Implicación de LKB1 en la patogénesis y progresión del cáncer de próstata.

303 p.El modelo actual de progresión tumoral es asumido como un proceso secuencial en el cual, mediante la acumulación de alteraciones genéticas y epigenéticas, las células cancerosas adquieren habilidades capacitadoras. Las quinasas maestras constituyen un potencial mecanismo mediante el cual un único evento genético podría reflejarse en múltiples alteraciones en diversas rutas de señalización. LKB1 es una quinasa maestra que ejerce sus funciones sobre la regulación del metabolismo, la proliferación y la polaridad celular. La hipótesis formulada y confirmada en esta tesis doctoral plantea que LKB1 actúa como un gen supresor de tumores en el cáncer de próstata. El estudio inmunohistoquímico y transcripcional sobre especímenes identificó un grupo de tumores de próstata en los que la expresión de LKB1 se encuentra reducida. El modelo transgénico condicional muestra que mientras que LKB1 como única deleción génica no es suficiente para promover el desarrollo tumoral en la próstata, su eliminación en el contexto de la heterocigosidad del supresor de tumores Pten da lugar a cáncer de células escamosas metastático y letal. El desarrollo de un sistema de estudio in vitro nos permitió demostrar que LKB1 inhibe la migración, invasión y el crecimiento independiente de anclaje. Este fenotipo resultó ser independiente de la actividad quinasa de LKB1 y coherente con la regulación negativa del oncogén CD24. Por último, nos propusimos definir estrategias terapéuticas eficaces en tumores de próstata deficientes en LKB1. Los resultados confirman el potencial de la fenformina en este contexto y revelan la selectividad de inhibidores de la chaperona HSP90 en células LKB1 negativas. En resumen, los resultados obtenidos demuestran la implicación causal de LKB1 en la supresión del cáncer de próstata y abren nuevas estrategias terapéuticas para aplicar medicina de precisión en base a la expresión de la quinasa

Increased micronuclei and nuclear abnormalities in buccal mucosa and oxidative damage in saliva from patients with chronic and aggressive periodontal diseases

Background and objective Periodontal disease is a chronic bacterial infection characterized by connective tissue breakdown and alveolar bone destruction because of inflammatory and immune response caused by periodontopathogens and long-term release of reactive oxygen species. A high number of reactive oxygen species result in periodontal tissue damage through multiple mechanisms such as lipid peroxidation, protein denaturation and DNA damage. The aim of this study was to evaluate DNA and oxidative damage in subjects with chronic or aggressive periodontitis and healthy controls. Material and methods Buccal mucosa cells and whole saliva were collected from 160 subjects, who were divided into three groups: subjects with chronic periodontitis (CP) (n = 58), subjects with aggressive periodontitis (AgP) (n = 42) and a control group (n = 60). DNA damage was determined by counting micronuclei (MN) and nuclear abnormalities (NAs) in exfoliated cells, including binucleated cells, cells with nuclear buds and karyolitic, karyorrhectic, condensed chromatin and pyknotic cells. The degree of oxidative stress was determined by quantifying 8-hydroxy-2'-deoxyguanosine (8-OHdG) in whole saliva. Results Subjects with CP or AgP presented significantly more ( p < 0.05) MN and NAs and higher levels of 8-OHdG ( p < 0.05) compared with the control group. Conclusion Our results indicate that subjects with periodontitis (CP or AgP) exhibited an increase in the frequency of MN, NAs and 8-OHdG, which is directly related to DNA damage. In addition, a positive correlation exists between oxidative stress produced by periodontitis disease and MN

Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression

Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultrahigh- performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultrahigh- performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa

Connection between genetic polymorphism of interleukin -1 beta with chronic periodontitis in peruvian adults

Objectives. To determine the connection between polymorphism IL-1B C(+3953/4)T and chronic periodontitis in adults. Materials and Methods. Case and control study. Individuals between 18 and 64 years of age were included; they were recruited through healthcare campaigns carried out in 2012 in different areas of the city of Lima with similar socio-economic characteristics. Dentists specialized in periodontics performed the diagnosis of the periodontal state of participants; genotyping was made through the PCR-RFLP technique. The data were analyzed by logistic regression. Results. The factors associated with chronic periodontitis were: age over 46 years (OR: 7.50, CI 95%: 1.85-6.37), higher education level achieved (OR: 0.43, CI 95%: 0.27-0.98), the presence of allele 2 in the polymorphism of IL-1B. The positive genotype (2-2) was associated with the presence of chronic periodontitis (OR: 2.06, CI 95%: 1.01-4.21). Conclusions. The presence of allele 2 in the polymorphism of IL-1B and the positive genotype (2-2) confers greater risk for the development of chronic periodontitis in the population of Peruvian adults under study

