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De Melo A.C.,Brazilian National Cancer Institute INCA | Paulino E.,Brazilian National Cancer Institute INCA | Garces A.H.I.,Brazilian National Cancer Institute INCA
Oxidative Medicine and Cellular Longevity | Year: 2017

The treatment of advanced gynecologic cancers remains palliative in most of cases. Although systemic treatment has entered into the era of targeted drugs the antitumor efficacies of current therapies are still limited. In this context there is a great need for more active treatment and rationally designed targeted therapies. The PI3K/AKT/mTOR is a signaling pathway in mammal cells that coordinates important cell activities. It has a critical function in the survival, growth, and proliferation of malignant cells and was object of important research in the last two decades. The mTOR pathway emerges as an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli and, through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including endometrial, cervical, and ovarian cancers. The present study reviewed the available evidence regarding the potential impact of some mTOR pathway inhibitors in the treatment of gynecological cancer. Few advances in medical management have occurred in recent years in the treatment of advanced or recurrent gynecological malignancies, and a poor prognosis remains. Rationally designed molecularly targeted therapy is an emerging and important option in this setting; then more investigation in PI3K/AKT/mTOR pathway-targeted therapies is warranted. © 2017 Andréia Cristina de Melo et al.

Szklo A.S.,Brazilian National Cancer Institute INCA | De Almeida L.M.,Brazilian National Cancer Institute INCA | Figueiredo V.C.,Public Health Studies Institute IESC | Autran M.,Brazilian National Cancer Institute INCA | And 3 more authors.
Preventive Medicine | Year: 2012

Objective: To evaluate the differences in cigarette smoking prevalence rates in Brazil between 1989 and 2008. Methodology: We calculated absolute and relative differences in smoking prevalences, overall and stratified by gender, age, place of residence, educational level and birth cohort. Data were obtained from random samples from two National Household Surveys (1989,n = 39,969; 2008,n = 38,461). GLM models were specified to obtain estimates and assess whether differences in proportions of smokers differed by categories of the stratification variables. Results: Adjusted absolute and relative differences in smoking prevalence rates between 1989 and 2008 were, respectively, -12.4% and -41.0%. Individuals aged 15-34years and those with 9 or more years of education presented larger relative declines than their counterparts (p s≤0.001). After stratification by birth cohort, men presented larger reductions than women, only in the absolute scale (p s≤0.001), with the exception of the youngest birth cohort (i.e.,1965-1974). Conclusions: In Brazil, several tobacco control measures have been adopted since 1986, in particular increasing taxation of tobacco products and strong health warnings, which may have contributed to the marked decline in smoking prevalence. It is important to understand the evolution of the tobacco epidemic to propose new actions to prevent initiation and encourage cessation among those who started/continued smoking. © 2011 Elsevier Inc.

Robbs B.K.,Brazilian National Cancer Institute INCA | Lucena P.I.,Brazilian National Cancer Institute INCA | Viola J.P.B.,Brazilian National Cancer Institute INCA
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

Nuclear factor of activated T cells (NFAT) was described as an activation and differentiation factor in T cells. NFAT1 protein is expressed in several cell types and has been implicated in the control of the cell cycle, death and migration. Overexpression or activation of NFAT1 has been demonstrated to induce cell death in different cell types, such as T lymphocytes, Burkitt's lymphoma, and fibroblasts. Although these findings indicate a role for NFAT1 transcription factor in control of cell death, the precise mechanisms involved in this process regulated by NFAT1 are still poorly understood. The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines that are important in driving proliferation and preventing apoptosis and is widely implicated in cell transformation and cancer development. We show that NFAT1 protein can cooperate with Ras/Raf/MEK/ERK, but not with the JNK, p38 or NFκB pathways in cell death induction. NFAT1 can induce a cell death pathway consistent with apoptosis, which can be shifted to programmed necrosis by caspase inhibitors. Finally, through screening genes involved in cell death regulation, although we determined that TNF-α, TRAIL and PAK7 genes were up-regulated, only TNF-α expression was responsible for cell death in this context. These data suggest that NFAT1 protein activation can shift oncogenic Ras/Raf/MEK/ERK signaling to acting as a tumor suppressor pathway. These data support a potential role for regulating NFAT1 expression in gene therapy in tumors that display an activated Ras pathway, which could lead to more specific, target-directed TNF-α expression and, thus, tumor suppression. © 2013 Elsevier B.V.

