Análisis genético del carcinoma de tiroides en una muestra de pacientes colombianos

204 p. Recurso ElectrónicoEl carcinoma de tiroides (CT) es la neoplasia más común del sistema endocrino y su incidencia en Colombia se ha incrementado en los últimos años. El cáncer es una enfermedad genética, esporádica o hereditaria, que puede desencadenarse por interacción de factores genéticos y ambientales. Diversos estudios epidemiológicos, han mostrado una relación entre el riesgo de padecer CT y el impacto de factores externos como: el estrato socioeconómico, el nivel educativo y el consumo de alcohol y cigarrillo. De otra parte, dado que existe una mayor incidencia en el género femenino, se ha planteado la posibilidad de encontrar diferencias de tipo hormonal, entre casos y controles sanos, evaluando factores como la planificación hormonal, la edad de la menarquia y menopausia, el número de hijos nacidos vivos y la lactancia. Teniendo en cuenta lo anterior, en el presente estudio, se analizaron dichos factores a partir de las entrevistas de 253 pacientes, pareados por género y lugar de procedencia, con controles sanos, mayores de 50 años y sin antecedentes familiares de cáncer en primer y segundo grado de consanguineidad. Se evidenció una mayor ocurrencia de cáncer de tiroides en las mujeres que en los hombres, con una relación de 8:1; el carcinoma papilar fue el más frecuente (93,5%), seguido por el folicular (5,9%) y medular (<1%). La edad promedio de diagnóstico fue de 46 años en casos con carcinoma papilar de tiroides (PTC, por sus siglas en inglés), y de 45 años en hombres y 60 años en mujeres con carcinoma folicular de tiroides (FTC, por sus siglas en inglés). El análisis del riesgo mediante el cálculo de Odds ratio (OR), reveló que existe un incremento significativo en el riesgo de padecer la enfermedad en pacientes de estrato socioeconómico medio-alto y el nivel de escolaridad superior, además, se presentó un incremento del riesgo en los casos que presentaron menarquia temprana, planificación hormonal y menopausia no funcional. De otra parte, en cuatro análisis GWAs de pacientes de Europa y Asia, se ha reportado el incremento de la susceptibilidad en personas con el alelo de riesgo para los polimorfismos de los SNPs: rs1867277, rs965513, rs944289, rs116909374, rs2439302, rs966423 y rs6983267, y considerando que no han sido estudiados en poblaciones de América del Sur, se realizó la genotipificación alelo especifica de estos polimorfismos, usando el sistema KASPAR. A partir de los genotipos obtenidos, se realizaron pruebas de equilibrio de Hardy Weingber (HW) y de asociación en el programa Plink, encontrándose que todos presentan un incremento significativo del riesgo, a excepción del rs966423, que no cumplió con el equilibrio de HW, por lo tanto, no se incluyó en los cálculos de OR individuales y combinados. El análisis combinado de los SNPs rs965513, rs944289, rs116909374, rs2439302 y rs6983267, reveló estar relacionados con una probabilidad tres veces superior en los portadores de 7 o más alelos riesgo. La mayor parte de los diagnósticos actuales no son concluyentes, pues se basan en la aspiración por aguja delgada (BACAF). Afortunadamente, ha tomado fuerza el diagnóstico molecular, basado en el análisis de mutaciones en genes como BRAF, asociados con el desarrollo, mal pronóstico, recurrencia, metástasis de la enfermedad y respuesta a tratamientos pre y post quirúrgicos. Por esta razón, se amplificó y secuenció el exón 15 del gen BRAF, en el ADN de 164 muestras de tejido tumoral tiroideo, encontrándose que la mutación V600E, se presentó en el 55% de las muestras de PTC, sin variaciones entre género y edad de diagnóstico, pero con una mayor frecuencia en casos con complicaciones como lesiones bilaterales, mayores a 1cm y con metástasis a ganglios linfáticos. Adicionalmente, se