Pesquisa de metilação aberrante do gene P15ink4b em leucemias agudas

Dissertação de Mestrado em Oncologia apresentada ao Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Port

El sistema jurídico ambiental: relaciones, conflictos y procesos en curso = The environmental legal system: relationships, conflicts and ongoing processes

El presente artículo tiene como objetivo analizar y describir el sistema jurídico ambiental en la Argentina, en particular, las principales relaciones, conflictos y procesos en curso. Partiendo deuna visión sistémica se identifican las principales relaciones e interrelaciones, las vinculaciones con las políticas formuladas y los sectores institucionales que ejecutan dichas políticas. Las acciones einteracciones que se producen demandan describir los procesos que se encuentran en curso, los cuales se vienen desarrollando desde la reforma constitucional de 1994 donde se inserta un nuevo ordenjurídico ambiental, que permite analizar las nuevas normativas, los mecanismos jurídicos y administrativos que se están implementando, destacar los principales cambios operados en el sistema ylos que se encuentran aún en desarrollo. Todo ello se expresa en múltiples situaciones que generan conflictos de distinto tipo: normativos, institucionales, jurídicos y administrativos manifestándose en elpropio sistema. Asimismo, nos proponemos analizar y describir el rol de la administración pública tanto en la ejecución de las políticas y normas, como en la interpretación y aplicación de las normas en el sistema, observando lo procesos que promueven e impactan.  ABSTRACT: The purpose of this article is to describe and analyze the environmental legal system in Argentina: the main relationships, conflicts and ongoing processes. Using a systemic vision, the mainrelationships and interrelationships observed in the system, the linkages with the policies formulated and the institutional sectors that implement the policies are identified. The actions and interactions thatoccur demand to describe the processes that are underway, since they have been developing since the constitutional reform of 1994 where a new environmental legal order is inserted, which allows analyzingthe new regulations, the legal and administrative mechanisms that are being implemented and highlighting the main changes operated in the system and those that are in progress. All this is expressed in multiple situations that generate conflicts of different types of normative,institutional, legal and administrative manifesting themselves in the system. Likewise, describe and analyze the role of public administration both in the execution of policies and standards, and in the interpretation and application of norms in the system, observing the processes that promote and impact

A novel spliced fusion of MLL with CT45A2 in a pediatric biphenotypic acute leukemia

Background: Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. Methods: Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia. Results: Fluorescence in situ hybridization of the patient G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences. Conclusion: We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted

Negative MR4·0 chronic myeloid leukaemia and its possible implications for treatment-free remission

© 2019 British Society for Haematology and John Wiley & Sons Ltd.ABL1 tyrosine kinase inhibitors (TKI) have dramatically improved the outcome for chronic myeloid leukaemia (CML) patients, resulting in a life expectancy that approaches that of the general population. Nevertheless, lifelong TKI therapy may have consequences, including chronic adverse events that can substantially impact patients’ quality of life, adherence to therapy and treatment success. Recently, several clinical discontinuation trials have demonstrated that 40–60% of chronic phase CML patients (CP-CML) who have achieved a stable deep molecular response (DMR) can stop therapy without relapsing (Breccia & Foà, 2018). Laboratory recommendations for scoring DMR were previously defined as MR4·0 [either detectable disease ⩽0·01% BCR-ABLIS (MR4·0 positive) or undetectable disease in cDNA with 10 000–31 999 ABL1 transcripts or 24 000–76 999 GUSB transcripts (MR4·0 negative)], MR4·5 [either detectable disease ⩽0·0032% BCR-ABLIS (MR4·5 positive) or undetectable disease in cDNA with 32 000–99 999 ABL1 transcripts or 77 000–239 999 GUSB transcripts (MR4·5 negative)], and MR5·0 [either detectable disease ⩽0·001% BCR-ABLIS (MR5·0 positive) or undetectable disease in cDNA with ⩾100 000 ABL1 transcripts or ⩾240 000 GUSB transcripts (MR5·0 negative)] (Cross et al, 2015).info:eu-repo/semantics/publishedVersio

Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

<p>Abstract</p> <p>Background</p> <p>A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in <it>MLL</it>-related leukemia. Recently, we have established the <it>MLL-SEPT2 </it>gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified <it>MLL </it>and <it>SEPT2 </it>gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of <it>MLL-SEPT2</it>-associated myeloid neoplasms so far described in the literature.</p> <p>Methods</p> <p>Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: <it>CBFB-MYH11 </it>(n = 13), <it>PML-RARA </it>(n = 12); <it>RUNX1-RUNX1T1 </it>(n = 12), normal karyotype (n = 11), and <it>MLL </it>gene fusions other than <it>MLL-SEPT2 </it>(n = 10). We also studied all three <it>MLL-SEPT2 </it>myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.</p> <p>Results</p> <p>When compared with normal controls, we found a 12.8-fold reduction of wild-type <it>SEPT2 </it>and <it>MLL-SEPT2 </it>combined expression in cases with the <it>MLL-SEPT2 </it>gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type <it>MLL </it>and <it>MLL-SEPT2 </it>combined expression (p = 0.028). The down-regulation of <it>SEPT2 </it>in <it>MLL-SEPT2 </it>myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other <it>MLL </it>gene fusions). In addition, <it>MLL </it>expression was also down-regulated in the group of <it>MLL </it>fusions other than <it>MLL-SEPT2</it>, when compared with the normal control group (p = 0.023)</p> <p>Conclusion</p> <p>We found a significant down-regulation of both <it>SEPT2 </it>and <it>MLL </it>in <it>MLL-SEPT2 </it>myeloid neoplasias. In addition, we also found that <it>MLL </it>is under-expressed in AML patients with <it>MLL </it>fusions other than <it>MLL-SEPT2</it>.</p

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Los antecedentes y el contexto normativo del amparo ambiental en la ley 10.208 de Córdoba

Aspectos generales del marco normativo nacional y provincial en los que se incorpora la ley 10.208. Los aspectos generales de la ley 10.208 y su vinculación específica con el amparo. La figura del amparo en el proceso de elaboración y en el texto sancionado de la ley 10.208.Fil: Juliá, Marta Susana. Universidad Católica de Córdoba. Facultad de Derecho y Ciencias Sociales; Argentina.Fil: Betroni, Stefani Helen. Universidad Nacional de Córdoba. Facultad de Derecho; Argentina.Fil: Bizarro, Valeria. Universidad Nacional de Córdoba. Facultad de Derecho; Argentina.Fil: Foradori, María Laura. Universidad Nacional de Córdoba. Facultad de Derecho; Argentina

Los antecedentes y el contexto normativo del amparo ambiental en la Ley 10.208 de Córdoba

Con la existencia de este marco normativo general conformado por los preceptos constitucionales y la Ley provincial 7343, en 2014 la Provincia de Córdoba sanciona la Ley 10.208 de Política Ambiental Provincial, en ejercicio de la facultad complementaria respecto de la Ley General 25.675 de Ambiente de Presupuestos Mínimos para el logro de una gestión sustentable y adecuada del ambiente, conforme a las competencias reconocidas en el tercer párrafo del art. 41 de la CN.Fil: Juliá, Marta Susana. Universidad Nacional de Córdoba. Facultad de Derecho y Ciencias Sociales. Centro de Investigaciones Juridícas y Sociales; ArgentinaFil: Betroni, Stefani Helen. Universidad Nacional de Córdoba. Facultad de Derecho y Ciencias Sociales. Centro de Investigaciones Juridícas y Sociales; ArgentinaFil: Foradori, María Laura. Universidad Nacional de Córdoba. Centro de Investigaciones Jurídicas y Sociales. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones Jurídicas y Sociales; ArgentinaFil: Bizarro, Valeria. Universidad Nacional de Córdoba. Centro de Investigaciones Jurídicas y Sociales. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones Jurídicas y Sociales; Argentina. Universidad Católica de Córdoba; Argentina. Universidad Empresarial Siglo XXI; Argentina. Universidad Nacional de Villa María; Argentin