Epigenome as a therapeutic target for lymphoma

Lymphomas are neoplasms derived from lymphoid cells at various stages of development and they are among the ten most frequent types of human cancer. Their incidence has dramatically increased in the past several decades. Although lymphomas are among the most curable tumors, the mortality rate of lymphoma is still very high. Thus, the development of novel treatment strategies and the identification of biological and genetic relevant targets are urgent. Genes involved in chromatin remodeling are very frequently altered in lymphomas, indicating the importance of aberrant epigenetic mechanisms, and providing a rationale to evaluate drugs targeting pathway deregulated in lymphomas. The aim of this work was to study the anti-lymphoma activity of novel epigenetic drugs, understanding their mechanism of action and identifying biologic and genetic features associated with responses. For this purpose, novel HDAC (ST7612AA1) and BET inhibitors (OTX015/MK-8628, BAY 1238097, BAY-7575 and BAY-5627) were studied in numerous lymphoma preclinical models. ST7612AA1 is a potent pan-histone deacetylase inhibitor, that targets and consequently inhibits different class I and class II HDACs. Here, in vitro and in vivo significant antitumor activity in lymphomas was demonstrated, which was linked with an ability to induce transcriptional changes of several genes involved in key biologic processes. OTX015/MK-8628 is a BET bromodomain inhibitor targeting BRD2-3-4 nuclear kinases and, here, it was tested as single agent and in combination with a series of conventional and targeted anti-lymphoma agents, in mature B-cell lymphomas. OTX015/MK-8628 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC and E2F1-regulated genes, cell cycle regulation, and chromatin structure. OTX015/MK-8628 presented in vitro synergism with several anti-cancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degree of sensitivity to OTX015/MK-8628 were identified, and it was found that OTX015/MK-8628 induced apoptosis only in a genetically defined subgroup of cells, derived from activated B-cell like DLBCL, bearing WT TP53, mutations in MYD88 and CD79B or CARD11. Finally, a set of three novel BET bromodomain inhibitors (BAY-7575, BAY-5627 and remarkably BAY 1238097) showed a wide pre-clinical antitumor activity in lymphoma models. These inhibitors affected important biologic pathways, such as MYC, NFKB, TLR and JAK/STAT. Through this work, new therapeutic strategies to target the epigenome of the lymphoma cells to possibly increase the curability of lymphoma patients could be developed

Jesuit missions and their contributions to the historical construcción of the territory. Basin of the river Passage. Salta, Argentina

El territorio de la Cuenca Hídrica del Río Pasaje o Juramento, en la provincia de Salta, Argentina, contiene un conjunto de sitios arqueológicos que interactúan como un sistema unívoco de bienes del patrimonio cultural colonial. Entre ellos destacan las ruinas de las Misiones Jesuíticas de San Esteban de Miraflores y San Juan Bautista de Valbuena que, a mediados del siglo XVIII, la Compañía de Jesús organizó para congregar a la población indígena con fines civilizatorios y de evangelización. El artículo, trabajado en base a los resultados del proyecto de Investigación “Urbanismo y Arquitectura en Sitios Patrimoniales de la Cuenca del rio Pasaje, Salta” (2018-2019) indaga en las líneas teóricas e históricas que le dieron origen a esos bienes; presenta los trabajos arqueológicos que produjeron nuevas evidencias en los primeros años del presente siglo y procesa documentos de archivo, gráficos, fotográficos y bibliográficos para profundizar los estudios sobre las configuraciones territoriales, físico-funcionales y edilicias, de esos nichos poco explorados de investigación desde el campo de la arquitectura y el urbanismo. El objetivo central es aportar nuevos conocimientos que permitan incentivar la elaboración de proyectos de investigación de carácter interdisciplinarios y de gestión local y provincial para la puesta en valor de esos sitios en el marco de un plan de desarrollo socioterritorial integral y sostenible.The territory of the Pasaje or Juramento River Water Basin, in the province of Salta, Argentina, contains a set of archaeological sites that interact as a system of colonial cultural heritage assets. Among them are the ruins of the Jesuit Missions of San Esteban de Miraflores and San Juan Bautista de Valbuena that, in the mid-eighteenth century, the company of Jesus organized to gather the indigenous population with civilizing fines and evangelization. The article, worked on the basis of the results of the research project “Urban Planning and Architecture in Patrimonial Sites of the Pasaje River Basin, Salta” (2018-2019), the theoretical and historical lines that give rise to these goods; present archaeological works that produce new evidence in the first years of this century and process documents, graphics, photographic and bibliographic to deepen studies on territorial, physical-functional and building rights, of those little explored niches of research from the Field of architecture and urbanism. The main objective is to provide new knowledge that can encourage the development of interdisciplinary research projects and local and provincial management for the enhancement of these sites in the framework of a comprehensive and sustainable socio-territorial development plan.Facultad de Arquitectura y Urbanism

Jesuit missions and their contributions to the historical construcción of the territory. Basin of the river Passage. Salta, Argentina