Modelo ECR aplicado a la industria láctea Colombiana

273 Páginas.En un mundo globalizado en donde los consumidores tienen poder de decisión, las industrial nacionales e internacionales deben estar preparadas para definir y redefinir sus estrategias acorde a las necesidades cambiantes del mercado, se hace necesario que modelos como ECR “Enfoque Conducta Resultado”, le permita a las industrias analizar sus acciones pasadas, presentes y futuras respecto al comportamiento de sus clientes y competidores, con el objetivo de definir y establecer cuál es la mejor estrategia a elegir. Por lo anterior, el presente trabajo de grado pretende analizar por medio del modelo ECR la industria lechera de Colombia tomando como referencias empresas tales como ALPINA Productos Alimenticios S.A., ALQUERIA S.A. y la Cooperativa Lechera Antioqueña COLANTA LTDA

Genome Damage in Rats after Transplacental Exposure to Jatropha dioica Root Extract

Jatropha dioica is traditionally used owing to its antiviral, antifungal, and antimicrobial properties. But, toxicological information regarding J. dioica root total extract is currently limited. The aim of this work was to evaluate in a rat model, the transplacental genotoxicity effect of J. dioica aqueous root total extract. Three different J. dioica aqueous root total extract doses (60, 100, and 300 mg/kg) were administered orally to Wistar rats during 5 days through the pregnancy term (16–21 days). Pregnant rats were sampled every 24 h during the last 6 days of gestation, and pubs were sampled at birth. Genome damage in dams and their newborn pups transplacentally exposed to J. dioica was evaluated by in vivo micronuclei assay. We evaluated the frequency of micronucleated erythrocytes (MNE), micronucleated polychromatic erythrocytes (MNPCE), and polychromatic erythrocytes (PCE) in peripheral blood samples from pups and MNPCE and PCE in pregnant rats. No genotoxic effect was observed after oral administration of the three different doses of aqueous root total extract of J. dioica in pregnant or in their newborn pubs, after transplacental exposure. A significant decrease in PCE frequency was noted in samples from pubs of rats treated with the highest dose of J. dioica extract. The aqueous total root extract of J. dioica at the highest dose tested in our research do have cytotoxic effect in pups transplacentally exposed to this plant extract. Moreover, neither a genotoxic nor a cytotoxic effect was observed in pregnant rats. In the present work, there was no evidence of genome damage in the rat model after transplacental exposure to J. dioica aqueous root total extract

PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer

[EN] Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.We are grateful to the Carracedo lab for valuable input, to Drs. Ana M. Aransay, James D. Sutherland and F. Elortza for technical advice, and Drs. Michelle Clasquin, Katie Sellers and Katya Marjon at Agios Pharmaceuticals for performing, processing and analyzing the metabolomics experiments. We thank the Basque Biobank for Research (BIOEF) for the support with prostate specimen acquisition and management. A.A-A. was funded by the Basque Government (predoctoral fellowship). V.T. is funded by Fundación Vasca de Innovación e Investigación Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia, the Basque Department of Health (2016111109) and the MICINN RTI2018-097267-B-I00. I.M. is supported by Fundación Cris Contra el Cáncer (PR_TPD_2020-19). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the department of education (IKERTALDE IT1106-16) and health (RIS3), the BBVA foundation, the MICINN (SAF2016-79381-R; PID2019-108787RB-I00 (FEDER/EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks RED2018-102769-T), the AECC (GCTRA18006CARR), Vencer el Cáncer Foundation, La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/ and the European Research Council (Starting Grant 336343, PoC 754627, Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII. We are grateful for the support of Mondravember and Movembergara. A.E. was supported by MCIN/AEI/10.13039/501100011033 and the EU programme NextGenerationEU/PRTR (IJC2020-043583-I). The work of JM Mato was supported by NIH grant R01CA172086 and SAF2017-88041-R. EB is funded by the MICINN (BFU2016-76872-R (FEDER/EU), PID2019-108112RB-I00, and Excellence Networks SAF2017-90794-REDT)

Anales del III Congreso Internacional de Vivienda y Ciudad "Debate en torno a la nueva agenda urbana"

