Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Indoor Versus Outdoor: Does Occupational Sunlight Exposure Increase Melanoma Risk? A Systematic Review.

INTRODUCTION: Melanoma is the fifth most common cancer diagnosed in the United States, representing 5.6% of all new cancer cases. There are conflicting reports correlating a relationship between primarily outdoor occupations, associated with increased exposure to direct sunlight, and the incidence of cutaneous melanoma. Our objective was to outline and critically evaluate the relevant literature related to chronic occupational exposure to sunlight and risk of developing cutaneous melanoma. METHODS: The study protocol for this systematic review was submitted to the International Prospective Register of Systematic Reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. For each relevant study included, the following information was extracted: author names, publication year, study name, study design, age, exposure assessment, outcome, comparison, number of cases, case ascertainment, and descriptive and adjusted statistics. Study quality and evidence certainty was assessed using the Grading of Recommendations, Assessment, Development and Evaluations model. RESULTS: The initial database search yielded 1629 articles for review and following full-text screening, a total of 14 articles were included for final analysis. Of the studies included, seven articles were retrospective case control and seven were cohort studies. The studies did not report any differences in the likelihood of cutaneous melanoma development based upon membership in the outdoor versus indoor occupation groups included in each study. CONCLUSIONS: Overall, the articles included in this systematic review did not report an increased risk of developing cutaneous melanoma among individuals with outdoor occupations. Further investigation is required to determine if other occupational or life-style-related risk factors exist, to help support the development of individualized skin screening recommendations and improve the early detection of melanoma in all populations.

Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a key role in breast cancer progression and metastasis. Effective therapeutic targeting of COX-2 would require the knowledge of whether a tumor is addicted to COX-2, and if we can counter the potential resistance to anti-COX-2 therapy. Herein we tested the hypothesis that celecoxib-resistance involves selection of cancer cells that overexpress COX-2. MATERIALS AND METHODS: We selected celecoxib-resistant (CER) variants from two metastatic cell lines, SUM149 inflammatory breast cancer (IBC) cell line and MDA-MB-231-BSC60 cell line, by culturing them in the presence of celecoxib. We measured the relative levels of COX-2 protein and its network components Bcl-2, Bcl-xL, and Bax in the parental cell lines and their CER variants by Western blotting. To determine whether celecoxib resistance would increase tumorigenicity, we performed an in vitro clonogenicity assay. We determined the statistical significance of differences between the groups using the two-sample t-test. RESULTS: Both the celecoxib-resistant cell lines SUM149-CER and BSC60-CER produced significantly higher levels of COX-2 protein than their parental counterparts (P < 0.05). The CER variants produced a reduced level of pro-apoptosis protein Bax (both cell lines) and increased levels of anti-apoptosis proteins Bcl-2 (BSC60) or Bcl-xL (SUM149). Importantly, the CER variants had significantly higher clonogenicity than their parental cell lines (P < 0.05). The siRNA-mediated COX-2 knockdown in SUM149-CER cell line resulted in a significant decrease in clonogenicity and in Bcl-xL and Bcl-2 protein levels, thus supporting our hypothesis. CONCLUSION: Celecoxib-resistant variant cells present in breast cancer cell lines overexpress COX-2, which is robustly linked with survival pathways and clonogenicity. Since COX-2 is important in the variant cancer cells of aggressive nature, it represents a good therapeutic target.

Flexibility sustains epithelial tissue homeostasis.

Epithelia surround our bodies and line most of our organs. Intrinsic homeostatic mechanisms replenish and repair these tissues in the face of wear and tear, wounds, and even the presence of accumulating mutations. Recent advances in cell biology, genetics, and live-imaging techniques have revealed that epithelial homeostasis represents an intrinsically flexible process at the level of individual epithelial cells. This homeostatic flexibility has important implications for how we think about the more dramatic cell plasticity that is frequently thought to be associated with pathological settings. In this review, we will focus on key emerging mechanisms and processes of epithelial homeostasis and elaborate on the known molecular mechanisms of epithelial cell interactions to illuminate how epithelia are maintained throughout an organism's lifetime.

Hair follicle regeneration suppresses Ras-driven oncogenic growth.

Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

Prevalencia de tabaquismo en estudiantes de sexto año de la carrera de medicina de la universidad nacional del nordeste 2019 / Prevalence of smoking in sixth-year medical students at the National University of the Northeast 2019

Introducción. El tabaco es una de las principales causas de muertes prevenibles en el mundo. Los estudiantes, a pesar de tener un factor protector como lo es su formación académica continúan consumiendo el mismo. Objetivo general. Establecer la prevalencia de tabaquismo activo y pasivo entre los estudiantes de 6to año de la carrera de Medicina. Objetivo específico. Determinar la actitud frente al tabaquismo: grado de motivación, etapa de la adicción y el nivel de dependencia; definir tiempo de inicio del mismo en relación con la progresión en la carrera. Materiales y métodos. Estudio cuantitativo, observacional, descriptivo, de corte transversal del 01 de enero al 30 de abril del año 2019. Los datos se obtuvieron mediante una encuesta estructurada multiple-choice, anónima y auto-administrada. Resultados. Se analizaron 160 encuestas. La prevalencia de fumadores fue del 10%, y 15.6% de exfumadores. El 53.1% estaban expuestos al humo ambiental (fumadores pasivos). El consumo promedio es de 6 cigarrillos/día. El 43.75% de la población de fumadores comenzó antes del primer año de la carrera y sólo un 12.5% en años avanzados de la carrera. El 31.25% fumaban entre los 30 a 60 minutos luego de despertar, mientras que el resto lo hacía pasada la hora. 12.5% de los fumadores encontraba difícil no fumar en los lugares donde está prohibido. El 87.5% les gustaría dejar de fumar, un 62.5% tiene "bastante" y "mucho" interés en dejarlo y un 37.5% que tiene poco o ningún interés. Conclusiones. Los resultados de este estudio permitirán orientar a políticas de salud pública para el control del consumo de tabaco y al mismo tiempo servir para la evaluación de las mismas. Palabras claves. Estudiantes, medicina, tabaquismo, prevalencia, actitud

