The Epigenetic Origin of Aneuploidy

Theodore Boveri, eminent German pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered to be a process of diversification that leads to survival of the fittest clones. According to Darwin’s theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; tumor suppressor gene silencing by CpG island promoter hypermethylation is perhaps the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosomal instability. We propose and support in this manuscript that not only genetics but also epigenetics, contribute in a major fashion to aneuploid cell formation

The Epigenetic Origin of Aneuploidy

Theodore Boveri, eminent German pathologist, observed aneuploidy in cancer cells more than a century ago and suggested that cancer cells derived from a single progenitor cell that acquires the potential for uncontrolled continuous proliferation. Currently, it is well known that aneuploidy is observed in virtually all cancers. Gain and loss of chromosomal material in neoplastic cells is considered to be a process of diversification that leads to survival of the fittest clones. According to Darwin’s theory of evolution, the environment determines the grounds upon which selection takes place and the genetic characteristics necessary for better adaptation. This concept can be applied to the carcinogenesis process, connecting the ability of cancer cells to adapt to different environments and to resist chemotherapy, genomic instability being the driving force of tumor development and progression. What causes this genome instability? Mutations have been recognized for a long time as the major source of genome instability in cancer cells. Nevertheless, an alternative hypothesis suggests that aneuploidy is a primary cause of genome instability rather than solely a simple consequence of the malignant transformation process. Whether genome instability results from mutations or from aneuploidy is not a matter of discussion in this review. It is most likely both phenomena are intimately related; however, we will focus on the mechanisms involved in aneuploidy formation and more specifically on the epigenetic origin of aneuploid cells. Epigenetic inheritance is defined as cellular information—other than the DNA sequence itself—that is heritable during cell division. DNA methylation and histone modifications comprise two of the main epigenetic modifications that are important for many physiological and pathological conditions, including cancer. Aberrant DNA methylation is the most common molecular cancer-cell lesion, even more frequent than gene mutations; tumor suppressor gene silencing by CpG island promoter hypermethylation is perhaps the most frequent epigenetic modification in cancer cells. Epigenetic characteristics of cells may be modified by several factors including environmental exposure, certain nutrient deficiencies, radiation, etc. Some of these alterations have been correlated with the formation of aneuploid cells in vivo. A growing body of evidence suggests that aneuploidy is produced and caused by chromosomal instability. We propose and support in this manuscript that not only genetics but also epigenetics, contribute in a major fashion to aneuploid cell formation

Anotación y descripción de textos digitales sin formato de la base de casos médicos de la Facultad de Medicina de la Universidad Nacional de Colombia

La Lingüística de Corpus es una metodología empírica ya que, a partir de grandes colecciones de textos -corpus o corpora- intenta describir las regularidades de las lenguas por medio de la implementación de programas computacionales, y así, simular los usos reales de ellas. Este trabajo aplica la Lingüística de Corpus a un conjunto de historias médicas electrónicas escritas en español nunca analizado lingüísticamente. De estas historias se desconoce la forma en que están escritas por parte de los médicos y las clases de palabras que utilizan cuando describen un suceso en una subdisciplina médica. El conjunto de datos está formado por 19 subdisciplinas médicas, las cuales contienen sus propias historias. Cada historia fue anotada en tres formas diferentes, lematización, tokenización y categoría gramatical (part-of-speech) por medio de TreeTagger. Posteriormente, las frecuencias de las anotaciones se describieron mediante AntConc. Los resultados encontrados para cada subdisciplina muestran las palabras con mayor frecuencia. Las palabras de clase cerrada son las más comunes y utilizadas. Algunas partes de las historias médicas fueron anotadas erróneamente. Por otra parte, se muestran ejemplos que dan a conocer la variabilidad de uso entre expresiones y abreviaturas por parte del personal médico. Además, la escritura médica de la Universidad Nacional de Colombia corrobora la Ley de Zipf

Fat-specific FUS-DDIT3-transgenic mice establish PPARgamma inactivation is required to liposarcoma development.

Peer reviewe

Routine management of locally advanced cervical cancer with concurrent radiation and cisplatin. Five-year results

