Switzerland. · Institute of Experimental Medicine, Czech Academy of Science, Prague and Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic. · Department of Hematology, Medical University of Lodz, Lodz, Poland. ·Int J Cancer · Pubmed #30672594.

ABSTRACT: Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (OR

2 Article Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms. 2018

Obazee, Ofure / Capurso, Gabriele / Tavano, Francesca / Archibugi, Livia / De Bonis, Antonio / Greenhalf, William / Key, Tim / Pasquali, Claudio / Milanetto, Anna Caterina / Hackert, Thilo / Fogar, Paola / Liço, Valbona / Dervenis, Christos / Lawlor, Rita T / Landoni, Luca / Gazouli, Maria / Zambon, Carlo Federico / Funel, Niccola / Strobel, Oliver / Jamroziak, Krzysztof / Cantù, Cinzia / Malecka-Panas, Ewa / Landi, Stefano / Neoptolemos, John P / Basso, Daniela / Talar-Wojnarowska, Renata / Rinzivillo, Maria / Andriulli, Angelo / Canzian, Federico / Campa, Daniele. ·Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo, Italy. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Pancreatic and Digestive Endocrine Surgery - Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy. · Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Im Neuenheimer Feld, Heidelberg, Germany. · Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy. · Department of Surgical Oncology and Hepatobiliary Surgery, Metropolitan General Hospital, Pireas, Greece. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Medicine - DIMED, University of Padova, Padova, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Hematology, Medical University of Lodz, Lodz, Poland. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Biology, University of Pisa, Pisa, Italy. · Genomic Epidemiology Group, German Cancer Research Centre (DKFZ), Heidelberg, Germany ·Carcinogenesis · Pubmed #29309705.

ABSTRACT: Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.

3 Article Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation. 2018

Campa, Daniele / Pastore, Manuela / Capurso, Gabriele / Hackert, Thilo / Di Leo, Milena / Izbicki, Jakob R / Khaw, Kay-Tee / Gioffreda, Domenica / Kupcinskas, Juozas / Pasquali, Claudio / Macinga, Peter / Kaaks, Rudolf / Stigliano, Serena / Peeters, Petra H / Key, Timothy J / Talar-Wojnarowska, Renata / Vodicka, Pavel / Valente, Roberto / Vashist, Yogesh K / Salvia, Roberto / Papaconstantinou, Ioannis / Shimizu, Yasuhiro / Valsuani, Chiara / Zambon, Carlo Federico / Gazouli, Maria / Valantiene, Irena / Niesen, Willem / Mohelnikova-Duchonova, Beatrice / Hara, Kazuo / Soucek, Pavel / Malecka-Panas, Ewa / Bueno-de-Mesquita, H B As / Johnson, Theron / Brenner, Herman / Tavano, Francesca / Fogar, Paola / Ito, Hidemi / Sperti, Cosimo / Butterbach, Katja / Latiano, Anna / Andriulli, Angelo / Cavestro, Giulia Martina / Busch, Olivier R C / Dijk, Frederike / Greenhalf, William / Matsuo, Keitaro / Lombardo, Carlo / Strobel, Oliver / König, Anna-Katharina / Cuk, Katarina / Strothmann, Hendrik / Katzke, Verena / Cantore, Maurizio / Mambrini, Andrea / Oliverius, Martin / Pezzilli, Raffaele / Landi, Stefano / Canzian, Federico. ·Department of Biology, University of Pisa, Pisa, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, S. Andrea Hospital 'Sapienza' University of Rome, Rome, Italy. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Clinical Gerontology Unit, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. · Division of Gastroenterology and Research Laboratory, Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy. · Institute of Experimental Medicine, Czech Academy of Sciences and Institute of Clinical and Experimental Medicine, Prague, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. · MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Visceral Surgery, Kantonsspital Aarau AG, Aarau, Switzerland. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Second Department of Surgery, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan. · Oncological Department, Azienda USL Toscana Nord Ovest, Oncological Unit of Massa Carrara, Carrara, Massa and Carrara, Italy. · Department of Medicine (DIMED), University of Padova, Padova, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. · Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan. · Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment, Bilthoven, The Netherlands. · Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, St Mary's Campus, London, United Kingdom. · Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Division of Clinical Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), Heidelberg, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy. · Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan. · Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. · Department of Surgery, Academic Medical Centre, Amsterdam, the Netherlands. · Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands. · Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Division of General and Transplant Surgery, University of Pisa, Pisa, Italy. · Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy. · Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine Sant'Orsola-Malpighi Hospital, Bologna, Italy. ·Int J Cancer · Pubmed #28913878.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (OR

4 Article PDAC-derived exosomes enrich the microenvironment in MDSCs in a 2017

Basso, Daniela / Gnatta, Elisa / Padoan, Andrea / Fogar, Paola / Furlanello, Sara / Aita, Ada / Bozzato, Dania / Zambon, Carlo-Federico / Arrigoni, Giorgio / Frasson, Chiara / Franchin, Cinzia / Moz, Stefania / Brefort, Thomas / Laufer, Thomas / Navaglia, Filippo / Pedrazzoli, Sergio / Basso, Giuseppe / Plebani, Mario. ·Department of Medicine - DIMED, University of Padova, Padova, Italy. · Department of Biomedical Sciences, University of Padova, Padova, Italy. · Proteomic Center, University of Padova, Padova, Italy. · Department of Woman and Child Health, Oncohematology Laboratory, University of Padova, Padova, Italy. · Eurofins Medigenomix GmbH, Ebersberg, Germany. · Comprehensive Biomarker Center GmbH (Recently re-named to Hummingbird Diagnostics GmbH), Heidelberg, Germany. · Association Wirsung Onlus, Padova, Italy. ·Oncotarget · Pubmed #29156694.

ABSTRACT: Tumor genetics and escape from immune surveillance concur in the poor prognosis of PDAC. In this study an experimental model was set up to verify whether CONCLUSION: PDAC-derived Exo from cells with

5 Article SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. 2017

Mohelnikova-Duchonova, Beatrice / Strouhal, Ondrej / Hughes, David J / Holcatova, Ivana / Oliverius, Martin / Kala, Zdenek / Campa, Daniele / Rizzato, Cosmeri / Canzian, Federico / Pezzilli, Raffaele / Talar-Wojnarowska, Renata / Malecka-Panas, Ewa / Sperti, Cosimo / Federico Zambon, Carlo / Pedrazzoli, Sergio / Fogar, Paola / Milanetto, Anna Caterina / Capurso, Gabriele / Delle Fave, Gianfranco / Valente, Roberto / Gazouli, Maria / Malleo, Giuseppe / Teresa Lawlor, Rita / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia / Vodicka, Pavel / Vodickova, Ludmila / Landi, Stefano / Tavano, Francesca / Gioffreda, Domenica / Piepoli, Ada / Pazienza, Valerio / Mambrini, Andrea / Pedata, Mariangela / Cantore, Maurizio / Bambi, Franco / Ermini, Stefano / Funel, Niccola / Lemstrova, Radmila / Soucek, Pavel. ·Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. · Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. · Department of Physiology &Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland. · Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic. · Department of Surgery, The University Hospital and Faculty of Medicine, Brno Bohunice, Czech Republic. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Italy. · Department of Medicine - DIMED, University of Padova, Italy. · Clinica Chirurgica 4, University of Padova, Italy. · Department of Laboratory Medicine, University-Hospital of Padova, Italy. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy. · ARC-NET Applied research on Cancer Centre, University and Hospital Trust of Verona, Verona, Italy. · Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic and First Faculty of Medicine, Charles University in Prague, Czech Republic. · Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy. · Blood Transfusion Service, Children's Hospital Meyer, Azienda Ospedaliero Universitaria, Florence, Italy. ·Sci Rep · Pubmed #28272475.