Nestal de Moraes G.,Brazilian National Cancer Institute INCA | Vasconcelos F.C.,Brazilian National Cancer Institute INCA | Delbue D.,Brazilian National Cancer Institute INCA | Mognol G.P.,Brazilian National Cancer Institute | And 3 more authors.
European Journal of Cell Biology | Year: 2013

Breast cancer is the leading cause of deaths in women around the world. Resistance to therapy is the main cause of treatment failure and still little is known about predictive biomarkers for response to systemic therapy. Increasing evidence show that Survivin and XIAP overexpression is closely associated with chemoresistance and poor prognosis in breast cancer. However, their impact on resistance to doxorubicin (dox), a chemotherapeutic agent widely used to treat breast cancer, is poorly understood. Here, we demonstrated that dox inhibited cell viability and induced DNA fragmentation and activation of caspases-3, -7 and -9 in the breast cancer-derived cell lines MCF7 and MDA-MB-231, regardless of different p53 status. Dox exposure resulted in reduction of Survivin and XIAP mRNA and protein levels. However, when we transfected cells with a Survivin-encoding plasmid, we did not observe a cell death-resistant phenotype. XIAP and Survivin silencing, either alone or in combination, had no effect on breast cancer cells sensitivity towards dox. Altogether, we demonstrated that breast cancer cells are sensitive to the chemotherapeutic agent dox irrespective of Survivin and XIAP expression levels. Also, our findings suggest that dox-mediated modulation of Survivin and XIAP might sensitize cells to taxanes when used in a sequential regimen. © 2013 Elsevier GmbH.

Maranhao E.T.,Brazilian National Cancer Institute INCA | Maranhao-Filho P.,Federal University of Rio de Janeiro
Arquivos de Neuro-Psiquiatria | Year: 2012

The authors highlights the importance of the vestibulo-ocular refex examination through the head impulse test as a diagnostic method for vestibular dysfunction as well as, and primarily, a bedside semiotic resource capable of differentiating between acute peripheral vestibu-lopathy and a cerebellar or brainstem infarction in emergency rooms.

De Freitas-Junior J.C.M.,Brazilian National Cancer Institute INCA | Morgado-Diaz J.A.,Brazilian National Cancer Institute INCA
Oncotarget | Year: 2016

Changes in glycosylation, which is one of the most common protein post-translational modifications, are considered to be a hallmark of cancer. N-glycans can modulate cell migration, cell-cell adhesion, cell signaling, growth and metastasis. The colorectal cancer (CRC) is a leading cause of cancer-related mortality and the correlation between CRC progression and changes in the pattern of expression of N-glycans is being considered in the search for new biomarkers. Here, we review the role of N-glycans in CRC cell biology. The perspectives on emerging N-glycan-related anticancer therapies, along with new insights and challenges, are also discussed.

Szklo A.S.,Brazilian National Cancer Institute INCA | Coutinho E.S.F.,Oswaldo Cruz Foundation
Addictive Behaviors | Year: 2010

Smoking is a worldwide public health problem, and various communication strategies aimed at its cessation have been used. The objective of this paper was to explore differences over time of two communication strategies (gain-framed versus loss-framed) in encouraging calls to a Quitline, according to smoker's degree of dependence. A study was conducted for four weeks among passengers of two selected subway stations in the city of Rio de Janeiro-Brazil (Naverage = 12,500 passengers a day per station). The interventions - large posters with images and text based on central theme "shortness-of-breath" - also contained the Quitline number. Call rate differences between the strategies, overall and specific per study week, were calculated. Light smokers exposed to the positive-content message called on average 2.2 times more often than those exposed to the negative-content message (p < 0.001). The absolute difference in call rates decreased after the first week of the study (p for the additive interaction between intervention and study week, 0.02). For heavy smokers, no differences between the two stations were observed. Additive interaction was found between type of smoker - light or heavy - and intervention (p = 0.02). The results suggest that short-term positive-content campaigns based on issues pertaining to individuals' daily routine could be effective in capturing light smokers. These results may have considerable public health impact, as the prevalence of less dependent smokers is much higher than that of heavier smokers. © 2010 Elsevier Ltd. All rights reserved.