El territorio de la Cuenca Hídrica del Río Pasaje o Juramento, en la provincia de Salta, Argentina, contiene un conjunto de sitios arqueológicos que interactúan como un sistema unívoco de bienes del patrimonio cultural colonial. Entre ellos destacan las ruinas de las Misiones Jesuíticas de San Esteban de Miraflores y San Juan Bautista de Valbuena que, a mediados del siglo XVIII, la Compañía de Jesús organizó para congregar a la población indígena con fines civilizatorios y de evangelización. El artículo, trabajado en base a los resultados del proyecto de Investigación “Urbanismo y Arquitectura en Sitios Patrimoniales de la Cuenca del rio Pasaje, Salta” (2018-2019) indaga en las líneas teóricas e históricas que le dieron origen a esos bienes; presenta los trabajos arqueológicos que produjeron nuevas evidencias en los primeros años del presente siglo y procesa documentos de archivo, gráficos, fotográficos y bibliográficos para profundizar los estudios sobre las configuraciones territoriales, físico-funcionales y edilicias, de esos nichos poco explorados de investigación desde el campo de la arquitectura y el urbanismo. El objetivo central es aportar nuevos conocimientos que permitan incentivar la elaboración de proyectos de investigación de carácter interdisciplinarios y de gestión local y provincial para la puesta en valor de esos sitios en el marco de un plan de desarrollo socioterritorial integral y sostenible.The territory of the Pasaje or Juramento River Water Basin, in the province of Salta, Argentina, contains a set of archaeological sites that interact as a system of colonial cultural heritage assets. Among them are the ruins of the Jesuit Missions of San Esteban de Miraflores and San Juan Bautista de Valbuena that, in the mid-eighteenth century, the company of Jesus organized to gather the indigenous population with civilizing fines and evangelization. The article, worked on the basis of the results of the research project “Urban Planning and Architecture in Patrimonial Sites of the Pasaje River Basin, Salta” (2018-2019), the theoretical and historical lines that give rise to these goods; present archaeological works that produce new evidence in the first years of this century and process documents, graphics, photographic and bibliographic to deepen studies on territorial, physical-functional and building rights, of those little explored niches of research from the Field of architecture and urbanism. The main objective is to provide new knowledge that can encourage the development of interdisciplinary research projects and local and provincial management for the enhancement of these sites in the framework of a comprehensive and sustainable socio-territorial development plan.Facultad de Arquitectura y Urbanism

Cutting Edge: Proangiogenic Properties of Alternatively Activated Dendritic Cells

Abstract Angiogenesis plays an important role in tissue remodeling and repair during the late phase of inflammation. In the present study, we show that human dendritic cells (DC) that matured in the presence of anti-inflammatory molecules such as calcitriol, PGE2, or IL-10 (alternatively activated DC) selectively secrete the potent angiogenic cytokine vascular endothelial growth factor (VEGF) isoforms VEGF165 and VEGF121. No VEGF production was observed in immature or classically activated DC. Also, the capacity to produce VEGF was restricted to the myeloid DC subset. When implanted in the chick embryo chorioallantoic membrane, alternatively activated DC elicit a marked angiogenic response, which is inhibited by neutralizing anti-VEGF Abs and by the VEGFR-2 inhibitor SU5416. Therefore, alternatively activated DC may contribute to the resolution of the inflammatory reaction by promoting VEGF-induced angiogenesis

Validation of cytogenetic-based risk stratification in primary myelofibrosis

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Does Subthalamic Deep Brain Stimulation Impact Asymmetry and Dyscoordination of Gait in Parkinson’s Disease?

Background. Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for selected Parkinson’s disease (PD) patients. Gait characteristics are often altered after surgery, but quantitative therapeutic effects are poorly described. Objective. The goal of this study was to systematically investigate modifications in asymmetry and dyscoordination of gait 6 months postoperatively in patients with PD and compare the outcomes with preoperative baseline and to asymptomatic controls without PD. Methods. A convenience sample of thirty-two patients with PD (19 with postural instability and gait disorder (PIGD) type and 13 with tremor dominant disease) and 51 asymptomatic controls participated. Parkinson patients were tested prior to the surgery in both OFF and ON medication states, and 6-months postoperatively in the ON stimulation condition. Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) I to IV and medication were compared to preoperative conditions. Asymmetry ratios, phase coordination index, and walking speed were assessed. Results. MDS-UPDRS I to IV at 6 months improved significantly, and levodopa equivalent daily dosages significantly decreased. STN-DBS increased step time asymmetry (hedges’ g effect sizes [95% confidence interval] between pre- and post-surgery: .27 [-.13, .73]) and phase coordination index (.29 [-.08, .67]). These effects were higher in the PIGD subgroup than the tremor dominant (step time asymmetry: .38 [-.06, .90] vs .09 [-.83, 1.0] and phase coordination index: .39 [-.04, .84] vs .13 [-.76, .96]). Conclusions. This study provides objective evidence of how STN-DBS increases asymmetry and dyscoordination of gait in patients with PD and suggests motor subtypes‐associated differences in the treatment response

Evaluation of Clinical and Immunological Markers for predicting Virological Failure in a HIV/AIDS treatment cohort in Busia, Kenya

In resource-limited settings where viral load (VL) monitoring is scarce or unavailable, clinicians must use immunological and clinical criteria to define HIV virological treatment failure. This study examined the performance of World Health Organization (WHO) clinical and immunological failure criteria in predicting virological failure in HIV patients receiving antiretroviral therapy (ART)

Hard-magnetic cell microscaffolds from electroless coated 3D printed architectures

We report the application of 3D printing and wet metallization to the fabrication of magnetically driven microscaffolds for cell delivery