Summary Introduction. Tobacco is one of the leading causes of preventable deaths in the world. The students, despite having a protective factor, as is their academic education, continue to consume it. Overall objective. To establish the prevalence of active and passive smoking, among the 6th year students of the Medicine career. Specific objective. Determine the attitude towards smoking: degree of motivation, stage of addiction and the level of dependence; define start time of the same in relation to the progression in the race. Materials and methods. Quantitative, observational, descriptive, cross-sectional study from January 1 to April 30 of the year 2019. The data was obtained through a structured multiple-choice, anonymous and self-administered survey. Results. 160 surveys were analyzed. The prevalence of smokers was 10%, and 15.6% of ex-smokers. 53.1% were exposed to environmental smoke (passive smoking). The average consumption is 6 cigarettes / day. 43.75% of the smoking population began before the first year of the race and only 12.5% in advanced years of the race. The 31.25% smoked between 30 to 60 minutes after waking up, while the rest did it after the hour. 12.5% of smokers found it difficult not to smoke in places where it is prohibited. 87.5% would like to quit smoking, 62.5% have "enough" and "a lot" interest in quitting and 37.5% have little or no interest. Conclusions. The results of this study will allow orienting public health policies for the control of tobacco consumption and at the same time serve for the evaluation of them. Keywords. Students, medicine, smoking, prevalence, attitude

Resumo Introdução. O tabaco é uma das principais causas de mortes evitáveis no mundo. Os alunos, apesar de terem como fator de proteção a sua formação acadêmica, continuam a consomem-lo. Objetivo geral. Estabelecer a prevalência de tabagismo ativo e passivo entre os alunos do 6º ano da carreira de Medicina. Objetivo específico. Determinar a atitude em relação ao tabagismo: grau de motivação, estágio da dependência e nível de dependência; definir a hora de início do mesmo em relação à progressão na corrida. Materiais e métodos. Estudo quantitativo, observacional, descritivo, seção transversal de 1 janeiro - 30 abril 2019. Os dados foram obtidos através de uma pesquisa estruturada de múltipla escolha, anônimo e auto-administrado. Resultados. 160 inquéritos foram analisados. A prevalência de fumantes foi de 10% e de 15,6% dos ex-fumantes. 53,1% foram expostos ao fumo ambiental (tabagismo passivo). O consumo médio é de 6 cigarros / dia. 43,75% da população de fumantes começaram antes do primeiro ano da carreira e apenas 12,5% nos anos avançados. Os 31,25% fumaram entre 30 a 60 minutos após o despertar, enquanto o restante o fez após a hora. 12,5% dos fumantes acharam difíceis não fumar em locais proibidos. 87,5% gostariam de parar de fumar, 62,5% têm interesse "suficiente" e "muito" em sair e 37,5% que têm pouco ou nenhum interesse. Conclusões. Os resultados deste estudo vão orientar políticas públicas de saúde para controle do consumo de tabaco e, ao mesmo tempo, servem para a avaliação do mesmo. Palavras chaves. Estudantes, medicina, tabagismo, prevalência, atitud.

Selection of metastatic breast cancer cells based on adaptability of their metabolic state.

A small subpopulation of highly adaptable breast cancer cells within a vastly heterogeneous population drives cancer metastasis. Here we describe a function-based strategy for selecting rare cancer cells that are highly adaptable and drive malignancy. Although cancer cells are dependent on certain nutrients, e.g., glucose and glutamine, we hypothesized that the adaptable cancer cells that drive malignancy must possess an adaptable metabolic state and that such cells could be identified using a robust selection strategy. As expected, more than 99.99% of cells died upon glutamine withdrawal from the aggressive breast cancer cell line SUM149. The rare cells that survived and proliferated without glutamine were highly adaptable, as judged by additional robust adaptability assays involving prolonged cell culture without glucose or serum. We were successful in isolating rare metabolically plastic glutamine-independent (Gln-ind) variants from several aggressive breast cancer cell lines that we tested. The Gln-ind cells overexpressed cyclooxygenase-2, an indicator of tumor aggressiveness, and they were able to adjust their glutaminase level to suit glutamine availability. The Gln-ind cells were anchorage-independent, resistant to chemotherapeutic drugs doxorubicin and paclitaxel, and resistant to a high concentration of a COX-2 inhibitor celecoxib. The number of cells being able to adapt to non-availability of glutamine increased upon prior selection of cells for resistance to chemotherapy drugs or resistance to celecoxib, further supporting a linkage between cellular adaptability and therapeutic resistance. Gln-ind cells showed indications of oxidative stress, and they produced cadherin11 and vimentin, indicators of mesenchymal phenotype. Gln-ind cells were more tumorigenic and more metastatic in nude mice than the parental cell line as judged by incidence and time of occurrence. As we decreased the number of cancer cells in xenografts, lung metastasis and then primary tumor growth was impaired in mice injected with parental cell line, but not in mice injected with Gln-ind cells.