Publications by authors named "Eva C Vaquero"

21 Publications

  • Page 1 of 1

Spectrum of Disease Manifestations in Patients with Selective Immunoglobulin E Deficiency.

J Clin Med 2021 Sep 15;10(18). Epub 2021 Sep 15.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.

Background: Selective IgE deficiency (SIgED) has been previously evaluated in selected patients from allergy units. This study investigates the effects of SIgED on the entire population in a hospital setting and sought to delineate in detail the clinical aspects of SIgED.

Methods: A retrospective study of the data obtained from electronic medical records of 52 adult patients (56% female) with a mean age of 43 years and IgE levels of <2.0 kU/L with normal immunoglobulin (Ig) IgG, IgA, and IgM levels, seen at our hospital, without selection bias, from 2010 to 2019.

Results: Recurrent upper respiratory infections were recorded in 18 (34.6%) patients, pneumonia was recorded in 16 (30.7%) patients, bronchiectasis was recorded in 16 (30.7%) patients, and asthma was recorded in 10 (19.2%) patients. Eighteen patients (34.6%) suffered autoimmune clinical manifestations either isolated (19%) or combining two or more diseases (15%), Hashimoto's thyroiditis being the most frequent (19%), which was followed by arthritis (10%) and thrombocytopenia and/or neutropenia (5.7%). Other less frequent associations were Graves' disease, primary sclerosing cholangitis, Sjögren's syndrome, and autoimmune hepatitis. Eczematous dermatitis (15.3%), chronic spontaneous urticaria (17.3%), and symptoms of enteropathy (21%) were also highly prevalent. Thirty percent of patients developed malignancies, with non-Hodgkin lymphomas (13.4%) being the most prevalent.

Conclusions: The clinical manifestations of SIgED encompass a variety of infectious, non-infectious complications, and malignancy. Since it cannot be ruled out that some type of selection bias occurred in the routine assessment of IgE serum Ievels, prospective studies are required to better characterize SIgED and to determine whether it should be added to the list of antibody deficiencies.
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http://dx.doi.org/10.3390/jcm10184160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466644PMC
September 2021

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth.

Gut 2019 08 20;68(8):1465-1476. Epub 2018 Oct 20.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background And Aims: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis.

Design: We analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of dosage. Furthermore, we explored a mechanistic model for DYRK1A activity.

Results: We showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling.

Conclusions: These findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.
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http://dx.doi.org/10.1136/gutjnl-2018-316128DOI Listing
August 2019

Zeb1 in Stromal Myofibroblasts Promotes -Driven Development of Pancreatic Cancer.

Cancer Res 2018 05 28;78(10):2624-2637. Epub 2018 Feb 28.

Gastrointestinal and pancreatic oncology research group, Hospital Clinic, Barcelona, CiberEHD, Spain.

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic and mutations (KPC) were crossed with haploinsufficient mice (Z). Extensive PDAC was prominent in all 20-week-old KPC;Z mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z littermates, with PDAC developing eventually in KPC;Z aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant ; this effect was not observed when using conditioned media from Z mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy. Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1882DOI Listing
May 2018

Endoscopic ultrasonography can avoid unnecessary laparotomies in patients with pancreatic adenocarcinoma and undetected peritoneal carcinomatosis.

Pancreatology 2017 Sep - Oct;17(5):858-864. Epub 2017 Aug 19.

Endoscopy Unit, Gastroenterology Department, ICMDiM, IDIBAPS, CIBEREHD, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalunya, Spain. Electronic address:

Background/objective: To assess the relationship between the presence of ascites detected by endoscopic ultrasonography (EUS) and peritoneal carcinomatosis (PC) in patients with pancreatic adenocarcinoma.

Methods: Consecutive patients who underwent a EUS for preoperative staging of a pancreatic adenocarcinoma between 1998 and 2014 were retrospectively reviewed. The diagnosis of PC was confirmed by histopathology or peritoneal fluid cytology. The main outcome of the study was the relationship of ascites at EUS and PC in patients with pancreatic cancer. Secondarily, to evaluate the relationship between this finding and survival as well as the development of PC during follow-up.