Faget D.V.,Brazilian National Cancer Institute INCA | Lucena P.I.,Brazilian National Cancer Institute INCA | Robbs B.K.,Brazilian National Cancer Institute INCA | Viola J.P.B.,Brazilian National Cancer Institute INCA
PLoS ONE | Year: 2012

The proteins belonging to the nuclear factor of activated T cells (NFAT) family of transcription factors are expressed in several cell types and regulate genes involved in differentiation, cell cycle and apoptosis. NFAT proteins share two conserved domains, the NFAT-homology region (NHR) and a DNA-binding domain (DBD). The N- and C-termini display two transactivation domains (TAD-N and TAD-C) that have low sequence similarity. Due to the high sequence conservation in the NHR and DBD, NFAT members have some overlapping roles in gene regulation. However, several studies have shown distinct roles for NFAT proteins in the regulation of cell death. The TAD-C shows low sequence similarity among NFAT family members, but its contribution to specific NFAT1-induced phenotypes is poorly understood. Here, we described at least two regions of NFAT1 TAD-C that confer pro-apoptotic activity to NFAT1. These regions extend from amino acids 699 to 734 and 819 to 850 of NFAT1. We also showed that the NFAT1 TAD-C is unable to induce apoptosis by itself and requires a functional DBD. Furthermore, we showed that when fused to NFAT1 TAD-C, NFAT2, which is associated with cell transformation, induces apoptosis in fibroblasts. Together, these results suggest that the NFAT1 TAD-C includes NFAT death domains that confer to different NFAT members the ability to induce apoptosis. © 2012 Faget et al.

Levy D.,Georgetown University | de Almeida L.M.,Brazilian National Cancer Institute INCA | Szklo A.,Brazilian National Cancer Institute INCA
PLoS Medicine | Year: 2012

Background: Brazil has reduced its smoking rate by about 50% in the last 20 y. During that time period, strong tobacco control policies were implemented. This paper estimates the effect of these stricter policies on smoking prevalence and associated premature mortality, and the effect that additional policies may have. Methods and Findings: The model was developed using the SimSmoke tobacco control policy model. Using policy, population, and smoking data for Brazil, the model assesses the effect on premature deaths of cigarette taxes, smoke-free air laws, mass media campaigns, marketing restrictions, packaging requirements, cessation treatment programs, and youth access restrictions. We estimate the effect of past policies relative to a counterfactual of policies kept to 1989 levels, and the effect of stricter future policies. Male and female smoking prevalence in Brazil have fallen by about half since 1989, which represents a 46% (lower and upper bounds: 28%-66%) relative reduction compared to the 2010 prevalence under the counterfactual scenario of policies held to 1989 levels. Almost half of that 46% reduction is explained by price increases, 14% by smoke-free air laws, 14% by marketing restrictions, 8% by health warnings, 6% by mass media campaigns, and 10% by cessation treatment programs. As a result of the past policies, a total of almost 420,000 (260,000-715,000) deaths had been averted by 2010, increasing to almost 7 million (4.5 million-10.3 million) deaths projected by 2050. Comparing future implementation of a set of stricter policies to a scenario with 2010 policies held constant, smoking prevalence by 2050 could be reduced by another 39% (29%-54%), and 1.3 million (0.9 million-2.0 million) out of 9 million future premature deaths could be averted. Conclusions: Brazil provides one of the outstanding public health success stories in reducing deaths due to smoking, and serves as a model for other low and middle income nations. However, a set of stricter policies could further reduce smoking and save many additional lives. Please see later in the article for the Editors' Summary. © 2012 Levy et al.

Szklo A.S.,Brazilian National Cancer Institute INCA | de Souza M.C.,Brazilian National Cancer Institute INCA | Szklo M.,Johns Hopkins University | de Almeida L.M.,Brazilian National Cancer Institute INCA
Tobacco Control | Year: 2015

Background Brazil has experienced a large decline in smoking prevalence due to several tobacco control policies that were implemented in the past 25 years. Previous population-wide studies found a consistent reduction over time in daily cigarette consumption among all socioeconomic groups. Objective To examine changes between 2008 and 2013 in tobacco behaviours and health-related conditions of smokers. Methods We used data obtained from two nationally-representative surveys conducted in 2008 and 2013 to estimate the prevalence of self-reported psychological and physical morbidity, and nicotine dependence markers, stratified by gender and sociodemographic groups. Generalised linear models were used to understand whether absolute differences in prevalence rates over time differed by categories of selected variables. Results For both genders, as smoking prevalence declined in Brazil, there has been an increase in the proportion of ever smokers who have quit. In addition, remaining smokers seem to be making more quitting attempts. Among men with low educational level or younger than 25 years-old, as compared to their counterparts, cessation rate showed an even greater increase over time. Moreover, the proportion of light smokers, which represent the vast majority of smokers, did not decrease. The percentage of poor health-conditions among remaining smokers nevertheless increased, particularly among women, which can make future cessation more challenging. Conclusions In Brazil, quitting rate is increasing, thus suggesting that tobacco control interventions implemented in Brazil in the past years seem to be effectively reaching the smoking population. This is strong evidence against the 'hardening hypothesis', which posits that remaining smokers decrease their willingness and ability to quit. © 2015 by the BMJ Publishing Group Ltd. All rights reserved.

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