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

Changuinola Virus Serogroup, New Genomes within the Genus Orbivirus (Family Reoviridae) Isolated in the Brazilian Amazon Region

We report here the first complete genome sequence of a Changuinola virus (CGLV) serotype Irituia virus (BE AN 28873) isolated from a wild rodent (Oryzomys goeldi) in the municipality of Ipixuna, State of Par&aacute;, northern Brazil. All genome segments showed similarity with those belonging to members of the genus Orbivirus, family Reoviridae

Air Travel Is Associated with Intracontinental Spread of Dengue Virus Serotypes 1–3 in Brazil

Dengue virus and its four serotypes (DENV-1 to DENV-4) infect 390 million people and are implicated in at least 25,000 deaths annually, with the largest disease burden in tropical and subtropical regions. We investigated the spatial dynamics of DENV-1, DENV-2 and DENV-3 in Brazil by applying a statistical framework to complete genome sequences. For all three serotypes, we estimated that the introduction of new lineages occurred within 7 to 10-year intervals. New lineages were most likely to be imported from the Caribbean region to the North and Northeast regions of Brazil, and then to disperse at a rate of approximately 0.5 km/day. Joint statistical analysis of evolutionary, epidemiological and ecological data indicates that aerial transportation of humans and/or vector mosquitoes, rather than Aedes aegypti infestation rates or geographical distances, determine dengue virus spread in Brazil

Low prevalence of renal, cardiac, pulmonary, and neurological extra-articular clinical manifestations in spondyloarthritis: analysis of the Brazilian Registry of Spondyloarthritis

OBJECTIVE: To describe the extra-articular manifestations (cardiac, renal, pulmonary, and neurological), usually not related to spondyloarthritis (SpA), in a large cohort of Brazilian patients. MATERIALS AND METHODS: This retrospective study analyzed 1,472 patients diagnosed with SpA and cared for at 29 health care centers distributed in the five major geographic regions in the country, participating in the Brazilian Registry of Spondyloarthritis (BRS). All patients were assessed for the prevalence of major extra-articular manifestations (cardiac, renal, pulmonary, and neurological), classified according to the diagnosis [ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease (IBD), undifferentiated spondyloarthritis (uSpA), and juvenile SpA], and according to the clinical presentation (axial, peripheral, mixed, and enthesitis). RESULTS: Of the patients with SpA assessed, 963 had AS, 271 PsA, 49 ReA, 48 arthritis associated with IBD, 98 uSpA, and 43 juvenile SpA. Cardiac involvement was reported in 44 patients (3.0%), pulmonary involvement in 19 (1.3%), renal involvement in 17 (1.2%), and neurological involvement in 13 patients (0.9%). Most patients with visceral involvement had AS or PsA, and the mixed (axial + peripheral) and/or predominantly axial clinical form. CONCLUSION: Cardiac, renal, pulmonary, and neurological extra-articular manifestations are quite infrequent in SpA, ranging from 0.9% to 3% in this large Brazilian cohort, and affected predominantly patients with AS and PsA.OBJETIVO: Descrever as manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas) geralmente não relacionadas às espondiloartrites (EpA) em uma grande coorte de pacientes brasileiros. MÉTODOS: Este estudo retrospectivo analisou 1.472 pacientes com o diagnóstico de EpA atendidos em 29 centros distribuídos pelas cinco principais regiões geográficas do Brasil, integrantes do Registro Brasileiro de Espondiloartrites. Todos os pacientes foram avaliados para a prevalência das principais manifestações extra-articulares (cardíacas, renais, pulmonares e neurológicas), divididas por diagnóstico [espondilite anquilosante (EA), artrite psoriásica (AP), artrite reativa (ARe), artrite associada a doença inflamatória intestinal (DII), EpA indiferenciada (EI) e EpA juvenil] e por forma clínica (axial, periférica, mista e entesítica). RESULTADOS: Dentre os pacientes avaliados com EpA, 963 apresentavam EA, 271 AP, 49 ARe, 48 artrite associada a DII, 98 EI e 43 EpA juvenil. Acometimento cardíaco foi observado em 44 pacientes (3,0%), seguido por acometimento pulmonar em 19 (1,3%), renal em 17 (1,2%) e neurológico em 13 pacientes (0,9%). A maioria dos casos de acometimento visceral ocorreu nos pacientes com EA ou AP e naqueles com forma clínica mista (axial e periférica) e/ou predominantemente axial. CONCLUSÃO: As manifestações extra-articulares cardíacas, renais, pulmonares e neurológicas são muito pouco frequentes nas EpA, variando de 0,9%-3% nesta grande coorte brasileira, estando mais associadas a EA e AP.37938

RELAÇÃO ENTRE A REGULAÇÃO AUTONÔMICA CARDÍACA E MECANISMOS AUDITIVOS: IMPORTÂNCIA PARA O CRESCIMENTO E DESENVOLVIMENTO

The literature has already demonstrated that auditory stimulation with music influences thecardiovascular system. In this study, we performed a literature review in order to investigate therelationship between auditory mechanisms and cardiac autonomic regulation. The selected studiesindicated that there is a strong correlation between noise intensity and vagal-sympathetic balance.Also, it was reported that music therapy improved heart rate variability in anthracycline-treatedbreast cancer patients. It was hypothesized that dopamine release in the striatal system induced bypleasure songs are involved in the cardiac autonomic regulation. Further studies are necessary toadd new elements in the literature to improve new therapies to treat cardiovascular disorders.A literatura já demonstrou que a estimulação auditiva por meio de música influencia o sistemacardiovascular. Neste estudo, foi realizada uma revisão da literatura, a fim de investigar a relaçãoentre os mecanismos auditivos e a regulação autonômica cardíaca. Os estudos selecionados indicaramforte correlação entre a intensidade do ruído e o equilíbrio simpatovagal. Além disso, foi relatadoque a terapia com música melhorou a variabilidade da frequência cardíaca em pacientes com câncerde mama tratados com antraciclinas. Postula-se que a dopamina liberada no sistema estriatal,induzida por canções alegres, está envolvida na regulação autonômica. Estudos posteriores sãonecessários para adicionar novos elementos na literatura, para melhorar a novas terapias e para otratar doenças cardiovasculares

The use of Open Reading frame ESTs (ORESTES) for analysis of the honey bee transcriptome

BACKGROUND: The ongoing efforts to sequence the honey bee genome require additional initiatives to define its transcriptome. Towards this end, we employed the Open Reading frame ESTs (ORESTES) strategy to generate profiles for the life cycle of Apis mellifera workers. RESULTS: Of the 5,021 ORESTES, 35.2% matched with previously deposited Apis ESTs. The analysis of the remaining sequences defined a set of putative orthologs whose majority had their best-match hits with Anopheles and Drosophila genes. CAP3 assembly of the Apis ORESTES with the already existing 15,500 Apis ESTs generated 3,408 contigs. BLASTX comparison of these contigs with protein sets of organisms representing distinct phylogenetic clades revealed a total of 1,629 contigs that Apis mellifera shares with different taxa. Most (41%) represent genes that are in common to all taxa, another 21% are shared between metazoans (Bilateria), and 16% are shared only within the Insecta clade. A set of 23 putative genes presented a best match with human genes, many of which encode factors related to cell signaling/signal transduction. 1,779 contigs (52%) did not match any known sequence. Applying a correction factor deduced from a parallel analysis performed with Drosophila melanogaster ORESTES, we estimate that approximately half of these no-match ESTs contigs (22%) should represent Apis-specific genes. CONCLUSIONS: The versatile and cost-efficient ORESTES approach produced minilibraries for honey bee life cycle stages. Such information on central gene regions contributes to genome annotation and also lends itself to cross-transcriptome comparisons to reveal evolutionary trends in insect genomes

Exposure of Phosphatidylserine on Leishmania amazonensis Isolates Is Associated with Diffuse Cutaneous Leishmaniasis and Parasite Infectivity

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of leishmaniasis, characterized by an inefficient parasite-specific cellular response and heavily parasitized macrophages. In Brazil, Leishmania (Leishmania) amazonensis is the main species involved in DCL cases. In the experimental model, recognition of phosphatidylserine (PS) molecules exposed on the surface of amastigotes forms of L. amazonensis inhibits the inflammatory response of infected macrophages as a strategy to evade the host immune surveillance. In this study, we examined whether PS exposure on L. amazonensis isolates from DCL patients operated as a parasite pathogenic factor and as a putative suppression mechanism of immune response during the infection. Peritoneal macrophages from F1 mice (BALB/c×C57BL/6) were infected with different L. amazonensis isolates from patients with localized cutaneous leishmaniasis (LCL) or DCL. DCL isolates showed higher PS exposure than their counterparts from LCL patients. In addition, PS exposure was positively correlated with clinical parameters of the human infection (number of lesions and time of disease) and with characteristics of the experimental infection (macrophage infection and anti-inflammatory cytokine induction). Furthermore, parasites isolated from DCL patients displayed an increased area in parasitophorous vacuoles (PV) when compared to those isolated from LCL patients. Thus, this study shows for the first time that a parasite factor (exposed PS) might be associated with parasite survival/persistence in macrophages and lesion exacerbation during the course of DCL, providing new insights regarding pathogenic mechanism in this rare chronic disease

De Novo assembly and transcriptome analysis of the mediterranean fruit fly ceratitis capitata early embryos

The agricultural pest Ceratitis capitata, also known as the Mediterranean fruit fly or Medfly, belongs to the Tephritidae family, which includes a large number of other damaging pest species. The Medfly has been the first non-drosophilid fly species which has been genetically transformed paving the way for designing geneticbased pest control strategies. Furthermore, it is an experimentally tractable model, in which transient and transgene-mediated RNAi have been successfully used. We applied Illumina sequencing to total RNA preparations of 8-10 hours old embryos of C. capitata, This developmental window corresponds to the blastoderm cellularization stage. In summary, we assembled 42,614 transcripts which cluster in 26,319 unique transcripts of which 11,045 correspond to protein coding genes; we identified several hundreds of long ncRNAs; we found an enrichment of transcripts encoding RNA binding proteins among the highly expressed transcripts, such as CcTRA-2, known to be necessary to establish and, most likely, to maintain female sex of C. capitata. Our study is the first de novo assembly performed for Ceratitis capitata based on Illumina NGS technology during embryogenesis and it adds novel data to the previously published C. capitata EST databases. We expect that it will be useful for a variety of applications such as gene cloning and phylogenetic analyses, as well as to advance genetic research and biotechnological applications in the Medfly and other related Tephritidae