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Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C

World Journal of Gastroenterology 2009年第41期15卷 5129-5140页

作者： juan ramón larrubia Selma Benito-Martínez Joaquín Miquel Miryam Calvino Eduardo Sanz-de-Villalobos Trinidad Parra-Cid Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Hepatitis C virus (HCV)-specific CD8+ T cells play an important role in the resolution of HCV infection. nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus. HCV has developed several mechanisms to escape immune control. One of these strategies is the upregulation of negative co-stimulatory molecules such us programmed death-1 (PD-1). This molecule is upregulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8+ T cells are exhausted with impairment of several effector mechanisms, such as: type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand (PD-L1). After this blockade, HCV-specificCD8+ T cells reacquire their functionality. nevertheless, functional restoration depends on PD-1 expression level. High PD-1-expressing intrahepatic HCV-specific CD8+ T cells do not restore their effector abilities after PD-1/PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gC1q receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response against HCV to succeed in clearing the infection.

关键词：共刺激分子程序化死亡丙型肝炎毒性反应慢性细胞

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Role of T cell death in maintaining immune tolerance during persistent viral hepatitis

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World Journal of Gastroenterology 2013年第12期19卷 1877-1889页

作者： juan ramón larrubia Megha Uttam Lokhande Silvia García-Garzón Joaquín Miquel Dolores Subirá Eduardo Sanz-de-Villalobos Translational Hepatology Unit Guadalajara University Hospital University of Alcalá

Virus-specific T cells play an important role in the resolution of hepatic infection. However, during chronic hepatitis infection these cells lack their effector functions and fail to control the virus. Hepatitis B virus and hepatitis C virus have developed several mechanisms to generate immune tolerance. One of these strategies is the depletion of virus-specific T cells by apoptosis. The immunotolerogenic liver has unique property to retain and activate na ve T cell to avoid the over reactivation of immune response against antigens which is exploited by hepatotropic viruses to persist. The deletion of the virus-specific T cells occurs by intrinsic (passive) apoptotic mechanism. The pro-apoptotic molecule Bcl-2 interacting mediator (Bim) has attracted increasing attention as a pivotal involvement in apoptosis, as a regulator of tissue homeostasis and an enhancer for the viral persistence. Here, we reviewed our current knowledge on the evidence showing critical role of Bim in viral-specific T cell death by apoptotic pathways and helps in the immune tolerance.

关键词： T cell death Specific cytotoxic T lymphocytes Hepatitis C virus immune tolerance Apoptosis Bcl-2 interacting mediator Liver tolerance Apoptotic pathways Viral hepatitis

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Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

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World Journal of Hepatology 2020年第10期12卷 754-765页

作者： Julia Peña-Asensio Eduardo Sanz-de-Villalobos Joaquín Miquel juan ramón larrubia Department of Systems Biology Guadalajara University Hospital.University of AlcaláGuadalajara E-19002GuadalajaraSpain Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara E-19002GuadalajaraSpain

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune *** antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even *** exhaustion process is progressive and depends on the infection duration and level of *** high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to *** development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta *** cytokine downregulates tumor necrosis factor receptor(TnFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TnFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion *** with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector *** process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease *** conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

关键词： Hepatitis C virus Tumor necrosis factor receptor-associated factor 1 CD8 Exhaustion Tumor necrosis family receptor superfamily member 9 Chronic hepatitis

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Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

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World Journal of Gastroenterology 2018年第17期24卷 1825-1838页

作者： Elia Moreno-Cubero Robert T Sánchez del Arco Julia Pena-Asensio Eduardo Sanz de Villalobos Joaquín Míquel juan ramón larrubia Translational Hepatology Unit Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Internal Medicine Service Guadalajara University HospitalUniversity of AlcaláGuadalajara 19002Spain Department of Biology of Systems University of AlcaláAlcaláde Henares(Madrid)28805Spain Department of Medicine and Medical Specialties University of AlcaláAlcaláde Henares(Madrid)28805Spain

Chronic hepatitis B(CHB) remains a challenging global health problem, with nearly one million related deaths per year. nucleos(t)ide analogue(nA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus(HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen(HBs Ag), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated nA therapy discontinuation after several years of nA treatment and before HBs Ag loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBs Ag seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure aclose follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host's immune system. Viral parameters that have been described as good predictors of response in HBe Ag(+) cases, have proven useless in HBe Ag(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe nA discontinuation in both groups.

关键词： CD8 Lamivudine nucleos(t)ide analogues Tenofovir Chronic hepatitis B Entecavir hepatitis B virus Treatment cessation

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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 costimulatory 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 Cytotoxi

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Prevalence of hepatocarcinoma-related hepatitis B virus mutants in patients in grey zone of treatment

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World Journal of Gastroenterology 2019年第38期25卷 5883-5896页

作者： Ana Isabel Gil-García Antonio Madejón Irene Francisco-Recuero Ana López-López Emiliana Villafranca Miriam Romero Araceli García Antonio Olveira Rocío Mena juan ramón larrubia Javier García-Samaniego Hepatology Unit Hospital Universitario La PazMadrid 28046Spain Centro de Investigación Biomédica en Red Instituto de Salud Carlos IIIMadrid 28029Spain Instituto de Investigación del Hospital Universitario la Paz Madrid 28046Spain Biochemistry Department Faculty of MedicineUniversidad Autónoma de MadridMadrid 28029Spain Instituto de Genética Médica y Molecular Hospital Universitario La PazMadrid 28046Spain Translational Hepatology Unit Hospital General Universitario de GuadalajaraGuadalajara 19002Castilla-La ManchaSpain

BACKGROUnD Antiviral treatment of patients with chronic hepatitis B(CHB)in the grey zone of treatment comands risk management in order to optimize the health *** this sense,the identification of HBV mutants related with an increased risk of hepatocellular carcinoma(HCC)could be useful to identify subpopulations with potential indication of antiviral *** To analyze the prevalence/persistence of hepatitis B virus(HBV)preS and basal core promoter(BCP)/precore/core variants associated to HCC development in CHB patients in the grey *** Work was designed as a longitudinal retrospective study,including 106 plasma samples from 31 patients with CHB in the grey zone of treatment:Hepatitis B e antigen negative,HBV-DnA levels between 12-20000 IU/mL,normal or discordant transaminase levels during follow up and mild/moderate necroinflammatory activity in liver biopsy or Fibroscan(up to 9.5 kPa).Serum HBVDnA was tested using the Abbott Real Time HBV Assay and the BCP/precore/core and the hepatitis B surface antigen(HBsAg)coding regions were analyzed in positive samples by PCR/bulk-sequencing to identify the HCCrelated HBV *** High-risk HCC related mutants were detected in 24(77%)patients:19(61%)in the BCP/precore/core,and 7(23%)in the HBsAg coding region(2 preS1 and 5 preS2 deletions).The prevalence of preS deletions was genotype-dependent:3/5(60%)patients with preS2 deletions and 1/2 with preS1 deletions were infected with the HBV-E *** HBV-E was the most prevalent in sub-Saharan patients,a correlation between preS deletions and ethnicity was also found:6/8(75%)sub-Saharan vs 1/19(5%)Caucasian patients had preS deletions(P=0.00016).Remarkably,this correlation was maintained in those patients infected with HBV-A,a minor genotype in sub-Saharan patients:2/2 patients infected with HBV-A from West Africa vs 0/6 of Caucasian origin had preS *** HCC related variants were the major strains and persisted over time(up to 48 mo).Pa

关键词： Hepatitis B virus Hepatocellular carcinoma PreS deletions Hepatitis B virus treatment Grey zone

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MicroRnA-630:A promising avenue for alleviating inflammation in diabetic kidney disease

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World Journal of Diabetes 2024年第7期15卷 1398-1403页

作者： Javier Donate-Correa Ainhoa González-Luis Jésica Díaz-Vera juan ramón Hernandez-Fernaud Research Unit University Hospital Nuestra Señora de Candelaria(UHNSC)Santa Cruz de Tenerife 38010Spain Department of Biochemistry MicrobiologyCell Biology and GeneticsInstituto de Tecnologías BiomédicasUniversidad de La LagunaSanta Cruz de Tenerife 38000Spain

Diabetic kidney disease(DKD)is one of the complications of diabetes,affecting millions of people *** relentless progression of this condition can lead to kidney failure,requiring life-altering interventions such as dialysis or *** evidence suggests that immunologic and inflammatory elements play an important role in initiating and perpetuating the damage inflicted on renal tissues,exacerbating the decline in organ ***-like receptors(TLRs)are a family of receptors that play a role in the activation of the innate immune system by the recognition of pathogen-associated molecular *** data from in vitro and in vivo studies have highlighted the critical role of TLRs,mainly TLR2 and TLR4,in the pathogenesis of *** the diabetic milieu,these TLRs recognize diabetic-associated molecular signals,triggering a proinflammatory cascade that initiates and perpetuates inflammation and fibrogenesis in the diabetic *** non-traditional strategies targeting TLR signaling with potential therapeutic implications in DKD have been *** of these approaches is the use of microRnAs,small non-coding RnAs that can regulate gene *** editorial comments on the results of this approach carried out in a rat model of diabetes by Wu et al,published in this issue of the World Journal of *** results of the experimental study by Wu et al shows that microRnA-630 decreased levels compared to non-diabetic ***,microRnA-630 exerted anti-inflammatory effects in the kidneys of diabetic rats through the modulation of *** findings indicate that the microRnA-630/TLR4 axis might represent a pathological mechanism of DKD and a potential therapeutic target capable of curbing the destructive inflammation characteristic of DKD.

关键词： Diabetes Diabetic kidney disease Inflammation Toll-like receptor 4 microRnA-630

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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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Brent *** Texas Intermediate in the US petro derivatives price formation

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Petroleum Science 2024年第1期21卷 729-739页

作者： Alejandro Almeida Antonio A.Golpe juan Manuel Martín-Alvarez Jose Carlos Vides Universidad Internacional de La Rioja Department of Quantitative Methods for Economics and BusinessLa RiojaSpain University of Huelva Department of Economics and Centro de Estudios Avanzados en FisicaMatematicas y Computacion and ICEIHuelvaSpain Complutense University of Madrid Department of Applied and Structural Economics and History and ICEIMadridSpain

In this paper,we apply the spatial panel model to explore the relationship between the dynamic of two types of crude oil prices(WTI and Brent crude oil)and their refined products over *** the turbulent months of 2011,when Cushing Oklahoma had reached capacity and the crude oil export ban removal in 2015 as breakpoints,we apply this method both in the full sample and the three resultant ***,results suggest our results show that both WTI and Brent display very similar behaviour with the refined ***,when attending to each regime,results derived from the first and third regimes are quite similar to the full sample ***,during the second regime,Brent crude oil became the benchmark in the petrol market,and it influenced the distillate ***,our model can let us determine the price-setters and price-followers in the price formation mechanism through refined *** results possess important considerations to policymakers and the market participants and the price formation.

关键词： Crude oil prices Spatial panel model Refined products Price formation

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Heavy Metals in Agricultural Soils of Constanza, Jarabacoa, San José de Ocoa, Azua, Barahona and San juan de la Maguana, Dominican Republic, 2022

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Journal of Geoscience and Environment Protection 2024年第1期12卷 64-79页

作者： ramón Delanoy Carime Matos-Espinosa Yamilesa Herrera de los Santos Institute of Physics Autonomous University of Santo Domingo Santo Domingo Dominican Republic Ministry of Higher Education Science and Technology Santo Domingo Dominican Republic

The objective of this study was to establish a baseline for future studies that aim to determine possible contamination from human, agricultural and industrial activities. As well as the determination of the indices of environmental or geological contamination and enrichment factors of heavy metals Cr, ni, Cu, Zn, As, Cd, Hg and Pb in agricultural soils of Constanza, Jarabacoa, Rancho Arriba and San José de Ocoa (SJO), municipalities located in the valleys of the Central mountain range of the Dominican Republic. The determination of the concentrations of heavy metals was carried out using the X-ray Fluorescence technique. Just like in Azua, San juan de la Maguana (SJM) y Barahona in the southwest. Producer municipalities of vegetables, rice, beans, corn, melon, watermelon, tomato, banana, avocado, sugar cane and fodder for cattle. The concentration of 160 mg·kg-1 Probable Effect Level (PEL) of Cr according to the SQuiRTs table (USEPA-nOAA) for agricultural soils, were exceeded in 50% of the samples in SJM, SJO, Jarabacoa and Constanza;in Barahona and Azua by 20%. The PEL of 42.8 mg·kg-1 of the ni was higher in more than 50% of the samples from SJM, Azua, Barahona and Jarabacoa;in SJO and Constanza at 35%. In the case of Cu with a PEL of 108 mg·kg-1 in SJO and Constanza, 5% of the samples exceeded its, in the other areas the concentrations were lower. Zn, As and Pb did not manage to exceed their respective PEL.

关键词： Soil Heavy Metals Constanza Azua X-Ray Fluorescence

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