Results: A total of 136 patients were included: 30 patients with local unresectable tumor or metastatic disease and 106 potentially-resectable candidates based on CT staging. EUS showed ascites in 27 (20%) patients, of whom 8 (29.6%) had PC. The sensitivity, specificity, PPV, NPV and accuracy of ascites by EUS in the detection of PC in this group of patients were 67%, 85%, 30%, 96% and 83%, respectively. Ascites detected by EUS was the only independent predictive factor of PC with an OR of 11 (CI 95%: 3-40). The detection of ascites by EUS was associated with a shorter survival (median survival time 7,3 months; range 0-60 vs 14.2 months; range 0-140) (p = 0.018) and earlier development of PC during follow-up (median 3.2 months, range 1.4-18.1 vs 12.7 months, range 5.4-54.8; p = 0.003).

Conclusion: The finding of ascites at EUS in patients with pancreatic adenocarcinoma is highly associated with PC and a poor outcome.
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http://dx.doi.org/10.1016/j.pan.2017.08.004DOI Listing
June 2018

[Recommendations for the diagnosis, staging and treatment of pre-malignant lesions and pancreatic adenocarcinoma].

Med Clin (Barc) 2016 Nov 7;147(10):465.e1-465.e8. Epub 2016 Oct 7.

Servicio de Oncología Médica, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, España; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, España.

Background And Objective: Clinical management of adenocarcinoma of the pancreas is complex, and requires a multidisciplinary approach. The same applies for the premalignant lesions that are increasingly being diagnosed. The current document is an update on the diagnosis and management of premalignant lesions and adenocarcinoma of the pancreas.

Patients And Methods: A conference to establish the basis of the literature review and manuscript redaction was organized by the Grupo Español Multidisciplinar en Cáncer Digestivo. Experts in the field from different specialties (Gastroenterology, Surgery, Radiology, Pathology, Medical Oncology and Radiation Oncology) met to prepare the present document.

Results: The current literature was reviewed and discussed, with subsequent deliberation on the evidence.

Conclusions: Final recommendations were established in view of all the above.
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http://dx.doi.org/10.1016/j.medcli.2016.07.033DOI Listing
November 2016

Impact of endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration on the management of pancreatic cystic lesions.

Eur J Gastroenterol Hepatol 2016 Sep;28(9):1094-9

aEndoscopy Unit, Hospital Clínic, IDIBAPS, CIBERehd Departments of bDigestive Surgery cGastroenterology, Hospital Clínic dDepartment of Gastroenterology, Hospital Vall d'Hebron, Barcelona eDepartment of Gastroenterology, Hospital de Terrassa, Terrassa fDepartment of Digestive Surgery, Hospital de Bellvitge, Hospitalet de Llobregat, Spain.

Background And Study Aims: Endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) are well-recognized techniques for the study of pancreatic cystic lesions (PCLs). However, little evidence exists on their impact on clinical care. The aim of this study is to determine how often EUS and EUS-FNA alter the diagnosis and management of patients with PCLs.

Patients And Methods: Eight physicians expert in pancreatic diseases were asked to report their diagnoses and management recommendations for 49 different PCLs. Clinical information was sequentially disclosed in a stepwise manner - progressively from clinical data plus computed tomography or MRI (level 1), to EUS (level 2) and EUS-FNA results including cytology, carcinoembryonic antigen, and amylase levels (level 3).

Results: EUS led to a change in the diagnosis and management in 30% [95% confidence interval (CI): 26-35%] and 19% (95% CI: 16-23%) of cases, respectively, usually to a more intensive approach (14%; 95% CI: 11-18%). EUS-FNA altered the diagnosis and management in an additional 39% (95% CI: 34-44%) and 21% (95% CI: 17-25%) of the evaluations, respectively. EUS-FNA also increased the consensus in the diagnosis among the specialists that ranged from fair with computed tomography/MRI (κ-index=0.32) to substantial with EUS-FNA (κ-index=0.43).

Conclusion: EUS and EUS-FNA impact the diagnosis and management of patients with PCLs; therefore, both are necessary in the workup of these patients. EUS-FNA markedly improves the agreement between physicians in terms of diagnosis, but not management. This study highlights the need for more research and standardization in the field.
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http://dx.doi.org/10.1097/MEG.0000000000000678DOI Listing
September 2016

Evidence-based Guidelines for the Management of Exocrine Pancreatic Insufficiency After Pancreatic Surgery.

Ann Surg 2016 Dec;264(6):949-958

*Department of Surgery, Hospital Clinico, University of Valencia, Valencia, Spain †Department of Surgery, Complejo Hospitalario Universitario de Vigo, Vigo, Spain ‡Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands §Department of Gastroenterology, Consorci Sanitari de Terrassa, Terrassa, Spain ¶Department of Gastroenterology, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain ||Department of Surgery, Università Vita e Salute, Ospedale San Raffaele IRCCS, Milano, Italy **Department of Surgery, Institut de Malalties Digestives I Metabòliques, Hospital Clínic, IDIBAPS, Barcelona, Spain ††Department of Medicine, Pancreas Center, University of Verona, Verona, Italy ‡‡Department of Endocrinology and Nutrition, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain. §§Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ¶¶Department of Surgery, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain. ||||Department of Surgery, Hospital Universitario de La Princesa, Madrid, Spain ***Department of Gastroenterology, Complejo Hospitalario de Navarra, Pamplona, Spain †††Unidad de Cirugía Hepato-bilio-pancreática y Trasplante, Hospital Universitari i Politecnic. La Fe, Valencia, Spain ‡‡‡NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK §§§Department of Gastroenterology, Hospital Clinico, University of Valencia, Valencia, Spain ¶¶¶Unit of Digestive Disease, Agencia Sanitaria Costa del Sol, Marbella, Málaga ||||||Department Digestive System, Sant'Orsola-Malpighi Hospital, Bologna, Italy ****Department of Surgery, Hospital Universitario de Guadalajara, Guadalajara, Spain ††††Department of HPB Surgery and Liver Transplantation, Hospital Carlos Haya, Malaga, Spain ‡‡‡‡Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain §§§§Department of Digestive Surgery- Division of HBP Surgery, Hospital Universitario Donostia, San Sebastián, Spain ¶¶¶¶Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, CiberEHD, Barcelona, Spain ||||||||Department of Gastroenterology, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain.

Objective: To provide evidence-based recommendations for the management of exocrine pancreatic insufficiency (EPI) after pancreatic surgery.

Background: EPI is a common complication after pancreatic surgery but there is certain confusion about its frequency, optimal methods of diagnosis, and when and how to treat these patients.

Methods: Eighteen multidisciplinary reviewers performed a systematic review on 10 predefined questions following the GRADE methodology. Six external expert referees reviewed the retrieved information. Members from Spanish Association of Pancreatology were invited to suggest modifications and voted for the quantification of agreement.

Results: These guidelines analyze the definition of EPI after pancreatic surgery, (one question), its frequency after specific techniques and underlying disease (four questions), its clinical consequences (one question), diagnosis (one question), when and how to treat postsurgical EPI (two questions) and its impact on the quality of life (one question). Eleven statements answering those 10 questions were provided: one (9.1%) was rated as a strong recommendation according to GRADE, three (27.3%) as moderate and seven (63.6%) as weak. All statements had strong agreement.

Conclusions: EPI is a frequent but under-recognized complication of pancreatic surgery. These guidelines provide evidence-based recommendations for the definition, diagnosis, and management of EPI after pancreatic surgery.
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http://dx.doi.org/10.1097/SLA.0000000000001732DOI Listing
December 2016

Autoimmune pancreatitis: a surgical dilemma.

Cir Esp 2014 Dec 24;92(10):645-53. Epub 2014 Jul 24.

