Targeting MAGE-C1/CT7 Expression Increases Cell Sensitivity to the Proteasome Inhibitor Bortezomib in Multiple Myeloma Cell Lines

The MAGE-C1/CT7 encodes a cancer/testis antigen (CTA), is located on the chromosomal region Xq26-27 and is highly polymorphic in humans. MAGE-C1/CT7 is frequently expressed in multiple myeloma (MM) that may be a potential target for immunotherapy in this still incurable disease. MAGEC1/CT7 expression is restricted to malignant plasma cells and it has been suggested that MAGE-C1/CT7 might play a pathogenic role in MM; however, the exact function this protein in the pathophysiology of MM is not yet understood. Our objectives were (1) to clarify the role of MAGE-C1/CT7 in the control of cellular proliferation and cell cycle in myeloma and (2) to evaluate the impact of silencing MAGE-C1/CT7 on myeloma cells treated with bortezomib. Myeloma cell line SKO-007 was transduced for stable expression of shRNA-MAGE-C1/CT7. Downregulation of MAGE-C1/CT7 was confirmed by real time quantitative PCR and western blot. Functional assays included cell proliferation, cell invasion, cell cycle analysis and apoptosis. Western blot showed a 70-80% decrease in MAGE-C1/CT7 protein expression in inhibited cells (shRNA-MAGE-C1/CT7) when compared with controls. Functional assays did not indicate a difference in cell proliferation and DNA synthesis when inhibited cells were compared with controls. However, we found a decreased percentage of cells in the G2/M phase of the cell cycle among inhibited cells, but not in the controls (p < 0.05). When myeloma cells were treated with bortezomib, we observed a 48% reduction of cells in the G2/M phase among inhibited cells while controls showed 13% (empty vector) and 9% (ineffective shRNA) reduction, respectively (p < 0.01). Furthermore, inhibited cells treated with bortezomib showed an increased percentage of apoptotic cells (Annexin V+/PI-) in comparison with bortezomib-treated controls (p < 0.001). We found that MAGE-C1/CT7 protects SKO-007 cells against bortezomib-induced apoptosis. Therefore, we could speculate that MAGE-C1/CT7 gene therapy could be a strategy for future therapies in MM, in particular in combination with proteasome inhibitors.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo Branch, BrazilUniversidade Federal de São Paulo, Disciplina Hematol & Hemoterapia, São Paulo, BrazilLudwig Inst Canc Res, Lab Mol Biol & Genom, São Paulo, BrazilRecepta Biopharma, Ludwig Inst Canc Res, São Paulo, BrazilInCor, Fac Med, Setor Vetores Virais, Lab Genet & Cardiol Mol, São Paulo, BrazilJohns Hopkins Univ, Sch Med, Dept Neurosurg, Ludwig Collaborat Grp, Baltimore, MD 21205 USAUniv Med Ctr Hamburg Eppendorf, Dept Med 2, Hamburg, GermanyUniversidade Federal de São Paulo, Disciplina Hematol & Hemoterapia, São Paulo, BrazilWeb of Scienc

In vitro Antiplasmodial Activities of Alkaloids Isolated from Roots of Worsleya procera (Lem.) Traub (Amaryllidaceae)

A combined phytochemical, crystallographic and biological study of Worsleya procera roots was performed. Fifteen alkaloids were identified by gas chromatography mass spectrometry (GC-MS) and seven of them were isolated. The structures of the alkaloids were elucidated by spectroscopic methods, and a detailed crystallographic study of tazettine was carried out. The isolated alkaloids and the obtained extracts were tested in vitro against Plasmodium falciparum (3D7 and K1 strains) and human hepatocarcinoma cells (HepG2) to assess their antiplasmodial and cytotoxic effects, respectively. One of the isolated alkaloid derivatives, lycorine, exhibited antiplasmodial activity against both sensitive (3D7) and resistant (K1) parasite strains in the low micromolar range (half-maximal sample inhibitory concentration (IC50) values of 2.5 and 3.1 µM, respectively) and displayed a low cytotoxicity profile, with a selectivity index greater than 100. Our findings indicate that lycorine is a hit for antimalarial drug discovery. Keywords: isoquinolinic alkaloids; Amaryllidaceae; Plasmodium falciparum; lycorine; tazettin

Rutin-functionalized multi-walled carbon nanotubes: molecular docking, physicochemistry and cytotoxicity in fibroblasts

Multi-Walled Carbon Nanotubes (MWCNT) have been functionalized with rutin through three steps (i. reaction step; ii. purification step; iii. drying step) and their physicochemical properties investigated with respect to morphological structure, thermal analysis, Fourier Transform Infrared Spectroscopy (FTIR), and cytotoxicity. The molecular docking suggested the rutin-functionalized MWCNT occurred by hydrogen bonds, which was confirmed by FTIR assays, corroborating the results obtained by thermal analyses. A tubular shape, arranged in a three-dimensional structure, could be observed. Mild cytotoxicity observed in 3T3 fibroblasts suggested a doseeffect relationship after exposure. These findings suggest the formation of aggregates of filamentous structures on the cells favoring the cell penetration.The authors acknowledge Classius Ferreira da Silva, from the Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, for the scanning electron microscopy analyses.info:eu-repo/semantics/publishedVersio

