Dorsomorphin reverses the mesenchymal phenotype of breast cancer initiating cells by inhibition of bone morphogenetic protein signaling

Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer

Reduced Expression of Sprouty1 Contributes to the Aberrant Proliferation and Impaired Apoptosis of Acute Myeloid Leukemia Cells

In most of the acute myeloid leukemia patients there is an aberrant tyrosine kinase activity. The prototype of Sprouty proteins was originally identified in Drosophila melanogaster as antagonists of Breathless, the mammalian ortholog of fibroblast growth factor receptor. Usually, SPRY family members are inhibitors of RAS signaling induced by tyrosine kinases receptors and they are implicated in negative feedback processes regulating several intracellular pathways. The present study aims to investigate the role of a member of the Sprouty family, Sprouty1, as a regulator of cell proliferation and growth in patients affected by acute myeloid leukemia. Sprouty1 mRNA and protein were both significantly down-regulated in acute myeloid leukemia cells compared to the normal counterpart, but they were restored when remission is achieved after chemotherapy. Ectopic expression of Sprouty1 revealed that it plays a key role in the proliferation and apoptotic defect that represent a landmark of the leukemic cells. Our study identified Sprouty1 as negative regulator involved in the aberrant signals of adult acute myeloid leukemia. Furthermore, we found a correlation between Sprouty1 and FoxO3a delocalization in acute myeloid leukemia (AML) patients at diagnosis, suggesting a multistep regulation of RAS signaling in human cancers

SIRT6 promotes metastasis and relapse in HER2-positive breast cancer

The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of Delta16HER2 tumors promoting the formation of higher number of tumor foci and metastases than controls. This phenotype of SIRT6-OE tumors is associated with cancer stem cell (CSC)-like features and tumor dormancy, and low senescence and oxidative DNA damage. Accordingly, a sub-set of HER2-positive breast cancer patients with concurrent SIRT6-OE has a significant poorer relapse-free survival (RFS) probability than patients with low expression of SIRT6. ChIP-seq, RNA-seq and RT-PCR experiments indicate that SIRT6-OE represses the expression of the T-box transcription factor 3 (Tbx3) by deacetylation of H3K9ac. Accordingly, loss-of-function mutations of TBX3 or low TBX3 expression levels are predictive of poor prognosis in HER2-positive breast cancer patients. Our work indicates that high levels of SIRT6 are indicative of poor prognosis and high risk of metastasis in HER2-positive breast cancer and suggests further investigation of TBX3 as a downstream target of SIRT6 and co-marker of poor-prognosis. Our results point to a breast cancer subtype-specific effect of SIRT6 and warrant future studies dissecting the mechanisms of SIRT6 regulation in different breast cancer subtypes

Representações sociais de residentes multiprofissionais acerca da idealização davivência na rede de atenção à saúde / Social representations of multiprofessional residents about idealization of life in the health care network

Este artigo tem como objetivo apresentar a percepção de residentes multiprofissionais em saúde acerca da vivência prática na Rede de Atenção à Saúde, à luz da teoria das representações sociais. Trata-se de um estudo qualitativo, descritivo-exploratório, desenvolvido no Hospital Universitário Regional dos Campos Gerais no ano de 2019. Considerou-se como população de estudo os residentes multiprofissionais em saúde (n=55), em seu primeiro ano de residência. Para a coleta de dados utilizou-se o Grupo Focal; e a pergunta norteadora única: ‘Qual importância você atribui à vivência prática na Rede de Atenção à Saúde? Por favor, expresse todas as suas opiniões’. Os dados foram analisados por meio do discurso do sujeito coletivo e à luz das Representações Sociais. Os resultados possibilitaram a extração da temática “Conhecimento do fluxo da rede de atenção à saúde” a qual emergiu quatro ideias centrais com seus respectivos discursos. A primeira ideia central discorre a potencialidade de contextualização teórico-prática angariada com a vivência prática nos diferentes níveis de atenção da rede. Além de propiciar o entendimento acerca do funcionamento da rede, permite potencializar o processo de trabalho dos residentes, garantindo encaminhamento correto do paciente na rede, maior resolubilidade e acolhimento diferenciado do cuidado em saúde, conforme observado nas ideias centrais subsequentes.  Ademais, os residentes expressaram a representação social inerente a maior valorização do SUS. Conclui-se que a representação social dos residentes multiprofissionais em saúde acerca da vivência na rede de atenção à saúde é enriquecedora, geradora de crescimento profissional e apropriação de conhecimentos científicos e ideológicos. 

Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6

Objective: Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM. Methods: To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle. Results: Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls. Conclusions: Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment

Perfil, sintomas e tratamento realizado em neonatos diagnosticados com sepse

Background and Objectives: Neonatal sepsis represents one of the main causes of morbidity and mortality in newborns. The aim of the present study was to know the profile, signs, symptoms and treatment performed in newborns diagnosed with sepsis, according to the final clinical condition (cure or death). Methods: retrospective, quantitative study. Data were collected from physical medical records of a Neonatal Intensive Care Unit (NICU) of a University Hospital (n=62). The newborns were divided into two groups: those who survived and those who died. Then, they were compared according to demographic and life characteristics of the newborn; signs and symptoms; identification of microorganisms and use of medicines. Data were analyzed by Fisher’s Exact test. (p≤0,05) and complied with the ethical guidelines (nº 2.133.726). Results: Of the newborns diagnosed with sepsis, 82% survived, of which those aged more than 30 weeks who remained in the NICU for more than eight days prevailed significantly (pJustificación y objetivos: la sepsis neonatal representa una de las principales causas de morbimortalidad en los recién nacidos. El objetivo de esta investigación fue conocer el perfil, signos, síntomas y tratamiento realizado en neonatos diagnosticados con sepsis, de acuerdo con el cuadro clínico final (cura o muerte). Métodos: investigación retrospectiva, cuantitativa realizada en prontuarios físicos de una Unidad de Terapia Intensiva Neonatal (UTIN) de un Hospital Universitario (n=62). Los neonatos fueron divididos en dos grupos: sobrevinientes y muertos, y fueron comparados según características demográficas y de vida del neonato; signos y síntomas; identificación de microorganismos y uso de medicamentos. Los datos fueron analizados por la prueba exacta de Fisher (p≤0.05) y la investigación cumplió con los preceptos éticos (No. 2.133.726). Resultados: De los neonatos con diagnósticos de sepsis, un 82% sobrevivió, de éstos prevalecieron significativamente los con más de 30 semanas, que permanecieron en la UTIN por más de ocho días (pJustificativa e Objetivos: A sepse neonatal representa uma das principais causas de morbimortalidade em recém-nascidos. O presente estudo objetivou conhecer o perfil, os sinais, sintomas e o tratamento realizado em neonatos diagnosticados com sepse, segundo quadro clínico final (cura ou óbito). Métodos: pesquisa retrospectiva, quantitativa. Os dados foram coletados de prontuários físicos de uma Unidade de Terapia Intensiva Neonatal (UTIN) de um Hospital Universitário (n=62). Os neonatos foram divididos em dois grupos: os que sobreviveram e os que vieram a óbito. Depois, foram comparados segundo características demográficas e de vida do neonato; sinais e sintomas; identificação de microrganismos e uso de medicamentos. Os dados foram analisados pelo teste Exato de Fisher (p≤0,05). Resultados: Dos neonatos com diagnóstico de sepse, 82% sobreviveram, dos quais prevaleceram significativamente os com mais de 30 semanas, que permaneceram na UTIN por mais de oito dias (p0,05). Conclusão: Os achados reforçam o conhecimento sobre o perfil dos neonatos com sepse e a importância do investimento em intervenções transversais durante o pré-natal, pós-parto e período neonatal, com vistas a reduzir as infecções neonatais e suas consequências. Descritores: Perfil de saúde. Sepse. Sepse neonatal. Recém-nascido

ATIVIDADE EXTENSIONISTA DA RESIDÊNCIA MULTIPROFISSIONAL EM SAÚDE DO IDOSO EM UMA COMUNIDADE DA ZONA RURAL

Introdução: Com o crescente envelhecimento da população, os serviços de saúde enfrentam o desafio da atenção integral ao idoso, cujo é ainda maior em idosos na zona rural. Neste interim desenvolveu-se um projeto de extensão para propiciar atenção multiprofissional em saúde aos idosos de uma comunidade rural. Objetivo: relatar as ações desenvolvidas pelo referido projeto. Metodologia: As ações são desenvolvidas por residentes multiprofissionais em saúde (RMS) do idoso e docentes em âmbito domiciliar pertencentes a uma zona rural do município de Ponta Grossa, Paraná. Contemplam a atenção gerontológica, com avaliação multidimensional da saúde do idoso, enfatizando a promoção de saúde, cuidado apoiado, empoderamento de idosos e familiares para o processo de envelhecimento ativo e saudável. Com vistas a potencializar o processo de trabalho da equipe extensionista e a comunicação efetiva entre profissionais da saúde da rede de atenção à saúde do município, a equipe desenvolveu-se uma caderneta de saúde do idoso. Resultados: A atenção gerontológica em equipe multiprofissional foi propiciada a 60 idosos garantindo a eles possibilidades construção de novas lógicas de produção do cuidado em saúde, através do fomento de ações educativo-preventivas, curativas e reabilitadoras em saúde, com base necessidades reais. A caderneta instrumento auxiliar das práticas em saúde, tem atingido de fato ao que se propõe, um veículo efetivo de comunicação na rede de atenção em saúde, de monitoramento e educação em saúde, capaz de transmitir valores e impulsionar mudanças no comportamento. Conclusão: O projeto tem contribuído para ampliar o acesso à atenção à saúde de idosos assistidos pela equipe extensionista, propiciado a melhora na condição de saúde destes sujeitos, na construção de um envelhecimento ativo e saudável. Para equipe executora, é um momento díspar de aprendizado inovador, que permite (re)construir profissionais inventivos e preparados para os desafios da atenção em saúde baseado em cenários da vida cotidiana

