A combined molecular clinical predictor of survival validated with the rtog-0525 cohort

For glioblastoma (GBM), survival classification has primarily relied on clinical criteria, exemplified by the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA). We sought to improve tumor classification by combining tumor biomarkers with the clinical RPA data. To accomplish this, we first developed 4 molecular biomarkers derived from gene expression profiling, a glioma CpG island methylator phenotype, a novel MGMT promoter methylation assay, and IDH1 mutations. A molecular predictor (MP) model was created with these 4 biomarkers on a training set of 220 retrospectively collected archival GBMtumors. ThisMPwas further combined with RPA classification to develop a molecular-clinical predictor (MCP). The median survivals for the combined, 4-class MCP were 65 months, 31 months, 13 months, and 9 months, which was significantly improved when compared with the RPA alone. The MCP was then applied to 725 samples from the RTOG-0525 cohort, showing median survival for each risk group of NR, 26 months, 16 months, and 11 months. The MCP was significantly improved over the RPA at outcome prediction in the RTOG 0525 cohort with a 33%increase in explained variation with respect to survival, validating the result obtained in the training set. To illustrate the benefit of the MCP for patient stratification, we examined progression-free survival (PFS) for patients receiving standard-dose temozolomide (SD-TMZ) vs. dose-dense TMZ (DD-TMZ) in RPA and MCP risk groups. A significant difference between DD-TMZ and SD-TMZ was observed in the poorest surviving MCP risk group with a median PFS of 6 months vs. 3 months (p ¼ 0.048, log-rank test). This difference was not seen using the RPA classification alone. In summary, we have developed a combined molecular-clinical predictor that appears to improve outcome prediction when compared with clinical variables alone. This MCP may serve to better identify patients requiring intensive treatments beyond the standard of care.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

Uncorrelatedness in growing networks with preferential survival of nodes

The emergence of uncorrelated growing networks is proved when nodes are removed either uniformly or under the preferential survival rule recently observed in the World Wide Web evolution. To this aim, the rate equation for the joint probability of degrees is derived, and stationary symmetrical solutions are obtained, by passing to the continuum limit. When a uniformly random removal of extant nodes and linear preferential attachment of new nodes are at work, we prove that the only stationary solution corresponds to uncorrelated networks for any removal rate r ∈ (0,1). In the more general case of preferential survival of nodes, uncorrelated solutions are also obtained. These results generalize the uncorrelatedness displayed by the (undirected) Barab´asi-Albert network model to models with uniformly random and selective (against low degrees) removal of nodes

Effect of Temperature on the Development and Survival of the Argentine Ant, Linepithema humile

The influence of temperature on the developmental times and survival of insects can largely determine their distribution. For invasive species, like the Argentine ant, Linepithema humile Mayr (Hymenoptera: Formicidae), these data are essential for predicting their potential range based on mechanistic models. In the case of this species, such data are too scarce and incomplete to make accurate predictions based on its physiological needs. This research provides comprehensive new data about brood survival and developmental times at a wide range of temperatures under laboratory conditions. Temperature affected both the complete brood development from egg to adult worker and each of the immature stages separately. The higher the temperature, the shorter the development times. Brood survival from egg to adult was low, with the maximum survival rate being only 16% at 26° C. Temperature also affected survival of each of the immature stages differently: eggs were negatively affected by high temperatures, while larvae were negatively affected by low temperatures, and the survival of pupae was apparently independent of environmental temperature. At 32° C no eggs survived, while at 18° C less than 2% of the eggs hatched into larva. The data from the present study are essential for developing prediction models about the distribution range of this tramp species based on its physiological needs in relation to temperature

Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells.

The acquisition of neuroendocrine (NE) characteristics by prostate cancer (PCa) cells is closely related to tumour progression and hormone resistance. The mechanisms by which NE cells influence PCa growth and progression are not fully understood. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in oncogenic processes, and MIF serum levels correlate with aggressiveness of PCa. Here, we investigated the regulation and the functional consequences of MIF expression during NE transdifferentiation of PCa cells. NE differentiation (NED) of LNCaP cells, initiated either by increasing intracellular levels of cAMP or by culturing cells in an androgen-depleted medium, was associated with markedly increased MIF release. Yet, intracellular MIF protein and mRNA levels and MIF gene promoter activity decreased during NED of LNCaP cells, suggesting that NED favours MIF release despite decreasing MIF synthesis. Adenoviral-mediated forced MIF expression in NE-differentiated LNCaP cells increased cell proliferation without affecting the expression of NE markers. Addition of exogenous recombinant MIF to LNCaP and PC-3 cells stimulated the AKT and ERK1/2 signalling pathways, the expression of genes involved in PCa, as well as proliferation and resistance to paclitaxel and thapsigargin-induced apoptosis. Altogether, these data provide evidence that increased MIF release during NED in PCa may facilitate cancer progression or recurrence, especially following androgen deprivation. Thus, MIF could represent an attractive target for PCa therapy.

Entre o medo da contaminação pelo HIV e as representações simbólicas da AIDS: o espectro do desespero contemporâneo

Este estudo pretende colaborar para uma melhor compreensão dos sentimentos provocados no ser humano vivendo em plena era da AIDS. A falta de informação e, por consequência, o desconhecimento sobre a AIDS, sua dinâmica de transmissão e as medidas preventivas adequadas, transformam a convivência com esta síndrome num fator estressante para muitas pessoas, gerando sentimentos de medo e suscitando a correlação com diferentes representações simbólicas ligadas à contaminação pelo HIV. Vários autores formularam modelos teóricos para explicar esta correlação. Neste trabalho procura-se verificar os sentimentos emergentes e a respectiva vinculação aos significados simbólicos da doença sob o prisma destas teorias. Foram entrevistadas 31 pessoas, sendo 10 estudantes de diferentes cursos superiores da Universidade de São Paulo e 21 detentos do Sistema Penitenciário do Estado de São Paulo. Os resultados obtidos mostraram que, apesar dos grupos apresentarem características diferentes entre si, ambos atribuiram à AIDS significados simbólicos ligados ao medo da contaminação pelo HIV

Conhecimentos sobre AIDS e alterações nas ações profissionais das manicures de Ribeirão Preto

Este estudo teve como objetivos avaliar os conhecimentos de manicures de Ribeirão Preto acerca de aspectos gerais sobre AIDS e as alterações ocorridas nas suas ações profissionais com o advento desta síndrome. Foram selecionadas 40 manicures no município de Ribeirão Preto-SP, através da lista telefônica e por indicação das próprias manicures. Os dados foram coletados através de entrevista individual, que foi norteada por um formulário estruturado. Os resultados evidenciaram que algumas das profissionais avaliadas apresentam conhecimento incorreto sobre noções básicas quanto a AIDS (meios de transmissão e de prevenção). Ressalta-se que os meios de esterilização utilizados por 100% delas não são eficazes para inativação do HIV.

Informação/educação em DST/AIDS/sexualidade humana - um relato de experiência de 14 anos

As autoras relatam suas experiências de 14 anos sobre informação/educação em Doenças Sexualmente Transmissíveis/Aids e Sexualidade Humana. Descrevem as ações implementadas, destacando os resultados positivos, bem como os negativos. Quanto aos resultados positivos destacam evidentemente a divulgação de informações sobre medidas preventivas acerca da infecção pelo HIV/AIDS, DST e aspectos da sexualidade humana a diversos segmentos da comunidade leiga e científica, bem como, o repasse do aprendizado adquirido nessas vivencias para o ensino de graduação, pós-graduação e desenvolvimento da pesquisa. Quanto aos negativos, perceberam a dificuldade em avaliar as ações de informações, ou seja palestras, por constituírem-se uma estratégia de comunicação praticamente unilateral. Nessa trajetória apontam alguns fatos que historicamente marcaram a implementação de ações oficiais.

Virological and Immunological Characterization of Novel NYVAC-Based HIV/AIDS Vaccine Candidates Expressing Clade C Trimeric Soluble gp140(ZM96) and Gag(ZM96)-Pol-Nef(CN54) as Virus-Like Particles.

The generation of vaccines against HIV/AIDS able to induce long-lasting protective immunity remains a major goal in the HIV field. The modest efficacy (31.2%) against HIV infection observed in the RV144 phase III clinical trial highlighted the need for further improvement of HIV vaccine candidates, formulation, and vaccine regimen. In this study, we have generated two novel NYVAC vectors, expressing HIV-1 clade C gp140(ZM96) (NYVAC-gp140) or Gag(ZM96)-Pol-Nef(CN54) (NYVAC-Gag-Pol-Nef), and defined their virological and immunological characteristics in cultured cells and in mice. The insertion of HIV genes does not affect the replication capacity of NYVAC recombinants in primary chicken embryo fibroblast cells, HIV sequences remain stable after multiple passages, and HIV antigens are correctly expressed and released from cells, with Env as a trimer (NYVAC-gp140), while in NYVAC-Gag-Pol-Nef-infected cells Gag-induced virus-like particles (VLPs) are abundant. Electron microscopy revealed that VLPs accumulated with time at the cell surface, with no interference with NYVAC morphogenesis. Both vectors trigger specific innate responses in human cells and show an attenuation profile in immunocompromised adult BALB/c and newborn CD1 mice after intracranial inoculation. Analysis of the immune responses elicited in mice after homologous NYVAC prime/NYVAC boost immunization shows that recombinant viruses induced polyfunctional Env-specific CD4 or Gag-specific CD8 T cell responses. Antibody responses against gp140 and p17/p24 were elicited. Our findings showed important insights into virus-host cell interactions of NYVAC vectors expressing HIV antigens, with the activation of specific immune parameters which will help to unravel potential correlates of protection against HIV in human clinical trials with these vectors. IMPORTANCE: We have generated two novel NYVAC-based HIV vaccine candidates expressing HIV-1 clade C trimeric soluble gp140 (ZM96) and Gag(ZM96)-Pol-Nef(CN54) as VLPs. These vectors are stable and express high levels of both HIV-1 antigens. Gag-induced VLPs do not interfere with NYVAC morphogenesis, are highly attenuated in immunocompromised and newborn mice after intracranial inoculation, trigger specific innate immune responses in human cells, and activate T (Env-specific CD4 and Gag-specific CD8) and B cell immune responses to the HIV antigens, leading to high antibody titers against gp140. For these reasons, these vectors can be considered vaccine candidates against HIV/AIDS and currently are being tested in macaques and humans.

