Carbonic anhydrase XII expression is linked to suppression of Sonic hedgehog ligand expression in triple negative breast cancer cells.

Aberrant activity of the hedgehog (Hh) pathway is prevalent in pathologies such as cancer. Improved understanding of Hh activity in the aggressive tumor cell phenotype is being pursued for development of targeted therapies. Recently, we described a link between Hh activity and carbonic anhydrase XII (CAXII) expression. Extracellular facing CAs (IX/XII) are highly expressed in hypoxia, contribute to tumor pH regulation and are thus of clinical interest. Here we have extended the investigation of potential interactions between Hh activity and CAXII utilizing genomic disruption/knockout of either GLI1 (the main transcriptional factor induced with Hh activity) or CAXII in the triple negative breast cancer cell lines MDA-MB-231 and BT-549. Knockout of GLI1 and CAXII significantly decreased hallmarks of tumor aggressiveness including proliferation and migration. Most intriguingly, CAXII knockout caused a massive induction of the Sonic hedgehog (Shh) ligand expression (gene and protein). This novel finding indicates that CAXII plays a potential role in suppression of Shh and may act in a feedback loop to regulate overall Hh activity. Enhanced knowledge of these CA-Hh interactions in future studies may be of value in understanding this currently 'incurable' subclass of breast cancer.

Effect of Landscape Changes on Water Quality and Health Status of Heptapterus mustelinus (Siluriformes, Heptapteridae).

Substances derived from anthropogenic activities induce changes in the physical and chemical characteristics of the aquatic environment. Physicochemical and biological studies are necessary to understand how changes in landscape affect the health of the aquatic environment. The main goal of this study was to evaluate how the landscape at different spatial scales affects (1) water quality and (2) the health status of Heptapterus mustelinus, based on several biomarkers. During the dry season, individuals were caught in three sites with different degrees of anthropogenic activity. The quality of the terrestrial environment was assessed using the Riparian Quality and Land Use Indices. The water quality condition was evaluated using a water quality index, and pesticides and pharmaceuticals were measured in water. The following biomarkers were analyzed in the fish: general health status (Condition Factor, Hepatosomatic index and energetic costs), enzymatic activity (GST, CAT, AchE), carbonyl content in proteins and histopathological responses in liver and gills. The most impacted sites by the presence of pesticides showed more alterations in the surrounding landscape; specially, changes in the riparian area. In this area, biomarkers denoted more damage than in sites with protected riparian zone. Conservation status of riparian ecosystems is crucial in the determination of rivers ecological quality. Our results demonstrate the importance of monitoring the environmental quality through an integrated analysis, using native fish to understand the effects of human activities on the biota.

Allergenic proteases cleave the chemokine CX3CL1 directly from the surface of airway epithelium and augment the effect of rhinovirus.

CX3CL1 has been implicated in allergen-induced airway CD4+ T-lymphocyte recruitment in asthma. As epidemiological evidence supports a viral infection-allergen synergy in asthma exacerbations, we postulated that rhinovirus (RV) infection in the presence of allergen augments epithelial CX3CL1 release. Fully differentiated primary bronchial epithelial cultures were pretreated apically with house dust mite (HDM) extract and infected with rhinovirus-16 (RV16). CX3CL1 was measured by enzyme-linked immunosorbent assay and western blotting, and shedding mechanisms assessed using inhibitors, protease-activated receptor-2 (PAR-2) agonist, and recombinant CX3CL1-expressing HEK293T cells. Basolateral CX3CL1 release was unaffected by HDM but stimulated by RV16; inhibition by fluticasone or GM6001 implicated nuclear factor-κB and ADAM (A Disintegrin and Metalloproteinase) sheddases. Conversely, apical CX3CL1 shedding was stimulated by HDM and augmented by RV16. Although fluticasone or GM6001 reduced RV16+HDM-induced apical CX3CL1 release, heat inactivation or cysteine protease inhibition completely blocked CX3CL1 shedding. The HDM effect was via enzymatic cleavage of CX3CL1, not PAR-2 activation, yielding a product mitogenic for smooth muscle cells. Extracts of Alternaria fungus caused similar CX3CL1 shedding. We have identified a novel mechanism whereby allergenic proteases cleave CX3CL1 from the apical epithelial surface to yield a biologically active product. RV16 infection augmented HDM-induced CX3CL1 shedding-this may contribute to synergy between allergen exposure and RV infection in triggering asthma exacerbations and airway remodeling.