Estresse na residência multiprofissional em saúde: natureza e magnitude / Stress in multiprofessional health residence: nature and magnitude

O objetivo do estudo foi investigar os fatores determinantes do estresse entre residentes multiprofissionais em saúde, bem como apreender os valores atribuídos pelos sujeitos em relação a esse fenômeno. Estudo transversal, quanti-qualitativo desenvolvido junto a 37 profissionais residentes. Para a avaliação quantitativa utilizou-se o ‘Inventário de Sintomas de Stress para Adultos de Lipp’ e à qualitativa, o grupo focal. O estresse incidiu em 30% dos residentes, com predomínio da fase de resistência (73%) e sintomas psicológicos (82%). Os principais fatores determinantes elencados foram: a rotina de trabalho no ambiente hospitalar e atuação dos residentes em cenários múltiplos. Sobre os desdobramentos do estresse emergiram as categorias: impacto da residência na vida diária e profissional. A prevalência do estresse entre os residentes foi expressiva, requerendo dos gestores dos programas de residência, dos gestores hospitalares e dos gestores dos demais cenários de prática uma postura reflexiva acerca do estresse e de seus agentes causais, com provimento de estratégias diretivas e qualificadas que busquem minimizar e prevenir esse fenômeno. 

Antioxidant and antiproliferative activities of different varieties of cauliflower (Brassica oleracea var. botrytis) after cooking processes.

Cauliflowers are well-known for their health benefits and they are becoming increasingly popular as a fresh vegetable significant source of nutritional antioxidants, such as vitamins and carotenoids, or biologically active dietary components, such as the polyphenols and glucosinolates [1]. Cauliflowers are also a rich source of nutrients such as calcium, zeaxanthin and lutein which have a protective action in eye health and they can also help in the prevention of cancer through the flavonoids known as quercetin or phytonutrient as sulforaphane [2]. Cultivation of coloured cauliflowers (Brassica oleracea var. botrytis) is spreading in Italy and this is also a consequence of the significant genetic improvement on the white type “Tardivo di Fano”, the green types “Verde di Macerata” and the violet type “Violetto di Catania” [3]. Recently, in the framework of a genetic improvement programme, pure lines of “orange type” were obtained [4]. Cooking as a domestic processing method has a great impact on food nutrients. Most vegetables are mainly consumed after being cooked, and cooking considerably affects their health-promoting compounds (glucosinolates, phenolic compounds, phytochemicals, and vitamin C). The cooking process is more important also to determine the quality and recovery of biological active components that characterized the different variety of cauliflowers selected. The aim of this work was to study the influence of these conditions during boiling water and microwave cooking on some properties of coloured cauliflowers. Total polyphenols, antioxidant activity, and antiproliferative activity on human breast adenocarcinoma cell line MDA-MB 231 were evaluated after cooking processes. The results showed that the antioxidant activity, tested using ABTS assay, was reduced during the cooking in all cauliflower varieties. An increase of antioxidant activity in orange and violet varieties was observed when tested with DPPH and FRAP assays. Furthermore, the phenolic substances increase in methanol extracts after cooking processes, especially with microwave treatment. The antiproliferative activity on MDA-MB 231 tumour cell line shows an increase in orange and violet cauliflower aqueous extracts cooked with microwave. In conclusion, the change of properties results lower for orange and violet cauliflowers respect to white or green varieties after cooking processes. In some case the cooking processes increase the antioxidant and antiproliferative activity. The best cooking method that preserves the healthy properties of all varieties of cauliflower is the microwave treatment. [1] Raiola A, Errico A, Petruk G, Monti DM, Barone A, Rigano MM. Bioactive Compounds In Brassicaceae Vegetables With A Role In The Prevention Of Chronic Diseases. Molecules. 2017;23(1), pii: E15. [2] Rosa EAS, Heaney RK, Fenwick GR, Portas CAM. Glucosinolates in Crop Plants, in Horticultural Reviews, Volume 19 (ed J. Janick), 2010, John Wiley & Sons, Inc., Oxford, UK. [3] Acciarri N, Sabatini E, Rotino GL, Ciriaci T, Pulcini L, Della Campa M, Maestrelli A. Breeding In Progress In New Typologies Of Orange Cauliflowers (Brassica oleracea var. botrytis) Proceedings of 5th International Symposium on Brassicas and the 16th Crucifer genetic Workshop. Lillehammer, Norway. 8-12 September 2008. [4] Lu S,Van Eck J, Zhou X, Lopez AB, O’Halloran DM, Cosman KM, Conlin BJ, Paolillo DJ, Garvin DF, Vrebalov J, Kochian, LV, Kupper H, Earle ED, Cao J, Lia L. The Cauliflower Or Gene Encodes A Dnaj Cysteine-Rich Domain-Containing Protein That Mediates High Levels Of β-Carotene Accumulation. Plant Cell 2006;18:3594-3605

HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient's immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment