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Previous studies have shown that local delivery of tumor antigen-specific CD8(+) T lymphocytes engineered to transiently express single-chain IL-12 mRNA is highly efficacious. Peritoneal dissemination of cancer is a frequent and often fatal patient condition usually diagnosed when the tumor burden is too large and hence uncontrollable with current treatment options. In this study, we have modeled intracavitary adoptive T cell therapy with OVA-specific OT-I T cells electroporated with IL-12 mRNA to treat B16-OVA and PANC02-OVA tumor spread in the peritoneal cavity. Tumor localization in the omentum and the effects of local T-cell encounter with the tumor antigens were monitored, the gene expression profile evaluated, and the phenotypic reprogramming of several immune subsets was characterized. Intraperitoneal administration of T cells promoted homing to the omentum more effectively than intravenous administration. Transient IL-12 expression was responsible for a favorable reprogramming of the tumor immune microenvironment, longer persistence of transferred T lymphocytes in vivo, and the development of immunity to endogenous antigens following primary tumor eradication. The efficacy of the strategy was at least in part recapitulated with the adoptive transfer of lower affinity transgenic TCR-bearing PMEL-1 T lymphocytes to treat the aggressive intraperitoneally disseminated B16-F10 tumor. Locoregional adoptive transfer of transiently IL-12-armored T cells appears to offer promising therapeutic advantages in terms of anti-tumor efficacy to treat peritoneal carcinomatosis.

Ten years after their availability, thrombopoietin receptor agonists (TPO-RA) have heralded a paradigm shift in the treatment of immune thrombocytopenia (ITP). This study was aimed to analyze the implementation of current recommendations in the standard practice of adult ITP patients, and how age may influence those changes.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) allele groups and alleles by PCR-SSP based typing in a total of 15,318 mixed ancestry Mexicans from all the states of the country divided into 78 sample sets, providing information regarding allelic and haplotypic frequencies and their linkage disequilibrium, as well as admixture estimates and genetic substructure. We identified the presence of 4268 unique HLA extended haplotypes across Mexico and find that the ten most frequent (HF > 1%) HLA haplotypes with significant linkage disequilibrium (Δ’≥0.1) in Mexico (accounting for 20% of the haplotypic diversity of the country) are of primarily Native American ancestry (A*02~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*08~DQB1*04, A*68~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*14~DQB1*03:01, A*24~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*04~DQB1*03:02, A*02~B*40:02~DRB1*04~DQB1*03:02, A*68~B*35~DRB1*04~DQB1*03:02, A*02~B*15:01~DRB1*04~DQB1*03:02). Admixture estimates obtained by a maximum likelihood method using HLA-A/-B/-DRB1 as genetic estimators revealed that the main genetic components in Mexico as a whole are Native American (ranging from 37.8% in the northern part of the country to 81.5% in the southeastern region) and European (ranging from 11.5% in the southeast to 62.6% in northern Mexico). African admixture ranged from 0.0 to 12.7% not following any specific pattern. We were able to detect three major immunogenetic clusters correlating with genetic diversity and differential admixture within Mexico: North, Central and Southeast, which is in accordance with previous reports using genome-wide data. Our findings provide insights into the population immunogenetic substructure of the whole country and add to the knowledge of mixed ancestry Latin American population genetics, important for disease association studies, detection of demographic signatures on population variation and improved allocation of public health resources. Fil: Barquera, Rodrigo. Max Planck Institute For The Science Of Human History; Alemania. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Hernández Zaragoza, Diana Iraíz. Técnicas Genéticas Aplicadas A la Clínica (tgac); México. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Bravo Acevedo, Alicia. Instituto Mexicano del Seguro Social; México Fil: Arrieta Bolaños, Esteban. Universitat Essen; Alemania Fil: Clayton, Stephen. Max Planck Institute For The Science Of Human History; Alemania Fil: Acuña Alonzo, Víctor. Instituto Nacional de Antropología E Historia, Mexico; México Fil: Martínez Álvarez, Julio César. Instituto Mexicano del Seguro Social; México Fil: López Gil, Concepción. Instituto Mexicano del Seguro Social; México Fil: Adalid Sáinz, Carmen. Instituto Mexicano del Seguro Social; México Fil: Vega Martínez, María del Rosario. Hospital Central Sur de Alta Especialidad; México Fil: Escobedo Ruíz, Araceli. Instituto Mexicano del Seguro Social; México Fil: Juárez Cortés, Eva Dolores. Instituto Mexicano del Seguro Social; México Fil: Immel, Alexander. Max Planck Institute For The Science Of Human History; Alemania. Christian Albrechts Universitat Zu Kiel; Alemania Fil: Pacheco Ubaldo, Hanna. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: González Medina, Liliana. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Lona Sánchez, Abraham. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Lara Riegos, Julio. Universidad Autónoma de Yucatán; México Fil: Sánchez Fernández, María Guadalupe de Jesús. Instituto Mexicano del Seguro Social; México Fil: Díaz López, Rosario. Hospital Central Militar, Mexico City; México Fil: Guizar López, Gregorio Ulises. Hospital Central Militar, Mexico City; México Fil: Medina Escobedo, Carolina Elizabeth. Instituto Mexicano del Seguro Social; México Fil: Arrazola García, María Araceli. Instituto Mexicano del Seguro Social; México Fil: Montiel Hernández, Gustavo Daniel. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; México Fil: Hernández Hernández, Ofelia. Técnicas Genéticas Aplicadas a la Clínica ; México Fil: Ramos de la Cruz, Flor del Rocío. Instituto Mexicano del Seguro Social; México Fil: Juárez Nicolás, Francisco. Instituto Nacional de Pediatría; México Fil: Pantoja Torres, Jorge Arturo. Instituto Mexicano del Seguro Social; México Fil: Rodríguez Munguía, Tirzo Jesús. Hospital General Norberto Treviño Zapata; México Fil: Juárez Barreto, Vicencio. Hospital Infantil de Mexico Federico Gomez; México Fil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina

Land‐use change can alter trophic interactions with wide‐ranging functional consequences, yet the consequences for aquatic food webs have been little studied. In part, this may reflect the challenges of resolving the diets of aquatic organisms using classical gut contents analysis, especially for soft‐bodied prey. We used next‐generation sequencing to resolve prey use in nearly 400 individuals of two predatory invertebrates (the Caddisfly, Rhyacophila dorsalis, and the Stonefly Dinocras cephalotes) in streams draining land with increasingly intensive livestock farming. Rhyacophila dorsalis occurred in all streams, whereas D. cephalotes was restricted to low intensities, allowing us to test whether: (i) apparent sensitivity to agriculture in the latter species reflects a more specialized diet and (ii) diet in R. dorsalis varied between sites with and without D. cephalotes. DNA was extracted from dissected gut contents, amplified without blocking probes and sequenced using Ion Torrent technology. Both predators were generalists, consuming 30 prey taxa with a preference for taxa that were abundant in all streams or that increased with intensification. Where both predators were present, their diets were nearly identical, and R. dorsalis's diet was virtually unchanged in the absence of D. cephalotes. The loss of D. cephalotes from more intensive sites was probably due to physicochemical stressors, such as sedimentation, rather than to dietary specialization, although wider biotic factors (e.g., competition with other predatory taxa) could not be excluded. This study provides a uniquely detailed description of predator diets along a land‐use intensity gradient, offering new insights into how anthropogenic stressors affect stream communities.

Anti-CTLA-4 monoclonal antibodies (mAb) that block the interaction of CTLA-4 with CD80 and CD86 such as tremelimumab and ipilimumab are currently being tested in the clinic for cancer treatment exploiting their properties to de-repress tumor-specific cellular immunity. Addition of the fully human anti-CTLA-4 (tremelimumab) to cultures of human T cells with allogenic dendritic cells (DCs) did not increase proliferation. Magnetic bead-mediated elimination of CD4(+) CD25(+) regulatory T cells (T(reg)) before setting up those alloreactive cultures also largely failed to increase primary proliferation. In contrast, predepletion of CD4(+) CD25(+) T(reg) and culture in the presence of tremelimumab synergistically resulted in increased proliferation and DC:T-cell aggregation. These effects were much more prominent in CD4 than in CD8 T cells. The synergy mechanism can be traced to enhanced CTLA-4 expression in effector cells as a result of T(reg) elimination, thereby offering more targets to the blocking antibody. Human T cells and allogenic DCs (derived both from healthy donors and advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-) IL-2Rγ(-/-) mice. In these conditions, tremelimumab injected intravenously did not significantly enhance alloreactive proliferation unless T(reg) cells had been predepleted. Synergistic effects in vivo were again largely restricted to the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade synergistically enhanced specific cytotoxicity raised in culture against autologous EBV-transformed cell lines. Taken together, these experiments indicate that tremelimumab therapy may benefit from previous or concomitant T(reg) depletion.