AIDS entre a população nipo-brasileira residente no município de São Paulo: dimensão e perfil do grupo estudado

O estudo teve como finalidade avaliar o avanço da epidemia da Aids entre os japoneses e seus descendentes, residentes no Município de São Paulo. Dimensionou-se o número de pessoas notificadas com a doença desde o início da epidemia até julho de 1994, identificando o perfil do grupo estudado em termos de idade, faixa etária, escolaridade, profissão/ ocupação, tipo de orientação sexual, forma de exposição ao vírus e tempo de sobreviria

Avaliação dos riscos da infecção pelo HIV segundo diferentes práticas sexuais na perspectiva de estudantes universitários e especialistas em HIV/AIDS

Avaliar as crenças acerca dos graus e riscos atribuídos pelos universitários a diferentes práticas sexuais e comparálas com a atribuição feita por especialistas em AIDS, constituíram o objetivo deste estudo. Um questionário composto por 25 itens (Escala de Probabilidade do tipo Likert), referentes à práticas/hábitos sexuais foi aplicado a alunos dos cursos de graduação em Enfermagem e Obstetrícia, Medicina, Psicologia, Farmácia-Bioquímica, que aquiesceram em respondê-lo. Através deanálise fatorial, usando-se o Sistema Varimax de Rotação, 25 itens foram distribuídos em sete fatores, sendo cinco itens excluídos. Dos 20 itens, 5 foram analisados neste trabalho, compondo dois fatores. O Fator X foi constituído pelos itens 1(sexo vaginal com preservativo) e 2(sexo anal com preservativo). No Fator Y foram alocados os itens: 3(relação com pessoa do sexo oposto), 4(relação vaginal sem preservativo) e 5(sexo anal sem preservativo). Em 80% dos 5 itens, observou-se que os estudantes apresentam conhecimento compatível ao preconizado pelos especialistas. Entretanto faz-se necessária a educação continuada a estes alunos, considerando-os enquanto pessoa e futuro profissional prestador de assistência aos indivíduos infectados pelo HIV ou com AIDS.

Sistema de informação em AIDS: limites e possibilidades

O artigo faz uma análise do atual Sistema de Informação (SI) em AIDS, apontando as dificuldades com que se defrontou ao buscar caracterizar o modo como ocorria e evoluía em 1995 a epidemia da AIDS na Administração Regional de Saúde de Pirituba-Perus (ARS-8) do município de São Paulo. São enumeradas algumas críticas que a Vigilância Epidemiológica e o SI vêm sofrendo nos últimos anos, tais como a centralização e a desagregação das informações; dados que contemplam aspectos eminentemente biológico e a utilização de formulários complexos. Estas questões somadas às dificuldades que se impuseram ao se buscar caracterizar a epidemia na região, revelou que o sistema, tal como se encontrava estruturado, dificultava a caracterização da epidemia e o acompanhamento sistemático pelos níveis locais de saúde. Chama-se a atenção para a necessidade de revisão da finalidade do SI em AIDS, da natureza e da qualidade dos dados coletados. Reitera-se a importância da integração dos diversos bancos de dados sócio-demográficos e do enfoque microlocalizado do Sl para o Distrito de Saúde.

Effects of the social environment on the survival and fungal resistance of ant brood

The phenotype of social animals can be influenced by genetic, maternal and environmental effects, which include social interactions during development. In social insects, the social environment and genetic origin of brood can each influence a whole suite of traits, from individual size to caste differentiation. Here, we investigate to which degree the social environment during development affects the survival and fungal resistance of ant brood of known maternal origin. We manipulated one component of the social environment, the worker/brood ratio, of brood originating from single queens of Formica selysi. We monitored the survival of brood and measured the head size and ability to resist the entomopathogenic fungus Beauveria bassiana of the resulting callow workers. The worker/brood ratio and origin of eggs affected the survival and maturation time of the brood and the size of the resulting callow workers. The survival of the callow workers varied greatly according to their origin, both in controls and when challenged with B. bassiana. However, there was no interaction between the fungal challenge and either the worker/brood ratio or origin of eggs, suggesting that these factors did not affect parasite resistance in the conditions tested. Overall, the social conditions during brood rearing and the origin of eggs had a strong impact on brood traits that are important for fitness. We detected a surprisingly large amount of variation among queens in the survival of their brood reared in standard queenless conditions, which calls for further studies on genetic, maternal and social effects influencing brood development in the social insects.