Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

Ras signaling pathways play an important role in cellular proliferation and survival, and inappropriate activation of Ras frequently results in cell transformation and cancer. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of the adult T-cell leukemia/lymphoma (ATLL), a severe malignancy that has a poor prognosis and exhibits resistance to conventional chemotherapy. Although the mechanisms involved in cell transformation by HTLV-1 have not been completely clarified, it is generally thought that Tax plays a pivotal role in the process. We have previously proposed that a functionally active Ras protein is needed for efficient anti-apoptotic activity of Tax. In this study we report data indicating that the apoptotic resistance of cells expressing Tax, constitutively or transiently, is linked to the intracellular levels of Ras-GTP. Indeed, we found that Tax-positive cells have a high content of active Ras, and that inhibition of Ras signaling, using the antagonist farnesyl thyosalicylic acid (FTS), increases their sensitivity to apoptosis. FTS treatment was also accompanied by a decrease in ERK, but not Akt, phosphorylation. Thus, all together our data suggest that the interaction between Tax and Ras could be important to ATLL pathogenesis, and indicate Ras as a possible target for therapeutic intervention in ATLL patients

Genetic Features of Metachronous Esophageal Cancer Developed in Hodgkin's Lymphoma or Breast Cancer Long-Term Survivors: An Exploratory Study.

Background Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms. Methods Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC). Results We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes. Conclusions Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis

Contaminantes em alimentos e orientação nutricional: reflexão teórica

Estudo de reflexão sobre as orientações nutricionais que são realizadas a população e que, na maior parte do mundo, enfatiza o consumo de frutas, verduras e legumes em maior quantidade em relação a alimentos industrializados, que por conterem maior quantidade de açúcar, sódio, e calorias aumentam o ganho de peso. No entanto, quando se lê a respeito das formas de cultivo dos alimentos in natura e sobre a qualidade dos alimentos cárneos e pescados, que são orientados para o consumo da população, surge à dúvida se há coerência entre a orientação e o consumo, uma vez que há relatos da contaminação desses alimentos por resíduos de agrotóxicos, contaminação do solo, da água e que não tem tido o devido destaque pelos órgãos estatais. Qual deveria ser a conduta perante a realidade que se apresenta? Uma perspectiva viável é a conscientização da população, que deve exigir melhores condições dos alimentos consumidos, além de resgatar práticas mais saudáveis como o cultivo de hortas orgânicas caseiras e adquirir o mínimo possível, alimentos industrializados. Longe de polemizar, esta reflexão visa incentivar uma visão crítica aos profissionais de saúde sobre seu papel na prevenção de doenças, e exigir alimentos mais saudáveis para o consumo humano.Reflection study on the nutritional guidelines given to the population, which, in most parts of the world, emphasize on the consumption of fruits, vegetables and legumes over industrialized foods, which contain more sugar, sodium and calories, and increase body weight. However, when one reads about the ways of cultivating fresh food and about the quality of meat and fish products destined for consumption, the question arises as to whether there is coherence between said guidance and consumption, given that there are reports of contamination of these foods by pesticide residues, as well as soil and water contamination, a topic scarcely addressed by state entities. What should be done to face this reality? A viable perspective is to raise awareness in the population, which should demand better quality foods, in addition to returning to healthier practices such as the cultivation of home-grown organic gardens and acquiring as few industrialized foods as possible. Far from causing controversy, this reflection aims to encourage a critical view in health professionals on their role in disease prevention and the demand for healthier foods for human consumption.Estudio de reflexión sobre las orientaciones nutricionales que se dan a la población y que, en la mayor parte del mundo, enfatizan el consumo de frutas, verduras y legumbres antes que los alimentos industrializados, que por contener mayor cantidad de azúcar, sodio y calorías, aumentan peso corporal. Sin embargo, cuando se lee acerca de las formas de cultivo de los alimentos frescos y sobre la calidad de los alimentos cárnicos y pescados, destinados al consumo de la población, surge la duda de si hay coherencia entre la orientación y el consumo, dado que hay relatos de contaminación de esos alimentos por residuos de pesticidas, contaminación del suelo, del agua, poco atendido por los órganos estatales. ¿Cuál debería ser la conducta ante la realidad que se presenta? Una perspectiva viable es la concientización de la población, que debe exigir mejores condiciones de los alimentos consumidos, además de rescatar prácticas más saludables como el cultivo de huertos orgánicos caseros y adquirir el mínimo posible, de alimentos industrializados. Lejos de polemizar, esta reflexión pretende incentivar una visión crítica a de los profesionales de la salud sobre su papel en la prevención de enfermedades, y exigir alimentos más saludables para el consumo humano

Association Between ERCC1 rs3212986 and ERCC2/XPD rs1799793 and OS in Patients With Advanced Esophageal Cancer

Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia. The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC. As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy. Among the EC patients referred to our Institution between 2004 and 2012, we selected a cohort of 180 patients diagnosed with a clinical tumor stage ranging from IIB and IVA. Patients were genotyped for four NER variants, two in the ERCC1 (rs11615 and rs3212986) and two in the ERCC2/XPD (rs1799793 and rs13181) genes. Kaplan–Meier analyses and Cox proportional hazards model were used to evaluate the associations of the selected variants with OS; association with response to neoadjuvant therapy was investigated using logistic regression. Results showed that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were significantly associated with shorter OS. On the contrary, response association analysis displayed that, while rs11615 and rs3212986 in ERCC1 were associated with response, both ERCC2/XPD variants were not. By creating survival prediction models, we showed that the rs3212986 and the rs1799793 have a better predictability of the tumor stage alone. Furthermore, they were able to improve the power of the clinical model (AUC = 0.660 vs. AUC = 0.548, p = 0.004). In conclusion, our results indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could be used as surrogate markers for a better stratification of EC patients with advanced resectable tumor

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy

Healthy food strategies efficiency : booklet and text message after standart intervention among health professionals - randomized clinical study

Orientador: Maria Inês MonteiroTese (doutorado) - Universidade Estadual de Campinas, Faculdade de EnfermagemResumo: Título: Eficácia de estratégias de alimentação saudável: uso de cartilha e mensagem de texto após intervenção padrão entre profissionais de saúde ¿ estudo clínico randomizado Introdução: A obesidade tornou-se um problema mundial, pois afeta diferentes classes sociais e faixas etárias. A alimentação tem sido relacionada como fator causal importante para essas doenças e a Organização Mundial da Saúde orienta os países para que estes criem estratégias que envolvam nutrição e atividade física, com o objetivo de deter o avanço da obesidade, sobrepeso e doenças crônicas no futuro. No Brasil, o Ministério da Saúde vem desenvolvendo estratégias, juntamente com a Coordenação Geral de Alimentação e Nutrição, como o Guia Alimentar da População Brasileira, direcionadas aos profissionais e à população sobre a importância da alimentação saudável. Atividades de intervenção vêm sendo testadas para identificar sua eficácia em promover mudança de estilo de vida, manutenção de perda de peso, aumento de atividade física e melhora dos padrões alimentares, com impacto em outras esferas da vida. Portanto, o objetivo deste estudo foi verificar a eficácia do uso de mensagens de texto via celular (SMS) em profissionais da saúde comparados à intervenção padrão. Método: estudo clínico randomizado ¿ ECR - (1:1), triplo cego, com trabalhadores de um hospital universitário público da região de Campinas-SP, recrutados por meio de convite via e-mail, amigos ou supervisores para uma palestra sobre alimentação saudável, e posterior seleção dos participantes. Os trabalhadores foram divididos em dois grupos (n=40): intervenção (que recebeu SMS, orientação individual e cartilha de alimentação saudável) e controle (que recebeu orientação individual e cartilha de alimentação saudável) durante 90 dias. Os sujeitos foram pesados, medidos e sua alimentação foi avaliada. No decorrer do estudo, cartazes sobre os temas abordados na palestra de intervenção foram afixados em todo o hospital. Resultados: houve mudança de medidas corporais, provavelmente, associadas à alteração na quantidade de alimento ingerido (calorias/kg). Foram observadas alterações no peso entre o início e o final (p>0,05) e Circunferência de Cintura CC (P>0,05) para os grupos intervenção e controle, entre o início e o final do estudo; Porcentagem de Gordura Corporal (%GC) em ambos os grupos, entre outras medidas corporais. Houve significância estatística quando se correlacionou por meio do modelo de regressões logísticas múltiplas (GEE), as variáveis: capacidade atual para o trabalho, vínculo de trabalho, saúde comparada, atividade física, comer compulsivo, consumo de refrigerante e Circunferência de Cintura (CA) com o Índice de Massa Corporal (IMC). Quanto às mudanças alimentares, houve poucas mudanças e não estatisticamente significantes. Conclusão: O uso das mensagens de texto e cartazes sobre alimentação saudável, além do aconselhamento nutricional individualizado aos participantes do estudo, pode ser uma fonte de empoderamento do trabalhador na escolha dos seus alimentos diários e mais uma ferramenta contra a obesidade e sobrepeso. Embora as mudanças alimentares não sejam as ideais, foi possível observar mudanças relativas às medidas corporais como a circunferência de cintura e a somatória de gordura corporal. A aceitação do grupo às mensagens de texto evidencia um caminho novo que poderá ser utilizado como parte de um processo de aprendizagem e motivação de trabalhadores para a mudança de práticas não só alimentares, mas também como promoção de atividade física e hábitos saudáveis de vida. A proposição de novos estudos, com maior número de participantes e extensão do período de tempo, para se avaliar o impacto das mudanças a longo prazo, trará novos elementos para promover hábitos saudáveis. Linha de pesquisa: Trabalho, Saúde e Educação. Palavras-chave: Saúde do trabalhador. Consumo alimentar. Sobrepeso. Obesidade. SMS. ECRAbstract: Title: Healthy food strategies efficiency: booklet and text message after standard intervention among health professionals - randomized clinical study Introduction: Obesity has become a worldwide problem, because it affects different social classes and age groups. The diet has been listed as an important causal factor for these diseases, and the World Health Organization has called for countries to create strategies that involve nutrition and physical activity, to stop the advance of obesity, overweight and chronic diseases in the future. In Brazil, the Ministry of Health has developed strategies along with the Food and Nutrition General Coordination, as the Food Guide of the Brazilian population, targeted at professionals and the public, about the importance of healthy eating. Intervention activities have been tested to identify their effectiveness in promoting change in lifestyle, weight loss maintenance, increased physical activity and improved dietary patterns, with an impact on other life areas. The aim of this study was to verify the effectiveness of the mobile phone via text message usage (SMS) in health professionals compared to standard intervention. During the study, posters on the topic covered in the lecture intervention was available throughout the hospital. Method: randomized clinical trial - RCT - (1: 1), triple blind, employees of a public university hospital in Campinas-SP region, recruited by invitation via email, friends or supervisors, for a lecture about healthy eating and subsequent selection of participants. The workers were divided into two groups (n = 40): intervention (who received SMS, individual guidance and healthy eating booklet) and control (who received individual guidance and healthy eating booklet) for 90 days. The subjects were weighed, measured and their diet was evaluated. Results: There was a change in body measurements, probably associated with the change in the amount of food intake (calories / kg). Changes in weight were observed between the beginning and the end (p> 0.05) and Circumference DC Waist (P> 0.05) in the intervention and control groups, between the beginning and end of the study; Percentage of body fat (% BF) in both groups, among other body measurements. There was statistical significance when we correlated, through the multiple logistic regression model (GEE), the variables: current capacity to work, work contract, health compared, physical activity, compulsive eating, soda consumption and Waist Circumference (AC) with Body Mass Index (BMI). As for dietary changes, there were a few changes, albeit not statistically significant. Conclusion: The use of text messages and posters about healthy eating, in addition to individualized nutritional counseling to participants, can be a means to promote worker empowerment in choosing their daily diet and one more tool against obesity and overweight. Although dietary changes are not ideal, we observed changes related to body measurements, such as waist circumference and the sum of body fat. Acceptance of group text messages shows a new path that can be used as part of a learning process and motivation of workers to change their practices, not only diet, but also as promotion of physical activity and healthy lifestyles. The proposal of new studies with a larger number of participants and longer period of time to assess the impact of long-term changes will bring new elements to promote healthy habits. Line of research: Work, Health and Education. Keywords: Occupational health. Food intake. Overweight. Obesity. SMS. RCTDoutoradoEnfermagem e TrabalhoDoutora em Enfermage

Ras signaling contributes to survival of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) Tax-positive T-cells

Ras signaling pathways play an important role in cellular proliferation and survival, and inappropriate activation of Ras frequently results in cell transformation and cancer. Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of the adult T-cell leukemia/lymphoma (ATLL), a severe malignancy that has a poor prognosis and exhibits resistance to conventional chemotherapy. Although the mechanisms involved in cell transformation by HTLV-1 have not been completely clarified, it is generally thought that Tax plays a pivotal role in the process. We have previously proposed that a functionally active Ras protein is needed for efficient anti-apoptotic activity of Tax. In this study we report data indicating that the apoptotic resistance of cells expressing Tax, constitutively or transiently, is linked to the intracellular levels of Ras-GTP. Indeed, we found that Tax-positive cells have a high content of active Ras, and that inhibition of Ras signaling, using the antagonist farnesyl thyosalicylic acid (FTS), increases their sensitivity to apoptosis. FTS treatment was also accompanied by a decrease in ERK, but not Akt, phosphorylation. Thus, all together our data suggest that the interaction between Tax and Ras could be important to ATLL pathogenesis, and indicate Ras as a possible target for therapeutic intervention in ATLL patients

DMET? (Drug-Metabolizing Enzymes and Transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity.

PURPOSE: 5-fluorouracil (5-FU) has been widely used since the 1980s, and it remains the backbone of many chemotherapeutic combination regimens. However, its use is often limited by the occurrence of severe toxicity. Although several reports have shown the detrimental effect of some dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) gene polymorphisms in patients undergoing 5-FU-based treatment, they account for only a minority of toxicities. METHODS: Looking for new candidate genetic variants associated with 5-FU-induced toxicity, we used the innovative genotyping microarray Affymetrix Drug-Metabolizing Enzymes and Transporters (DMET)™ Plus GeneChip that interrogates 1,936 genetic variants distributed in 231 genes involved in drug metabolism, excretion, and transport. To reduce variability, we analyzed samples from colorectal cancer patients who underwent fairly homogenous treatments (i.e., Machover or Folfox) and experienced G3 or G4 toxicity; control patients were matched for therapy and selected from those who did not disclose toxicity (G0-G1). RESULTS: Pharmacogenetic genotyping showed no significant difference in DPYD and TYMS genetic variants distribution between cases and controls. However, other polymorphisms could account for 5-FU-induced toxicity, with the CHST1 rs9787901 and GSTM3 rs1799735 having the strongest association. CONCLUSIONS: Although exploratory, this study suggests that genetic polymorphisms not directly related to 5-FU pharmacokinetics and pharmacodynamics are involved in 5-FU-induced toxicity. Our data also indicates DMET™ microarray as a valid approach to discover new genetic determinants influencing chemotherapy-induced toxicity

Predictive role of host constitutive variants in neoadjuvant therapy of esophageal cancer

Chemoradiotherapy followed by surgery is at present the standard therapeutic approach for esophageal cancer (EC) in patients with resectable tumor. However, response to neoadjuvant therapy is characterized by a strong interpatient variability, and the identification of markers predictive of outcome is mandatory. In this review, taking into account the currently available literature, we report the impact that host genetic variables can have on EC neoadjuvant therapy. We mainly focused on the gene variants involved in the pharmacokinetics and pharmacodynamics of the common chemotherapeutic drugs used to treat EC patients, commented on the weakness of the present knowledge, and discussed the future strategies to achieve a more personalized and effective EC treatment