Primary Breast Angiosarcoma: Comparative Transcriptome Analysis.

Primary breast angiosarcoma, with de novo appearance and not associated with exposure to radiation or lymphedema, is a rare pathology representing less than 0.05% of the neoplasms related to this organ. The pathology is characterized by its aggressiveness, poor prognosis, and difficulties in its differential diagnosis. This article reports the case of a 55-year-old white woman with no family history of cancer, with a rapidly growing mass in the left mammary gland that ulcerates and bleeds. It is confirmed as primary breast angiosarcoma by immunostaining in the tumor tissue for CD31, CD34, and FLI-1. In addition, a sample of neoplastic and healthy tissues is collected from the patient for RNA sequencing; the results are contrasted with a tissue sample from a patient with Luminal A subtype of breast cancer, as well as data from other cases of angiosarcoma available in public databases. These findings revealed a genetic profile associated with the immune and inflammatory response in the patient's sample when compared to available angiosarcoma data; these molecular patterns are consistent with other recent studies. Due to the rarity of the disease, the studies carried out on each patient contribute to the expanding knowledge of the etiology and molecular pathways that are still partially known and continue to be the subject of research. Aside from a comparative transcriptome study, this article aims to provide an update on the state of knowledge about this disease.

Profile of Chromosomal Alterations, Chromosomal Instability and Clonal Heterogeneity in Colombian Farmers Exposed to Pesticides.

Pesticides are a group of environmental pollutants widely used in agriculture to protect crops, and their indiscriminate use has led to a growing public awareness about the health hazards associated with exposure to these substances. In fact, exposure to pesticides has been associated with an increased risk of developing diseases, including cancer. In a study previously published by us, we observed the induction of specific chromosomal alterations and, in general, the deleterious effect of pesticides on the chromosomes of five individuals exposed to pesticides. Considering the importance of our previous findings and their implications in the identification of cytogenetic biomarkers for the monitoring of exposed populations, we decided to conduct a new study with a greater number of individuals exposed to pesticides. Considering the above, the aim of this study was to evaluate the type and frequency of chromosomal alterations, chromosomal variants, the level of chromosomal instability and the clonal heterogeneity in a group of thirty-four farmers occupationally exposed to pesticides in the town of Simijacá, Colombia, and in a control group of thirty-four unexposed individuals, by using Banding Cytogenetics and Molecular Cytogenetics (Fluorescence in situ hybridization). Our results showed that farmers exposed to pesticides had significantly increased frequencies of chromosomal alterations, chromosomal variants, chromosomal instability and clonal heterogeneity when compared with controls. Our results confirm the results previously reported by us, and indicate that occupational exposure to pesticides induces not only chromosomal instability but also clonal heterogeneity in the somatic cells of people exposed to pesticides. This study constitutes, to our knowledge, the first study that reports clonal heterogeneity associated with occupational exposure to pesticides. Chromosomal instability and clonal heterogeneity, in addition to reflecting the instability of the system, could predispose cells to acquire additional instability and, therefore, to an increased risk of developing diseases.

Biomarkers of susceptibility and effect in car painters exposed to organic solvents.

INTRODUCTION: Car painters are routinely exposed to organic solvents classified as carcinogenic and mutagenic substances. OBJECTIVE: To characterize the population susceptibility and evaluate the genotoxic effects of exposure to organic solvents. METHODS: A cross-sectional study comparing a group of car painters exposed to organic solvents with a non-exposed group. CYP2E1 polymorphisms and the presence of micronuclei in lymphocytes were determined. RESULTS: One hundred twenty-two workers participated in the study: 62 who worked in car paint shops and were exposed to solvents, and 60 who were not exposed. There were statistically significant differences between the two groups regarding micronucleated cells and nucleoplasmic bridges frequencies (p= 0.042 and p= 0.046, respectively; exact likelihood ratio). Significant differences were found at the interaction between the CYP2E1 genotype c1c1 and occupational exposure to solvents, with higher frequencies of micronuclei (p= 0.013) and micronucleated cells (p= 0.015). However, when the frequencies of micronuclei, micronucleated cells and nucleoplasmic bridges in the exposure group were compared between the c1c1 and c2c2/c1c2 allele groups of the CYP2E1 polymorphism, statistically significant differences were found. CONCLUSIONS: This study confirms that when workers with CYP2E1 polymorphisms, specifically the c1c1 genotype, are exposed to organic solvents, they are more likely to have somatic cell mutations, a condition associated with increased susceptibility to diseases such as cancer.

