988 resultados para Tumor survival
Resumo:
Sequencing technologies and new bioinformatics tools have led to the complete sequencing of various genomes. However, information regarding the human transcriptome and its annotation is yet to be completed. The Human Cancer Genome Project, using ORESTES (open reading frame EST sequences) methodology, contributed to this objective by generating data from about 1.2 million expressed sequence tags. Approximately 30 of these sequences did not align to ESTs in the public databases and were considered no-match ORESTES. On the basis that a set of these ESTs could represent new transcripts, we constructed a cDNA microarray. This platform was used to hybridize against 12 different normal or tumor tissues. We identified 3421 transcribed regions not associated with annotated transcripts, representing 83.3 of the platform. The total number of differentially expressed sequences was 1007. Also, 28 of analyzed sequences could represent noncoding RNAs. Our data reinforces the knowledge of the human genome being pervasively transcribed, and point out molecular marker candidates for different cancers. To reinforce our data, we confirmed, by real-time PCR, the differential expression of three out of eight potentially tumor markers in prostate tissues. Lists of 1007 differentially expressed sequences, and the 291 potentially noncoding tumor markers were provided.
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Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.
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Transplantation of pancreatic islets constitutes a promising alternative treatment for type 1 diabetes. However, it is limited by the shortage of organ donors. Previous results from our laboratory have demonstrated beneficial effects of recombinant human prolactin (rhPRL) treatment on beta cell cultures. We therefore investigated the role of rhPRL action in human beta cell survival, focusing on the molecular mechanisms involved in this process. Human pancreatic islets were isolated using an automated method. Islet cultures were pre-treated in the absence or presence of rhPRL and then subjected to serum starvation or cytokine treatment. Beta cells were labelled with Newport green and apoptosis was evaluated using flow cytometry analysis. Levels of BCL2 gene family members were studied by quantitative RT-PCR and western blot. Caspase-8, -9 and -3 activity, as well as nitric oxide production, were evaluated by fluorimetric assays. The proportion of apoptotic beta cells was significantly lowered in the presence of rhPRL under both cell death-induced conditions. We also demonstrated that cytoprotection may involve an increase of BCL2/BAX ratio, as well as inhibition of caspase-8, -9 and -3. Our study provides relevant evidence for a protective effect of lactogens on human beta cell apoptosis. The results also suggest that the improvement of cell survival may involve, at least in part, inhibition of cell death pathways controlled by the BCL2 gene family members. These findings are highly relevant for improvement of the islet isolation procedure and for clinical islet transplantation.
Resumo:
beta-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (alpha(2A)/alpha(2C)-ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca(2+)](i) transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca(2+)](i) transient, carvedilol had no effect on peak [Ca(2+)](i) transient but also increased [Ca(2+)] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca(2+) transients and the net balance of cardiac Ca(2+) handling proteins while carvedilol preferentially improved cardiac redox state. (C) 2008 Elsevier Inc. All rights reserved.
Resumo:
The influence of different densities of the algae Pseudokirchneriella subcapitata on the chronic toxicity of cadmium to Ceriodaphnia dubia was investigated. The importance of algal cells as a source of metal to zooplankton was studied by exposing P. subcapitata cells to free cadmium ions and supplying the algae as food to C. dubia. The results of a bifactorial analysis (metal versus food levels) showed that metal toxicity to zooplankton was dependent on food level. Significant toxic effects on the fecundity and survival of C. dubia were observed at low metal concentrations with high algal density. Algae contaminated with Cd2+ were less toxic to cladoceran than was the Cd2+ in solution. Green algae retained cadmium and released low metal concentration in the test medium. We concluded that algal cells are an important route of exposure to metal and a factor that has an appreciable influence on the expression of metal toxicity to daphnids. (C) 2007 Elsevier Inc. All rights reserved.
Resumo:
Protoporphyrin IX (PpIX) is a porphyrin derivative that is accumulated in cancerous tissue in consequence of the tumor-specific metabolic alterations. The aim of this study was to evaluate the accumulation of PpIX in mice bearing renal cell carcinoma by spectroscopy analysis. A total of 24 male Balb/c mice, 6 weeks old, were divided into six groups: Normal (without inoculation of tumor cells) and 4, 8, 13, 16, and 20 days after inoculation of tumor cells. The orthotopic tumor model of renal cancer was used. Murine renal cell carcinoma (Renca cells) were inoculated into the subcapsular space of the kidney. Normal and tumor-bearing kidneys in different progression stages were removed and analyzed by ex-vivo spectroscopy and by microscopy, for tumor histometric analysis. Emission spectra were obtained by exciting the samples at 405 nm. Significant differences between normal and tumor-bearing kidneys in autofluorescence shape occurred in the 600-700 nm spectral region. A good correlation was found between emission band intensity at 635 nm and the tumor area.
