Pi‐29

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110026/1/cptclpt200664.pd

Evaluación de las características hidroquímicas de antiguos cauces del Río Dulce en Villa Nueva, provincia de Santiago del Estero

El acceso al agua segura, en pequeñas localidades como Villa Nueva, es un problema de vieja data. El Área de estudio está situada en el sector SO de la provincia de Santiago del Estero, y geomorfológicamente se ubica en el tramo medio de la Llanura Aluvial del Río Dulce. Se caracteriza por una sucesión de antiguos cauces colmatados y entrelazados. El trabajo de investigación se orientó hacia la caracterización hidroquímica del acuífero libre, y su utilización como soporte de almacenamiento y de recarga en forma natural o artificial, para el abastecimiento de agua destinada al consumo humano. Mediante perforaciones se realizaron estudios granulométricos de los sedimentos que permitieron obtener una aproximación acerca de la permeabilidad. Los análisis físico-químicos de las muestras de agua obtenidas, no superan los límites tolerables de las aguas seguras, excepto una de ellas, que supera la concentración de sulfatos.Access to safe water, in small towns like Villa Nueva, is a long-standing problem. The research area is located in the SW sector of the province of Santiago del Estero, and geomorphologically is located in the middle stretch of the Dulce River Floodplain. It is characterized by a succession of former channels silted and intertwined. The research work was oriented towards free aquifer hydrochemical characterization, and their use as storage media and recharge in natural or artificial, for the supply of water for human consumption. Through perforations were made sediments grain size determination studies, we have obtained an approximation concerning permeability. The physico-chemical analysis of water samples obtained do not exceed tolerable limits of safe water, except one, which exceeds the concentration of sulfates.Universidad Nacional de La Plat

Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109858/1/cptclpt2011174.pd

Estimating breast tissue-specific DNA methylation age using next-generation sequencing data

Background DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. Methods Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. Results Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10−31) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7 years older than respective chronological age (p = 1.8 × 10−8). In age-matched analyses, tumor breast tissue appeared 12 and 13 years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10−6 and 1.0 × 10−6, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10−6, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). Conclusions The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples

Evolución del comportamiento físico químico de los pozos en Termas de Rio Hondo como aporte al diagnóstico de situación actual

En la Provincia de Santiago del Estero, la Ciudad de Termas de Rio Hondo constituye un importante ce ntro urbano turístico invernal. Posee en el subsuelo, aguas termales usadas en balneoterapia con propiedades termomedicinales. La extracción excesiva en época de temporada invernal asociadas al turismo, genera un desfasaje entre las demandas potenciales y la disponibilidad del recurso, alterando el sistema. La geoquímica, provee información sobre la distribución de los elementos químicos y su evolución espacial y temporal en el sistema hídrico, caracterizando el agua de los acuíferos y definiendo problemas ambientales. La metodología, se basó en la selección de resultados de análisis físico-químicos existentes y actuales comparados, respecto a TSD. Las anomalías observadas en la concentración de los iones, respecto a las profundidades de explotación están asociadas a la presión antrópica del sistema.In the province of Santiago del Estero, the City of Termas de Rio Hondo is a major urban center winter resort. It has in the subsurface thermal properties used in balneotherapy termomedicinales. Excessive extraction in times of winter season associated with tourism, generates a potential mismatch between the demands and resource availability, altering the system. The geochemistry, provides information on the distribution of chemical elements and their spatial and temporal evolution in the water system, characterizing water aquifers and defining environmental problems. The methodology was based on the selection of results of physicochemical analysis of existing and current compared with respect to TSD. The anomalies observed in the concentration of ions, with respect to depths of operation are associated with human pressure system.Universidad Nacional de La Plat

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects

Background: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. Methods: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. Results: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. Conclusion: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes

TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer

Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition