Crosstalk Between Kinases, Phosphatases And Mirnas In Cancer.

Reversible phosphorylation of proteins, performed by kinases and phosphatases, is the major post translational protein modification in eukaryotic cells. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a vast array of diseases, including cancer. Cancer research has produced increasing evidence that kinase and phosphatase activity can be compromised by mutations and also by miRNA silencing, performed by small non-coding and endogenously produced RNA molecules that lead to translational repression. miRNAs are believed to target about one-third of human mRNAs while a single miRNA may target about 200 transcripts simultaneously. Regulation of the phosphorylation balance by miRNAs has been a topic of intense research over the last years, spanning topics going as far as cancer aggressiveness and chemotherapy resistance. By addressing recent studies that have shown miRNA expression patterns as phenotypic signatures of cancers and how miRNA influence cellular processes such as apoptosis, cell cycle control, angiogenesis, inflammation and DNA repair, we discuss how kinases, phosphatases and miRNAs cooperatively act in cancer biology.

A New Goniothalamin N-acylated Aza-derivative Strongly Downregulates Mediators Of Signaling Transduction Associated With Pancreatic Cancer Aggressiveness.

In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.

[strategies For Tackling Absenteeism In Dental Appointments In The Family Health Units Of A Large Municipality: Action Research].

The aim of this study was to analyze the reasons for missed appointments in dental Family Health Units (FHU) and implement strategies to reduce same through action research. This is a study conducted in 12 FHUs in Piracicaba in the State of São Paulo from January, 1 to December, 31 2010. The sample was composed of 385 users of these health units who were interviewed over the phone and asked about the reasons for missing dental appointments, as well as 12 dentists and 12 nurses. Two workshops were staged with professionals: the first to assess the data collected in interviews and develop strategy, and the second for evaluation after 4 months. The primary cause for missed appointments was the opening hours of the units coinciding with the work schedule of the users. Among the strategies suggested were lectures on oral health, ongoing education in team meetings, training of Community Health Agents, participation in therapeutic groups and partnerships between Oral Health Teams and the social infrastructure of the community. The adoption of the single medical record was the strategy proposed by professionals. The strategies implemented led to a 66.6% reduction in missed appointments by the units and the motivating nature of the workshops elicited critical reflection to redirect health practices.

Antitumor Activity Of Irradiated Riboflavin On Human Renal Carcinoma Cell Line 786-o.

Riboflavin (vitamin B2) is a precursor for coenzymes involved in energy production, biosynthesis, detoxification, and electron scavenging. Previously, we demonstrated that irradiated riboflavin (IR) has potential antitumoral effects against human leukemia cells (HL60), human prostate cancer cells (PC3), and mouse melanoma cells (B16F10) through a common mechanism that leads to apoptosis. Hence, we here investigated the effect of IR on 786-O cells, a known model cell line for clear cell renal cell carcinoma (CCRCC), which is characterized by high-risk metastasis and chemotherapy resistance. IR also induced cell death in 786-O cells by apoptosis, which was not prevented by antioxidant agents. IR treatment was characterized by downregulation of Fas ligand (TNF superfamily, member 6)/Fas (TNF receptor superfamily member 6) (FasL/Fas) and tumor necrosis factor receptor superfamily, member 1a (TNFR1)/TNFRSF1A-associated via death domain (TRADD)/TNF receptor-associated factor 2 (TRAF) signaling pathways (the extrinsic apoptosis pathway), while the intrinsic apoptotic pathway was upregulated, as observed by an elevated Bcl-2 associated x protein/B-cell CLL/lymphoma 2 (Bax/Bcl-2) ratio, reduced cellular inhibitor of apoptosis 1 (c-IAP1) expression, and increased expression of apoptosis-inducing factor (AIF). The observed cell death was caspase-dependent as proven by caspase 3 activation and poly(ADP-ribose) polymerase-1 (PARP) cleavage. IR-induced cell death was also associated with downregulation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)/protein serine/threonine kinase B/extracellular signal-regulated protein kinase 1/2 (Src/AKT/ERK1/2) pathway and activation of p38 MAP kinase (p38) and Jun-amino-terminal kinase (JNK). Interestingly, IR treatment leads to inhibition of matrix metalloproteinase-2 (MMP-2) activity and reduced expression of renal cancer aggressiveness markers caveolin-1, low molecular weight phosphotyrosine protein phosphatase (LMWPTP), and kinase insert domain receptor (a type III receptor tyrosine kinase) (VEGFR-2). Together, these results show the potential of IR for treating cancer.

Imatinib Restores Vasp Activity And Its Interaction With Zyxin In Bcr-abl Leukemic Cells.

Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP.

Recentes avanços e novas perspectivas dos eletrodos íon-seletivos

This paper describes the recent progress in the development of polymeric membranes for ion-selective electrodes. The importance of knowing the mechanism of potential development in membranes for ion-selective electrodes to reach lower detection limits and improve selectivity are discussed. Recent advances and future trends of research on ion-selective electrodes are also reported.

Flora arbustivo-arbórea do fragmento de floresta estacional semidecidual do Ribeirão Cachoeira, município de Campinas, SP

An inventory of the woody flora (trees and shrubs), was carried out in the Ribeirão Cachoeria forest (233.7ha, 650m high, 46°55'58''W, 22°50'13''S), the second largest and best conserved fragment of semideciduous tropical forest in the municipality of Campinas, São Paulo state, Southeastern Brazil. The soil is a red-yellow podsol and the climate is of Köppen's Cwag type. Collections were made from August/1996 to September/1997. Only fertile individuals with a perimeter at breast height of 9cm or greater were included in the survey. One hyndred and seventhy five species were identified, belonging to 119 genera and 49 families. The most important families were Myrtaceae (14 species), Rutaceae and Fabaceae (13), Caesalpiniaceae (11), Solanaceae (9), and Rubiaceae (8). Some species were found for the first time in the region: Tachigali multijuga Benth. and Schoepfia brasiliensis A.DC. The flowering peak for most species was from August to October. Maximum fruit production was from August to November. Most species are zoochoric (58%), but 23% were anemochoric and 19% autochoric. The floristic composition of this forest and another 20 forests from São Paulo state were compared. The results obtained indicate the existence of distinct groups of forests. The most homogeneus group contains forests from the municipality of Campinas with similarity of 40%. This suggests that these forests are possibly fragments of a original continuous forest in the Campinas region.

Study of the surface hardness and modulus of elasticity of conventional and microwave-cured acrylic resins

The aim of this study was to evaluate the following acrylic resins: Clássico®, QC-20® and Lucitone®, recommended specifically for thermal polymerization, and Acron MC® and VIPI-WAVE®, made for polymerization by microwave energy. The resins were evaluated regarding their surface nanohardness and modulus of elasticity, while varying the polymerization time recommended by the manufacturer. They were also compared as to the presence of water absorbed by the samples. The technique used was nanoindentation, using the Nano Indenter XP®, MTS. According to an intra-group analysis, when using the polymerization time recommended by the manufacturer, a variation of 0.14 to 0.23 GPa for nanohardness and 2.61 to 3.73 GPa for modulus of elasticity was observed for the thermally polymerized resins. The variation for the resins made for polymerization by microwave energy was 0.15 to 0.22 GPa for nanohardness and 2.94 to 3.73 GPa for modulus of elasticity. The conclusion was that the Classico® resin presented higher nanohardness and higher modulus of elasticity values when compared to those of the same group, while Acron MC® presented the highest values for the same characteristics when compared to those of the same group. The water absorption evaluation showed that all the thermal polymerization resins, except for Lucitone®, presented significant nanohardness differences when submitted to dehydration or rehydration, while only Acron MC® presented no significant differences when submitted to a double polymerization time. Regarding the modulus of elasticity, it was observed that all the tested materials and products, except for Lucitone®, showed a significant increase in modulus of elasticity when submitted to a lack of hydration.

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure.

Vigilância de eventos adversos pós-vacinação e segurança de programas de imunização

O objetivo da revisão foi analisar aspectos conceituais e operacionais de sistemas de vigilância de eventos adversos pós-vacina. Foram incluídos artigos disponíveis em formato eletrônico, publicados entre 1985 e 2009, selecionados nas bases Medline/PubMed, com as palavras-chave: "adverse events following vaccine", "adverse events following vaccine surveillance", "post-marketing surveillance" e "safety vaccine" e "Phase IV clinical trials", e excluídos aqueles com foco em tipos específicos desses eventos. Foram apontados os principais aspectos que justificam a importância dos eventos adversos pós-vacina em saúde pública, os instrumentos que garantem a segurança das vacinas e as finalidades, atributos, tipos, interpretações de dados, limitações e novos desafios da vigilância de eventos adversos pós-vacina, bem como estratégias para aumentar sua sensibilidade. A revisão é concluída com desafios para os próximos anos, visando à segurança e confiabilidade dos programas de vacinação.

Cobertura vacinal em menores de dois anos a partir de registro informatizado de imunização em Curitiba, PR

OBJETIVO: Avaliar o programa de imunização de crianças de 12 e de 24 meses de idade, com base no registro informatizado de imunização. MÉTODOS: Estudo descritivo em amostra probabilística de 2.637 crianças nascidas em 2002 e residentes em Curitiba, PR. As fontes de dados foram: registro informatizado de imunização do município, Sistema de Informação de Nascidos Vivos e inquérito domiciliar para casos com registro incompleto. As coberturas foram estimadas aos 12 e aos 24 meses de vida e analisadas segundo características socioeconômicas de cada distrito sanitário e o vínculo das crianças aos serviços de saúde. Foram analisadas a abrangência, completude e duplicidades do registro informatizado de imunização. RESULTADOS: A cobertura do esquema de imunização foi de 95,3% aos 12 meses sem diferenças entre os distritos e de 90,3% aos 24 meses, tendo sido mais elevada em um distrito com piores indicadores socioeconômicos (p = 0,01). A proporção de vacinas, segundo o tipo, aplicadas antes e após a idade recomendada foi de até 0,9% e até 32,2%, respectivamente. A cobertura do registro informatizado de imunização foi de 98% na amostra estudada, o sub-registro de doses de vacinas foi de 11% e a duplicidade de registro foi de 20,6%. Os grupos que apresentaram maiores coberturas foram: crianças com cadastro definitivo, aquelas com três ou mais consultas pelo Sistema Único de Saúde e as atendidas em Unidades Básicas de Saúde que adotam plenamente a Estratégia de Saúde da Família. CONCLUSÕES: A cobertura vacinal em Curitiba mostrou-se elevada e homogênea entre os distritos, e o vínculo com os serviços de saúde foi fator importante para tais resultados. O registro informatizado de imunização mostrou-se útil no monitoramento da cobertura vacinal; no entanto, é importante a prévia avaliação do seu custo-efetividade para que seja amplamente utilizado pelo Programa Nacional de Imunização.

Association between osteoporosis and rheumatoid arthritis in women: a cross-sectional study

CONTEXT AND OBJECTIVES: Osteoporosis has frequently been observed in patients with rheumatoid arthritis. The present study was undertaken in order to evaluate factors associated with osteoporosis among women with rheumatoid arthritis. DESIGN AND SETTING: Cross-sectional study, carried out in a public hospital in São Paulo. METHODS: The participants were 83 women with rheumatoid arthritis (53.7 ± 10.0 years old). Bone mineral density (BMD) and body composition were measured by dual energy X-ray absorptiometry. The patients were divided into three groups according to BMD: group 1, normal BMD (n = 24); group 2, osteopenia (n = 38); and group 3, osteoporosis (n = 21). Tests were performed to compare differences in means and correlations, with adjustments for age, duration of disease and cumulative corticosteroid. The relationships between clinical factors, physical activity score, dietary intake, body composition and biochemical parameters were analyzed using linear regression models. RESULTS: Mean calcium, vitamin D and omega-6 intakes were lower than the recommendations. Associations were found between BMD and age, disease duration, parathyroid hormone concentration and fat intake. The linear regression model showed that being older, with more years of disease and lower weight were negatively correlated with BMD [Total femur = 0.552 + 0.06 (weight) + 0.019 (total physical activity) - 0.05 (age) - 0.003 (disease duration); R² = 48.1; P < 0.001]. CONCLUSION: The present study indicates that nutritional factors and body composition are associated with bone mass in women with rheumatoid arthritis.

O efeito da restrição calórica na longevidade

A restrição calórica (RC) é uma das formas de intervenção nutricional mais amplamente discutida para se estender o tempo de vida em uma variedade de espécies, inclusive seres humanos. A RC parece reduzir a incidência de doenças relacionadas à idade. O mecanismo clássico que poderia explicar o efeito do consumo calórico no envelhecimento está relacionado à redução da gordura corporal e à sinalização da insulina, somada às espécies reativas de oxigênio produzidas durante a respiração que causam danos oxidativos ao DNA e ao RNA das células, promovendo o processo de envelhecimento e o aumento do risco de doenças. No entanto, o efeito da RC na longevidade em humanos ainda não está bem estabelecido e mais estudos são necessários para que os mecanismos celulares e moleculares responsáveis pelos efeitos terapêuticos da restrição calórica sejam elucidados. Além disso, é necessário diferenciar os efeitos benéficos da restrição calórica daqueles relacionados a hábitos alimentares saudáveis.

Influência da mídia em universitárias brasileiras de diferentes regiões

A mídia tem impacto na satisfação com a imagem corporal e risco para o desenvolvimento de transtornos alimentares. OBJETIVO: Avaliar a influência da mídia em universitárias e possíveis associações com idade, estado nutricional, renda e escolaridade do chefe da família. MÉTODOS: 2.489 estudantes do sexo feminino das cinco regiões do Brasil responderam à Sociocultural Attitudes Towards Appearance Scale (SATAQ-3). O escore na SATAQ foi comparado entre as regiões por meio de uma análise de variância. Uma análise de covariância foi utilizada para verificar a influência das variáveis estudadas no escore da SATAQ. Uma regressão logística foi realizada para verificar a interferência conjunta das variáveis em relação à influência da mídia. RESULTADOS: Não foram encontradas diferenças regionais na SATAQ total (p = 0,164) e subescalas Internalização atlética (p = 0,293) e Pressão (p = 0,150); houve diferença para as subescalas Internalização geral (p = 0,010) e Informação (p = 0,002). Idade, estado nutricional e renda influenciaram o resultado. CONCLUSÕES: O escore total na SATAQ foi similar entre as regiões, mas o Sul e o Nordeste apresentaram maiores pontuações para subescalas Internalização geral e Informação respectivamente. Estudantes com menos de 25 anos, com excesso de peso e maior renda foram em média mais influenciadas pela mídia.