ABSTRACT: Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

6 Article Blood expression of matrix metalloproteinases 8 and 9 and of their inducers S100A8 and S100A9 supports diagnosis and prognosis of PDAC-associated diabetes mellitus. 2016

Moz, Stefania / Basso, Daniela / Padoan, Andrea / Bozzato, Dania / Fogar, Paola / Zambon, Carlo-Federico / Pelloso, Michela / Sperti, Cosimo / Vigili de Kreutzenberg, Saula / Pasquali, Claudio / Pedrazzoli, Sergio / Avogaro, Angelo / Plebani, Mario. ·Department of Medicine - DIMED, University of Padova, via Giustiniani 2, 35128 Padova, Italy. · Department of Laboratory Medicine, University Hospital of Padova, via Giustiniani 2, 35128 Padova, Italy. Electronic address: daniela.basso@sanita.padova.it. · Department of Laboratory Medicine, University Hospital of Padova, via Giustiniani 2, 35128 Padova, Italy. · Department of Surgical, Oncological and GastroenterologicalSciences - DISCOG, University of Padova, via Giustiniani 2, 35128 Padova, Italy. · Associazione Wirsung-onlus, via Giustiniani 2, 35128 Padova, Italy. · Department of Medicine - DIMED, University of Padova, via Giustiniani 2, 35128 Padova, Italy; Department of Laboratory Medicine, University Hospital of Padova, via Giustiniani 2, 35128 Padova, Italy. ·Clin Chim Acta · Pubmed #26923392.

ABSTRACT: BACKGROUND: Based on the knowledge that matrix metalloproteinases (MMPs) and S100A8/A9 synergistically work in causing PDAC-associated type 2 diabetes mellitus (T2DM), we verified whether tissue and blood MMP8, MMP9, S100A8 and S100A9 expression might help in distinguishing PDAC among diabetics. METHODS: Relative quantification of MMP8, MMP9, S100A8 and S100A9 mRNA was performed in tissues obtained from 8 PDAC, 4 chronic pancreatitis (ChrPa), 4 non-PDAC tumors and in PBMCs obtained from 30 controls, 43 T2DM, 41 ChrPa, 91 PDAC and 33 pancreatic-biliary tract tumors. RESULTS: T2DM was observed in PDAC (66%), in pancreatic-biliary tract tumors (64%) and in ChrPa (70%). In diabetics, with or without PDAC, MMP9 tissue expression was increased (p<0.05). Both MMPs increased in PDAC and MMP9 increased also in pancreatic-biliary tract tumors PBMCs. In diabetics, MMP9 was independently associated with PDAC (p=0.025), but failed to enhance CA 19-9 discriminant efficacy. A highly reduced S100A9 expression, found in 7 PDAC, was significantly correlated with a reduced overall survival (p=0.015). CONCLUSIONS: An increased expression of tissue and blood MMP9 reflects the presence of PDAC-associated diabetes mellitus. This finding fits with the hypothesized role of MMPs as part of the complex network linking cancer to diabetes.

7 Article TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. 2015

Campa, Daniele / Rizzato, Cosmeri / Stolzenberg-Solomon, Rachael / Pacetti, Paola / Vodicka, Pavel / Cleary, Sean P / Capurso, Gabriele / Bueno-de-Mesquita, H B As / Werner, Jens / Gazouli, Maria / Butterbach, Katja / Ivanauskas, Audrius / Giese, Nathalia / Petersen, Gloria M / Fogar, Paola / Wang, Zhaoming / Bassi, Claudio / Ryska, Miroslav / Theodoropoulos, George E / Kooperberg, Charles / Li, Donghui / Greenhalf, William / Pasquali, Claudio / Hackert, Thilo / Fuchs, Charles S / Mohelnikova-Duchonova, Beatrice / Sperti, Cosimo / Funel, Niccola / Dieffenbach, Aida Karina / Wareham, Nicholas J / Buring, Julie / Holcátová, Ivana / Costello, Eithne / Zambon, Carlo-Federico / Kupcinskas, Juozas / Risch, Harvey A / Kraft, Peter / Bracci, Paige M / Pezzilli, Raffaele / Olson, Sara H / Sesso, Howard D / Hartge, Patricia / Strobel, Oliver / Małecka-Panas, Ewa / Visvanathan, Kala / Arslan, Alan A / Pedrazzoli, Sergio / Souček, Pavel / Gioffreda, Domenica / Key, Timothy J / Talar-Wojnarowska, Renata / Scarpa, Aldo / Mambrini, Andrea / Jacobs, Eric J / Jamroziak, Krzysztof / Klein, Alison / Tavano, Francesca / Bambi, Franco / Landi, Stefano / Austin, Melissa A / Vodickova, Ludmila / Brenner, Hermann / Chanock, Stephen J / Delle Fave, Gianfranco / Piepoli, Ada / Cantore, Maurizio / Zheng, Wei / Wolpin, Brian M / Amundadottir, Laufey T / Canzian, Federico. ·Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic. · Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN. · Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy. · Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic. · 1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. · Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · German Cancer Consortium (DKTK), Heidelberg, Germany. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. · Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. · Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Medicine - DIMED, University of Padua, Padua, Italy. · Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT. · Department of Epidemiology, Harvard School of Public Health, Boston, MA. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY. · Surgical Clinic 4, University of Padua, Padua, Italy. · Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Epidemiology Research Program, American Cancer Society, Atlanta, GA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD. · Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology, University of Washington, Seattle, WA. · Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN. ·Int J Cancer · Pubmed #25940397.

ABSTRACT: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

8 Article Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1. 2014

Basso, Daniela / Bozzato, Dania / Padoan, Andrea / Moz, Stefania / Zambon, Carlo-Federico / Fogar, Paola / Greco, Eliana / Scorzeto, Michele / Simonato, Francesca / Navaglia, Filippo / Fassan, Matteo / Pelloso, Michela / Dupont, Sirio / Pedrazzoli, Sergio / Fassina, Ambrogio / Plebani, Mario. ·Department of Laboratory Medicine, University-Hospital of Padova, Via Giustiniani 2, 35128 Padova, Italy. daniela.basso@sanita.padova.it. ·Cell Commun Signal · Pubmed #24670043.

ABSTRACT: BACKGROUND: In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. RESULTS: NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation). CONCLUSIONS: The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.

9 Article Pancreatic tumors and immature immunosuppressive myeloid cells in blood and spleen: role of inhibitory co-stimulatory molecules PDL1 and CTLA4. An in vivo and in vitro study. 2013

Basso, Daniela / Fogar, Paola / Falconi, Massimo / Fadi, Elisa / Sperti, Cosimo / Frasson, Chiara / Greco, Eliana / Tamburrino, Domenico / Teolato, Sara / Moz, Stefania / Bozzato, Dania / Pelloso, Michela / Padoan, Andrea / De Franchis, Giuseppe / Gnatta, Elisa / Facco, Monica / Zambon, Carlo-Federico / Navaglia, Filippo / Pasquali, Claudio / Basso, Giuseppe / Semenzato, Gianpietro / Pedrazzoli, Sergio / Pederzoli, Paolo / Plebani, Mario. ·Department of Medicine, University of Padova, Padova, Italy. daniela.basso@sanita.padova.it ·PLoS One · Pubmed #23359812.

ABSTRACT: BACKGROUND: Blood and spleen expansion of immature myeloid cells (IMCs) might compromise the immune response to cancer. We studied in vivo circulating and splenic T lymphocyte and IMC subsets in patients with benign and malignant pancreatic diseases. We ascertained in vitro whether pancreatic adenocarcinoma (PDAC)-associated IMC subsets are induced by tumor-derived soluble factors and whether they are immunosuppressive focusing on the inhibitory co-stimulatory molecules PDL1 and CTLA4. METHODOLOGY AND PRINCIPAL FINDINGS: 103 pancreatic and/or splenic surgical patients were enrolled including 52 PDAC, 10 borderline and 10 neuroendocrine tumors (NETs). Lymphocytes and IMCs were analysed by flow cytometry in blood, in spleen and in three PDAC cell conditioned (CM) or non conditioned PBMC. PDL1 and CTLA4 were studied in 30 splenic samples, in control and conditioned PBMC. IMCs were FACS sorted and co-coltured with allogenic T lymphocytes. In PDAC a reduction was found in circulating CD8(+) lymphocytes (p = 0.004) and dendritic cells (p = 0.01), which were reduced in vitro by one PDAC CM (Capan1; p = 0.03). Blood myeloid derived suppressive cells (MDSCs) CD33(+)CD14(-)HLA-DR(-) were increased in PDAC (p = 0.022) and were induced in vitro by BxPC3 CM. Splenic dendritic cells had a higher PDL1 expression (p = 0.007), while CD33(+)CD14(+)HLA-DR(-) IMCs had a lower CTLA4 expression (p = 0.029) in PDAC patients. In vitro S100A8/A9 complex, one of the possible inflammatory mediators of immune suppression in PDAC, induced PDL1 (p = 0.018) and reduced CTLA4 expression (p = 0.028) among IMCs. IMCs not expressing CTLA4 were demonstrated to be immune suppressive. CONCLUSION: In PDAC circulating dendritic and cytotoxic T cells are reduced, while MDSCs are increased and this might favour tumoral growth and progression. The reduced CTLA4 expression found among splenic IMCs of PDAC patients was demonstrated to characterize an immune suppressive phenotype and to be consequent to the direct exposure of myeloid cells to pancreatic cancer derived products, S100A8/A9 complex in particular.

10 Article Usefulness of MALDI-TOF/MS identification of low-MW fragments in sera for the differential diagnosis of pancreatic cancer. 2013

Padoan, Andrea / Seraglia, Roberta / Basso, Daniela / Fogar, Paola / Sperti, Cosimo / Moz, Stefania / Greco, Eliana / Marchet, Alberto / de Manzoni, Giovanni / Zambon, Carlo-Federico / Navaglia, Filippo / Cristadoro, Luigi / Di Chiara, Alda / Nitti, Donato / Pedrazzoli, Sergio / Pavanello, Girolamo / Plebani, Mario. ·Department of Laboratory Medicine, University of Padova, Italy. ·Pancreas · Pubmed #23271396.

ABSTRACT: OBJECTIVES: To identify new biomarkers of pancreatic cancer (PaCa), we performed MALDI-TOF/MS analysis of sera from 22 controls, 51 PaCa, 37 chronic pancreatitis, 24 type II diabetes mellitus (DM), 29 gastric cancer (GC), and 24 chronic gastritis (CG). METHODS: Sera were purified by Sep-Pak C18 before MALDI-TOF/MS Anchorchip analysis. RESULTS: Features present in at least 5% of all spectra were selected (n = 160, m/z range, 1200-5000). At univariate analysis, 2 features (m/z 2049 and 2305) correlated with PaCa, 3 (m/z 1449, 1605, and 2006) with DM. No feature characterized gastric cancer or chronic gastritis. Ten-fold cross-validation binary recursive partitioning trees were obtained for patients' classification. The tree (CA 19-9, age, m/z 2006, 2599, 2753, and 4997), built considering only patients with diabetes, allowed a distinction between DM [area under the receiver operating characteristic curve (AUC), 0.997], chronic pancreatitis (AUC, 0.968), and PaCa (AUC, 0.980), with an overall correct classification rate of 89%. The tree including CA 19-9, 1550, and 2937 m/z features, achieved an AUC of 0.970 in distinguishing localized from advanced PaCa. MALDI-TOF-TOF analysis revealed the 1550 feature as a fragment of Apo-A1, which was determined as whole protein and demonstrated to be closely correlated with PaCa. CONCLUSIONS: The findings made demonstrate a role for serum peptides identified using MALDI-TOF/MS for addressing PaCa diagnosis.

11 Article Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium. 2013

Campa, Daniele / Rizzato, Cosmeri / Capurso, Gabriele / Giese, Nathalia / Funel, Niccola / Greenhalf, William / Soucek, Pavel / Gazouli, Maria / Pezzilli, Raffaele / Pasquali, Claudio / Talar-Wojnarowska, Renata / Cantore, Maurizio / Andriulli, Angelo / Scarpa, Aldo / Jamroziak, Krzysztof / Delle Fave, Gianfranco / Costello, Eithne / Khaw, Kay-Tee / Heller, Anette / Key, Tim J / Theodoropoulos, George / Malecka-Panas, Ewa / Mambrini, Andrea / Bambi, Franco / Landi, Stefano / Pedrazzoli, Sergio / Bassi, Claudio / Pacetti, Paola / Piepoli, Ada / Tavano, Francesca / di Sebastiano, Pierluigi / Vodickova, Ludmila / Basso, Daniela / Plebani, Mario / Fogar, Paola / Büchler, Markus W / Bugert, Peter / Vodicka, Pavel / Boggi, Ugo / Neoptolemos, John P / Werner, Jens / Canzian, Federico. ·German Cancer Research Center (DKFZ), Heidelberg, Germany. d.campa@dkfz.de ·Dig Liver Dis · Pubmed #23206934.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going.

12 Article Pancreatic cancer alters human CD4+ T lymphocyte function: a piece in the immune evasion puzzle. 2011

Fogar, Paola / Basso, Daniela / Fadi, Elisa / Greco, Eliana / Pantano, Giorgia / Padoan, Andrea / Bozzato, Dania / Facco, Monica / Sanzari, Maria Colomba / Teolato, Sara / Zambon, Carlo-Federico / Navaglia, Filippo / Semenzato, Gianpietro / Pedrazzoli, Sergio / Plebani, Mario. ·Department of Laboratory Medicine, University of Padova, Padova, Italy. ·Pancreas · Pubmed #21792088.

ABSTRACT: OBJECTIVES: To verify whether the dysregulation of CD4 T cells concurs in worsening the outcome of pancreatic cancer, we compared the effects of pancreatic cancer and other gastrointestinal cancer cell-conditioned media on the (1) proliferation, migration, and differentiation of CD4 T cells and (2) expansion of CD4 memory (CD45RO), naive (CD45RA), activated (CD69), and regulatory (CD25) subsets. METHODS: After culture of CD4 T cells in control, pancreatic (BxPC3, Capan1, MiaPaCa2), or gastrointestinal cancer (AGS, HepG2, HT29) cell-conditioned media, we evaluated proliferation, migration, interferon γ (IFNγ) production, and CD45RA, CD45RO, CD69, and CD25 membrane expression in control and conditioned CD4 T cells. RESULTS: Only pancreatic cancer-conditioned media (1) inhibited CD4 T-cell proliferation (P < 0.001) and migration under human stromal cell-derived factor-α chemotaxis (P < 0.001) and (2) induced CD4 T-cell IFNγ production (P < 0.05) and the expansion of the CD69-positive subset (P < 0.001) with respect to the control, with no changes being found in the CD45RA, CD45RO, and CD25 subsets. CONCLUSIONS: The in vitro findings achieved in the present study demonstrate that pancreatic cancer cells inhibit CD4 T-cell proliferation and migration, induce IFNγ production, and favor a CD69 subset expansion, suggesting that CD4 T cells play an important role in pancreatic cancer immune evasion.

13 Article Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N-terminal peptide (NT-S100A8). 2011

Basso, Daniela / Greco, Eliana / Padoan, Andrea / Fogar, Paola / Scorzeto, Michele / Fadi, Elisa / Bozzato, Dania / Moz, Stefania / Navaglia, Filippo / Zambon, Carlo-Federico / Seraglia, Roberta / De Carlo, Eugenio / Valerio, Anna / Reggiani, Carlo / Pedrazzoli, Sergio / Plebani, Mario. ·Department of Laboratory Medicine, University of Padua, Padua, Italy. ·J Cell Physiol · Pubmed #20717964.

ABSTRACT: After isolating NT-S100A8 from pancreatic cancer (PC) tissue of diabetic patients, we verified whether this peptide alters PC cell growth and invasion and/or insulin release and [Ca(2+)](i) oscillations of insulin secreting cells and/or insulin signaling. BxPC3, Capan1, MiaPaCa2, Panc1 (PC cell lines) cell growth, and invasion were assessed in the absence or presence of 50, 200, and 500 nM NT-S100A8. In NT-S100A8 stimulated β-TC6 (insulinoma cell line) culture medium, insulin and [Ca(2+)] were measured at 2, 3, 5, 10, 15, 30, and 60 min, and [Ca(2+)](i) oscillations were monitored (epifluorescence) for 3 min. Five hundred nanomolars NT-S100A8 stimulated BxPC3 cell growth only and dose dependently reduced MiaPaCa2 and Panc1 invasion. Five hundred nanomolars NT-S100A8 induced a rapid insulin release and enhanced β-TC6 [Ca(2+)](i) oscillations after both one (F = 6.05, P < 0.01) and 2 min (F = 7.42, P < 0.01). In the presence of NT-S100A8, [Ca(2+)] in β-TC6 culture medium significantly decreased with respect to control cells (F = 6.3, P < 0.01). NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IκB-α, but it independently activated Akt and NF-κB signaling in PC cells. In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-κB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling.

14 Article Analogs of vitamin E epitomized by alpha-tocopheryl succinate for pancreatic cancer treatment: in vitro results induce caution for in vivo applications. 2010

Greco, Eliana / Basso, Daniela / Fadi, Elisa / Padoan, Andrea / Fogar, Paola / Zambon, Carlo-Federico / Navaglia, Filippo / Bozzato, Dania / Moz, Stefania / Pedrazzoli, Sergio / Plebani, Mario. ·Department of Laboratory Medicine, University of Padova, Padova, Italy. ·Pancreas · Pubmed #20562578.

ABSTRACT: OBJECTIVES: alpha-Tocopheryl succinate (alpha-TOS) is thought to be toxic only for cancer cells. We ascertained in vitro alpha-TOS effects on pancreatic cancer (PC) and normal cell growth and verified whether the combination of nontoxic alpha-TOS and 5-fluorouracil (5-FU) doses causes cancer cell death and whether alpha-TOS effects are mediated by the proapoptotic proteins Bax/Bak and/or SMAD4/DPC4 status. METHODS: Five PC cell lines, myoblasts, normal monocytes, wild-type (WT) and Bax/Bak double knockout mouse embryonic fibroblast (MEF) cells, and permanently SMAD4/DPC4-transfected PSN1 cells were cultured in 1% and 10% fetal calf serums (FCSs), without or with alpha-TOS (5-500 micromol/L). Nontoxic 5-FU (0.0001 mmol/L) and alpha-TOS alone or in combination were also evaluated. RESULTS: Only PSN1 PC cell line, which had SMAD4/DPC4 homozygous deletion, was sensitive to nontoxic alpha-TOS doses (5 micromol/L in 1% FCS and 50 micromol/L in 10% FCS). A 20-micromol/L alpha-TOS inhibited MEF-WT, not MEF-double knockout growth. Only PSN1 cells were sensitive to nontoxic 5-FU and alpha-TOS combination. SMAD4/DPC4 transfection restored PSN1 resistance to the effects of combined 5-FU and alpha-TOS effects. CONCLUSIONS: Only a minority of PC cells are sensitive to the antiproliferative effects of alpha-TOS, any sensitivity appearing to be correlated with SMAD4/DPC4 homozygous deletion and Bax/Bak expression.