The ADMR Receptor Mediates the Effects of Adrenomedullin on Pancreatic Cancer Cells and on Cells of the Tumor Microenvironment

Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting. All cell lines expressed and secreted AM as indicated by ELISA. The growth of each of the cell lines was stimulated by exogenous AM and inhibited by the antagonist AMA. AM also stimulated in vitro angiogenesis assessed by polygon formation of endothelial cell lines. SiRNA-mediated silencing of ADMR, but not CRLR, reduced basal growth of all cells examined and reduced polygon formation of endothelial cells in vitro. Orthotopic tumors developed with shADMR bearing cancer cells had dramatically reduced primary tumor volume (>90%) and lung and liver metastasis compared to shControl bearing cells. To validate ADMR as a potential therapeutic target, in vivo studies were conducted using neutral nanoliposomes to systemically deliver human siRNA to ADMR to silence human cancer cells and mouse siRNA to ADMR to silence mouse tumor stromal cells. Systemic silencing of both human and mouse ADMR had no obvious adverse effects but strongly reduced tumor development.ADMR mediates the stimulatory effects of AM on cancer cells and on endothelial and stellate cells within the tumor microenvironment. These data support the further development of ADMR as a useful target treatment of pancreatic cancer

American palm ethnomedicine: A meta-analysis

<p>Abstract</p> <p>Background</p> <p>Many recent papers have documented the phytochemical and pharmacological bases for the use of palms (<it>Arecaceae</it>) in ethnomedicine. Early publications were based almost entirely on interviews that solicited local knowledge. More recently, ethnobotanically guided searches for new medicinal plants have proven more successful than random sampling for identifying plants that contain biodynamic ingredients. However, limited laboratory time and the high cost of clinical trials make it difficult to test all potential medicinal plants in the search for new drug candidates. The purpose of this study was to summarize and analyze previous studies on the medicinal uses of American palms in order to narrow down the search for new palm-derived medicines.</p> <p>Methods</p> <p>Relevant literature was surveyed and data was extracted and organized into medicinal use categories. We focused on more recent literature than that considered in a review published 25 years ago. We included phytochemical and pharmacological research that explored the importance of American palms in ethnomedicine.</p> <p>Results</p> <p>Of 730 species of American palms, we found evidence that 106 species had known medicinal uses, ranging from treatments for diabetes and leishmaniasis to prostatic hyperplasia. Thus, the number of American palm species with known uses had increased from 48 to 106 over the last quarter of a century. Furthermore, the pharmacological bases for many of the effects are now understood.</p> <p>Conclusions</p> <p>Palms are important in American ethnomedicine. Some, like <it>Serenoa repens </it>and <it>Roystonea regia</it>, are the sources of drugs that have been approved for medicinal uses. In contrast, recent ethnopharmacological studies suggested that many of the reported uses of several other palms do not appear to have a strong physiological basis. This study has provided a useful assessment of the ethnobotanical and pharmacological data available on palms.</p

Measuring proliferation in breast cancer: practicalities and applications

Various methods are available for the measurement of proliferation rates in tumours, including mitotic counts, estimation of the fraction of cells in S-phase of the cell cycle and immunohistochemistry of proliferation-associated antigens. The evidence, advantages and disadvantages for each of these methods along with other novel approaches is reviewed in relation to breast cancer. The potential clinical applications of proliferative indices are discussed, including their use as prognostic indicators and predictors of response to systemic therapy

Maturation of Eugenia pyriformis seeds under different hydric and thermal conditions

O presente estudo tem como objetivo analisar a maturação e a dispersão de sementes de Eugenia pyriformis Cambess. produzidas em diferentes anos, verificando a influência das variações hídricas e térmicas do ambiente sobre suas características físicas e fisiológicas no momento em que são dispersas. Frutos com diferentes estágios de desenvolvimento foram coletados da região de São Paulo, entre 2003 e 2010 e das regiões de Campinas e Lavras, em 2009 e 2010 e foram analisados quanto ao tamanho e à cor. As sementes foram extraídas dos frutos e analisadas quanto ao conteúdo de massa seca, teor de água, germinação e vigor. Os resultados evidenciaram que a maturação das sementes ocorre de forma dessincronizada à maturação dos frutos, levando em média 45 dias (430 graus-dia), sendo mais demorada em períodos chuvosos ou de temperaturas mais baixas. Sementes de qualidade fisiológica mais elevada foram produzidas em anos chuvosos e quando a amplitude térmica foi maior. Conclui-se, portanto, que as variações hídricas e térmicas do ambiente e do período de formação influenciam sobre a maturação das sementes de uvaieira podendo, inclusive, determinar o ciclo de formação e a qualidade final dessas sementes.This study aims to analyze the maturation and dispersal of Eugenia pyriformis Cambess. seeds produced in different years, and the influence of variation in thermal and hydric environment on seed physical and physiological characteristics at dispersal. Fruits at different developmental stages were harvested in the city of São Paulo between 2003 and 2010, as well as in the cities of Campinas and Lavras, in 2009 and 2010 and analyzed for size and color. The seeds were extracted from the fruits and their dry mass, water content, germination and vigor were assessed. Results showed that seed maturation is unsynchronized to the maturation of the fruit, taking 45 days on average (430 growing degree-days), longer in rainy times or lower temperatures. Seeds with higher physiological quality were produced in rainy years and when the temperature range was larger. We concluded therefore that hydric and thermal environmental variations during development influence the maturation of Eugenia pyriformis seeds and are able to determine the formation cycle and the final seed quality.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Instituto de Botânica Programa de Pós-Graduação em Biodiversidade Vegetal e Meio AmbientePrataviera ConsultoriaDow AgroSciences Regulatory Sciences and Government AffairsUniversidade Estadual Paulista Instituto de Biociências Programa de Pós-Graduação em Ciências BiológicasInstituto Agronômico de Campinas Centro de Ecofisiologia e BiofísicaUniversidade Federal de Lavras (UFLA) Departamento de Ciências FlorestaisInstituto de Botânica Núcleo de Pesquisas em SementesUniversidade Estadual Paulista Instituto de Biociências Programa de Pós-Graduação em Ciências BiológicasCNPq: 477640/2009-5FAPESP: 05/04139-

Adrenomedullin and tumour microenvironment

Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed

Probability Density Functions for Droplet Sizing in Aerosol Transport Modelling

This paper introduces a stochastic model for the prediction of aerosol droplet size distribution and amount delivered via a piping system. Curves generated by probability density functions are presented to describe the droplet sizes before and after a transport system. The model has been applied to a number of different scenarios, including horizontal, inclined or vertical pipes and their combinations using bends. Given an initial aerosol, with a log-normal distribution of droplet diameters, the prediction is a skewed outlet distribution. An extreme case of a coiled pipe has further been used to test the model fully. This latter case has been validated experimentally for a range of lengths from 2 m to 8 m, including droplet sizing by laser diffraction. The model presented is also suitable for applications that rely on atomisation and transport of particles, for example, spray drying or cooling, film coating and fuel combustion

Order-preserving Biclustering Based on FCA and Pattern Structures

International audienceBiclustering is similar to formal concept analysis (FCA), whose objective is to retrieve all maximal rectangles in a binary matrix and arrange them in a concept lattice. FCA is generalized to more complex data using pattern structure. In this article, we explore the relation of biclustering and pattern structure. More precisely, we study the order-preserving biclusters, whose rows induce the same linear order across all columns