Maturation of Marginal Zone and Follicular B Cells Requires B Cell Activating Factor of the Tumor Necrosis Factor Family and Is Independent of B Cell Maturation Antigen

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way

Frecuencia de subtipos morfológico-inmunofenotípico de leucemias agudas enviadas a Hematopatología, IICS-UNA para su caracterización.

La citometría de flujo es muy útil para la inmunofenotipificación de leucemias y actualmente se la utiliza en la práctica clínica para diferenciar, caracterizar y clasificar las leucemias. Esto, resulta indispensable para elegir la terapia adecuada. Objetivo: determinar la frecuencia de subtipos leucémicos morfológico-inmunofenotípicos con un estudio observacional descriptivo transversal en médula ósea y sangre periférica de adultos y niños, en la Sección de Hematopatología del Departamento de Patología del Instituto de Investigaciones en Ciencias de la Salud de la Universidad Nacional de Asunción.CONACYT - Consejo Nacional de Ciencias y TecnologíaPROCIENCI

Lymphotropic viruses EBV, KSHV and HTLV in Latin America: Epidemiology and associated malignancies. A literature-based study by the RIAL-CYTED

The Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) and human T-lymphotropic virus (HTLV-1) are lymphomagenic viruses with region-specific induced morbidity. The RIAL-CYTED aims to increase the knowledge of lymphoma in Latin America (LA), and, as such, we systematically analyzed the literature to better understand our risk for virus-induced lymphoma. We observed that high endemicity regions for certain lymphomas, e.g., Mexico and Peru, have a high incidence of EBV-positive lymphomas of T/NK cell origin. Peru also carries the highest frequency of EBV-positive classical Hodgkin lymphoma (HL) and EBV-positive diffuse large B cell lymphoma, not otherwise specified (NOS), than any other LA country. Adult T cell lymphoma is endemic to the North of Brazil and Chile. While only few cases of KSHV-positive lymphomas were found, in spite of the close correlation of Kaposi sarcoma and the prevalence of pathogenic types of KSHV. Both EBV-associated HL and Burkitt lymphoma mainly affect young children, unlike in developed countries, in which adolescents and young adults are the most affected, correlating with an early EBV seroconversion for LA population despite of lack of infectious mononucleosis symptoms. High endemicity of KSHV and HTLV infection was observed among Amerindian populations, with differences between Amazonian and Andean populations.Fil: Chabay, Paola Andrea. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Lens, Daniela. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Hassan, Rocio. National Cancer Institute “José Alencar Gomes da Silva”; BrasilFil: Rodríguez Pinilla, Socorro María. University Hospital, Fundación Jiménez Díaz; EspañaFil: Valvert Gamboa, Fabiola. Cancer Institute and National League against Cancer; GuatemalaFil: Rivera, Iris. Salvadoran Institute of Social Security; El SalvadorFil: Huamán Garaicoa, Fuad. Santiago de Guayaquil Catholic University; EcuadorFil: Ranuncolo, Stella Maris. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barrionuevo, Carlos. National University of San Marcos; PerúFil: Morales Sánchez, Abigail. Children’s Hospital of Mexico Federico Gómez; MéxicoFil: Scholl, Vanesa. No especifíca;Fil: de Matteo, Elena Noemí. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Preciado, María Victoria. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Fuentes Pananá, Ezequiel M.. Children’s Hospital of Mexico Federico Gómez; Méxic

Selective Induction of Cell Death in Melanoma Cell Lines through Targeting of Mcl-1 and A1

Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies

Organic waste biorefineries: looking towards implementation

The concept of biorefinery expands the possibilities to extract value from organic matter in form of either bespoke crops or organic waste. The viability of biorefinery schemes depends on the recovery of higher-value chemicals with potential for a wide distribution and an untapped marketability. The feasibility of biorefining organic waste is enhanced by the fact that the biorefinery will typically receive a waste management fee for accepting organic waste. The development and implementation of waste biorefinery concepts can open up a wide array of possibilities to shift waste management towards higher sustainability. However, barriers encompassing environmental, technical, economic, logistic, social and legislative aspects need to be overcome. For instance, waste biorefineries are likely to be complex systems due to the variability, heterogeneity and low purity of waste materials as opposed to dedicated biomasses. This article discusses the drivers that can make the biorefinery concept applicable to waste management and the possibilities for its development to full scale. Technological, strategic and market constraints affect the successful implementations of these systems. Fluctuations in waste characteristics, the level of contamination in the organic waste fraction, the proximity of the organic waste resource, the markets for the biorefinery products, the potential for integration with other industrial processes and disposal of final residues are all critical aspects requiring detailed analysis. Furthermore, interventions from policy makers are necessary to foster sustainable bio-based solutions for waste management

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Secuenciación masiva en el estudio de pacientes con citopenias persistentes

El diagnóstico y manejo de pacientes con citopenias persistentes (anemia, trombopenia y/o neutropenia) representa un gran desafío diagnóstico y un problema de salud. Una proporción mayoritaria de estos pacientes corresponden a Síndromes Mielodisplásicos (SMD) y el resto a citopenias de significado incierto con o sin hematopoyesis clonal. La evidencia actual muestra que el estudio de variantes génicas en pacientes con citopenias o SMD por secuenciación masiva (NGS) contribuye a mejorar el diagnóstico, a la estratificación pronóstica y en la decisión terapéutica. En este proyecto hemos diseñado y validado técnica y clínicamente un panel de NGS para el estudio de pacientes con neoplasias mieloides. Hemos implementado dicho estudio en el workflow diagnóstico de pacientes portadores de citopenias persistente y en SMD. Esto hace que el diagnóstico molecular de estas patologías, como lo realizábamos en forma tradicional (gen por gen), comience ser sustituido por la NGS que permite estudiar en forma simultánea múltiples genes y regiones génicas. Desde el punto de vista clínico iniciamos la caracterización molecular completa de nuestra población de pacientes con citopenias de origen incierto y en pacientes con SMD. Los hallazgos encontrados hasta el momento fueron similares a los publicados en la literatura internacional. En conclusión: contamos en nuestro país con une herramienta diagnóstica validada para el estudio de pacientes con neoplasias mieloides que permitirá conocer mejor el pronóstico, adecuar el tratamiento e identificar nuevos blancos terapéuticos.Agencia Nacional de Investigación e Innovació

Germline CEBPA Mutation in Familial Acute Myeloid Leukemia

Myeloid Neoplasms with germline predisposition become part of 2016 World Health Organization (WHO) classification of hematological malignancies since 2016. CCAAT/enhancer binding protein-alpha (CEBPA) is a myeloid transcription factor located in chromosome 19q. Acute myeloid leukemia (AML) with biallelic mutations of CEBPA AML with recurrent genetic abnormalities according to WHO classification. The inheritance of a germline CEBPA mutation predisposes to the development of AML with autosomal dominant inheritance. Familial CEBPA AML share characteristics with somatic CEBPA AML. However, a higher relapse incidence is reported. We present the case of a 46-years-old male with family history of acute leukemia who was diagnosed with single mutated CEBPA acute myeloid leukemia. The same mutation was found in two of his siblings. The clinical suspicion and proper diagnosis of familial cases is necessary, especially when a related allogenic transplant is indicated in order to select an adequate donor

Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect

Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8(+) T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials

Activity of the calcineurin pathway in patients on the liver transplantation waiting list: factors of variability and response to tacrolimus inhibition. Pierre Marquet Institutions and affiliations

International audienceBACKGROUND:We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC).METHODS:The calcineurin pathway activity was explored ex vivo in stimulated and nonstimulated PBMC from 19 patients. The inhibition of NFATC1+ translocation to PBMC, expression of intracellular IL-2, and membrane CD25 in different T-cell subsets were measured by multiparametric flow cytometry before and after exposure to TAC. We also studied the influence on the individual response of polymorphisms in 3 key genes of the calcineurin pathway: PPIA, PPP3CA, and IL2RA.RESULTS:All pharmacodynamics profiles closely fitted an I/Imax sigmoid model. Interindividual variability was higher in nonstimulated than in stimulated conditions, as well as in the presence of TAC. IL-2+CD8+ cells at TAC Imax showed the highest interindividual variability, suggesting its usefulness as a biomarker of individual TAC effects integrating many different sources of regulation and variability. Moreover, in the absence of TAC, patients with end-stage liver disease exhibited lower NFATC1 translocation and T-cell activation than healthy volunteers from a previous study under similar conditions. Multivariate statistical analysis showed strong and significant associations between TAC pharmacodynamic parameters and 2 polymorphisms in the gene-coding cyclophilin A (rs8177826 and rs6850).CONCLUSIONS:We show the feasibility of using nonstimulated PBMCs to explore the calcineurin pathway under more physiologic conditions and point toward potential biomarkers for TAC pharmacodynamic monitoring