Abstract
Background
Survivin and its alternative splice forms are involved in critical cellular processes, including cell division and programmed cell death. Survivin is expressed in the majority of ...human cancers, but minimally in differentiated normal tissues. Expression levels correlate with tumor aggressiveness and resistance to therapy.
Results
In the present study, we identify and characterize a novel survivin isoform that we designate survivin 2α. Structurally, the transcript consists of 2 exons: exon 1 and exon 2, as well as a 3' 197 bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nucleotides, predicting a truncated 74 amino acid protein. Survivin 2α is expressed at high levels in several malignant cell lines and primary tumors. Functional assays show that survivin 2α attenuates the anti-apoptotic activity of survivin. Subcellular localization and immunoprecipitation of survivin 2α suggests a physical interaction with survivin.
Conclusion
We characterized a novel survivin splice variant that we designated survivin 2α. We hypothesize that survivin 2α can alter the anti-apoptotic functions of survivin in malignant cells. Thus survivin 2α may be useful as a therapeutic tool in sensitizing chemoresistant tumor cells to chemotherapy.
Survivin is an inhibitor of apoptosis protein that also plays critical roles in regulating the cell cycle and mitosis. Its prominent expression in essentially all human malignancies, and low or ...absent expression in most normal tissues, suggests that it would be an ideal target for cancer-directed therapy. Impeding development of safe and effective survivin antagonists for clinical use is a lack of understanding of the molecular mechanisms by which survivin differentially affects apoptosis and cell division, in normal and malignant cells. We show that the diverse functional roles of survivin can be explained, in part, by its heterodimerization with survivin splice variants in tumor cells. Survivin and survivin-DeltaEx3 interact within the mitochondria where they may inhibit mitochondrial-dependent apoptosis. If the expression of all survivin forms is eliminated by siRNA transfections, cells undergo both apoptosis and defective cell division. Overall, we provide new insights suggesting that targeting specific survivin isoforms, rather than survivin alone, may selectively and effectively destroy tumor cells. These findings are likely to have a significant impact in the design of biologic agents for clinical therapy.
AimIn response to the coronavirus 2019 disease (COVID-19) pandemic, governments worldwide implemented measures to prevent infection, resulting in restricted school activities, restricted children’s ...freedom of movement, and increased risk of violence and injuries at home, including traumatic brain injury (TBI), among children. In Brazil, the consequences of the COVID-19 pandemic on the causes, severity, and mortality of pediatric TBI have not yet been investigated. Thus, our study aimed to determine whether the COVID-19 pandemic has affected the epidemiology of pediatric TBI among Brazilian children.Materials and methodsWe investigated the patients with TBI aged <18 years who visited a tertiary trauma center in Brazil in 2019 and 2020. TBI-related variables, such as classification, mechanism, clinical manifestations, need for intervention, morbidity, and mortality, were recorded. Furthermore, we used a nationwide databank to collect information on mortality from external causes of trauma and violence in the pediatric population in 2019 and 2020. The Mann-Whitney test was used to compare quantitative variables related to the mechanisms and severity of TBI in both periods in order to determine the impact of the COVID-19 pandemic.ResultsOf the patients with traumatic brain injury, 1371 visited the trauma center in 2019 and 1052 in 2020. No difference was noted in the incidence rate of abusive head trauma between these periods (p=0.142) or in mortality from violence in Brazil. Recreational causes of pediatric TBI increased during the first year of the COVID-19 pandemic in Brazil and falls from bicycles significantly increased during the pandemic (p<0.001).ConclusionA global reduction in pediatric admissions to emergency rooms as well as no impact on mortality and severity of pediatric TBI were observed during the COVID-19 pandemic in Brazil. Additionally, a public education program regarding child safety during recreational activities, particularly how to avoid falls from bicycles was recommended.
Apoptosis is an essential process during normal neuronal development. Approximately one-half of the neurons produced during neurogenesis die before completion of CNS maturation. To characterize the ...role of the inhibitor of apoptosis gene, survivin, during neurogenesis, we used the Cre-loxP-system to generate mice lacking survivin in neuronal precursor cells. Conditional deletion of survivin starting at embryonic day 10.5 leads to massive apoptosis of neuronal precursor cells in the CNS. Conditional mutants were born at the expected Mendelian ratios; however, these died shortly after birth from respiratory insufficiency, without primary cardiopulmonary pathology. Newborn conditional mutants showed a marked reduction in the size of the brain associated with severe, mutifocal apoptosis in the cerebrum, cerebellum, brainstem, spinal cord, and retina. Caspase-3 and caspase-9 activities in the mutant brains were significantly elevated, whereas bax expression was unchanged from controls. These results show that survivin is critically required for the survival of developing CNS neurons, and may impact on our understanding of neural repair, neural development, and neurodegenerative diseases. Our study is the first to solidify a role for survivin as an antiapoptotic protein during normal neuronal development in vivo.
Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural ...killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B-induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only-treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin.
A presença da sarcotesta pode prejudicar a germinação e desenvolvimento das plântulas. O objetivo deste trabalho foi identificar métodos favoráveis à remoção da sarcotesta para a promoção da ...germinação de sementes de Jaracatia spinosa, cujas sementes foram submetidas aos seguintes tratamentos: 1- sem remoção da sarcotesta; 2- remoção com fricção sobre peneira, com adição de areia; 3- remoção com fricção sobre peneira com adição de cal; 4- remoção com o uso de liquidificador, 5- remoção com despolpador de sementes; e 6- remoção com solução química (imersão, por 30 min, numa solução composta por 1.0 L de água, 3.5 mL de hipoclorito de sódio, 3.0 mL de ácido muriático e 22.5g de soda cáustica), em que as sementes foram avaliadas quanto à percentagem de germinação, Índice de Velocidade de Emergência (IVE) e comprimento da parte aérea de plântulas. O método mais favorável à remoção da sarcotesta e promoção da germinação das sementes de jaracatiá foi a fricção sobre peneira com a adição de areia.
NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. ...Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked, male lethal disorder, as well as the mouse mutations bare patches and striated. In the present study, we have investigated the subcellular localization of tagged proteins encoded by wild-type and selected mutant murine Nsdhl alleles using confocal microscopy. In addition to an ER localization commonly found for enzymes of post-squalene cholesterol biosynthesis, we have identified a novel association of NSDHL with lipid droplets, which are endoplasmic reticulum (ER)-derived cytoplasmic structures that contain a neutral lipid core. We further demonstrate that trafficking through the Golgi is necessary for ER membrane localization of the protein and propose a model for the association of NSDHL with lipid droplets. The dual localization of NSDHL within ER membranes and on the surface of lipid droplets may provide another mechanism for regulation of the levels and sites of accumulation of intracellular cholesterol.
Atenção primária à saúde e seu papel na reabilitação Campos, Valdemberto Salomão Modesto Jacó Pereira; Rêgo, Luiz Flávio Teixeira; Neto, José Alves Tenório ...
Brazilian Journal of Development,
02/2023, Letnik:
9, Številka:
2
Journal Article
INTRODUÇÃO: A principal estratégia para melhorar o acesso à saúde é através da Estratégia de Saúde da Família e Comunidade (ESFC), o que inclui o maior acesso à reabilitação. OBJETIVO: Este trabalho ...visa esclarecer o papel da APS na reabilitação dos usuários atendidos pelas USFs. METODOLOGIA: Revisão narrativa da literatura. Os trabalhos incluídos devem ser encontrados dos Descritores em Ciências da Saúde (DeCS) “Fisiatria”, “Atenção primária à saúde” e “Reabilitação” nas bases de dados PubMed, SciElo, Google Acadêmico e UpToDate e seguir os critérios de inclusão. RESULTADOS: Foram encontrados 68 documentos, 17 foram selecionados. 9 foram utilizados na produção deste trabalho. REVISÃO DE LITERATURA: A Reabilitação Baseada na Comunidade auxilia a Atenção Básica no atendimento de pessoas em reabilitação nas áreas atendidas. Para isso, o cuidado longitudinal é necessário para acompanhamento do paciente, família e comunidade, uma vez que a perda da capacidade funcional altera toda a dinâmica das relações da pessoa. O apoio matricial é definido como uma estratégia para aproximar as áreas de saúde da assistência integral ao paciente e propiciar uma percepção holística do acompanhamento. Objetivos Realistas são criados junto à equipe para traçar o tratamento. CONCLUSÃO: Pode-se dizer que a APS atua na identificação, prevenção, tratamento longitudinal e acompanhamento contínuo dos pacientes em RCB, assim como oferece suporte à família e comunidade em que o paciente está inserido, pois todo o grupo familiar é afetado.