Unidad de Cirugía Hepato-Bilio-Pancreática, Servicio de Cirugía General y Digestiva, Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic de Barcelona, Barcelona, España.

Autoimmune pancreatitis (AIP) is defined as a particular form of pancreatitis that often manifests as obstructive jaundice associated with a pancreatic mass or an obstructive bile duct lesion, and that has an excellent response to corticosteroid treatment. The prevalence of AIP worldwide is unknown, and it is considered as a rare entity. The clinical and radiological presentation of AIP can mimic bilio-pancreatic cancer, presenting difficulties for diagnosis and obliging the surgeon to balance decision-making between the potential risk presented by the misdiagnosis of a deadly disease against the desire to avoid unnecessary major surgery for a disease that responds effectively to corticosteroid treatment. In this review we detail the current and critical points for the diagnosis, classification and treatment for AIP, with a special emphasis on surgical series and the methods to differentiate between this pathology and bilio-pancreatic cancer.
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http://dx.doi.org/10.1016/j.ciresp.2014.01.013DOI Listing
December 2014

Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: report of two cases.

Pancreatology 2014 Jul-Aug;14(4):316-8. Epub 2014 May 9.

Exocrine Pancreatic Diseases Research Group, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBEREHD, Barcelona, Spain. Electronic address:

Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation.
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http://dx.doi.org/10.1016/j.pan.2014.04.032DOI Listing
April 2015

[Recommendations of the Spanish Pancreatic Club on the diagnosis and treatment of chronic pancreatitis: part 2 (treatment)].

Gastroenterol Hepatol 2013 Jun-Jul;36(6):422-36. Epub 2013 Apr 30.

Unidad Pancreática, Hospital General Universitario de Alicante, Alicante, España.

Chronic pancreatitis (CP) is a complex disease with a wide spectrum of clinical manifestations ranging from asymptomatic disease to disabling forms or serious complications. The management of CP frequently differs among geographical areas and even among centers. These differences are due to the scarcity of high-quality studies and clinical practice guidelines that focus on the diagnosis and treatment of this disease. The aim of the Spanish Pancreatic Club was to create evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. These experts were selected on the basis of their clinical and research experience in CP. A list of questions was drawn up and each question was then reviewed by two panelists. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. Levels of evidence were based on the classification of the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus process, recommendations were established for the management of pain, pseudocysts, biliary and duodenal stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.
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http://dx.doi.org/10.1016/j.gastrohep.2012.12.003DOI Listing
April 2014

[Recommendations of the Spanish Pancreatic Club on the diagnosis and treatment of chronic pancreatitis: part 1 (diagnosis)].

Gastroenterol Hepatol 2013 May 6;36(5):326-39. Epub 2013 Apr 6.

Unidad Pancreática, Hospital General Universitario de Alicante, Alicante, España.

Chronic pancreatitis (CP) is a relatively uncommon, complex and highly heterogeneous disease. There is no clear pattern applicable to the initial stages of CP, which hampers its early diagnosis. Some of the complications of CP, especially chronic pain, can be difficult to manage. There is wide variation in the diagnosis and treatment of CP and its complications among centers and health professionals. The Spanish Pancreatic Club has developed a consensus document on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts in this disease. A list of questions was drawn up. Each question was reviewed by two experts. These questions were then used to produce a draft, which was discussed in a face-to-face meeting with all the participants. The first part of the consensus document focusses on the diagnosis of CP and its complications.
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http://dx.doi.org/10.1016/j.gastrohep.2012.12.004DOI Listing
May 2013

Guidelines for the use and interpretation of assays for monitoring autophagy.

Autophagy 2012 Apr;8(4):445-544

Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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http://dx.doi.org/10.4161/auto.19496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404883PMC
April 2012

Expanding roles of ZEB factors in tumorigenesis and tumor progression.

Am J Cancer Res 2011 20;1(7):897-912. Epub 2011 Aug 20.

