Suicide gene therapy on spontaneous canine melanoma: correlations between in vivo tumors and their derived multicell spheroids in vitro

To validate the use of multicellular spheroids to predict the efficacy of herpes simplex thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene therapy in the respective in vivo tumors, we established and characterized 15 melanoma-derived cell lines from surgically excised melanoma tumors. Three HSVtk-lipofected cell lines were not sensitive to GCV in any culture configuration, other five displayed similar sensitivity as monolayers or spheroids, and only one resulted more sensitive when grown as spheroids. Other six cell lines manifested a relative multicellular resistance (MCR) phenotype growing as spheroids, compared with the same cells growing as monolayers. The reverse correlation between the MCR and the monolayers survival to HSVtk/GCV suggests that one of the main causes of MCR would be the rapid cell repopulation after suicide gene treatment. The high correlation of MCR with the spheroids radial growth and with the mitotic index of the respective originary tumors supported this re-growth involvement. A remarkable finding was the high correlation in HSVtk/GCV sensitivity between in vivo tumor and the corresponding derived cell lines growing as spheroids (R 2 0.85). This strongly encourages the implementation of spheroids as highly realistic experimental model for optimizing and predicting the in vivo response of the respective tumors to therapeutic strategies.Fil: Gil Cardeza, Maria Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; ArgentinaFil: Villaverde, Marcela Solange. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fiszman, Gabriel Leon. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Altamirano, Natalia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; ArgentinaFil: Cwirenbaum, R. A.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; ArgentinaFil: Glikin, Gerardo Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; ArgentinaFil: Finocchiaro, Liliana Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr. Ángel Roffo". Unidad de Transferencia Genética; Argentin

Networks of neuroinjury semantic predications to identify biomarkers for mild traumatic brain injury

OBJECTIVE: Mild traumatic brain injury (mTBI) has high prevalence in the military, among athletes, and in the general population worldwide (largely due to falls). Consequences can include a range of neuropsychological disorders. Unfortunately, such neural injury often goes undiagnosed due to the difficulty in identifying symptoms, so the discovery of an effective biomarker would greatly assist diagnosis; however, no single biomarker has been identified. We identify several body substances as potential components of a panel of biomarkers to support the diagnosis of mild traumatic brain injury. METHODS: Our approach to diagnostic biomarker discovery combines ideas and techniques from systems medicine, natural language processing, and graph theory. We create a molecular interaction network that represents neural injury and is composed of relationships automatically extracted from the literature. We retrieve citations related to neurological injury and extract relationships (semantic predications) that contain potential biomarkers. After linking all relationships together to create a network representing neural injury, we filter the network by relationship frequency and concept connectivity to reduce the set to a manageable size of higher interest substances. RESULTS: 99,437 relevant citations yielded 26,441 unique relations. 18,085 of these contained a potential biomarker as subject or object with a total of 6246 unique concepts. After filtering by graph metrics, the set was reduced to 1021 relationships with 49 unique concepts, including 17 potential biomarkers. CONCLUSION: We created a network of relationships containing substances derived from 99,437 citations and filtered using graph metrics to provide a set of 17 potential biomarkers. We discuss the interaction of several of these (glutamate, glucose, and lactate) as the basis for more effective diagnosis than is currently possible. This method provides an opportunity to focus the effort of wet bench research on those substances with the highest potential as biomarkers for mTBI

Automatic summarization of MEDLINE citations for evidence-based medical treatment: A topic-oriented evaluation

AbstractAs the number of electronic biomedical textual resources increases, it becomes harder for physicians to find useful answers at the point of care. Information retrieval applications provide access to databases; however, little research has been done on using automatic summarization to help navigate the documents returned by these systems. After presenting a semantic abstraction automatic summarization system for MEDLINE citations, we concentrate on evaluating its ability to identify useful drug interventions for 53 diseases. The evaluation methodology uses existing sources of evidence-based medicine as surrogates for a physician-annotated reference standard. Mean average precision (MAP) and a clinical usefulness score developed for this study were computed as performance metrics. The automatic summarization system significantly outperformed the baseline in both metrics. The MAP gain was 0.17 (p<0.01) and the increase in the overall score of clinical usefulness was 0.39 (p<0.05)

Differences in colour gamut obtained with three synthetic red food colourants compared with three natural ones: pH and heat stability

The current trend in European markets towards natural ingredients has stimulated the interest in natural colourants. When it is decided to replace a colourant, normally a synthetic colourant with a natural one, it is interesting to know how the colour would be perceived, by locating their coordinates in the a*b*-diagram. The colours of three red natural colourants and three red synthetic ones have been compared. The natural colourants would be visually perceived as less intense than the synthetic colourants; this perception could be a signal of high quality as recognised and accepted by consumers. The hue (hab) of the natural colourants was red-bluish while the synthetic ones showed a red-orange character and they were located in a wider area of hue, having values apart from the rest, thus they could not be replaceable. The synthetic colourants showed less colour differences than the natural ones when subjected to pH variations and heat treatments.Comisión Interministerial de Ciencia y Tecnología AGL2009-12785-C02-0

Graph-Based Methods for Discovery Browsing with Semantic Predications

We present an extension to literature-based discovery that goes beyond making discoveries to a principled way of navigating through selected aspects of some biomedical domain. The method is a type of “discovery browsing” that guides the user through the research literature on a specified phenomenon. Poorly understood relationships may be explored through novel points of view, and potentially interesting relationships need not be known ahead of time. In a process of “cooperative reciprocity” the user iteratively focuses system output, thus controlling the large number of relationships often generated in literature-based discovery systems. The underlying technology exploits SemRep semantic predications represented as a graph of interconnected nodes (predication arguments) and edges (predicates). The system suggests paths in this graph, which represent chains of relationships. The methodology is illustrated with depressive disorder and focuses on the interaction of inflammation, circadian phenomena, and the neurotransmitter norepinephrine. Insight provided may contribute to enhanced understanding of the pathophysiology, treatment, and prevention of this disorder

Autoantibodies against muscarinic receptors in breast cancer. Its role in tumor angiogenesis.

The presence of autoantibodies in cancer has become relevant in recent years. We demonstrated that autoantibodies purified from the sera of breast cancer patients activate muscarinic acetylcholine receptors in tumor cells. Immunoglobulin G (IgG) from breast cancer patients in T1N0Mx stage (tumor size¡Ü2 cm, without lymph node metastasis) mimics the action of the muscarinic agonist carbachol stimulating MCF-7 cell proliferation, migration and invasion. Angiogenesis is a central step in tumor progression because it promotes tumor invasion and metastatic spread. Vascular endothelial growth factor-A (VEGF-A) is the main angiogenic mediator, and its levels have been correlated with poor prognosis in cancer. The aim of the present work was to investigate the effect of T1N0Mx-IgG on the expression of VEGF-A, and the in vivo neovascular response triggered by MCF-7 cells, via muscarinic receptor activation. We demonstrated that T1N0Mx-IgG (10−8 M) and carbachol (10−9 M) increased the constitutive expression of VEGF-A in tumor cells, effect that was reverted by the muscarinic antagonist atropine. We also observed that T1N0Mx-IgG and carbachol enhanced the neovascular response produced by MCF-7 cells in the skin of NUDE mice. The action of IgG or carbachol was reduced in the presence of atropine. In conclusion, T1N0Mx-IgG and carbachol may promote VEGF-A production and neovascularization induced by breast tumor cells via muscarinic receptors activation. These effects may be accelerating breast tumor progression.Fil: Lombardi, Maria Gabriela. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Estudios Farmacologicos y Botánicos; Argentina;Fil: Negroni, María Pía.Fil: Pelegrina, Laura Tatiana. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Estudios Farmacologicos y Botánicos; Argentina;Fil: Castro, Maria Ester. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Estudios Farmacologicos y Botánicos; Argentina;Fil: Fiszman, Gabriel Leon. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr.Ángel Roffo"; Argentina;Fil: Azar, María Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr.Ángel Roffo"; Argentina;Fil: Cresta Morgado Carlos. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Dr.Ángel Roffo"; Argentina;Fil: Sales Maria Elena. Consejo Nacional de Invest.cientif.y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Centro de Estudios Farmacologicos y Botánicos; Argentina

Foreign Investment Law: Encouragement Versus Restraint--Mexico, Cuba, and the Caribbean Basin Initiative

Third World nations have been attempting to balance foreign investment needs with the desire to both control economic development and retain the benefits of this development within their borders. Mexico and Cuba have recently enacted or revised their foreign investment laws. The Article examines these laws in detail and determines what balance these nations have struck between development and control and what compromises have been made. The Article then examines the Caribbean Basin Initiative to see what balance the United States, a capital exporter, finds optimal and to examine how the United States trade and investment laws differ both legally and in terms of projected practical effect from the Mexican and Cuban foreign investment laws

Semantic memory of bilinguals.

PsychologyDoctor of Philosophy (PhD