Introducción: el síndrome del intestino irritable (SII) es una patología controvertida, donde ante la escasez de evidencia científica las recomendaciones sobre su manejo clínico y su definición vienen determinadas por métodos de consenso de expertos. Objetivo: obtener la opinión de los médicos de nuestro país implicados en el manejo de pacientes con SII y conocer los puntos de acuerdo en las principales cuestiones clínicas que plantea. Material y métodos: se realizó un estudio Delphi a nivel nacional mediante dos envíos a 100 médicos de atención primaria y gastroenterólogos. El cuestionario incluía preguntas sobre el concepto, diagnóstico y tratamiento del SII, evaluando el grado de acuerdo entre los participantes. Resultados: el 55% de los encuestados completó los dos envíos. Se obtuvo acuerdo respecto a los síntomas que caracterizan al SII y los de alarma. No existió una actitud clara ante el paciente sin síntomas de alarma, pero sí acuerdo respecto a la realización de colonoscopia en su presencia. Se señaló la necesidad de realizar estudios complementarios en mayores de 40 años. En el tratamiento no encontramos una actitud uniforme, aunque parece existir una orientación diferente según el síntoma predominante. Conclusiones: los médicos participantes en el estudio demuestran a través de sus respuestas un buen conocimiento conceptual del SII, si bien las discrepancias observadas en las cuestiones sobre diagnóstico y tratamiento demuestran la complejidad y falta de uniformidad que existe en el manejo diario de este síndrome. Introduction: lack of evidence in most clinical situations regarding irritable bowel syndrome (IBS) enhances the importance of an expert's opinion, which will guide management and even the concept underlying the disease. Objective: to delve into the knowledge and degree of agreement on main clinical skills for this syndrome among physicians involved in its management. Material and method: two rounds of a Delphi survey were conducted on 100 physicians: general practitioners (GPs) and gastroenterologists. The questionnaire evaluated agreement among participants in some aspects regarding the definition, diagnosis, and treatment of IBS. Results: fifty-five percent of participants completed the two-round survey. Agreement was achieved regarding the definition of typical symptoms and red flags characterizing IBS. Although there was no consensus regarding the appropriate management of patients without alarm symptoms, the performance of a colonoscopy on any patient presenting red flags was suggested. Patients were thought to require a wider examination when older than 40. A well defined line of IBS treatment was not found, albeit most physicians tended to choose it depending on the main complaint. Conclusion: interviewed physicians showed adequate theoretical knowledge of IBS, but lack of uniformity on diagnosis and treatment approach reflects the controversial day-by-day management of this syndrome.

"Aims. The aim of this study is to develop a set of guidelines for the clinical management of neuropathic pain (NP), a disorder suffered by up to 5% of the population, specifically for use by the Spanish-speaking community, in order to improve the quality of medical care and to standardise the treatments offered in medical centres. Development. The paper describes the methodology used to search for guidelines concerning the clinical management of NP in databases, written communications and other resources, and the results of this search are presented. The research group is split into three groups: anatomicalphysiological, diagnosis and therapeutic approach, each of which defines the nature of the papers that used to design the protocol." Objetivo. Desarrollar unas guías de práctica clínica para el dolor neuropático (DN), un trastorno que se manifiesta hasta en el 5% de la población, específicamente para la comunidad de habla hispana, con el fin de mejorar la calidad del cuidado médico y estandarizar los tratamientos en los centros clínicos. Desarrollo. Se describe la metodología de búsqueda de guías de práctica clínica de DN en bases de datos, comunicaciones escritas y otros recursos, y se muestran los hallazgos. El grupo investigador se distribuye en tres grupos: aproximación anatomofisiológica, aproximación diagnóstica y aproximación terapéutica, cada uno de los cuales define la pertinencia de los artículos que se utilizarán para diseñar el protocolo. Las políticas de este editor no han sido verificadas por RoMEO