The ZEB family of transcription factors regulates key factors during embryonic development and cell differentiation but their role in cancer biology has only more recently begun to be recognized. Early evidence showed that ZEB proteins induce an epithelial-to-mesenchymal transition linking their expression with increased aggressiveness and metastasis in mice models and a wide range of primary human carcinomas. Reports over the last few years have found that ZEB proteins also play critical roles in the maintenance of cancer cell stemness, control of replicative senescence, tumor angiogenesis, overcoming of oncogenic addiction and resistance to chemotherapy. These expanding roles in tumorigenesis and tumor progression set ZEB proteins as potential diagnostic, prognostic and therapeutic targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196287PMC
November 2011

[In patients with abdominal pain and a history of high alcohol intake, which tests allow the presence of chronic pancreatitis to be confirmed or excluded?].

Authors:
Eva C Vaquero

Gastroenterol Hepatol 2009 Apr 22;32(4):315-7. Epub 2009 Apr 22.

Servei de Gastroenterologia, Institut Clínic de Malaties Digestives i Metabòliques, Hospital Clínic, Barcelona, España.

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http://dx.doi.org/10.1016/j.gastrohep.2008.10.007DOI Listing
April 2009

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes.

Autophagy 2008 Feb 21;4(2):151-75. Epub 2007 Nov 21.

Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654259PMC
http://dx.doi.org/10.4161/auto.5338DOI Listing
February 2008

Tocotrienols: balancing the mitochondrial crosstalk between apoptosis and autophagy.

Autophagy 2007 Nov-Dec;3(6):652-4

Department of Gastroenterology, Hospital Clinic (CIBEREHD), Barcelona, Spain.

Tocotrienols are a group of natural vitamin E compounds with patent antitumoral effects, mostly based on their ability to induce apoptosis in cancer cells. In activated pancreatic stellate cells (PSCs) we have determined that tocotrienols elicit a dramatic mitochondrial destabilization followed by initiation of non-necrotic forms of programmed cell death, namely apoptosis and autophagy. PSCs are the main cell type involved in the generation of pancreatic fibrosis, and their removal is critical to limit the fibrogenic process. Noteworthy, tocotrienol death-promoting actions are exclusively directed to activated PSCs, but not to their quiescent counterparts nor to terminally differentiated acinar cells. Here, we hypothesize that the transformed phenotype of PSCs may include "activated" mitochondria, which can be used by tocotrienols to trigger autophagic and apoptotic signaling. We propose that mitochondria are the cornerstone of cell sensitivity to tocotrienols, and suggest possible mechanisms, that may be interconnected, on how tocotrienols may govern mitochondrial death pathways.
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http://dx.doi.org/10.4161/auto.5088DOI Listing
January 2008

Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway.

Gastroenterology 2007 Jun 12;132(7):2518-32. Epub 2007 Apr 12.

Digestive System Research Unit, Institut de Recerca Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background & Aims: Selective removal of activated pancreatic stellate cells (PSCs) through induction of their own programmed death is a goal of therapeutic interest in patients with chronic pancreatitis. Here, we investigated the effects of tocotrienols on PSC death outcomes.

Methods: Activated and quiescent PSCs and acinar cells from rat pancreas were treated with vitamin E derivatives alpha-tocopherol; individual alpha-, beta-, gamma-, and delta-tocotrienols; and a tocotrienol rich fraction (TRF) from palm oil.

Results: TRF, but not alpha-tocopherol, reduced viability of activated PSC by setting up a full death program, independent of cell cycle regulation. Activated PSCs died both through apoptosis, as indicated by increased DNA fragmentation and caspase activation, and through autophagy, as denoted by the formation of autophagic vacuoles and LC3-II accumulation. In contrast to alpha-tocopherol, TRF caused an intense and sustained mitochondrial membrane depolarization and extensive cytochrome c release. Caspase inhibition with zVAD-fmk suppressed TRF-induced apoptosis but enhanced autophagy. However, mitochondrial permeability transition pore blockade with cyclosporin A completely abolished the deadly effects of TRF. beta-, gamma-, and delta-tocotrienol, but not alpha-tocotrienol nor alpha-tocopherol, reproduced TRF actions on activated PSCs. TRF death induction was restricted to activated PSCs because it did not cause apoptosis either in quiescent PSCs or in acinar cells.