Valoración de la exposición a plaguicidas en cultivos extensivos de la Argentina y su potencial impacto sobre la salud / Pesticides exposure assessment in extensive crops in Argentina and their potential impact on health

A nivel nacional no hay descripciones espaciales o analíticas para el diagnóstico deexposición a plaguicidas.ObjetivosDescribir la distribución espacial de la exposición a plaguicidas en Argentina y suasociación con indicadores de carga de cáncer. Construir índices incorporando prácticaslaborales y de vida, y validarlos con biomarcadores y salud de sujetos laboralmenteexpuestos y sus familias.MétodosPara describir la distribución espacial de la exposición y su asociación con indicadoresde carga de cáncer se construyeron dos índices globales: de exposición a plaguicidas(IEP) y de impacto ambiental total (IIAT). Se estudiaron sus distribuciones espaciales,y mediante un estudio ecológico nacional se analizó la asociación con las tasas demortalidad de cáncer total, mama y próstata. Otros dos índices de exposición construidoscon información individual de agroaplicadores de Córdoba fueron validados a partir deluso de resultados de biomarcadores (actividad de butirilcolinestrasa y genotoxicidad)y de salud de sujetos laboralmente expuestos; y se compararon con sus respectivoscontroles. Por último, se analizaron las condiciones de salud de niños de esas familias.ResultadosEl área pampeana agrupa IEP mayores al promedio nacional. Los mayores IIAT fueronpara 2,4-D y clorpirifos en igual zona. Los altos IIAT de cipermetrina y clorpirifos seasocian con más mortalidad de cáncer de mama; los de glifosato y clorimuron, conla de cáncer total en varones. Los síntomas generales, cardiorrespiratorios, dérmicosy daño genotóxico fueron mayores en aplicadores, pero no se asocian a niveles deexposición. Los niños presentan síntomas irritativos en un 30%; más de la mitad estánexpuestos a aplicaciones, vive a menos de 500 metros de depósitos y van a escuelas a500 metros de campos fumigados. Un 20% asiste en tareas de campo, sin elementosde protección personal ni cobertura de obra social

Biomarcadores de exposición a plaguicidas / Occupational pesticide exposure and their association with effect biomarkers

La exposición a plaguicidas, durante todas las etapas de su uso, puede tener efectos adversos en la salud y el medio ambiente. Estos efectos no siempre están relacionados con lesiones inmediatas y aparentes, sino que pueden tardar incluso años en manifestarse. La utilización de biomarcadores en estudios epidemiológicos, como son las evaluaciones de daño genético, permiten la detección temprana de un riesgo incrementado de desarrollar diversas patologías, definiendo estados de prepatogénesis, como neoplasias, problemas reproductivos, malformaciones y enfermedades cardiovasculares. Los estudios de biomonitoreo en poblaciones agrícolas publicados desde la década de los años 70 indican resultados muy diversos, dada la amplia variedad de biomarcadores citogenéticos analizados y la heterogeneidad de las poblaciones incluidas en dichos estudios. En etapas previas de esta investigación se han descripto factores personales y contextuales vinculados con la exposición a plaguicidas entre trabajadores agrícolas, diseñado escalas de exposición a plaguicidas y descripto condiciones de salud percibida por agroaplicadores terrestres de la Provincia de Córdoba. Este trabajo presenta biomarcadores de daño citogenético, aportando nuevos elementos para la detección de grupos de riesgo, la comprensión de la red causal de las patologías asociadas a tales exposiciones y proponer herramientas preventivas. (AU)

Exposure to pesticides, during all stages of use, may have adverse effects on health and the environment. These effects are not always related to immediate and apparent injuries, but may even take years to manifest. The use of biomarkers in epidemiological studies, such as evaluations of genetic damage, allow the early detection of an increased risk of developing various pathologies, defining states of prepathogenesis, such as neoplasms, problems Reproductive, malformations and cardiovascular diseases. Biomonitoring Studies in agricultural populations published since the decade of the years 70 indicate very different results, given the wide variety of cytogenetic biomarkers analyzed and the heterogeneity of the populations included in these studies. In previous stages of this research have described personal and contextual factors linked to pesticide exposure among agricultural workers, designed scales of exposure to pesticides and described health conditions perceived by agrochemicals applicators of the province of Cordoba. This paper presents biomarkers of cytogenetic damage, providing new elements for the detection of risk groups, understanding the causal network of pathologies associated with such exhibits and proposing preventive tools. (AU)

Role of the hypoxic microenvironment in the antitumor activity of tyrosine kinase inhibitors.

The tumor microenvironment is characterized, not only by marked gradients in drug concentration, but also by gradients in the rate of cell proliferation and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Hypoxia is also an important environmental factor in chronic myeloid leukemia (CML), because bone marrow is intrinsically hypoxic in nature. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase coactivation as an important mechanism by which cancer cells achieve chemoresistance. Recent work suggests that Src activation might play a prominent role in the response to hypoxia to promote cell survival, progression, and metastasis of a variety of human cancer. Other studies also established a functional link between Bcr-Abl and the Src family tyrosine kinases. It is well known that mutations can also cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer as in CML. Leukemic cells carrying chromosomal alteration, are sensitive to imatinib that induces complete remission in most patients. This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor (TKI). There is a considerable interest in understanding how activated signaling pathways enhance tumor cell survival under hypoxia, because this might lead to the introduction of more effective treatments to target these resistant subpopulations. For all these reasons it is important to identify new TKIs which are also active in hypoxia, the real tumor microenvironment, as possible alternative therapy.

Clinical accuracy of updated version of the Phadebas RAST test.

The clinical sensitivity and specificity of an updated version of the Phadebas RAST test were superior to that of the conventional Phadebas system. In comparison to a three-hour first incubation, an overnight first stage incubation did not contribute to an improvement in the over-all clinical effectiveness of the test system. However, the prolonged first stage incubation did contribute to a better resolution between the normal, non-atopic control group and the atopic patient population.