Publications by authors named "Xavier Molero"

36 Publications

Chronic pancreatitis for the clinician. Part 2: Treatment and follow-up. Interdisciplinary Position Paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees.

Gastroenterol Hepatol 2021 Jun 23. Epub 2021 Jun 23.

CIBERehd, Instituto de Salud Carlos III, Madrid, España; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Servei de Gastroenterologia, ICMDiM, Hospital Clínic, Barcelona, España; Gastrointestinal and Pancreatic Oncology Research Group, Hospital Clínic, Barcelona, España.

Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.
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http://dx.doi.org/10.1016/j.gastrohep.2021.05.016DOI Listing
June 2021

Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees.

Gastroenterol Hepatol 2021 Jun 19. Epub 2021 Jun 19.

CIBERehd, Instituto de Salud Carlos III, Madrid, España; Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, España; Servei de Gastroenterologia, ICMDiM, Hospital Clínic, Barcelona, España; Gastrointestinal and Pancreatic Oncology Research Group, Hospital Clínic , Barcelona, España.

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http://dx.doi.org/10.1016/j.gastrohep.2021.05.017DOI Listing
June 2021

Acquired hepatocerebral degeneration in a metastatic neuroendocrine tumor long-term survivor - an update on neuroendocrine neoplasm's treatment: A case report.

World J Hepatol 2021 May;13(5):611-619

Medical Oncology Department, Vall d'Hebron University Hospital, Vall Hebron Institute of Oncology, Barcelona 08035, Catalunya, Spain.

Background: Metastatic small bowel low-grade neuroendocrine tumors (NETs) have a good prognosis. Surgery is the only curative treatment; however, this may induce advanced liver disease, particularly in long-term survivor patients. Acquired hepatocerebral degeneration or Parkinsonism in cirrhosis is characterized by rapidly progressive extrapyramidal symptoms in patients with advanced liver disease.

Case Summary: A 70-year-old man presented to the emergency department with diminished consciousness and disorientation, and was diagnosed with hepatic encephalopathy. The patient was diagnosed in 1993 with a metastatic small bowel NET, for which he twice underwent hepatic surgery, with metastatic resection in 1993 and a right hepatectomy in 2002 to remove two hepatic metastases. In 2003, the patient started first-line chemotherapy and in 2004 started the first of three consecutive biological treatments, followed by radio-molecular therapy, achieving stable disease for 14 years. Disease progression was identified and he underwent an endoscopic retrograde cholangiopancreatography. However, in 2019 advanced liver disease was identified. We diagnosed the development of acquired hepatocerebral degeneration, an unusual long-term side effect after multiple hepatic procedures.

Conclusion: The importance of regular and ongoing surveillance in long-term NET survivors who undergo hepatic procedures should be integrated into the therapeutic management plan, as some of these negative outcomes could be prevented.
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http://dx.doi.org/10.4254/wjh.v13.i5.611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173341PMC
May 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma.

Int J Cancer 2021 04 15;148(8):2048-2058. Epub 2021 Jan 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.
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http://dx.doi.org/10.1002/ijc.33464DOI Listing
April 2021

Motor dysfunction of the gut in cystic fibrosis.

Neurogastroenterol Motil 2020 09 31;32(9):e13883. Epub 2020 May 31.

Digestive System Research Unit, University Hospital Vall d'Hebron; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain.

Background: Cystic fibrosis (CF) is a multisystem disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Cystic fibrosis transmembrane conductance regulator is extensively expressed in the intestine and has an important role in the regulation of the viscosity and pH of gut secretions. Several studies have reported a delay in small bowel and colonic transit times in patients with CF which have been attributed to the secretory dysfunction. Our aim was to determine whether intestinal contractility is affected in these patients.

Methods: Consecutive patients with CF referred to our institution between 2014 and 2017 (n = 16) were prospectively investigated using automated non-invasive techniques for morpho-functional evaluation of the gut developed in our laboratory. On separate days, intraluminal images of the gut were obtained by capsule endoscopy and external images by abdominal MRI. Analysis of images (endoluminal and external) was performed with original, previously validated programs based on computer vision and machine learning techniques and compared with age- and sex-matched controls.

Key Results: Patients with CF exhibited important reduction in contractile activity and increased retention of static turbid luminal content in the small bowel by endoluminal image analysis. Morpho-volumetric analysis of MRI images found increased ileo-colonic volumes in CF. Significant correlations between abnormalities detected by intraluminal and external imaging techniques were found. The presence and severity of digestive symptoms were not related to abnormal gut function.

Conclusion And Inferences: Impaired transit and pooling of gut contents in patients with CF is associated with impaired intestinal motility.
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http://dx.doi.org/10.1111/nmo.13883DOI Listing
September 2020

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

Gut 2021 02 14;70(2):319-329. Epub 2020 May 14.

National Cancer Registry Ireland, Cork, Ireland.

Objectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).

Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.

Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (OR=1.08, 95% CI: 0.86 to 1.29, OR=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).

Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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http://dx.doi.org/10.1136/gutjnl-2019-319990DOI Listing
February 2021

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

Pancreatology 2020 Jun 8;20(4):579-585. Epub 2020 Apr 8.

Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.

Background: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP.

Methods: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Results: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers.

Conclusions: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.
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http://dx.doi.org/10.1016/j.pan.2020.03.014DOI Listing
June 2020

Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships.

Cancer Epidemiol Biomarkers Prev 2020 05 12;29(5):1009-1018. Epub 2020 Feb 12.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, Sweden.

Background: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study.

Methods: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape.

Results: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely.

Conclusions: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations.

Impact: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1027DOI Listing
May 2020

Antibiotic therapy in acute pancreatitis: From global overuse to evidence based recommendations.

Pancreatology 2019 Jun 19;19(4):488-499. Epub 2019 Apr 19.

First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.

Background: Unwarranted administration of antibiotics in acute pancreatitis presents a global challenge. The clinical reasoning behind the misuse is poorly understood. Our aim was to investigate current clinical practices and develop recommendations that guide clinicians in prescribing antibiotic treatment in acute pancreatitis.

Methods: Four methods were used. 1) Systematic data collection was performed to summarize current evidence; 2) a retrospective questionnaire was developed to understand the current global clinical practice; 3) five years of prospectively collected data were analysed to identify the clinical parameters used by medical teams in the decision making process, and finally; 4) the UpToDate Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was applied to provide evidence based recommendations for healthcare professionals.

Results: The systematic literature search revealed no consensus on the start of AB therapy in patients with no bacterial culture test. Retrospective data collection on 9728 patients from 22 countries indicated a wide range (31-82%) of antibiotic use frequency in AP. Analysis of 56 variables from 962 patients showed that clinicians initiate antibiotic therapy based on increased WBC and/or elevated CRP, lipase and amylase levels. The above mentioned four laboratory parameters showed no association with infection in the early phase of acute pancreatitis. Instead, procalcitonin levels proved to be a better biomarker of early infection. Patients with suspected infection because of fever had no benefit from antibiotic therapy.

Conclusions: The authors formulated four consensus statements to urge reduction of unjustified antibiotic treatment in acute pancreatitis and to use procalcitonin rather than WBC or CRP as biomarkers to guide decision-making.
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http://dx.doi.org/10.1016/j.pan.2019.04.003DOI Listing
June 2019

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches.

Int J Cancer 2019 04 26;144(7):1540-1549. Epub 2018 Oct 26.

Department of Gastroenterology, Hospital del Mar/Parc de Salut Mar, Barcelona, Spain.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.
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http://dx.doi.org/10.1002/ijc.31866DOI Listing
April 2019

Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations.

Clin Immunol 2018 10 29;195:49-58. Epub 2018 Jul 29.

Immunology Division, Hospital Universitari Vall d'Hebron (HUVH), Vall d'Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Catalonia, Spain; Jeffrey Model Foundation Excellence Center, Barcelona, Catalonia, Spain; Area of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Catalonia, Spain. Electronic address:

Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.
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http://dx.doi.org/10.1016/j.clim.2018.07.015DOI Listing
October 2018

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

Oleic acid chlorohydrin, a new early biomarker for the prediction of acute pancreatitis severity in humans.

Ann Intensive Care 2018 Jan 9;8(1). Epub 2018 Jan 9.

Department of Experimental Pathology, IIBB-CSIC, IDIBAPS, c/Rosselló 161, 7°, 08036, Barcelona, Spain.

Background: The early prediction of the severity of acute pancreatitis still represents a challenge for clinicians. Experimental studies have revealed the generation of specific halogenated lipids, in particular oleic acid chlorohydrin, in the early stages of acute pancreatitis. We hypothesized that the levels of circulating oleic acid chlorohydrin might be a useful early prognostic biomarker in acute pancreatitis in humans.

Methods: In a prospective, multicenter cohort study, plasma samples collected within 24 h after presentation in the emergency room from 59 patients with acute pancreatitis and from 9 healthy subjects were assessed for oleic acid chlorohydrin levels.

Results: Pancreatitis was mild in 30 patients, moderately severe in 16 and severe in 13. Oleic acid chlorohydrin levels within 24 h after presentation were significantly higher in patients that later progressed to moderate and severe acute pancreatitis. Using 7.49 nM as the cutoff point, oleic acid chlorohydrin distinguished mild from moderately severe-to-severe pancreatitis with high sensitivity/specificity (96.6/90.0%) and positive/negative predictive values (90.3/96.4%). Using 32.40 nM as the cutoff value sensitivity, specificity, positive and negative predictive values were all 100% for severe acute pancreatitis. It was found to be a better prognostic marker than BISAP score, hematocrit at 48 h, SIRS at admission, persistent SIRS or C-reactive protein at 48 h.

Conclusions: Oleic acid chlorohydrin concentration in plasma is elevated in patients with acute pancreatitis on admission and correlates with a high degree with the final severity of the disease, indicating that it has potential to serve as an early prognostic marker for acute pancreatitis severity.
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http://dx.doi.org/10.1186/s13613-017-0346-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768584PMC
January 2018

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

Gut 2019 01 20;68(1):130-139. Epub 2017 Nov 20.

Analytical Epidemiology and Health Impact Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori (INT), Milan, Italy.

Objective: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation.

Design: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models.

Results: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application.

Conclusion: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.
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http://dx.doi.org/10.1136/gutjnl-2017-314828DOI Listing
January 2019

[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

Reduced risk of pancreatic cancer associated with asthma and nasal allergies.

Gut 2017 02 1;66(2):314-322. Epub 2015 Dec 1.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Objective: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk.

Design: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model.

Results: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk.

Conclusions: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.
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http://dx.doi.org/10.1136/gutjnl-2015-310442DOI Listing
February 2017

[Chronic diarrhoea: Definition, classification and diagnosis].

Gastroenterol Hepatol 2016 Oct 21;39(8):535-59. Epub 2015 Nov 21.

Servicios de Digestivo, Hospital Clínic, Barcelona, España; Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), España.

Chronic diarrhoea is a common presenting symptom in both primary care medicine and in specialized gastroenterology clinics. It is estimated that >5% of the population has chronic diarrhoea and nearly 40% of these patients are older than 60 years. Clinicians often need to select the best diagnostic approach to these patients and choose between the multiple diagnostic tests available. In 2014 the Catalan Society of Gastroenterology formed a working group with the main objective of creating diagnostic algorithms based on clinical practice and to evaluate diagnostic tests and the scientific evidence available for their use. The GRADE system was used to classify scientific evidence and strength of recommendations. The consensus document contains 28 recommendations and 6 diagnostic algorithms. The document also describes criteria for referral from primary to specialized care.
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http://dx.doi.org/10.1016/j.gastrohep.2015.09.018DOI Listing
October 2016

Standards not that standard.

J Biol Eng 2015 1;9:17. Epub 2015 Oct 1.

Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de València, C. Catedràtic José Beltrán 2, 46980 Paterna, Spain.

There is a general assent on the key role of standards in Synthetic Biology. In two consecutive letters to this journal, suggestions on the assembly methods for the Registry of standard biological parts have been described. We fully agree with those authors on the need of a more flexible building strategy and we highlight in the present work two major functional challenges standardization efforts have to deal with: the need of both universal and orthogonal behaviors. We provide experimental data that clearly indicate that such engineering requirements should not be taken for granted in Synthetic Biology.
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http://dx.doi.org/10.1186/s13036-015-0017-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591577PMC
October 2015

[Assessment and treatment of acute pancreatitis. Position document of the Catalan Society of Gastroenterology, Catalan Society of Surgery and Catalan Society of the Pancreas].

Gastroenterol Hepatol 2015 Feb 6;38(2):82-96. Epub 2014 Nov 6.

Servicio de Digestivo, Hospital Universitari Vall d'Hebron, Barcelona, España.

The incidence of acute pancreatitis (AP) is increasing. AP is one of the gastrointestinal diseases that most frequently requires hospital admission in affected individuals. In the last few years, considerable scientific evidence has led to substantial changes in the medical and surgical treatment of this disease. New knowledge of the physiopathology of AP indicates that its severity is influenced by its systemic effects (organ failure), especially if the disease is persistent, and also by local complications (fluid collections or necrosis), especially if these become infected. Treatment should be personalized and depends on the patient's clinical status, the location of the necrosis, and disease stage.
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http://dx.doi.org/10.1016/j.gastrohep.2014.09.006DOI Listing
February 2015

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

Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice.

Gut 2015 Jun 18;64(6):937-47. Epub 2014 Jul 18.

Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

Objective: Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis.

Design: Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1(-/-) mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI.

Results: Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1(-/-) mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1(-/-) mice. Upon induction of acute pancreatitis, Mnk1(-/-) mice show impaired eIF4E phosphorylation, activation of c-Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo.

Conclusions: Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis.
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http://dx.doi.org/10.1136/gutjnl-2013-306068DOI Listing
June 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404883PMC
http://dx.doi.org/10.4161/auto.19496DOI Listing
April 2012

Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis.

Gut 2012 Aug 23;61(8):1187-96. Epub 2011 Sep 23.

Grup de Recerca en Patologia Pancreàtica Exocrina, Institut de Recerca Hospital Universitari Vall d'Hebron, Pg Vall d'Hebron 119-129, Barcelona 08035, Spain.

Objectives: During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis.

Design: Wild-type and genetically modified mice (Hnf1α(-/-) and Ptf1a(+/-)) were used. After caerulein or L-arginine induced pancreatitis, blood or pancreata were processed for enzymatic assays, ELISA, histology, immunohistochemistry, western blotting and quantitative reverse transcriptase-PCR. Nr5a2 promoter reporter and chromatin immunoprecipitation assays for Hnf1α were also performed.

Results: After caerulein pancreatic injury, expression of acinar and endocrine genes rapidly decreased, but eventually recovered, depicting distinct cell-type-specific patterns. Pdx1 and Hnf1α mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1α protein levels were also reduced and recovered gradually. These changes were associated with transient impairment of exocrine and endocrine function, including abnormal glucose tolerance. On l-arginine pancreatitis, changes in Ptf1a, Pdx1 and Hnf1α gene and protein expression were recapitulated. Reduced Hnf1α and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1α(-/-) and Ptf1a(+/-) mice. Moreover, Hnf1α(-/-) mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1α(-/-) mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1α as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1α binds to, and regulates, the promoter of Nr5a2, coding an orphan nuclear receptor that regulates acinar gene expression.

Conclusions: Dynamic changes in gene expression occur on pancreatitis induction, determining altered exocrine and endocrine function. This analysis uncovers roles for Hnf1α in the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of Nr5a2.
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http://dx.doi.org/10.1136/gutjnl-2011-300360DOI Listing
August 2012

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis.

Am J Physiol Gastrointest Liver Physiol 2011 Nov 18;301(5):G846-55. Epub 2011 Aug 18.

Grup de Recerca en Patologia Pancreàtica Exocrina, Hospital Universitari Vall d'Hebron, Institut de Recerca, Universitat Autònoma de Barcelona, CIBER-EHD, Barcelona, Spain.

Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chronic-like pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, α-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-β1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-β1 (185 ± 40 vs. 15 ± 2 ng/ml; P <0.01) that was blunted by TRF (53 ± 19; P < 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. α-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 ± 0.3% vs. 0.2 ± 0.2%), collagen network complexity (fractal dimension 1.52 ± 0.03 vs. 1.42 ± 0.01; P < 0.001), and inhomogeneity (lacunarity 0.63 ± 0.03 vs. 0.40 ± 0.02; P < 0.001), which were all reduced by TRF (1.3 ± 0.4%, 1.43 ± 0.02%, and 0.51 ± 0.03%, respectively; P < 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r = 0.88) and both parameters with pancreatic weight (r = -0.91 and -0.79, respectively). TRF administered only before pancreatitis best, but not fully, recapitulated the beneficial effects of TRF. Tocotrienols improve quantitative measures of chronic pancreatic damage. They may be of benefit in human chronic pancreatitis.
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http://dx.doi.org/10.1152/ajpgi.00485.2010DOI Listing
November 2011

The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma.

J Pathol 2009 Oct;219(2):205-13

Institut Municipal d'Investigació Mèdica, Hospital del Mar, Barcelona, Spain.

Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) are associated with major changes in cell differentiation. These changes may be at the basis of the increased risk for PDAC among patients with chronic pancreatitis. Polycomb proteins are epigenetic silencers expressed in adult stem cells; up-regulation of Polycomb proteins has been reported to occur in a variety of solid tumours such as colon and breast cancer. We hypothesized that Polycomb might play a role in preneoplastic states in the pancreas and in tumour development/progression. To test these ideas, we determined the expression of PRC1 complex proteins (Bmi1 and Ring1b) during pancreatic development and in pancreatic tissue from mouse models of disease: acute and chronic pancreatic injury, duct ligation, and in K-Ras(G12V) conditional knock-in and caerulein-treated K-Ras(G12V) mice. The study was extended to human pancreatic tissue samples. To obtain mechanistic insights, Bmi1 expression in cells undergoing in vitro exocrine cell metaplasia and the effects of Bmi1 depletion in an acinar cancer cell line were studied. We found that Bmi1 and Ring1B are expressed in pancreatic exocrine precursor cells during early development and in ductal and islet cells-but not acinar cells-in the adult pancreas. Bmi1 expression was induced in acinar cells during acute injury, in acinar-ductal metaplastic lesions, as well as in pancreatic intraepithelial neoplasia (PanIN) and PDAC. In contrast, Ring1B expression was only significantly and persistently up-regulated in high-grade PanINs and in PDAC. Bmi1 knockdown in cultured acinar tumour cells led to changes in the expression of various digestive enzymes. Our results suggest that Bmi1 and Ring1B are modulated in pancreatic diseases and could contribute differently to tumour development.
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http://dx.doi.org/10.1002/path.2585DOI Listing
October 2009
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