Conclusions: Tocotrienols selectively trigger activated pancreatic stellate cell death by targeting the mitochondrial permeability transition pore. Our findings unveil a novel potential for tocotrienols to ameliorate the fibrogenesis associated with chronic pancreatitis.
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http://dx.doi.org/10.1053/j.gastro.2007.03.107DOI Listing
June 2007

Extracellular matrix stimulates reactive oxygen species production and increases pancreatic cancer cell survival through 5-lipoxygenase and NADPH oxidase.

Am J Physiol Gastrointest Liver Physiol 2005 Dec 21;289(6):G1137-47. Epub 2005 Jul 21.

Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles, CA 90073, USA.

The extracellular matrix (ECM) facilitates pancreatic cancer cells survival, which is of central importance for pancreatic adenocarcinoma that is highly fibrotic. Here, we show that reactive oxygen species (ROS) mediate the prosurvival effect of ECM in human pancreatic cancer cells. Fibronectin and laminin stimulated ROS production and NADPH oxidase activation in pancreatic cancer cells. Both pharmacological and molecular approaches show that fibronectin stimulated ROS production through activation of NADPH oxidase and NADPH oxidase-independent pathways and that 5-lipoxygenase (5-LO) mediates both these pathways. Analyses of the mechanisms of ROS production by ECM proteins and growth factors indicate that activation of NADPH oxidase (Nox4) is a common mechanism employed both by ECM proteins and growth factors to increase ROS in pancreatic cancer cells. We also found that Nox4 is present in human pancreatic adenocarcinoma tissues and that these tissues display membrane NADPH oxidase activity. ECM proteins and growth factors activate NADPH oxidase through different mechanisms; in contrast to ECM proteins, growth factors activate NADPH oxidase through 5-LO-independent mechanisms. Inhibition of 5-LO or NADPH oxidase with pharmacological inhibitors of these enzymes and with Nox4 or 5-LO antisense oligonucleotides markedly stimulated apoptosis in cancer cells cultured on fibronectin. Our results indicate that ROS generation via 5-LO and downstream NADPH oxidase mediates the prosurvival effect of ECM in pancreatic cancer cells. These mechanisms may play an important role in pancreatic cancer resistance to treatments and thus represent novel therapeutic targets.
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http://dx.doi.org/10.1152/ajpgi.00197.2005DOI Listing
December 2005

Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in pancreatic cancer cells.

J Biol Chem 2004 Aug 23;279(33):34643-54. Epub 2004 May 23.

Departments of Medicine, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.

One reason why pancreatic cancer is so aggressive and unresponsive to treatments is its resistance to apoptosis. We report here that reactive oxygen species (ROS) are a prosurvival, antiapoptotic factor in pancreatic cancer cells. Human pancreatic adenocarcinoma MIA PaCa-2 and PANC-1 cells generated ROS, which was stimulated by growth factors (serum, insulin-like growth factor I, or fibroblast growth factor-2). Growth factors also stimulated membrane NAD(P)H oxidase activity in these cells. Both intracellular ROS and NAD(P)H oxidase activity were inhibited by antioxidants tiron and N-acetylcysteine and the inhibitor of flavoprotein-dependent oxidases, diphenylene iodonium, but not by inhibitors of various other ROS-generating enzymes. Using Rho(0) cells deficient in mitochondrial DNA, we showed that a nonmitochondrial NAD(P)H oxidase is a major source of growth factor-induced ROS in pancreatic cancer cells. Among proteins that have been implicated in NAD(P)H oxidase activity, MIA PaCa-2 and PANC-1 cells do not express the phagocytic gp91(phox) subunit but express several nonphagocytic oxidase (NOX) isoforms. Transfection with Nox4 antisense oligonucleotide inhibited NAD(P)H oxidase activity and ROS production in MIA PaCa-2 and PANC-1 cells. Inhibiting ROS with the antioxidants, Nox4 antisense, or MnSOD overexpression all stimulated apoptosis in pancreatic cancer cells as measured by internucleosomal DNA fragmentation, phosphatidylserine externalization, cytochrome c release, and effector caspase activation. The results show that growth factor-induced ROS produced by NAD(P)H oxidase (probably Nox4) protect pancreatic cancer cells from apoptosis. This mechanism may play an important role in pancreatic cancer resistance to treatment and thus represent a novel therapeutic target.
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http://dx.doi.org/10.1074/jbc.M400078200DOI Listing
August 2004

Extracellular matrix proteins protect pancreatic cancer cells from death via mitochondrial and nonmitochondrial pathways.

Gastroenterology 2003 Oct;125(4):1188-202

Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073, USA.

Background And Aims: Pancreatic cancer is a very aggressive malignancy. Normal cells die through apoptosis when detached from extracellular matrix (ECM), but the role of ECM in cancer cell survival is poorly understood. Here, we determined the effects of ECM proteins on death responses and underlying signaling pathways in human pancreatic cancer cells.

Methods: We measured apoptosis and necrosis, caspase activation, and mitochondrial dysfunction in MIA PaCa-2 and PANC-1 pancreatic carcinoma cells both detached and attached to ECM proteins.

Results: Detachment of pancreatic cancer cells from ECM did not induce classic apoptosis, as it does in normal cells, but induced necrosis and apoptosis associated with secondary necrosis. It caused a pronounced mitochondrial depolarization and release of cytochrome c and Smac/DIABLO. However, as different from normal cells, cytochrome c release did not result in downstream caspase activation. Executioner caspases were activated in detached pancreatic cancer cells independent of cytochrome c. Laminin and fibronectin, but not collagen I, markedly increased pancreatic cancer cell survival by inhibiting both mitochondrial dysfunction (leading to inhibition of necrosis) and caspase activity (leading to decreased apoptotic DNA fragmentation).

Conclusions: ECM proteins greatly protect pancreatic cancer cells from death by mechanisms different from those operating in normal cells. The results suggest ECM proteins and their receptors as potential targets for treatment of pancreatic cancer.
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http://dx.doi.org/10.1016/s0016-5085(03)01203-4DOI Listing
October 2003

Curcumin ameliorates ethanol and nonethanol experimental pancreatitis.

Am J Physiol Gastrointest Liver Physiol 2003 Jan;284(1):G85-95

Research Center for Alcoholic Liver and Pancreatic Diseases and Department of Medicine, University of California, Los Angeles and Veterans Affairs Greater Los Angeles Healthcare System, 90073, USA.

Treatments for pancreatitis are limited. Activation of transcription factor NF-kappaB, a key regulator of inflammatory molecule expression, is an early event in experimental pancreatitis and correlates with the inflammatory response. We report here that curcumin, a natural phytochemical known to inhibit NF-kappaB and activator protein (AP)-1, another important proinflammatory transcription factor, ameliorates pancreatitis in two rat models. In both cerulein pancreatitis and pancreatitis induced by a combination of ethanol diet and low-dose CCK, curcumin improved the severity of the disease as measured by a number of parameters (histology, serum amylase, pancreatic trypsin, and neutrophil infiltration). Curcumin markedly inhibited NF-kappaB and AP-1 activation, assessed by DNA binding and degradation of inhibitory IkappaB proteins, and the induction of mRNAs for cytokines IL-6 and TNF-alpha, the chemokine KC, and inducible nitric oxide synthase in pancreas. Curcumin also blocked CCK-induced NF-kappaB and AP-1 activation in isolated pancreatic acini. Our findings indicate that blocking key signals of the inflammatory response ameliorates pancreatitis in both ethanol and nonethanol models. They suggest that curcumin, which is currently in clinical trials for cancer prevention, may be useful for treatment of pancreatitis.
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http://dx.doi.org/10.1152/ajpgi.00138.2002DOI Listing
January 2003
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