Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma.

Peña-Asensio, J.; Calvo, H.; Torralba, M.; Miquel, J.; Sanz-de-Villalobos, E.; Larrubia, J.-R. Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma. Cancers 2021, 13, 1922.Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.Instituto de Salud Carlos IIIEuropean Regional Development Fund (ERDF)European UnionGilead Fellowship Programm

Necrosis retiniana externa progresiva por virus varicela-zóster en paciente con infección por VIH

A patient with an AIDS stage HIV infection and a thoracic herpes zoster treated with acyclovir, presents with visual loss as a consequence of a bilateral progressive outer retinal necrosis (PORN) caused by varicella-zoster virus. Despite of treatment, the patient doesn’t recover visual acuity. An early diagnostic suspicion and treatment are essential for a better prognosis.Paciente con infección por VIH estadio SIDA y herpes zóster torácico tratado con aciclovir, que debuta con pérdida de visión secundaria a necrosis retiniana externa progresiva bilateral por virus varicela-zóster (VVZ). A pesar del tratamiento, el paciente evoluciona desfavorablemente con severo déficit visual. La sospecha diagnóstica precoz y el tratamiento temprano son esenciales para un mejor pronóstico

High seroprevalence against SARS-CoV-2 among faculty of medicine and health sciences personnel and students of the University of Alcalá, Spain: contributing factors

Purpose: Seroprevalence against SARS-CoV-2 within university systems is poorly studied, making evidence-based discussions of educational system reopening difficult. Moreover, few studies evaluate how antibodies against SARS-CoV-2 are maintained over time. We assessed serological response against the SARS-CoV-2 virus among our university students and staff. Patients and Methods: In this prospective cohort study, seroprevalence was determined in 705 randomly selected volunteers, members of the Faculty of Medicine and Health Sciences of the University of Alcala, using a chemiluminescent Siemens&apos; SARS-CoV-2 immunoassay for total antibodies. Positive samples were tested for IgG and IgM/IgA using VIRCLIA (R) MONOTEST (Vircell). A first analysis took place during June 2020, and in those testing positive, a determination of secondary outcomes was performed in November 2020. Results: A total of 130 subjects showed anti-SARS-CoV-2 antibodies (18.5%, 95% CI, 15.8-21.5%). Of these, IgM/IgA was positive in 27 and indeterminate in 19; IgG was positive in 118, indeterminate in 1. After 23 weeks, among 102 volunteers remeasured, IgG became undetectable in 6. Presence of antibodies was associated, in multivariable logistic regression, with exposure to infected patients (31.3%) [OR 1.84, 95% CI, 1.14-2.96; P = 0.012], presence of COVID-19 symptoms (52.4%) [OR 6.88, 95% CI, 4.28-11.06; P < 0.001], and confirmed earlier infection (82.9%) [OR 11.87, 95% CI, 4.26-33.07; P < 0.001]. Conclusions: The faculty of medicine and health sciences personnel and students of our university showed a high infection rate for SARS-CoV-2 during 2020 associated with providing clinical care to infected patients. This emphasizes the importance of the performance of continuous surveillance methods of the most exposed health personnel, including health science students

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Envejecimiento y Fragilidad en el paciente con infección por VIH

El presente trabajo aborda el concepto de fragilidad, la epidemiología en población general y en pacientes que viven con infección por VIH (PVCV)y su importancia. Se describen los principales instrumentos que detectan y cuantifican la fragilidad y analiza el impacto que la fragilidad tiene en la morbi-mortalidad. Se estudian cuáles son las estrategias terapéuticas ante la fragilidad haciendo hincapié en la terapia multicomponente. Por último, esta revisión se centra en la fragilidad en el paciente con infección por VIH. Se estudia la prevalencia y las variables asociadas con la fragilidad en esta población específica. Se señalan las dificultades del estudio en este grupo de pacientes dado los problemas metodológicos en el diagnóstico con escalas no validadas y se insiste en la necesidad de una herramienta que de forma rápida permita evaluar la fragilidad para alertar de una comorbilidad, o para iniciar un programa de intervención multidisciplinar.This paper addresses the concept of fragility, epidemiology in the general population and in patients living with HIV infection (PLWH) and its importance. The main instruments that detect and quantify fragility are described. Impact that fragility has on morbidity and mortality are analyzed. Therapeutic strategies on fragility are studied, emphasizing multicomponent therapy. Finally, this review focuses on frailty in patients with HIV infection. The prevalence and variables associated with frailty in this specific population are studied. The difficulties of the study in this group of patients are pointed out given the methodological problems in the diagnosis with non-validated scales and the need for a tool that quickly assesses the fragility to alert a comorbidity, or to start a program of multidisciplinary intervention

Actualización en el tratamiento de la coinfección por VIH y VHC en pacientes adultos

El presente artículo es una revisión sobre el tratamiento del VHC en pacientes infectados por el VIH. Se aborda brevemente el contexto epidemiológico, la interacción existente entre ambos virus, y la historia natural e inmunopatogenia del VHC. Posteriormente se analizan las estrategias históricas (que incluían el interferón pegilado) y las actuales con los nuevos agentes antivirales directos. Se profundiza en las indicaciones, el concepto de respuesta viral sostenida, la eficacia, la toxicidad, y el tratamiento en situaciones especiales como la infección aguda por VHC o el trasplante hepático. Por último, se aborda la evolución de la fibrosis hepática, el trasplante hepático, el riesgo de hepatocarcinoma y el impacto poblacional de la curación de la infección por VHC.This article is a review of the treatment of HCV in HIV-infected patients. The epidemiological context, the interaction between both viruses, and the natural history and immunopathogenesis of HCV are briefly addressed. Subsequently, the historical strategies (including pegylated interferon) and the current ones with the new direct antiviral agents are analyzed. The indications, the concept of sustained viral response, efficacy, toxicity, and treatment in special situations such as acute HCV infection or liver transplantation are deepened. Finally, the progress of liver fibrosis, hepatic transplantation, the risk of hepatocellular carcinoma and population impact of curing HCV infection is discussed

Vida lectora

Se crea una biblioteca de aula para fomentar el hábito lector de los alumnos de ESO. Pare ello, se les pide que lleven a clase libros que hayan leido para prestárselos a sus compañeros. Se plantean como objetivos que los alumnos lleguen a disfrutar de la lectura como enriquecimiento personal; que comprendan la diversidad de la gente y de culturas a través de la literatura; que sean capaces de comprender el contenido de los textos y de resumirlos; que valoren la lengua escrita como instrumento para satisfacer las necesidades de comunicación; que consideren la lectura como una fuente de información, aprendizaje y placer; y que conozcan y apliquen las normas básicas de funcionamiento de una biblioteca. Durante el curso se realizan cuatro lecturas obligatorias de las que posteriormente los alumnos realizan una ficha con la sinopsis del libro, y su valoración, que después tendrá que exponer ante el resto de sus compañeros. Se procura que alguna de estas lecturas sea de un libro del que exista alguna adaptación al cine o del que se pueda mantener algún contacto con su autor. Adjunta fichas y trabajos de los alumnos.Madrid (Comunidad Autónoma). Consejería de Educación. Dirección General de Ordenación AcadémicaMadridMadrid (Comunidad Autónoma). Subdirección General de Formación del Profesorado. CRIF Las Acacias; General Ricardos 179 - 28025 Madrid; Tel. + 34915250893ES

Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8 + T Cell Response during Chronic Hepatitis C

Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.MINECOInstituto de Salud Carlos IIIEuropean CommissionGilead Fellowship ProgrammeEuropean Regional Development Fund (ERDF