realizó la detección por PCR aleloespecifica de esta mutación en muestras de sangre de 239 pacientes, las cuales fueron homocigotas para el alelo silvestres en su totalidad, confirmando la naturaleza esporádica y especificidad de la mutación V600E en este tipo histológico.The thyroid carcinoma (CT) is the most common endocrine neoplasia and its incidence in Colombia has increased in recent years. Cancer is a genetic, sporadic or inherited disease that can be triggered by interaction of genetic and environmental factors. Several epidemiological studies have shown a relationship between the risk of CT and the impact of external factors such as: socioeconomic status, educational level and consumption of alcohol and cigarettes. Moreover, since there is a higher incidence in females, has raised the possibility of finding hormonal differences between cases and healthy controls, it has evaluated factors such as hormonal planning, age at menarche and menopause, the number of live births and breastfeeding. Considering the above, in the present study, we evaluated these factors using interviews of 253 patients, matched by gender and geographical origin, with healthy controls, older than 50 years and without family history of cancer in first and second degree of consanguinity. An increased occurrence of TC was evident in women than in men, with a ratio of 8:1; papillary carcinoma was the most frequent (93.5%), followed by follicular (5.9%) and medullar (<1%). The average age at diagnosis was 46 years in cases with PTC, 45 in men and 60 in women with FTC. Risk analysis by calculating odds ratio (OR), revealed a significant increase in the risk of disease in patients with medium-high socioeconomic status and higher educational level, also it showed an increased risk in cases with early menarche, hormonal contraception and artificial menopause. Moreover, in four analyzes GWAs of patients from Europe and Asia, has reported increased susceptibility in people with risk allele for polymorphisms (SNPs): rs1867277, rs965513, rs944289, rs116909374, rs2439302, rs966423 and rs6983267 and considering that they have not been studied in populations of South America, we genotyped these polymorphisms by allele specific PCR, using KASPAR system. From the genotypes obtained we performed Hardy Weinberg (HW) and association tests in thesoftware Plink, finding that all are involved in a significantly increased risk, except for rs966423, which did not fulfilled the HW equilibrium test, therefore, it was not included in the calculations of individual and combined OR. The combined analysis of SNPs: rs965513, rs944289, rs116909374, rs2439302 and rs6983267, showed a three-fold increased probability of disease in carriers of 7 or more risk alleles. Most of the current diagnosis are inconclusive, since they are based on fine needle aspiration (FNA). Fortunately, molecular diagnostics have gained strength, based on the analysis of mutations in genes such as BRAF, associated with the development, poor prognosis, recurrence, metastasis of the disease and response to pre and post surgical treatments. For this reason, we amplified and sequenced exon 15 of the BRAF gene in DNA in 164 tumor samples of thyroid, finding that the V600E mutation occurred in 55% of samples PTC, without differences between genders and age of diagnosis, but it was more often in cases with complications such as: bilateral lesions, size bigger than 1 cm and with lymph node metastases. Additionally, we performed the detection by allele specific PCR of this mutation in blood samples from 239 patients and all of they were homozygous for the wild allele, confirming that V600E is a sporadic and specificity mutation in this histological type. Keywords: Thyroid carcinoma, Genotyping, Blood and Tissue DNA, V600E mutation, BRAF, susceptibility gene SNPs

