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The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.). Supported by a grant (PI19/00545, to Dr. Martín) from the Ministry of Science and Innovation through the Carlos III Institute of Health–Fondo de Investigación Sanitaria; by a grant from the Biomedical Research Networking Center on Cardiovascular Diseases (to Drs. Martín, Sánchez-Madrid, and Ibáñez); by grants (S2017/BMD-3671-INFLAMUNE-CM, to Drs. Martín and Sánchez-Madrid; and S2017/BMD-3867-RENIM-CM, to Dr. Ibáñez) from Comunidad de Madrid; by a grant (20152330 31, to Drs. Martín, Sánchez-Madrid, and Alfonso) from Fundació La Marató de TV3; by grants (ERC-2011-AdG 294340-GENTRIS, to Dr. Sánchez-Madrid; and ERC-2018-CoG 819775-MATRIX, to Dr. Ibáñez) from the European Research Council; by grants (SAF2017-82886R, to Dr. Sánchez-Madrid; RETOS2019-107332RB-I00, to Dr. Ibáñez; and SAF2017-90604-REDT-NurCaMeIn and RTI2018-095928-BI00, to Dr. Ricote) from the Ministry of Science and Innovation; by Fondo Europeo de Desarrollo Regional (FEDER); and by a 2016 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation to Dr. Martín. The National Center for Cardiovascular Research (CNIC) is supported by the Carlos III Institute of Health, the Ministry of Science and Innovation, the Pro CNIC Foundation, and by a Severo Ochoa Center of Excellence grant (SEV-2015-0505). Mr. Blanco-Domínguez is supported by a grant (FPU16/02780) from the Formación de Profesorado Universitario program of the Spanish Ministry of Education, Culture, and Sports. Ms. Linillos-Pradillo is supported by a fellowship (PEJD-2016/BMD-2789) from Fondo de Garantía de Empleo Juvenil de Comunidad de Madrid. Dr. Relaño is supported by a grant (BES-2015-072625) from Contratos Predoctorales Severo Ochoa para la Formación de Doctores of the Ministry of Economy and Competitiveness. Dr. Alonso-Herranz is supported by a fellowship from La Caixa–CNIC. Dr. Caforio is supported by Budget Integrato per la Ricerca dei Dipartimenti BIRD-2019 from Università di Padova. Dr. Das is supported by grants (UG3 TR002878 and R35 HL150807) from the National Institutes of Health and the American Heart Association through its Strategically Focused Research Networks. Sí

Introducción: El cáncer gástrico es una de las principales causas de muerte por cáncer en Chile. No existe consenso acerca del tratamiento. Objetivos: Conocer características clínicas y patrón de tratamiento de pacientes con cáncer gástrico recién diagnosticado. Material y Método: Pacientes chilenos mayores de 18 años con diagnóstico reciente de adenocarcinoma gástrico primario, enrolados en 13 centros de diferentes regiones de Chile. Datos obtenidos en dos visitas dentro de período de 10 meses: basal (características del tumor y paciente, plan de tratamiento) y fin de estudio (tratamiento inicial completado). Se presentan datos de visita basal. Resultados: Entre 2005 y 2008, 523 pacientes enrolados. Mediana edad 61,3 años. Diagnóstico por endoscopia en 98,5% pacientes. Localización: corporal 35,8%, proximal 35,4% y antral 23,9%. Clasificación histopatológica más usada fue clasificación OMS, y tipo histopatológico más frecuente fue tubular 53,1%. Etapificación clínica AJCC/UICC (disponible en 37,6% de pacientes) distribuida en: 0 y I - 23,3%, II -18,3%, III - 20,8%, IV - 37,6%. Principal característica clínica para elección de terapia planeada fue etapificación clínica (49,9%). Plan de tratamiento consideró cirugía en 440 pacientes (84,1%). En mayoría de casos, plan terapéutico decidido por cirujano (54,9%) o equipo multidisciplinario (42,3%). Conclusiones: REGATE es el estudio de registro prospectivo multicéntrico más grande desarrollado en Chile. Datos visita basal informan que diagnóstico se establece frecuentemente en etapas avanzadas. Cirugía es alternativa terapéutica más frecuentemente indicada; terapias (neo-) adyuvantes sólo son ofrecidas a uno de cuatro pacientes. Datos visita fin de estudio proveerá visión completa del diagnóstico y tratamiento de estos pacientes. Background: Gastric cancer is one of the leading causes of cancer-related deaths in Chile and worldwide. No consensus exists for therapeutic management. Aim: To assess clinical features and practice patterns of patients with newly diagnosed gastric cancer in Chile. Method: Chilean patients > 18 years old with newly diagnosed primary gastric adenocarcinoma enrolled by thirteen centers from different regions of Chile. Target sample size calculated according to gastric cancer prevalence in Chile. Data collected from two visits within a 10-month timeframe: baseline (patients and tumor features, treatment plan) and end of study (completion of initial treatment). Herein, baseline visit data is presented. Results: Between 2005 and 2008, 523 patients enrolled. Median age 61.3 years. Diagnosis by endoscopy in 98.5% patients. Location: body 35.8%, proximal 35.4%, and antral 23.9%. Most frequently used histopathological classification was WHO classification, with tubular adenocarcinoma being most frequent finding (53.1%). AJCC/UICC clinical staging (available in 31.1% of patients) was: 0 and I - 23.3%, II - 18.3%, III- 20.8%, IV - 37.6%. Therapeutic choice based mainly on clinical staging (49.9%) and included surgery in 440 patients (84.1%). Therapy planned by surgeon (54.9%) or multidisciplinary team (42.3%). Conclusions: REGATE is the largest prospective multicenter registry study performed in Chile. Basal visit data report that diagnosis is established frequently at advanced stages. Surgery is the most frequent therapeutic choice, (neo-) adjuvant therapies are only planned in one out of four patients. End of study visit data will provide the full scope of diagnosis and treatment of these patients.

During immunologic synapse (IS) formation, human CD38 redistributes to the contact area of T cell-antigen-presenting cell (APC) conjugates in an antigen- dependent manner. Confocal microscopy showed that CD38 preferentially accumulated along the contact zone, whereas CD3-ζ redistributed toward the central zone of the IS. APC conjugates with human T cells or B cells transiently expressing CD38-green fluorescent protein revealed the presence of 2 distinct pools of CD38, one localized at the cell membrane and the other in recycling endosomes. Both pools were recruited to the T/APC contact sites and required antigen-pulsed APCs. The process appeared more efficient in T cells than in APCs. CD38 was actively recruited at the IS of T cells by means of Lck-mediated signals. Overex- pression of CD38 in T cells increased the levels of antigen-induced intracellular calcium release. Opposite results were obtained by down-regulating surface CD38 expression by means of CD38 siRNA. CD38 blockade in influenza HA-specific T cells inhibited IL-2 and IFN-γ production, PKCe phosphorylation at Thr538, and PKC6 recruitment to the IS induced by antigen-pulsed APCs. These results reveal a new role for CD38 in modulating antigen-mediated T-cell responses during IS formation. © 2008 by The American Society of Hematology., This work was supported by grants from the Ministerio de Educación y Ciencia (MEC; SAF2002-00721, and SAF2005-06056-C02-01 to J.S.), the Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía (P05-CVI-00908 to J.S.), the Instituto Carlos III-FIS, Ministerio de Sanidad y Consumo (FIS03/0389 and FIS06/1502 to M.Z.), and by grants from the Italian Association for Cancer Research (AIRC), FIRMS, and MIUR (to F.M.). Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Health and Consumer Affairs and the Pro-CNIC Foundation. M.Z. was supported by a Ramón y Cajal contract from MEC. P.M. was supported by a FPI Fellowship from MEC. P.M. was a PhD candidate at University of Granada (Spain), and this work was submitted in partial fulfillment of the requirement for the PhD.

Background: Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated. Methods: We studied association of restoration of functional HIV-1-specific CD8+ T cell responses after stimulation with Gag-adjuvant-primed DC with ART duration, exhaustion, metabolic and memory cell subsets profiles. Findings: HIV-1-specific CD8+ T cell responses from a larger proportion of PLWH on long-term ART (more than 10 years; LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, functional improvement of CD8+ T cells from PLWH on short-term ART (less than a decade; ST-ARTp) after DC treatment was limited. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolysis induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+ PD1− cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Interpretation: Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines. Funding: NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants, NIH (R21AI140930), MINECO/FEDER RETOS (RTI2018-097485-A-I00) and CIBERINF grants

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.