MobiSaúde: Sistema de Informação para Visitas Domiciliares na Área de Saúde / MobiSaúde: Information System for Home Visits in the Health Area

Com a popularização de dispositivos móveis e o aumento das capacidades dos mesmos, houve a integração entre sistemas de informação da área de saúde e estes dispositivos, chamada de mHealth. Neste trabalho discutimos um SIS voltado para visitas domiciliares medicas, com foco na coleta de dados e nas dificuldades envolvendo a locomoção do agente realizador

Molecular evolution of zika virus during its emergence in the 20th century

Zika virus (ZIKV) is a mosquito-borne flavivirus first isolated in Uganda in 1947. Although entomological and virologic surveillance have reported ZIKV enzootic activity in diverse countries of Africa and Asia, few human cases were reported until 2007, when a Zika fever epidemic took place in Micronesia. In the context of West Africa, the WHO Collaborating Centre for Arboviruses and Hemorrhagic Fever at Institut Pasteur of Dakar (http://www.pasteur.fr/recherche/banques/CRORA/) reports the periodic circulation of ZIKV since 1968. Despite several reports on ZIKV, the genetic relationships among viral strains from West Africa remain poorly understood. To evaluate the viral spread and its molecular epidemiology, we investigated 37 ZIKV isolates collected from 1968 to 2002 in six localities in Senegal and Côte d'Ivoire. In addition, we included strains from six other countries. Our results suggested that these two countries in West Africa experienced at least two independent introductions of ZIKV during the 20th century, and that apparently these viral lineages were not restricted by mosquito vector species. Moreover, we present evidence that ZIKV has possibly undergone recombination in nature and that a loss of the N154 glycosylation site in the envelope protein was a possible adaptive response to the Aedes dalzieli vector.Institute Pasteur of Dakar in SenegalFAPESP (Fundação de Amparo a Pesquisa do Estado de Sao Paulo, Brazil) projects #00/04205-6FAPESP (Fundação de Amparo a Pesquisa do Estado de Sao Paulo, Brazil) projects #08/17013-6FAPESP (Fundação de Amparo a Pesquisa do Estado de Sao Paulo, Brazil) projects#10/19341-4CAPES studentship, AI (project #12/04818-5)FAPESP scholarships and PMAZCNPq-PQNIH, R01-AI06914

Rarity of monodominance in hyperdiverse Amazonian forests.

Tropical forests are known for their high diversity. Yet, forest patches do occur in the tropics where a single tree species is dominant. Such "monodominant" forests are known from all of the main tropical regions. For Amazonia, we sampled the occurrence of monodominance in a massive, basin-wide database of forest-inventory plots from the Amazon Tree Diversity Network (ATDN). Utilizing a simple defining metric of at least half of the trees ≥ 10 cm diameter belonging to one species, we found only a few occurrences of monodominance in Amazonia, and the phenomenon was not significantly linked to previously hypothesized life history traits such wood density, seed mass, ectomycorrhizal associations, or Rhizobium nodulation. In our analysis, coppicing (the formation of sprouts at the base of the tree or on roots) was the only trait significantly linked to monodominance. While at specific locales coppicing or ectomycorrhizal associations may confer a considerable advantage to a tree species and lead to its monodominance, very few species have these traits. Mining of the ATDN dataset suggests that monodominance is quite rare in Amazonia, and may be linked primarily to edaphic factors

Hysteretic Behavior of Proprotein Convertase 1/3 (PC1/3)

The proprotein convertases (PCs) are calcium-dependent proteases responsible for processing precursor proteins into their active forms in eukariotes. The PC1/3 is a pivotal enzyme of this family that participates in the proteolytic maturation of prohormones and neuropeptides inside the regulated secretory pathway. In this paper we demonstrate that mouse proprotein convertase 1/3 (mPC1/3) has a lag phase of activation by substrates that can be interpreted as a hysteretic behavior of the enzyme for their hydrolysis. This is an unprecedented observation in peptidases, but is frequent in regulatory enzymes with physiological relevance. The lag phase of mPC1/3 is dependent on substrate, calcium concentration and pH. This hysteretic behavior may have implications in the physiological processes in which PC1/3 participates and could be considered an additional control step in the peptide hormone maturation processes as for instance in the transformation of proinsulin to insulin

Presence and extent of the primary health care attributes among children hospitalized for pneumonia

OBJECTIVE: to analyze the presence and extent of the primary health care attributes among children hospitalized for pneumonia.METHOD: observational and retrospective study with hospital-based case-control design, developed in three hospitals associated to the Brazilian Unified Health System, located in a city of the State of São Paulo, Brazil. The study included 690 children under five years old, with 345 cases and 345 controls.RESULTS: both groups scored high for access to health services. In contrast, high scores for attributes such as longitudinality and coordination of care were observed for the controls. Despite low scores, integrality and family counseling were also high for the controls.CONCLUSION: knowledge of the aspects involving the primary health care attributes and its provision for child care are very important because they have the potential to support professionals and managers of the Brazilian Unified Health System in the organization of health services