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Molecular epidemiology and putative origin of hepatitis C virus in random volunteers from Argentina

World Journal of Gastroenterology 2013年第35期19卷 5813-5827页

作者： Noemí del Pino José Raúl Oubia Francisco Rodríguez-Frías Juan Ignacio Esteban maría Buti Teresa Otero Josep Gregori Damir García-Cehic Silvia Camos maría cubero Rosario Casillas Jaume Guàrdia Rafael Esteban Josep Quer Apunlab Laboratories Institute of Medical Microbiology and Parasitology (IMPAM) UBA-CONICET Department of MicrobiologyParasitology and Immunology Faculty of Medicine University of Buenos Aires CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos Ⅲ and Biochemistry Department Hospital Universitari Vall d’Hebrón (HUVH) CIBERehd del Instituto de Salud Carlos Ⅲ Autonomous University of Barcelona and Liver Unit Internal Medicine Lab. Malalties Hepatiques Vall d’Hebron Institut de Recerca (VHIR) Hospital Universitari Vall d’Hebrón (HUVH) Unitat de Diagnostic Molecular HUVH Liver Unit Internal Medicine Lab Malalties Hepatiques VHIR-HUVH Roche Diagnostics SL CIBERehd del Instituto de Salud Carlos Ⅲ Liver Unit Internal Medicine Lab MalaltiesHepatiques VHIR-HUVH Liver Unit and Biochemistry Department HUVH

AIM:To study the subtype prevalence and the phylogenetic relatedness of hepatitis C virus(HCV)sequences obtained from the Argentine general population,a large cohort of individuals was ***:Healthy Argentinian volunteers(n=6251)from 12 provinces representing all geographical regions of the country were *** parents or legal guardians of individuals younger than 18 years provided informed written consent for *** corresponding written permission from all municipal authorities was obtained from each city or town where subjects were to be *** RNA reverse transcription-polymerase chain reaction products were sequenced and phylogenetically *** 5’untranslated region(5’UTR)was used for RNA detection and initial genotype *** NS5B polymerase region,encompassing nt 8262-8610,was used for ***:An unexpectedly low prevalence of HCV infection in the general population(0.32%)was *** data contrasted with previous studies that reported rates ranging from 1.5%to 2.5%,mainly performed in selected populations of blood donors or vulnerable *** latter values are in keeping with the prevalence reported by the 2007 Argentinian HCV Consensus(approximately 2%).HCV subtypes weredistributed as follows:1a(25%),1b(25%),2c(25%),3a(5%),and 2j(5%).Two isolates ascribed either to genotype 1(5%)or to genotype 3(5%)by 5’UTR phylogenetic analysis could not be *** 1a sequences comprised a highly homogeneous population and clustered with United States ***1b sequences represented a heterogeneous population,suggesting that this genotype might have been introduced from different *** subtype 2c sequences clustered close to the 2c reported from Italy and Southern ***:HCV has a low prevalence of 0.32%in the studied general population of *** pattern of HCV introduction and transmission in Argentina appears to be a consequence of multiple events and different

关键词： Hepatitis C virus NS5B subtyping Molecular epidemiology Hepatitis C virus Argentina Hepatitis C virus 5’ untranslated region

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Data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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Neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-cubero Joaquín Fernández-Irigoyen Enrique Santamaría Clinical Neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

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Specific CD8^+ T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis

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World Journal of Gastroenterology 2016年第28期22卷 6469-6483页

作者： Elia Moreno-cubero Juan-Ramón Larrubia Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Biology of Systems University of Alcalá Department of Medicine and Medical Specialties University of Alcalá

Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8+ T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8+ T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.

关键词： Hepatocellular carcinoma CD8+ T cells Immune checkpoint modulation Chronic viral hepatitis Cytotoxic T-lymphocyte antigen-4 Programmed cell death protein-1

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Extracellular vesicles in liver disease and beyond

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World Journal of Gastroenterology 2018年第40期24卷 4519-4526页

作者： Laura Morán Francisco Javier cubero Department of Immunology Ophthalmology and ORLComplutense University School of MedicineMadrid 28040Spain 12 de Octubre Health Research Institute(imas12) Madrid 28041Spain