INTRODUCCIÓN: Los pintores de vehículos automotores están rutinariamente expuestos a agentes como los solventes orgánicos, capaces de producir efectos mutágenos y carcinógenos. OBJETIVO: Caracterizar la susceptibilidad poblacional y evaluar los efectos genotóxicos debidos a la exposición a solventes orgánicos. MÉTODOS: Estudio de corte transversal que comparó a un grupo de pintores de carros expuestos a solventes orgánicos con un grupo de personas no expuestas. Fueron determinados tanto los polimorfismos de CYP2E1 como la presencia de micronúcleos en linfocitos. RESULTADOS: Participaron 122 personas, 62 trabajadores de talleres de pintura de autos expuestos a solventes y 60 personas no expuestas. Con relación al cuestionario Q 16, 32% de los expuestos refirieron síntomas sugestivos de neurotoxicidad. Las frecuencias de células micronucleadas y de puentes nucleoplásmicos fueron significativamente mayores en los expuestos que en los no expuestos: p= 0.042 y p= 0.046, respectivamente, Razón de verosimilitud exacta). Fueron halladas diferencias significativas en la interacción de CYP2E1 (c1c1) y la exposición ocupacional a solventes, con mayores frecuencias de micronúcleos (p= 0.013) y de células micronucleadas (p= 0.015). CONCLUSIONES: Este estudio reafirma que los trabajadores expuestos a solventes orgánicos con polimorfismos de CYP2E1, específicamente con genotipo c1c1, tienen mayor probabilidad de presentar mutaciones en las células somáticas, condición asociada con una mayor susceptibilidad a enfermedades como el cáncer.

Biomarkers of susceptibility and effect in car painters exposed to organic solvents / Biomarcadores de susceptibilidad y efecto en pintores de carros expuestos a solventes orgánicos

Abstract Introduction: Car painters are routinely exposed to organic solvents classified as carcinogenic and mutagenic substances. Objective: To characterize the population susceptibility and evaluate the genotoxic effects of exposure to organic solvents. Methods: A cross-sectional study comparing a group of car painters exposed to organic solvents with a non-exposed group. CYP2E1 polymorphisms and the presence of micronuclei in lymphocytes were determined. Results: One hundred twenty-two workers participated in the study: 62 who worked in car paint shops and were exposed to solvents, and 60 who were not exposed. There were statistically significant differences between the two groups regarding micronucleated cells and nucleoplasmic bridges frequencies (p=0.042 and p=0.046, respectively; exact likelihood ratio). Significant differences were found at the interaction between the CYP2E1 genotype c1c1 and occupational exposure to solvents, with higher frequencies of micronuclei (p= 0.013) and micronucleated cells (p= 0.015). However, when the frequencies of micronuclei, micronucleated cells and nucleoplasmic bridges in the exposure group were compared between the c1c1 and c2c2/c1c2 allele groups of the CYP2E1 polymorphism, statistically significant differences were found. Conclusions: This study confirms that when workers with CYP2E1 polymorphisms, specifically the c1c1 genotype, are exposed to organic solvents, they are more likely to have somatic cell mutations, a condition associated with increased susceptibility to diseases such as cancer