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In this paper, we compare three residuals to assess departures from the error assumptions as well as to detect outlying observations in log-Burr XII regression models with censored observations. These residuals can also be used for the log-logistic regression model, which is a special case of the log-Burr XII regression model. For different parameter settings, sample sizes and censoring percentages, various simulation studies are performed and the empirical distribution of each residual is displayed and compared with the standard normal distribution. These studies suggest that the residual analysis usually performed in normal linear regression models can be straightforwardly extended to the modified martingale-type residual in log-Burr XII regression models with censored data.
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Interval-censored survival data, in which the event of interest is not observed exactly but is only known to occur within some time interval, occur very frequently. In some situations, event times might be censored into different, possibly overlapping intervals of variable widths; however, in other situations, information is available for all units at the same observed visit time. In the latter cases, interval-censored data are termed grouped survival data. Here we present alternative approaches for analyzing interval-censored data. We illustrate these techniques using a survival data set involving mango tree lifetimes. This study is an example of grouped survival data.
Resumo:
In this study, regression models are evaluated for grouped survival data when the effect of censoring time is considered in the model and the regression structure is modeled through four link functions. The methodology for grouped survival data is based on life tables, and the times are grouped in k intervals so that ties are eliminated. Thus, the data modeling is performed by considering the discrete models of lifetime regression. The model parameters are estimated by using the maximum likelihood and jackknife methods. To detect influential observations in the proposed models, diagnostic measures based on case deletion, which are denominated global influence, and influence measures based on small perturbations in the data or in the model, referred to as local influence, are used. In addition to those measures, the local influence and the total influential estimate are also employed. Various simulation studies are performed and compared to the performance of the four link functions of the regression models for grouped survival data for different parameter settings, sample sizes and numbers of intervals. Finally, a data set is analyzed by using the proposed regression models. (C) 2010 Elsevier B.V. All rights reserved.
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The effects of refrigeration, freezing and substitution of milk fat by inulin and whey protein concentrate (WPC) on Lactobacillus acidophilus La-5 viability and resistance to gastric and enteric simulated conditions in synbiotic guava mousses effects were investigated. Refrigerated mousses supplemented with WPC presented the best probiotic viability. ranging from 7.77 to 6.24 log cfu/g during 28 days of storage. The highest probiotic populations, above 7.45 log cfu/g, were observed for all frozen mousses during 112 days of storage. Decreased L acidophilus survival during the in vitro gastrointestinal simulation was observed both for refrigerated and frozen mousses. Nonetheless, for the refrigerated mousses, the addition of inulin enhanced the probiotic survival during the in vitro assays in the first week of storage. L acidophilus survival in simulated gastrointestinal fluids was also improved through freezing. The frozen storage may be used to provide increased shelf-life for synbiotic guava mousses. Even though the protective effect of inulin and WPC on the probiotic microorganism tested was shown to be more specific for the refrigerated products, the partial replacement of milk fat by these ingredients may also help, as it improves the nutritional value of mousses in both storage conditions. (C) 2009 Elsevier B.V. All rights reserved.
Resumo:
Lipocalins are beta-barrel proteins, which share three conserved motifs in their amino acid sequence. In this study, we identified by a peptide mapping approach, a seven-amino acid sequence related to one of these motifs (motif 2) that modulates cell survival. A synthetic peptide based on an insect lipocalin displayed cytoprotective activity in serum-deprived endothelial cells and leucocytes. This activity was dependent on nitric oxide synthase. This sequence was found within several lipocalins, including apolipoprotein D, retinol binding protein, lipocalin-type prostaglandin D synthase, and many unknown proteins, suggesting that it is a sequence signature and a lipocalin conserved property. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
Resumo:
The simultaneous effects of different binary co-cultures of Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus rhamnosus and Bifidobacterium lactis with Streptococcus thermophilus and of different prebiotics on the production of fermented milk were investigated in this paper. In particular, we determined and compared the kinetics of acidification of milk either as such or supplemented with 4% (w/w) maltodextrin, oligofructose and polydextrose, as well as the probiotic survival, chemical composition (pH, lactose, lactic acid and protein contents), fatty acids profile and conjugate linoleic acid (CIA) content of fermented milk after storage at 4 degrees C for 24 h. Fermented milk quality was strongly influenced both by the co-culture composition and the selected prebiotic. Depending on the co-culture, prebiotic addition to milk influenced to different extent kinetic acidification parameters. All probiotic counts were stimulated by oligofructose and polydextrose, and among these B. lactis always exhibited the highest counts in all supplemented milk samples. Polydextrose addition led to the highest post-acidification. Although the contents of the main fatty acids were only barely influenced. the highest amounts of conjugated linoleic acid (38% higher than in the control) were found in milk fermented by S. thermophilus-L. acidophilus co-culture and supplemented with maltodextrin. (C) 2008 Elsevier B.V. All rights reserved.
Resumo:
Farnesol (FOH) is a non-sterol isoprenoid produced by dephosphorylation of farnesyl pyrophosphate, a catabolite of the cholesterol biosynthetic pathway. These isoprenoids inhibit proliferation and induce apoptosis. It has been shown previously that FOH triggers morphological features characteristic of apoptosis in the filamentous fungus Aspergillus nidulans. Here, we investigate which pathways are influenced through FOH by examining the transcriptional profile of A. nidulans exposed to this isoprenoid. We observed decreased mRNA abundance of several genes involved in RNA processing and modification, transcription, translation, ribosomal structure and biogenesis, amino acid transport and metabolism, and ergosterol biosynthesis. We also observed increased mRNA expression of genes encoding a number of mitochondrial proteins and characterized in detail one of them, the aifA, encoding the Apoptosis-Inducing Factor (AIF)-like mitochondrial oxidoreductase. The Delta aifA mutant is more sensitive to FOH (about 8.0% and 0% survival when exposed to 10 and 100 mu M FOH respectively) than the wild type (about 97% and 3% survival when exposed to 10 and 100 mu M FOH respectively). These results suggest that AifA is possibly important for decreasing the effects of FOH and reactive oxygen species. Furthermore, we showed an involvement of autophagy and protein kinase C in A. nidulans FOH-induced apoptosis.
Resumo:
This paper reports the purification and biochemical/pharmacological characterization of two myotoxic phospholipases A(2) (PLA(2)S) from Bothrops brazili venom, a native snake from Brazil. Both myotoxins (MTX-I and II) were purified by a single chromatographic step on a CM-Sepharose ion-exchange column up to a high purity level, showing M-r similar to 14,000 for the monomer and 28,000 Da for the dimer. The N-terminal and internal peptide amino acid sequences showed similarity with other myotoxic PLA2S from snake venoms, MTX-I belonging to Asp49 PLA(2) class, enzymatically active, and MTX-II to Lys49 PLA(2)S, catalytically inactive. Treatment of MTX-I with BPB and EDTA reduced drastically its PLA(2) and anticoagulant activities, corroborating the importance of residue His48 and Ca2+ ions for the enzymatic catalysis. Both PLA(2)S induced myotoxic activity and dose-time dependent edema similar to other isolated snake venom toxins from Bothrops and Crotalus genus. The results also demonstrated that MTXs and cationic synthetic peptides derived from their 115-129 C-terminal region displayed cytotoxic activity on human T-cell leukemia (JURKAT) lines and microbicidal effects against Escherichia coli, Candida albicans and Leishmania sp. Thus, these PLA(2) proteins and C-terminal synthetic peptides present multifunctional properties that might be of interest in the development of therapeutic strategies against parasites, bacteria and cancer. (C) 2008 Elsevier Inc. All rights reserved.
Resumo:
The aim of this study was to investigate the immunomodulatory effects of glucocorticoids on the immune response to Strongyloides venezuelensis in mice. Balb/c mice were infected with S. venezuelensis and treated with Dexamethasone (Dexa) or vehicle. Dexa treatment increased circulating blood neutrophil numbers and inhibited eosinophil and mononuclear cell accumulation in the blood, bronchoalveolar, and peritoneal fluid compared with control animals. Moreover, Dexa decreased tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-3 (IL-3), IL-4, IL-5, IL-10, and IL-12 production in the lungs and circulating immunoglobulin G1. (IgG1), IgG2a, and IgE antibody levels while increasing the overall parasite burden in the feces and intestine. Dexa treatment enhanced the fertility of female nematodes relative to untreated and infected mice. In summary, the alterations in the immune response induced by Dexa resulted in a blunted, aberrant immune response associated with increased parasite burden. This phenomenon is similar to that observed in S. stercoralis-infected humans who are taking immunosuppressive or antiinflammatory drugs, including corticosteroids.