Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection

Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.

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

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.

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

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.

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

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-specific CD8^＋ T cells reacquire their functionality. Nevertheless, functional restoration depends on PD-1 expression level. High PD-l-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 gClq 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 aclainst HCV to succeed in clearing the infection.

Occult hepatitis B virus infection:A complex entity with relevant clinical implications

Occult hepatitis B virus(HBV) infection is a world-wide entity,following the geographical distribution of detectable hepatitis B.This entity is defined as the persistence of viral genomes in the liver tissue and in some instances also in the serum,associated to negative HBV surface antigen serology.The molecular basis of the occult infection is related to the life cycle of HBV,which produces a covalently closed circular DNA that persists in the cell nuclei as an episome,and serves as a template for gene transcription.The mechanism responsible for the HBsAg negative status in occult HBV carriers is a strong suppression of viral replication,probably due to the host’s immune response,co-infection with other infectious agents and epigenetic factors.There is emerging evidence of the potential clinical relevance of occult HBV infection,since this could be involved in occult HBV transmission through orthotopic liver transplant and blood transfusion,reactivation of HBV infection during immunosuppression,impairing chronic liver disease outcome and acting as a risk factor for hepatocellular carcinoma.Therefore it is important to bear in mind this entity in cryptogenetic liver diseases,hepatitis C virus/ HIV infected patients and immunosupressed individuals.It is also necessary to increase our knowledge in this fascinating field to define better strategies to diagnose and treat this infection.

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

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.

DNA-guided hepatitis B treatment,viral load is essential,but not sufficient

Hepatitis B virus （HBV） infection is a global public health problem that concerns 350 million people worldwide. Individuals with chronic hepatitis B （CriB） are at increased risk of developing liver cirrhosis, hepatic de-compensation and hepatocellular carcinoma. To maintain undetectable viral load reduces chronic infection complications. There is no treatment that eradicates HBV infection. Current drugs are expensive, are associated with adverse events, and are of limited efficacy. Current guidelines try to standardize the clinical practice. Nevertheless, controversy remains about management of asymptomatic patients with CriB who are hepatitis B e antigen （HBeAg）-positive with normal alanine aminotransferase, and what is the cut-off value of viral load to distinguish HBeAg- negative CriB patients and inactive carriers. We discuss in detail why DNA level alone is not sufficient to begin treatment of CriB.

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

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.

Ambispective comparative study of two surgical strategies for liver hydatidosis

AIM:To investigate the morbidity,mortality,recurrence and technical aspects of two distinct surgical strategies that were implemented in successive periods.METHODS:Ninty-two patients with 113 cysts underwent surgical procedures.The study was divided into 2 periods.Data from first period(P1) were compiled retrospectively.The surgical strategy was conservative surgery.The second period(P2) included a prospective study conducted according to a protocol following the criterion that radical procedures should be performed whenever it is technically feasible.RESULTS:Patients of both periods showed no statistically significant differences in age,gender,cyst location or mortality.Among the P2 group,patients exhibited more preoperative jaundice,and cyst size was smaller(P < 0.05).Changes in surgical strategy increased the rate of radical surgery,decreases morbidity and in-hospital stay(P < 0.001).A negative result in P2 was the death of two old patients(4.8%) who had undergone conser-vative treatments.The rate of radical surgery in P2 was around 75%.CONCLUSION:Radical surgery should be the technique of choice whenever it is feasible,because it diminishes morbidity and in-hospital stay.Conservative surgery must be employed only in selected cases.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV 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 control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,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 machinery.HCV 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 deletion.To 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 proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

The Global Role of Kidney Transplantation

World Kidney Day on March 8th 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness.Anything that is both cheaper and better,but is not actually the dominant therapy,must have other drawbacks that prevent replacement of all dialysis treatment by transplantation.The barriers to universal transplantation as the therapy for end stage kidney disease include the economic limitations which,in some countries place transplantation,appropriately,at a lower priority than public health fundamentals such as clean water,sanitation and vaccination.Even in high income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients,but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical,surgical and nursing workforces with the required expertise.These problems have solutions which involve the full range of societal,professional,governmental and political environments.World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit.

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

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 response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This 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 phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In 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.

ERP Effects of Word Exposure and Orthographic Knowledge on Lexical Decisions in Spanish

Orthographic knowledge is affected by language processing, which is associated with word exposure. This study used event-related potentials (ERP) to explore this association in Spanish-speaking adults with different levels of orthographic competence (High Spelling Skills: HSS;Low Spelling Skills: LSS) while they performed a lexical decision task on previously exposed words (1 or 5 times). Both groups benefited from the exposure rate, but HSS reached significantly higher correct and faster responses, particularly with repeated words. Word recognition potential (RP) amplitude was higher bilaterally in HSS group, especially with repeated words, while P220 was found to be right-lateralized and sensitive to word exposure. Also, the amplitude of P600 varied as a function of word exposure and positively correlated with reading speed. Results suggest that LSS group is less sensitive to word exposure and fails to automatize strategies to word recognition that affect reading fluency.

Numerical Model of Ultra-High Molecular Weight Polyethylene Abrasive Wear Tests

Ultra-high molecular weight polyethylene (UHMWPE) has been used in orthopedics as one of the materials for artificial joints in knee, hip and spine prostheses, most of the implanted joints are designed so that the metal of the prosthesis is articulate against a polymeric material, however the main problems is the average life time of the UHMWPE due to wear, and the particles generated by the friction of the metal on the articulation of the polymer are the most common inducer of osteolysis, generating a loosening of the implant leading to an imminent failure resulting in the total replacement of the prosthesis. In this investigation a numerical model of abrasive wear was made using the classic Archard wear equation applied to dynamic simulation of finite element analysis (FEA) of the micro-abrasion test using a subroutine written in Fortran language linked to the finite element software to predict the rate of wear. The results of the numerical model were compared with tests of abrasive wear in the laboratory, obtaining a margin of error below 5%,concluding that the numerical model is feasible for the prediction of the rate of wear and could be applied in knowing the life cycle of joint prostheses or for the tribological analysis in industrial machinery or cutting tools. The wear coefficient (K) was obtained from the grinding tests depending on the depth of stroke of the crater, which was analyzed by 3D profilometry to obtain the wear rate and the wear constant.

Neuropathology of Schizophrenia

The paper is to study the structural changes in cortex and cerebellum of autopsies of subjects with schizophrenia. In the Pathology Department of the Psychiatric Hospital ＂Fray Bernardino ,Avarez＂, there are 410 autopsy cases with diagnosis of mental disease, from which 52 match schizophrenia. The aim of this work is to describe structural changes in the autopsy material and make markers in order to confirm neurodevelopment alterations. The tissues were preserved in formol, paraffin-embedded; cut into 5-7 μm slices; stained with H-E （Hematoxilin and Eosin）, Bielschowsky, crystal fast of violet. The observed changes were brain asymmetry, cortical dysplasia, neuronal distortion, axon bifurcation, neuronophagia and generalized demyelination. Schizophrenia is the result of several happenings, it is important to devise new treatment strategies for prevention and genetic counseling for population.

Impact of timing of adjuvant radiotherapy on locoregional control in patients with high-risk endometrial cancer

Aim:High-risk endometrial cancer has a higher risk of regional and distant recurrence.We sought to examine our institutional experience regarding the timing of adjuvant radiotherapy and local failure(LF),locoregional failure(LRF),distant failure(DF),and overall survival(OS).Methods:We retrospectively reviewed a database of patients with high-risk endometrial cancer treated with sequential chemotherapy followed by adjuvant external beam radiation therapy(EBRT)with or without brachytherapy from 2012 to 2019.Results:One hundred thirty-one patients were identified.The median age at diagnosis was 65(range 32-81).The most prevalent FIGO stages were IIIB(28.2%,n=37),IIIC1(19.8%,n=26),and IIIA(17.6%,n=23).Of the patients,29%(n=38)had positive lymph nodes and 71%(n=93)had negative lymph nodes.The most prevalent histology was endometrioid(71%,n=93),serous(12.2%,n=16),clear cell(9.2%,n=12),and other(7.6%,n=10).Moreover,100%(n=131)of the patients completed EBRT.The mean EBRT dose was 49.6 Gy(range 45-50.4).The median number of days between surgery and EBRT was 212.4 days(range 103-219).The mean brachytherapy dose was 14.7 Gy(range 12-30).The cumulative incidence of LF was 6.1%,LRF was 19%,DF was 19%,and the median survival was 33.4 months.For patients who completed EBRT 180 days after surgery,LRF(HR 3.55[1.23-10.2],P=0.013),LF(HR 1.91[0.4-8.9],P=0.429),DF(HR 0.91[0.41-2],P=0.806),and OS(HR 0.92[0.33-2.6],P=0.87).Conclusion:In our cohort of patients with high-risk endometrial cancer treated with chemotherapy followed by radiotherapy,delaying RT was associated with an increased risk of LRF but no differences in DF or OS.

Saturation effect of up-conversion luminescence from erbium-doped,silicatitania sol-gel powders

The intensity of the visible up-conversion luminescence could be limited by a saturation effect produced by increased pump power. Visible up-conversion luminescence was obtained in erbium doped,silica-titania sol gel powders under dynamical pumping at 1532 nm. The saturation effect was studied for erbium radiative transitions 2H9/2→4I15/2 （410 nm）,2H11/2→4I15/2 （530 nm）,4S3/2→4I15/2 （550 nm）,2H9/2→4I13/2 （567 nm） and 4F9/2→4I15/2 （675 nm）. The recorded up-conversion luminescence decreased when increasing excitation power. The results suggested that the saturation effect was determined by the pump power,the sample composition and the lifetimes of the corresponding first excited states.