Resumen Introducción: Los pintores de vehículos automotores están rutinariamente expuestos a agentes como los solventes orgánicos, capaces de producir efectos mutágenos y carcinógenos. Objetivo: Caracterizar la susceptibilidad poblacional y evaluar los efectos genotóxicos debidos a la exposición a solventes orgánicos. Métodos: Estudio de corte transversal que comparó a un grupo de pintores de carros expuestos a solven tes orgánicos con un grupo de personas no expuestas. Fueron determinados tanto los polimorfismos de CYP2E1 como la presencia de micronúcleos en linfocitos. Resultados: Participaron 122 personas, 62 trabajadores de talleres de pintura de autos expuestos a solventes y 60 personas no expuestas. Con relación al cuestionario Q 16, 32% de los expuestos refirieron síntomas sugestivos de neurotoxicidad. Las frecuencias de células micronucleadas y de puentes nucleoplásmicos fueron significativamente mayores en los expuestos que en los no expuestos: p= 0.042 y p= 0.046, respectivamente, Razón de verosimilitud exacta). Fueron halladas diferencias significativas en la interacción de CYP2E1 (c1c1) y la exposición ocupacional a solventes, con mayores frecuencias de micronúcleos (p= 0.013) y de células micronucleadas (p= 0.015). Conclusiones: Este estudio reafirma que los trabajadores expuestos a solventes orgánicos con polimorfismos de CYP2E1, específicamente con genotipo c1c1, tienen mayor probabilidad de presentar mutaciones en las células somáticas, condición asociada con una mayor susceptibilidad a enfermedades como el cáncer

Chromosomal Instability in Farmers Exposed to Pesticides: High Prevalence of Clonal and Non-Clonal Chromosomal Alterations.

INTRODUCTION: An important economic activity in Colombia is agricultural production and farmers are frequently exposed to pesticides. Occupational exposure to pesticides is associated with an increased incidence of various diseases, including cancer, Parkinson's disease, Alzheimer's disease, reproductive disorders, and birth defects. However, although high genotoxicity is associated with these chemicals, information about the type and frequency of specific chromosomal alterations (CAs) and the level of chromosomal instability (CIN) induced by exposure to pesticides is scarce or absent. METHODS: In this study, CAs and CIN were assessed in peripheral blood lymphocytes (PBLs) from five farmers occupationally exposed to pesticides and from five unexposed individuals using GTG-banding and molecular cytogenetic analysis. RESULTS: A significant increase in clonal and non-clonal chromosomal alterations was observed in pesticide-exposed individuals compared with unexposed individuals (510±12,2 vs 73±5,7, respectively; p<0.008). Among all CAs, monosomies and deletions were more frequently observed in the exposed group. Also, a high frequency of fragilities was observed in the exposed group. CONCLUSION: Together, these findings suggest that exposure to pesticides could be associated with CIN in PBLs and indicate the need for the establishment of educational programs on safety precautions when handling pesticides, such as wearing gloves, masks and boots, changing clothes and maintaining proper hygiene, among others. Further evaluation in other similar studies that include a greater number of individuals exposed to pesticides is necessary.

Intervención integral al paciente polimedicado / Global intervention in the polymedicated patient

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Determinación del polimorfismo C677T de metilentetrahidrofolato reductasa (MTHFR) en una población piloto de estudiantes de la Universidad del Rosario / Preliminary population study of Methylenetetrahydrofolate Reductase (MTHFR) C677T polymorphism determination in a pilot group of students from the University of Rosario

Introducción: la 5, 10-metilentetrahidrofolato reductasa (MTHFR) es una enzima clave en el metabolismo del folato; sus polimorfismos se han asociado al aumento de riesgo de padecer enfermedad coronaria, problemas obstétricos en mujeres gestantes, desarrollo de fetos con defectos de cierre del tubo neural y susceptibilidad a algunos tipos de cáncer. Este gen presenta una variación polimórfica de nucleótido único, que consiste en un cambio de C por T en la posición 677 el cual afecta de manera notable su actividad enzimática. Objetivo: Dada la importancia de esta enzima y la heterogeneidad genética de la población colombiana se realizó un estudio para determinar las frecuencias alélicas y genotípicas del polimorfismo C677T de MTHFR en individuos sanos, debido a que en el país sólo se han realizado estudios que involucran metodología de casos y controles. Materiales y métodos: Este polimorfismo se estudió a partir de ADN de una muestra poblacional de 206 estudiantes. Adicionalmente, se calcularon las frecuencias globales de Colombia utilizando los datos de controles sanos reportados en otros estudios. Resultados: En la muestra evaluada se detectó un desequilibrio Hardy-Weinberg, mientras que en los datos globales colombianos se encontró que la población está en equilibrio. Conclusión: la frecuencia poblacional del alelo T parece estar sometida a una presión de selección positiva, dado su incremento en la población a pesar de su efecto deletéreo. Un estudio español reporta resultados similares y argumenta como causa probable de este cambio en la frecuencia alélica de T la suplementación con ácido fólico a futuras madres.

Introduction: the 5, 10-methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism; their polymorphisms have been associated with heart disease risk increase, obstetric problems, neural tube defects in fetuses and cancer susceptibility. This gene has a single nucleotide polymorphism, a C-T change at nucleotide 677, which affects significantly its enzymatic activity. Objective: because of the biological importance of this enzyme and the Colombian population genetic heterogeneity characteristic, a study was performed to determine allele and genotype frequencies of MTHFR C677T polymorphism in healthy individuals, taking into account that in Colombia there are only studies that have involved case-control methodology. Methods: we analyzed this polymorphism trough the amplification of the DNA of a 206 students sample population. Additionally, Colombian overall frequencies were calculated, using data from healthy controls reported in other studies. Results: a Hardy-Weinberg disequilibrium was found in the sample tested. For the Colombian data, we found that the global population was in equilibrium. Conclusion: T allele population frequency seems to be under positive selection pressure, which is reflected in the population allele increase, despite its deleterious effect. A Spanish study reported similar results and identified folic acid supplementation on expectant mothers as a probably cause of this change.

[Genetic variability in Neotropical deer genera (Mammalia: Cervidae) according to DNA microsatellite loci]. / Variabilidad genética en géneros de ciervos neotropicales (Mammalia: Cervidae) según loci microsatelitales.

Species conservation programs are highly based on analyses of population genetics. We compared eight Neotropical Cervidae (Mazama americana, M. gouzaoubira, M. rufina, Odocoileus virginianus, Hippocamelus antisensis, Pudu mephistopholes, Ozotoceros bezoarticus and Blastoceros dichotomus) and some European and Asian Cervidae (Cervus elaphus, C. nippon, Capreolus capreolus, C. pygargus and Dama dama). The European species C. elaphus was our standard for a high degree of genetic variability: we used a Scottish population originated in the mix of diverse Western European subspecies. On the contrary, Cervus nippon (a population from Scotland with a founder effect) was our standard for a depauperated population. The M. americana, M. gouzaoubira and O. virginianus samples had high diversity values close to our C. elaphus population (H = 0.64, 0.70 and 0.61, respectively), while M. rufina was very low, close to C. nippon. Several sample sets of Mazama and Odocoileus yielded a homozygote excess, probably due to the Wahlund (subdivison) effect. There was no evidence of recent bottleneck events.

Variabilidad genética en géneros de ciervos neotropicales (Mammalia: Cervidae) según loci microsatelitales

Genetic variability in Neotropical deer genera (Mammalia: Cervidae) according to DNA microsatellite loci. Species conservation programs are highly based on analyses of population genetics. We compared eight Neotropical Cervidae (Mazama americana, M. gouzaoubira, M. rufina, Odocoileus virginianus, Hippocamelus antisensis, Pudu mephistopholes, Ozotoceros bezoarticus and Blastoceros dichotomus) and some European and Asian Cervidae (Cervus elaphus, C. nippon, Capreolus capreolus, C. pygargus and Dama dama). The European species C. elaphus was our standard for a high degree of genetic variability: we used a Scottish population originated in the mix of diverse Western European subspecies. On the contrary, Cervus nippon (a population from Scotland with a founder effect) was our standard for a depauperated population. The M. americana, M. gouzaoubira and O. virginianus samples had high diversity values close to our C. elaphus population (H= 0.64, 0.70 and 0.61, respectively), while M. rufina was very low, close to C. nippon. Several sample sets of Mazama and Odocoileus yielded a homozygote excess, probably due to the Wahlund (subdivison) effect. There was no evidence of recent bottleneck events. Rev. Biol. Trop. 57 (3): 879-904. Epub 2009 September 30.

Los programas de conservación de especies se apoyan fuertemente en estudios de genética poblacional. En el presente estudio, reportamos diversos análisis genéticopoblacionales en ocho especies de cérvidos neotropicales (Mazama americana, M. gouzaoubira, M. rufina, Odocoileus virginianus, Hippocamelus antisensis, Pudu mephistopholes, Ozotoceros bezoarticus y Blastoceros dichotomus) y, adicionalmente, en varias especies de cérvidos europeos y asiáticos (Cervus elaphus, C. nippon, Capreolus capreolus, C. pygargus and Dama dama). Una de esas especies europeas, la población de Cervus elaphus en Escocia, fue tomada como una población con un grado muy elevado de diversidad genética ya que proviene del cruce de diferentes grupos de ciervos rojos procedentes de diversas subespecies de la Europa continental. Desde una perspectiva de una diversidad genética depauperada, se tomó el nivel encontrado en una población de ciervos sika (Cervus nippon) en Escocia, que prácticamente no mostró variabilidad a nivel molecular. Respecto a esos dos casos que consideramos como de elevada y escasa variabilidad genética, encontramos que las poblaciones analizadas de Mazama americana, M. gouzaoubira y Odocoileus virginianus estuvieron cerca del límite máximo encontrado para el ciervo rojo escocés (H=0.64, 0.70 y 0.61, respectivamente), mientras que M. rufina mostró el más bajo grado de variabilidad genética de las especies neotropicales, cercano al extremo mínimo presentado por C. nippon. Algunas de las muestras de Mazama y de Odocoileus, tomadas a nivel macrogeográfico, mostraron un exceso de homocigotos debido, probablemente, a la existencia de efecto Wahlund (efecto de subdivisión). Ninguna de las especies analizadas parece haber atravesado un cuello de botella reciente.

Relaciones filogenéticas entre géneros de ciervos neotropicales (Artiodactyla: Cervidae) mediante secuenciación de ADN mitocondrial y marcadores microsatelitales

Phylogenetic relationships among Neotropical deer genera (Artiodactyla: Cervidae) by means of DNAmt sequences and microsatellite markers. The current work shows two molecular phylogenetic analyses on Neotropical deers. In the first analysis, the mitochondrial control region (D-loop) was sequenced in six Odocoileinae species from Latin America, using the sequences of two Muntiacinae as outgroups. The results obtained were as follows: A sequence of Mazama americana showed a striking relationship with several sequences of Odocoileus in contrast to that expected, since this M. americana haplotype, from a Mexican origin, was not associated with several Bolivian Mazama sequences analyzed. This could put forward that this genera is not monophyletic. On the other hand, these Bolivian Mazama formed a clade with Pudu puda and Ozotoceros bezoarticus. Likely, an Odocoileus virginianus sequence from the Central area of Colombia showed a more strong relationship with a Northamerican O. heminonus sequence than with the other O. virginianus sequences of Colombian origin as well. This could be explained by means of various different hypotheses. The first is the existence of common ancestral haplotypes between both species. Another one is the reiterative hybridization among both Odocoileus species before the migration of O. virginianus from North America to South America. Moreover, the maximum parsimony analysis showed an intense relationship between the Muntiacinae and this Neotropical Cervidae clade. In addition, and adding credence to the relevant polyphyletism found in Mazama by means of the mitochondrial control region DNA sequences, a second analysis with 16 DNA microsatellite loci also showed a higher genetic relationship between M. americana and O. virginianus, than between the first species regard to Mazama gouazoubira. Rev. Biol. Trop. 55 (2): 723-741. Epub 2007 June, 29.

El presente trabajo muestra dos análisis moleculares sobre la filogenia de los cérvidos neotropicales. En uno se secuenció la región control del mtDNA (D-loop) de seis especies de Odocoileinae, utilizándose las secuencias de dos Muntiacinae como elementos externos. Se evidenciaron los siguientes resultados: La secuencia de una Mazama americana, de origen mexicano, presentó una fuerte relación filogenética con las diversas secuencias estudiadas de Odocoileus, contrario a lo esperado ya que, a priori, debería haberse asociado con las secuencias analizadas de otros ejemplares de Mazama de origen boliviano. Esto pone en evidencia que este género no es monofilético. A su vez, las secuencias de los ejemplares bolivianos de Mazama formaron una agrupación con secuencias de Pudu puda y O. bezoarticus. Una secuencia de O. virginianus, del área central de Colombia, presentó más relación con la secuencia de un O. hemionus norteamericano que con las restantes secuencias analizadas de O. virginianus, también de origen colombiano. Esto puede reflejar varias explicaciones hipotéticas, tales como la existencia de haplotipos ancestrales comunes entre ambas especies de Odocoileus, hasta la hibridación en Norteamérica entre ambos taxones antes de su penetración en Sudamérica. Los análisis de máxima parsimonia presentan una especial relación entre los Muntiacinae y el clado de los ciervos sudamericanos. El segundo análisis filogenético hizo uso de 16 marcadores nucleares microsatélites. Aunque, en principio, estos marcadores no son los más recomendables para estudios filogenéticos intergenéricos, los resultados muestran, al igual que el ADN mitocondrial, una mayor relación entre M. americana y O. virginianus que entre la primera especie y M. gouzaoubira.

[Phylogenetic relationships among Neotropical deer genera (Artiodactyla: Cervidae) by means of DNAmt sequences and microsatellite markers]. / Relaciones filogenéticas entre géneros de ciervos neotropicales (Artiodactyla: Cervidae) mediante secuenciación de ADN mitocondrial y marcadores microsatelitales.

The current work shows two molecular phylogenetic analyses on Neotropical deers. In the first analysis, the mitochondrial control region (D-loop) was sequenced in six Odocoileinae species from Latin America, using the sequences of two Muntiacinae as outgroups. The results obtained were as follows: A sequence of Mazama americana showed a striking relationship with several sequences of Odocoileus in contrast to that expected, since this M. americana haplotype, from a Mexican origin, was not associated with several Bolivian Mazama sequences analyzed. This could put forward that this genera is not monophyletic. On the other hand, these Bolivian Mazama formed a clade with Pudu puda and Ozotoceros bezoarticus. Likely, an Odocoileus virginianus sequence from the Central area of Colombia showed a more strong relationship with a Northamerican O. heminonus sequence than with the other O. virginianus sequences of Colombian origin as well. This could be explained by means of various different hypotheses. The first is the existence of common ancestral haplotypes between both species. Another one is the reiterative hybridization among both Odocoileus species before the migration of O. virginianus from North America to South America. Moreover, the maximum parsimony analysis showed an intense relationship between the Muntiacinae and this Neotropical Cervidae clade. In addition, and adding credence to the relevant polyphyletism found in Mazama by means of the mitochondrial control region DNA sequences, a second analysis with 16 DNA microsatellite loci also showed a higher genetic relationship between M. americana and O. virginianus, than between the first species regard to Mazama gouazoubira.