Pessoas com Transtorno do Espectro Autista (TEA) têm como característica principal déficits sociocomunicativos, necessitando, dependendo do grau, de um acompanhante para um suporte intenso e em tempo ...integral que, geralmente, vem da sua mãe biológica. Em decorrência dos comportamentos ansiosos, hiperativos, déficits de adaptação, déficits de comunicação e interação do autista há prejuízos no seu desenvolvimento, comunicação e socialização, além de interferir na rotina da família e, principalmente, na saúde mental e física da mãe. O recebimento do diagnóstico pode ser um alívio ou um sofrimento, gerando repercussões negativas ou positivas na percepção materna. Essas mulheres passam por um processo de aceitação do diagnóstico e da condição dos seus filhos. As críticas negativas, exclusão social, regras de gênero e sobrecarga de deveres favorecem o surgimento de acometimentos psiquiátricos na mãe de filho com TEA. Além do próprio transtorno, comorbidades frequentes também dificultam o manejo dessas crianças pela progenitora. Dependendo do significado dado ao diagnóstico do seu filho, as cuidadoras podem ter diversas formas de lidar com a vivência diária, mas sabe-se que isso interfere diretamente na saúde de suas mentes. Deve ser ressaltada a importância dos profissionais de saúde para nortear essas mães, uma vez que elas os vêem como autoridades de informação e se baseiam nos dados informados para tomada de decisão. Eles fazem parte das formas de apoio fornecidas e percebidas pelas mulheres que exercem a maternidade de filhos com o transtorno. A forma, tipo, qualidade e intimidade envolvidos no apoio são significativos para a percepção do suporte pela mãe. São necessários mais estudos para entender melhor a situação dessas mães no Brasil e no mundo, pois a literatura nacional é escassa. Dessa forma será possível cuidar de quem cuida.
Survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, is widely expressed in transformed cell lines and in many different primary cancer cells, including both hematopoietic and ...non-hematopoietic malignancies. It is not expressed in many non-malignant adult tissues, but is essential for fetal development, as demonstrated by conventional gene-targeting experiments in mice that show embryonic lethality at day 4–6 of development. In adult cancers, including lymphoma and many epithelial carcinomas (colon, breast, gastric) the expression level of survivin, as assayed by immunohistochemical analysis and RT-PCR, correlates with overall survival.
We have designed a novel gene therapy approach that takes advantage of the high expression levels of survivin in malignant cells, in which the survivin promoter is used to drive the expression of a suicide gene to kill cancer cells by programmed cell death. Our system is based on perforin-independent granzyme B cytotoxicity and therefore does not require pro-drug activation. We designated it SAGA, for survivin and granzyme apoptosis. We used Jurkat cells as an in vitro model for T-cell leukemia, and 697Bcl2 cells as a model for pre-B Bcl2-expressing leukemia, to show this approach is more efficient in killing leukemic cells than conventional chemotherapy. Jurkat cells responded to both vincristine therapy and SAGA whereas 697Bcl2 were unaffected by vincristine, but responded to SAGA. Cell growth curves of Jurkat cells and 697Bcl2 cells are shown in Figure 1. Our approach not only inhibits cell growth, but also induces apoptosis. We detected apoptotic events by Annexin V staining and by changes in mitochondrial potential, as early as 12 hours post-treatment. Rates of early apoptotic events are shown in Table 1. In addition to these events, we also documented DNA fragmentation and caspase-3 activation in treated cells. Cytotoxicity was clearly visible by microscopic analysis 24 hours post-treatment (Figure 2). Our results strongly suggest that survivin-driven suicide gene therapy effectively enhances cell death of leukemic blasts derived from two common sub-types of ALL, one of which expresses the potent anti-apoptotic inhibitor, Bcl-2, known to be clinically more resistant to standard therapy. Experiments evaluating the in vivo effects of SAGA in mouse leukemia models are currently underway.
Cell death at 24 hours
Early ApoptosisNecrosiscontrolvincristineSAGAcontrolvincristineSAGAT-ALL2%46%41%2%18%19%B-ALL1%2%29%0.4%1%30%
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