Crecimiento y viabilidad celular de microalgas: efecto del medio de cultivo

In Aquaculture, the use of microalgae is fundamental in the first feeding of native fish species, since their optimal nutritional level favors survival. Successful production of microalgae under laboratory conditions depends on the culture medium used during the cryopreservation stage of production. Agricultural fertilizers can be used as a low-cost alternative culture media that promotes cell growth and cryopreservation. The objective was to evaluate the effect of two culture media on population growth (PG) and post-thawing viability (PTV) of three microalgal species (Chlorella sp., Desmodesmus sp., and Ankistrodesmus sp.). The PG and PTV were evaluated for F/2 Guillard and Nutrifoliar® culture media. Instantaneous growth rate (K), doubling time (dt), yield (y), and maximum density (md) were evaluated for PG in both culture media. For VCP, 5 and 10 % methanol was used in six treatments. The PTV was classified as no cell damage (NCD), cell damage (CD), and marked lesions (ML). Population growth did not differ among microalgae (p &gt;0.05). T1 resulted in the lowest dt for Desmodesmus sp., (p &lt;0.05). T2 showed the highest y and md for the three microalgae (p &lt;0.05). Regarding post-thawing cell viability, the highest NCD for Chlorella sp. at day (d) 0 was similar between T3 and T4, and at d 5 it occurred in T6; for Desmodesmus sp., at d 0 it occurred in T6, and at d 5 it was similar between T6 and T1; for Ankistrodesmus sp., at d 0 and d 5 it occurred in T3. It is concluded that the culture medium Nutrifoliar®, is a viable alternative and of low cost for the culture and the cryopreservation of microalgae of fresh water.En acuicultura, el uso de microalgas es fundamental en la primera alimentación de especies nativas de peces, pues su óptimo nivel nutricional favorece la sobrevivencia. El éxito de la producción de microalgas depende, entre otras, del medio de cultivo empleado. Los fertilizantes agrícolas usados como medio de cultivo son una alternativa de bajo costo que favorece el crecimiento celular y la criopreservación. El objetivo fue evaluar el efecto de dos medios de cultivo sobre el crecimiento poblacional (CP) y la viabilidad celular post-descongelación (VCP) de microalgas Chlorella sp., Desmodesmus sp., y Ankistrodesmus sp. Se evaluó el CP y VCP los medios de cultivo F/2 Guillard, y Nutrifoliar®. Para el CP en ambos tratamientos se determinó: crecimiento (k), tiempo de duplicación (td), rendimiento (r) y densidad máxima (dm). Para VCP se empleó metanol al 5 y 10 %, en seis tratamientos. La VCP se clasificó: sin daño celular (SDC), daño celular (DC) y lesiones marcadas (LM). El crecimiento poblacional fue igual para las tres microalgas (p&gt;0,05). El T1 tuvo el menor td para Desmodesmus sp. (p&lt;0,05). El T2 presentó el mayor r y dm para las tres microalgas (p &lt;0,05). En la viabilidad celular post-descongelación, el mayor porcentaje SDC para Chlorella sp., al día (d) cero, fue similar en T3 y T4 y al d cinco fue en T6; para Desmodesmus sp, al d cero fue en T6 y al d cinco fue similar en T6 y T1; mientras que, para Ankistrodesmus sp, al d cero y cinco se presentó en T3. Se concluye que el medio de cultivo Nutrifoliar®, es una alternativa viable y de bajo costo para el cultivo y la criopreservación de microalgas de agua dulce

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Background: TheBRCA1c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluateBRCA1c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. Methods: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity aroundBRCA1c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surroundingBRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. Results: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was similar to 100 generations in Iberia and that it was introduced to South America early during the European colonization period. Conclusions: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

BACKGROUND: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. METHODS: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. RESULTS: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period. CONCLUSIONS: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

Peer reviewe

Measurement of the top quark forward-backward production asymmetry and the anomalous chromoelectric and chromomagnetic moments in pp collisions at √s = 13 TeV

Abstract The parton-level top quark (t) forward-backward asymmetry and the anomalous chromoelectric (d̂ t) and chromomagnetic (μ̂ t) moments have been measured using LHC pp collisions at a center-of-mass energy of 13 TeV, collected in the CMS detector in a data sample corresponding to an integrated luminosity of 35.9 fb−1. The linearized variable AFB(1) is used to approximate the asymmetry. Candidate t t ¯ events decaying to a muon or electron and jets in final states with low and high Lorentz boosts are selected and reconstructed using a fit of the kinematic distributions of the decay products to those expected for t t ¯ final states. The values found for the parameters are AFB(1)=0.048−0.087+0.095(stat)−0.029+0.020(syst),μ̂t=−0.024−0.009+0.013(stat)−0.011+0.016(syst), and a limit is placed on the magnitude of | d̂ t| &lt; 0.03 at 95% confidence level. [Figure not available: see fulltext.

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

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Measurement of t(t)over-bar normalised multi-differential cross sections in pp collisions at root s=13 TeV, and simultaneous determination of the strong coupling strength, top quark pole mass, and parton distribution functions

Peer reviewe

An embedding technique to determine ττ backgrounds in proton-proton collision data

An embedding technique is presented to estimate standard model tau tau backgrounds from data with minimal simulation input. In the data, the muons are removed from reconstructed mu mu events and replaced with simulated tau leptons with the same kinematic properties. In this way, a set of hybrid events is obtained that does not rely on simulation except for the decay of the tau leptons. The challenges in describing the underlying event or the production of associated jets in the simulation are avoided. The technique described in this paper was developed for CMS. Its validation and the inherent uncertainties are also discussed. The demonstration of the performance of the technique is based on a sample of proton-proton collisions collected by CMS in 2017 at root s = 13 TeV corresponding to an integrated luminosity of 41.5 fb(-1).Peer reviewe