In vitro targeting of Polo-like kinase 1 in bladder carcinoma: Comparative effects of four potent inhibitors

Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with advanced bladder cancer has changed very little over the past 30 years. In the present study we tested and compared the in vitro antitumor activities of four different inhibitors of Polo-like kinase 1 (PLK1) (BI 2536, BI 6727, GW843682X, and GSK461364), against 3 bladder carcinoma cell lines RT4, 5637 and T24. The impact on radiosensitivity and drug interactions in simultaneous treatments with cisplatin, methotrexate, and doxorubicin were also investigated. Our results showed that PLK1 inhibition prevented cell proliferation and clonogenicity, causing significant inhibition of invasion of tumor cells, though modest differences were observed between drugs. Moreover, all PLK1 inhibitors induced G2/M arrest, with the subsequent induction of death in all 3 cell lines. Drug interactions studies showed auspicious results for all PLK1 inhibitors when combined with the commonly used cisplatin and methotrexate, though combinations with doxorubicin showed mostly antagonistic effects. Comparably, the four PLK1 inhibitors efficiently sensitized cells to ionizing radiation. Our findings demonstrate that irrespective of the inhibitor used, the pharmacological inhibition of PLK1 constrains bladder cancer growth and dissemination, providing new opportunities for future therapeutic intervention. However, further laboratorial and preclinical tests are still needed to corroborate the usefulness of using them in combination with other commonly used chemotherapeutic drugs. © 2013 Landes Bioscience.

Diversity of Mycosphaerella spp. and Teratosphaeria spp. in Eucalyptus globulus plantations in Brazil

Among the most important diseases affecting Eucalyptus is Mycosphaerella Leaf Disease (MLD) caused by Mycosphaerella spp. and Teratosphaeria spp. MLD has led to significant losses in eucalypt plantations in the South and Southeast Region of Brazil, as well as in several countries such as Portugal, Spain, South Africa and Australia. Symptoms of MLD include localized necrotic spots, early defoliation in juvenile plants, stem cankers, early death of branches, and in some cases, atrophy and death. In the present study, single spore isolations from leaves of E. globulus from five locations in Brazil allowed the differentiation of species of Mycosphaerella and Teratosphaeria based on ascospore germination and growth in culture. These isolates were also subjected to sequence analysis of the ribosomal RNA internal transcribed spacer regions, which allowed their identification to species level. The results of this study showed that six species of Mycosphaerella and four species of Teratosphaeria were associated with leaves showing symptoms of MLD in E. globulus plantations in various locations of Brazil. © 2013 KNPV.

Vida e morte em To the Lighthouse: o conflito dos opostos tramado entre o jogo com o tempo e a intertextualidade

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Reduction of infant mortality in Latin America and the Caribbean: uneven progress requiring a variety of responses

Infant mortality has unquestionably declined throughout Latin America over the last decade, even under conditions of low and unstable economic growth and a meagre overall reduction of poverty in the region. The declines in infant mortality vary from one country to another. The persistence of high infant mortality rates is related to low income, teenage pregnancy and lack of access to basic services, as well as to the lack of appropriate health care infrastructure. At the same time, both the rural population as a whole, and the indigenous and Afro-descendent population in particular, has fallen markedly behind, with overall infant mortality rates much higher than among the rest of the population. Moreover, the cause and incidence of death in this age group have been changing according with the changes in neonatal and post-neonatal deaths. Our editorial line-up has created space for opinions from adolescents and youth, as well as from policy experts on the problem, its causes, and approaches to dealing with infant mortality. We also offer succinct information on a broad range of programmes—utilizing various interventions—in different countries of the region regarding maternal and infant care, in an attempt to bring about a reduction in mortality.

Estilo e metalinguagem na literatura de Monteiro Lobato

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Identification of Novel Compounds Inhibiting Chikungunya Virus-Induced Cell Death by High Throughput Screening of a Kinase Inhibitor Library

Chikungunya virus (CHIKV) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. The re-emergence of CHIKV has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. Unfortunately, no effective treatment is currently available. The present study reports the use of resazurin in a cell-based high-throughput assay, and an image-based high-content assay to identify and characterize inhibitors of CHIKV-infection in vitro. CHIKV is a highly cytopathic virus that rapidly kills infected cells. Thus, cell viability of HuH-7 cells infected with CHIKV in the presence of compounds was determined by measuring metabolic reduction of resazurin to identify inhibitors of CHIKV-associated cell death. A kinase inhibitor library of 4,000 compounds was screened against CHIKV infection of HuH-7 cells using the resazurin reduction assay, and the cell toxicity was also measured in non-infected cells. Seventy-two compounds showing >= 50% inhibition property against CHIKV at 10 mu M were selected as primary hits. Four compounds having a benzofuran core scaffold (CND0335, CND0364, CND0366 and CND0415), one pyrrolopyridine (CND0545) and one thiazol-carboxamide (CND3514) inhibited CHIKV-associated cell death in a dose-dependent manner, with EC50 values between 2.2 mu M and 7.1 mu M. Based on image analysis, these 6 hit compounds did not inhibit CHIKV replication in the host cell. However, CHIKV-infected cells manifested less prominent apoptotic blebs typical of CHIKV cytopathic effect compared with the control infection. Moreover, treatment with these compounds reduced viral titers in the medium of CHIKV-infected cells by up to 100-fold. In conclusion, this cell-based high-throughput screening assay using resazurin, combined with the image-based high content assay approach identified compounds against CHIKV having a novel antiviral activity -inhibition of virus-induced CPE - likely by targeting kinases involved in apoptosis.

Dental anomalies in children submitted to antineoplastic therapy

Cancer is the third most frequent cause of death in children in Brazil. Early diagnosis and medical advances have significantly improved treatment outcomes, which has resulted in higher survival rates and the management of late side effects has become increasingly important in caring for these patients. Dental abnormalities are commonly observed as late effects of antineoplastic therapy in the oral cavity. The incidence and severity of the dental abnormalities depend on the child's age at diagnosis and the type of chemotherapeutic agent used, as well as the irradiation dose and area. The treatment duration and aggressivity should also be considered. Disturbances in dental development are characterized by changes in shape, number and root development. Enamel anomalies, such as discoloration, opacities and hypoplasia are also observed in these patients. When severe, these abnormalities can cause functional and esthetic sequelae that have an impact on the children's and adolescents' quality of life. General dentists and pediatric dentists should understand these dental abnormalities and how to identify them aiming for early diagnosis and appropriate treatment.

Hypothermia and Early Neonatal Mortality in Preterm Infants

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Determinant factors for mortality of patients receiving mechanical ventilation and effects of a protocol muscle training in weaning

Introduction: Prognostic factors are used in the Intensive Care Unit (ICU) to predict morbidity and mortality , especially in patients on mechanical ventilation (MV ) . Training protocols are used in MV patients with the aim of promoting the success of the weaning process. Objective: To assess which variables determine the outcome of patients undergoing mechanical ventilation and compare the effects of two protocols for weaning. Method: Patients under MV for more than 48 hours had collected the following information: sex, age , ideal weight, height , Acute Physiology and Chronic Health Evaluation (APACHE II), risk of mortality, Glasgow Coma Scale (GCS) and index Quick and perfunctory (IRRS) breathing. Patients with unsuccessful weaning performed one of weaning protocols: Progressive T - tube or tube - T + Threshold ® IMT. Patients were compared for outcome (death or non- death in the ICU ) and the protocols through the t test or Mann-Whitney test was considered significant when P <0.05. Results: Of 128 patients evaluated 56.25% were men, the mean age was 60.05 ± 17.85 years and 40.62 % patients died, and they had higher APACHE II scores, mortality risk, time VM and IRRS GCS and the lower value (p<0.05). The age, initial and final maximal inspiratory pressure, time of weaning and duration of MV was similar between protocols. Conclusion: The study suggests that the GCS, APACHE II risk of mortality, length of MV and IRRS variables determined the evolution of MV patients in this sample. Not found differences in the variables studied when comparing the two methods of weaning.

Nutritional parameters are associated with mortality in acute kidney injury

OBJECTIVE: The objective of this study was to perform a nutritional assessment of acute kidney injury patients and to identify the relationship between nutritional markers and outcomes.METHOD: This was a prospective and observational study. Patients who were hospitalized at the Hospital of Botucatu School of Medicine were evaluated between January 2009 and December 2011. We evaluated a total of 133 patients with a clinical diagnosis of acute kidney injury and a clinical presentation suggestive of acute tubular necrosis. We explored the associations between clinical, laboratory and nutritional markers and in hospital mortality. Multivariable logistic regression was used to adjust for confounding and selection bias.RESULTS: Non-survivor patients were older (67 +/- 14 vs. 59 +/- 16 years) and exhibited a higher prevalence of sepsis (57.1 vs. 21.4%) and higher Acute Tubular Necrosis-Individual Severity Scores (0.60 +/- 0.22 vs. 0.41 +/- 0.21) than did survivor patients. Based on the multivariable analysis, laboratorial parameters such as blood urea nitrogen and C-reactive protein were associated with a higher risk of death (OR: 1.013, p = 0.0052; OR: 1.050, p = 0.01, respectively), and nutritional parameters such as low calorie intake, higher levels of edema, lower resistance based on bioelectrical impedance analysis and a more negative nitrogen balance were significantly associated with a higher risk of death (OR: 0.950, p = 0.01; OR: 1.138, p = 0.03; OR: 0.995, p = 0.03; OR: 0.934, p = 0.04, respectively).CONCLUSIONS: In acute kidney injury patients, a nutritional assessment seems to identify nutritional markers that are associated with outcome. In this study, a low caloric intake, higher C-reactive protein levels, the presence of edema, a lower resistance measured during a bioelectrical impedance analysis and a lower nitrogen balance were significantly associated with risk of death in acute kidney injury patients.

The symbology of the sea in Lygia Bojunga Nunes's work: a reflection on utopian and dystopian framing

The ambivalent image of the sea is recurrent in Bojunga Nunes’s work. It receives a lot of symbolic meanings in her production, being sometimes a positive and sometimes a negative element. Thus, the sea is used in a utopic way, as a place for pleasure and leisure, and in a dystopic way, as scenery of a rite of passage, which includes the pain and suffering, part of the rite of passage that characterizes the bildungsromans. So, if in some texts the sea assumes a utopic character, being a place of snuggle, security, the ideal to reach, in others it is represented as dystopic, a place of distress, asphyxia and death. In this text we will study the hypothesis that, even in its dark symbolic meaning, in the author’s work the sea is an element of reflection and revelation. Thereby, it assumes metaphorically a sense of magnification of the reader’s expectative, being an element of emancipation. The objective of this text is to present a reflection on the sea’s symbolism on the mentioned texts and its importance for the reader’s formation.

Low serum potassium levels increase the infectious-caused mortality in peritoneal dialysis patients: a propensity-matched score study

Background and ObjectivesHypokalemia has been consistently associated with high mortality rate in peritoneal dialysis. However, studies investigating if hypokalemia is acting as a surrogate marker of comorbidities or has a direct effect in the risk for mortality have not been studied. Thus, the aim of this study was to analyze the effect of hypokalemia on overall and cause-specific mortality.Design, Setting, Participants and MeasurementsThis is an analysis of BRAZPD II, a nationwide prospective cohort study. All patients on PD for longer than 90 days with measured serum potassium levels were used to verify the association of hypokalemia with overall and cause-specific mortality using a propensity match score to reduce selection bias. In addition, competing risks were also taken into account for the analysis of cause-specific mortality.ResultsThere was a U-shaped relationship between time-averaged serum potassium and all-cause mortality of PD patients. Cardiovascular disease was the main cause of death in the normokalemic group with 133 events (41.8%) followed by PD-non related infections, n=105 (33.0%). Hypokalemia was associated with a 49% increased risk for CV mortality after adjustments for covariates and the presence of competing risks (SHR 1.49; CI95% 1.01-2.21). In contrast, in the group of patients with K < 3.5mEq/L, PD-non related infections were the main cause of death with 43 events (44.3%) followed by cardiovascular disease (n=36; 37.1%). For PD-non related infections the SHR was 2.19 (CI95% 1.52-3.14) while for peritonitis was SHR 1.09 (CI95% 0.47-2.49).ConclusionsHypokalemia had a significant impact on overall, cardiovascular and infectious mortality even after adjustments for competing risks. The causative nature of this association suggested by our study raises the need for intervention studies looking at the effect of potassium supplementation on clinical outcomes of PD patients.

Are metabolic syndrome and its components associated with 5-year mortality in chronic obstructive pupmonary disease patients?

The aim of this study was to evaluate the risk of mortality according to the presence of metabolic syndrome in chronic obstructive pulmonary disease (COPD) patients who were followed for 5 years. We did not establish the influence of metabolic syndrome on mortality rate. However, an increase of 100 mg of triglycerides was associated with a 39% increase in the probability of death in the period of the study (hazard ratio 1.39, 95% confidence interval 1.06-1.83).

Nanoparticles increase the efficacy of cancer chemopreventive agents in cells exposed to cigarette smoke condensate

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery.

Plasma Steroid Dynamics in Late- and Near-term Naturally and Artificially Conceived Bovine Pregnancies as Elucidated by Multihormone High-resolution LC-MS/MS

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)