Acta de congresoEl III Congreso Internacional de Vivienda y Ciudad “Debates en torno a la NUEVa Agenda Urbana”, ha sido una apuesta de alto compromiso por acercar los debates centrales y urgentes que tensionan el pleno ejercicio del derecho a la ciudad. Para ello las instituciones organizadoras (INVIHAB –Instituto de Investigación de Vivienda y Hábitat y MGyDH-Maestría en Gestión y Desarrollo Habitacional-1), hemos convidado un espacio que se concretó con potencia en un debate transdisciplinario. Convocó a intelectuales de prestigio internacional, investigadores, académicos y gestores estatales, y en una metodología de innovación articuló las voces académicas con las de las organizaciones sociales y/o barriales en el Foro de las Organizaciones Sociales que tuvo su espacio propio para dar voz a quienes están trabajando en los desafíos para garantizar los derechos a la vivienda y los bienes urbanos en nuestras ciudades del Siglo XXI

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Evaluación del consumo de macronutrientes, Sodio, Calcio y Azúcares añadidos de acuerdo a las recomendaciones de la OMS en adolescentes de 9 a 18 años de Cuenca y Nabón

Antecedentes: La adolescencia es un periodo de crecimiento acelerado en donde se producen una serie de cambios físicos, lo que origina una mayor demanda de necesidades nutricionales, tanto de energía como de carbohidratos, proteínas, grasas, vitaminas y minerales. Estas características condicionan la posibilidad de producirse deficiencias nutricionales en esta edad si la ingesta no es la adecuada. Objetivo: El objetivo de este estudio es evaluar el consumo de macronutrientes, sodio, calcio y azúcar añadido en adolescentes de Cuenca y Nabón de acuerdo a las recomendaciones establecidas por la OMS. Materiales y método: Un estudio descriptivo transversal fue realizado desde enero 2008 hasta abril 2009 en 765 adolescentes de 8vo, 9no y 10mo de educación básica de Cuenca y Nabón (Ecuador). La recolección de la ingesta dietaria fue mediante recordatorio de 24 horas aplicado en 2 días no consecutivos. Se utilizó el Software Lucille 0.1 para el ingreso y el cálculo de la ingesta de alimentos. El análisis de los datos fue realizado mediante el programa estadístico STATA 12, donde se determinó el consumo diario de nutrientes ajustado para la energía total y se calculó el porcentaje de adolescentes que cumple con las recomendaciones de la OMS. Resultados: La ingesta de carbohidratos (80%), grasas (76%) y proteínas (67%), en la mayoría de los adolescentes se encuentran dentro del rango recomendado por la OMS; sin embargo, en el caso del consumo de sodio y azúcar añadido, los valores de más de la mitad de los adolescentes están por encima de las recomendaciones. Así también, solo alrededor del 1% de la población estudiada cumple con los requerimientos diarios de consumo de calcio. Conclusión: Esta población de adolescentes presenta un desequilibrio en la ingesta dietética, especialmente de micronutrientes y azúcar añadido. Por lo que se ven necesarios programas de intervención en alimentación saludable y prevención de la obesidad e hipertensión sobre todo en las instituciones educativasBackground: The Adolescence is a period of accelerated growth in which a series of physical changes occur, leading to a greater demand for nutritional needs, energy, carbohydrates, proteins, fats, vitamins and minerals. These characteristics determine the possibility of nutritional deficiencies that occur at this age if the intake is not adequate. Objective: The objective of this study is to evaluate the intake of macronutrients, sodium, calcium and added sugar in adolescents of Cuenca and Nabón according to the recommendations established by the WHO. Materials and method: A cross-sectional descriptive study was conducted from January 2008 to April 2009 in 765 adolescents from 8th, 9th and 10th grade basic education in Cuenca and Nabón (Ecuador). The collection of dietary intake was through a reminder of 24-hours that was applied in 2 non-consecutive days. The Software Lucille 0.1 was used for the intake and calculation of ingested food. Data analysis was performed using the statistical program STATA 12, which determined the daily intake of nutrients that were adjusted for the total energy and calculated according to the percentage of adolescents that follows the WHO recommendations. Results: The intake of carbohydrates (80%), fats (76%) and proteins (67%) in most adolescents are within the range recommended by the WHO; however, in the case of consumption of sodium and added sugar, the values of more than half of adolescents are above recommendations. Thus, only about 1% of the population studied meets the daily requirements of calcium consumption. Conclusion: This population of adolescents presents an imbalance in dietary intake, especially of micronutrients and added sugar. Therefore, intervention programs in healthy eating and prevention of obesity and hypertension are necessary especially in educational institutionsCuenc