Extracellular vesicles(EVs) are membrane-derived vesicles which can be released by different cell types, including hepatocytes, hepatic stellate cells and immune cells in normal and pathological conditions. EVs carry lipids, proteins, coding and non-coding RNAs and mitochondrial DNA causing modifications on the recipient cells. These vesicles are considered potential biomarkers and therapeutic agents for human diagnostic and prognostic due to their function as intercellular mediators of cell-cell communication within the liver and between other organs. However, the development and optimization of methods for EVs isolation is required to characterize their biological functions as well as their potential as a treatment option in the clinic. Nevertheless, many questions remain unanswered related to the function of EVs under physiological and pathological conditions. In the current editorial, the results obtained in different studies that investigated the role of intrahepatic EVs during liver diseases, including drug-induced liver injury, non-alcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic liver disease and hepatocellular carcinoma and extrahepatic EVs in remote organs during pathological events such as pulmonary disease, cardiovascular diseases, neurodegenerative disorders e.g., Alzheimer's disease, Parkinson's disease and multiple sclerosis as well as in immunopathological processes, are discussed. Although much light needs to be shed on the mechanisms of EVs, these membranederived vesicles represent both a novel promising diagnostic, and a therapeutic tool for clinical use that we emphasize in the current editorial.

关键词： Extracellular vesicles microRNA Hepatocytes Drug-induced liver injury Alcoholic liver disease Nonalcoholic fatty liver disease Non-alcoholic steatohepatitis Hepatocellular carcinoma

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Efficacy and safety of XEN 45 gel stent alone or in combination with phacoemulsification in advanced open angle glaucoma patients: 1-year retrospective study

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International Journal of Ophthalmology(English edition) 2020年第8期13卷 1250-1256页

作者： Teresa Laborda-Guirao Juan M cubero-Parra Antonio Hidalgo-Torres Department of Glaucoma Hospital La ArruzafaCordoba 14012Spain

AIM:To assess the effectiveness of the XEN 45 gel stent,either alone or combined with cataract surgery,in advanced stage open angle glaucoma(OAG)***:Retrospective and single-center study conducted on consecutive OAG patients who underwent a XEN 45 gel stent implantation surgery,between July 2017 and September *** primary efficacy end-point was the mean intraocular pressure(IOP)reduction at the end of the follow-up *** was defined as an IOP reduction of at least 20%and an IOP value≤18 mm Hg without(complete)or with(qualified)hypotensive ***:Seventy-four patients(80 eyes)were included in the *** the overall study sample,XEN implant significantly reduced IOP from 21.0(19.8 to 22.1)mm Hg at baseline to 9.3(8.2 to 10.4),10.7(9.6 to 11.9),13.4(12.2 to 14.7),14.5(13.6 to 15.4),14.7(13.8 to 15.6),and 14.7(13.9 to 15.4)mm Hg at 1 d,1 wk,1,3,6,and 12 mo of follow-up,respectively(P<0.0001 each).In the overall study population,at the end of the study the mean IOP reduction was 27.4%(23.3%to 31.5%).Adjusted IOP reduction was similar in XEN and XEN+phacoemulsification groups[30.0(23.4 to 36.4)mm Hg vs 24.8(18.4 to 31.2)mm Hg,respectively,P=0.2939].At the last follow-up visit,52(65.0%)eyes were considered success,29(36.3%)eyes as complete success and 23(28.7%)as qualified *** number of hypotensive medications was significantly reduced from 2.8(2.7 to 3.0)at baseline to 1.1(0.8 to 1.3),P<***-Meier survival analysis did not find any difference in the success rate between XEN and XEN+PHACO,mean hazard ratio 0.56,95%CI 0.26 to 1.23;P=*** was performed in 7(8.8%)eyes at months 1(n=3);3(n=2);4(n=1)and 11(n=1).Eleven(13.8%)eyes presented adverse ***:XEN implant,either alone or in combination with phacoemulsification,significantly reduced the IOP and the number of hypotensive medications in patients with OAG in advanced stage.

关键词： open angle glaucoma advanced stage XEN implant intraocular pressure minimally-invasive glaucoma surgery

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Commercialization of disruptive innovations:Literature review and proposal for a process framework

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International Journal of Innovation Studies 2021年第3期5卷 127-144页

作者： Javier Nieto cubero Saheed Adebayo Gbadegeshin Carolina Consolación Design Processes Research Group EINACentre Universitari de Disseny I ArtUniversitat Autonoma De Barcelona08017BarcelonaSpain Department of Management and Entrepreneurship Turku School of EconomicsUniversity of Turku20014TurkuFinland Department of Management ETSEBCUniversitat Politecnica De Catalunya08034BarcelonaSpain

The challenges of disruptive innovations have gained significant attention from both academics and practitioners,commercialization being one of the most critical *** the same time,however,it is the less studied area of disruptive ***,this article examined scholarly papers on the commercialization of disruptive innovations through a multidisciplinary systematic literature *** resulted in the analysis of 64 high-quality peer-reviewed academic *** analysis highlighted the commercialization models and main constructs that are affecting the commercialization process:market orientation,market learning,user’s involvement,market configuration,adoption networks and stakeholders,and innovation *** study evidences how commercialization has evolved from a later stage in innovation to influence even the early phases of innovation,characterized in turn by exploration,learning and ecosystem creation ***,the analysis led to a proposition that established an integrated commercialization model for high uncertainty *** model has three phases:1)Concept/value proposition validation,2)Business model validation&market creation,and 3)Creating sales in the majority ***,the article contributes to a better understanding of commercialization processes in high uncertainty innovations,bridging also the academic-practitioner divide.

关键词： Disruptive innovation Radical innovation Emerging technologies Commercialization process market creation Scale-up Lean start-up

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Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control

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World Journal of Gastroenterology 2015年第12期21卷 3480-3491页

作者： Juan-Ramón Larrubia Elia Moreno-cubero Joaquín Miquel Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá Department of Medicine and Medical Specialties University of Alcalá Department of Biology of Systems University of Alcalá

Hepatitis C virus(HCV)-specific cytotoxic T cell(CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response(SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in na?ve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatmentinduced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferonfree regimes, based on direct-acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.

关键词： Hepatitis C virus Chronic hepatitis Hepatitis C vi

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Dissecting the molecular pathophysiology of drug-induced liver injury

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World Journal of Gastroenterology 2018年第13期24卷 1373-1385页

作者： Hui Ye Leonard J Nelson Manuel Gómez del Moral Eduardo martínez-Naves Francisco Javier cubero Department of Immunology Ophtalmology and ORLComplutense University School of MedicineMadrid 28040Spain 12 de Octubre Health Research Institute(imas12) Madrid 28041Spain Institute for BioEngineering(Human Liver Tissue Engineering Faraday BuildingThe University of EdinburghThe King BuildingsMayfield RoadEdinburgh EH9 3 JLScotlandUnited Kingdom Department of Cell Biology Complutense University School of MedicineMadrid 28040Spain

Drug-induced liver injury(DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways.

关键词： signaling pathways acetaminophen Drug-induced liver injury cell death reactive oxygen species

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Adaptive immune response during hepatitis C virus infection

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World Journal of Gastroenterology 2014年第13期20卷 3418-3430页

作者： Juan Ramon Larrubia Elia Moreno-cubero Megha Uttam Lokhande Silvia Garcia-Garzon Alicia Lazaro Joaquin Miquel Cristian Perna Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcalaE-19002 GuadalajaraSpain Department of Medicine and Medical Specialities School of MedicineUniversity of AlcalaE-28801 Alcala de HenaresSpain

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular *** is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune *** damage and disease progression during HCV infection are driven by both viral and host ***,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic *** is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and *** impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic *** this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

关键词： Hepatitis C, Adaptive immune response, Hepatitis C virus-specific cytotoxic T cells, Hepatitis C virus-specific T helper cells, T regs, Hepatitis C virus escape mutations, Anergy, Apoptosis, Chemotaxis

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Clinical scenarios for the use of S100β as a marker of hepatic encephalopathy

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World Journal of Gastroenterology 2016年第17期22卷 4397-4402页

作者： Andrés Duarte-Rojo Astrid Ruiz-margáin Ricardo U Macias-Rodriguez Francisco Javier cubero José Estradas-Trujillo Rosa Ma Munoz-Fuentes Aldo Torre University of Arkansas for Medical Sciences Little Rock AR 72205 United States Department of Gastroenterology Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Mexico City 14000 Mexico Department of Internal Medicine III University Hospital RWTH Aachen 52074 Aachen Germany Department of Immunology Complutense University School of Medicine 28040 Madrid Spain

AIM: To evaluate the association between serum concentrations of S100β in patients with cirrhosis and the presence of low grade hepatic encephalopathy (HE).METHODS: This was a cross-sectional study. The population was categorized into four groups healthy subjects, cirrhosis without HE, cirrhosis with covert hepatic encephalopathy (CHE) and cirrhosis with overt HE. Kruskal-Wallis, Mann Whitney’s U with Bonferroni adjustment Spearman correlations and area under the ROC were used as ***: A total of 61 subjects were included, 46 cirrhotic patients and 15 healthy volunteers. S100β values were different among all groups, and differences remained significant between groups 1 and 2 (P 0.13 ng/mL as the best cutoff value of S100β for the diagnosis of HE (sensitivity 83.3%, specificity 63.6%).CONCLUSION: Serum concentrations of S100β are higher in patients with cirrhosis than in healthy volunteers, and are further increased in the presence of hepatic encephalopathy. The results suggest that serum biomarkers such as S100β could help in the correct characterization of incipient stages of HE.

关键词： Hepatic encephalopathy S100β protein Astrocyte Psychometric hepatic encephalopathy score Critical flicker frequency

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