Caspases in virus-infected cells contribute to recognition by CD8+ T lymphocytes

CD8(+) cytotoxic T lymphocytes recognize infected cells in which MHC class I molecules present pathogen-derived peptides that have been processed mainly by proteasomes. Many infections induce a set of proteases, the caspases involved in apoptosis or inflammation. In this study, we report that processing and presentation of a short vaccinia virus-encoded Ag can take place also by a nonproteasomal pathway, which was blocked in infected cells with chemical inhibitors of caspases. By cleaving at noncanonical sites, at least two caspases generated antigenic peptides recognized by T lymphocytes. The sites and the peptidic products were partially overlapping but different to those used and produced by proteasomes in vitro. Antigenic natural peptides produced in infected cells by either pathway were quantitatively and qualitatively similar. Finally, coexpression of the natural vaccinia virus protein B13, which is an inhibitor of caspases and apoptosis, impaired Ag presentation by the caspase pathway in infected cells. These data support the hypothesis that numerous cellular proteolytic systems, including those induced during infection, such as caspases involved in apoptosis or in inflammation, contribute to the repertoire of presented peptides, thereby facilitating immunosurveillance.This work was supported by grants provided by the European Union, Ministerio de Ciencia e Innovación, Comunidad de Madrid, and Instituto de Salud Carlos III (to M.D.V.) and Programa Ramón y Cajal, Comunidad de Madrid, and Instituto de Salud Carlos III (to D.L.). G.L.S. is a Wellcome Principal Research Fellow.S

Influence of Unstable Shoes on Women With Lumbopelvic Postpartum Pain: Randomized Clinical Trial

[Abstract] Background: Back pain is a normal symptom during pregnancy and is expected to become worse beyond the first three months after childbirth. Objectives: To determine the effectiveness of wearing unstable shoes instead of conventional shoes, regarding pain intensity, low back mobility and stability, among women with lumbopelvic pain (LPP) during the postpartum period. Design and setting: Prospective, single-blinded, randomized clinical trial conducted at a podiatry and physiotherapy clinical center. Methods: A nine-week program of wearing either unstable shoes (A) or conventional shoes (B) was implemented. The following outcomes were measured in three assessments: pain intensity, using a visual analogue scale (VAS); low-back mobility, using a modified Schober test; and stability, using a pressure platform. Results: The lateral stability speed, anterior stability speed and anterior center of pressure (COP) showed significant (P < 0.05) decreases in the unstable shoes group after nine weeks, in relation to the conventional group. Intra-group measurements showed significant differences (P < 0.05) in VAS between the second and third assessments and between the first and third assessments in both groups. Intra-group evaluations also showed statistically significant differences (P < 0.05) in the lateral stability speed and anterior stability speed. Conclusions: Unstable shoes were effective in decreasing the pain intensity at five and nine weeks in women with postpartum LPP. In addition, their use produced decreases in lateral stability speed, anterior stability speed and anterior COP at nine weeks

Depresión y deterioro cognitivo. Estudio basado en la población mayor de 65 años.

Durante el Estudio 10/66 "Prevalencia y factores de riesgo del Síndrome Demencial y la Enfermedad de Alzheimer "en el Policlínico Ana Betancourt del Municipio Playa en Ciudad de La Habana, se realizó una investigación basada en la población que incluyó una muestra comunitaria de 307 adultos, mayores de 65 años, seleccionados por muestreo intencional, con el objetivo de estimar la prevalencia del deterioro cognitivo y de depresión. Se aplicaron los criterios del DSM IV, del NINCDS y de la ADRDA mediante el algoritmo diagnostico 10/66, y se obtuvo como resultado una prevalencia baja de Trastorno Cognitivo Mínimo y de depresión Mayor y alta del Síndrome Demencial en la población estudiada.  Palabras Clave: Prevalencia, Demencia, Trastornos cognitivos, Depresión

Trabajadores pobres y pobreza en el trabajo: concepto y evolución de la pobreza en la oculación: el impacto de las últimas reformas legales

Secretaría de Estado de Investigación, Desarrollo e InnovaciónFondo Europeo de Desarrollo Regional (FEDER) de la Unión Europe

Alojamientos protegidos para enfermos mentales crónicos 1: Perfil epidemiológico, síntomas, calidad de vida y autoestima en dos muestras de sujetos

En este estudio se comparan los síntomas psicopatológicos, la calidad de vida y la autoestima de dos muestras de pacientes mentales crónicos, unos que residen en 2 alojamientos protegidos y otros en espera de hacerlo. También se precisa el perfil epidemiológico de los pacientes. Este tipo de alojamientos se presentan desde hace algunas décadas como la alternativa a los hospitales psiquiátricos tradicionales, que funcionaban en la práctica como recursos residenciales. Su utilidad ha sido considerada desde diferentes puntos de vista, a nivel clínico, asistencial, funcional y económico. A diferencia de otros hallazgos, en nuestro estudio no se aprecia una mejor calidad de vida de los pacientes que viven en dichos alojamientos frente a los que no lo hacen. Tampoco están mejor psicopatológicamente ni tienen mayor autoestima. Se sugieren modificaciones metodológicas en el diseño que permitan controlar ciertas variables que pueden influir en los resultados.In this study the psychopathology symptoms, the quality of life and the selfesteem of two samples of patient mental chronic are compared, some housed in protected lodgings and others while waiting for making it. It is also described the epidemic profile of the patients. This type of lodgings is presented for some decades like the alternative to the traditional psychiatric hospitals that worked in the practice as residential resources. Their utility has been considered from different points of view, at clinical, assistance, functional and economic level. Contrary to other discoveries, in our study a better quality of the patients' life is not appreciated that live in this lodgings in front of those that don't make it. Neither they are better psychopathologically neither they have bigger self-esteem. Methodological modifications are suggested in the design to control certain variables that can influence in the results

Recent reforms in Spanish housing markets: an evaluation using a DSGE model

After a long academic debate, Spain finally repealed in 2012 the deduction for home purchase. The abrogation took effect in 2013. In parallel, the VAT for the purchase of new housing was increased after a short period in which it had a reduced rate. The aim of this paper is to assess the macroeconomic effects of these two relevant housing market reforms. In order to do that, we use a dynamic stochastic general equilibrium (DSGE) model calibrated to capture the key ratios of the Spanish economy. The model includes a housing market, covering both the rental market side and the property market side and credit-constrained agents. We find that these measures drive down housing prices and have a negative impact on output and employment in the construction sector. However, in the long run, this last effect is offset by the benefits of a reduction in distortionary taxes

Immunotherapy moves to the early-stage setting in non-small cell lung cancer: emerging evidence and the role of biomarkers

Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

Background Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Methods Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. Results CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFN gamma signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Conclusions Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC

Anti-IL-6 Receptor Tocilizumab in Refractory Graves? Orbitopathy: National Multicenter Observational Study of 48 Patients

Graves’ orbitopathy (GO) is the most common extrathyroidal manifestation of Graves’ disease (GD). Our aim was to assess the e cacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves’ Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age standard deviation 51 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 0.25 vs. 0.9 0.16; p = 0.0001), CAS (4.64 1.5 vs. 1.05 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 4.1 vs. 16.73 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 2.1 months, low disease activity (CAS 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or ine cacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from “Instituto de Salud Carlos III” (ISCIII) (Spain)

Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain : OSIREX-Spanish Lung Cancer Group

AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number : NCT03790397