BACKGROUND: Globally, cervical cancer primarily affects socially disadvantaged women. Five randomized trials were the foundation for adopting cisplatin-based chemotherapy during radiation as the standard of care for high-risk patients after primary radical hysterectomy who require adjuvant radiation and for locally advanced patients treated with definitive radiation. These results were obtained in clinical trials performed in carefully prepared academic centers; hence, we sought to determine whether these results could be reproduced when patients were treated on an out-of-protocol basis. METHODS: We reviewed the files of 294 patients with locally advanced cervical cancer who received radiation plus weekly cisplatin as routine management between 1999 to 2003, and analyzed treatment compliance, response rate, toxicity, and survival. RESULTS: A total of 294 patients who received radiation and cisplatin were analyzed. Mean age was 43.8 years (range, 26–68 years). The majority of cases were squamous cell carcinoma (87.8%), and distribution according to International Federation of Gynecology and Obstetrics (FIGO) stage was as follows: IB2-IIA, 23%; IIB, 53.3%, and IIIB, 23%; there were only two IVA cases. Overall, 96% of patients completed external beam, and intracavitary therapy. The majority of patients (67%) received the planned six courses of weekly cisplatin. Complete responses were achieved in 243 (83%) patients, whereas 51 (17%) had either persistent (32 patients, 10.8%) or progressive (19 patients, 6.4%) disease. At median follow-up (28 months; range, 2–68 months), 36 patients (12.2%) have relapsed (locally 30.5, and systemically, 69.5%). The most common toxicities were hematologic and gastrointestinal, in the majority of cases considered mild-moderate. At median follow-up (28 months; range, 2–68 months), overall and progression-free survival are 76.5 and 67%, respectively. CONCLUSION: Our results support use of chemoradiation with six weekly applications of cisplatin at 40 mg/m(2 )during external radiation for routine management of locally advanced cervical cancer

Procesos tecnológicos y métodos de control en la hidrólisis de proteínas

Los hidrolizados de proteínas se utilizan ampliamente en tecnología alimentaria por sus propiedades nutricionaleso funcionales (solubilidad, poder emulsificante, capacidad espumante). En este trabajo se describen las técnicasempleadas para la obtención de estos hidrolizados y se comparan los diferentes métodos usados para el control deestos preparados: determinación del grado de hidrólisis, tamaño de los péptidos, distribución de pesos molecularesy contenido en aminoácidos y péptidos

Intoxicaciones agudas por productos químicos: análisis de los primeros 15 años del Sistema Español de Toxicovigilancia (SETv)

Fundamentos: Existen pocos estudios epidemiológicos, sobre todo de tipo multicéntrico, sobre las intoxicaciones agu-das a causa de productos químicos agroindustriales y del hogar en España. El objetivo de este trabajo fue describir el perfil epi-demiológico y clínico de estas intoxicaciones en nuestro país, y analizar su evolución temporal. Métodos: El Sistema Español de Toxicovigilancia (SETv) es un registro prospectivo que incluye a 32 Servicios de Urgencias y Unidades de Cuidados intensivos de España. Se realizó un es-tudio descriptivo observacional de las intoxicaciones agudas por agentes químicos (excluyendo drogas y fármacos) en sus primeros 15 años de funcionamiento (1999-2014). Las comparaciones de proporciones se realizaron mediante las pruebas de Chi-cuadrado o exacta de Fisher, y entre pares de grupos independientes con la prueba de Mann-Whitney. Se consideraron significativos los valo-res de probabilidad menores de 0, 05.Resultados: Los 10.548 casos estudiados presentaban una edad media de 38, 41 (±22, 07) años, siendo significativamente su-perior en las mujeres (p=0, 0001). El 67, 7% de las intoxicaciones ocurrieron en el hogar, y las vías de entrada más frecuentes fueron la respiratoria (48, 3%), la digestiva (35, 3%) y la ocular (13, 1%). Los grupos tóxicos más frecuentes fueron los gases tóxicos (31%), los cáusticos (25, 6%) y los gases irritantes (12, 1%). Un 76, 2% de los casos requirieron tratamiento (27, 2% con antídotos). Ingresó en un centro hospitalario un 20, 6% de las personas, con una es-tancia media de 32 (±151, 94) días, con diferencias significativas para los plaguicidas y disolventes (p=0, 02). Presentaron secuelas al alta un 2, 1%. La mortalidad fue del 1, 4% (146 pacientes), con una edad media de 62, 08 años (±19, 58; p=0, 0001). Conclusiones: En las intoxicaciones por productos quími-cos, las medidas preventivas deben centrarse fundamentalmente en el ámbito doméstico, controlando las fuentes de exposición al monóxido de carbono y la manipulación de los productos de lim-pieza, fundamentalmente los líquidos cáusticos y la generación de gases irritantes al mezclarlos. OBJECTIVE: There are few epidemiological studies on acute poisonings from pesticides, industrials and household products in Spain. The objective of this work is to describe the epidemiological and clinical profile of acute poisonings by chemical products in our country, and analyze their annual evolution. METHODS: The Spanish Toxicovigilance System (SETv) is a prospective registry that includes 32 Emergency Departments and Intensive Care Units in Spain. An observational descriptive study of acute poisoning by chemical agents (excluding pharmacological products and illicit drugs) was carried out, within 1999-2014. Statistical analysis was performed using Chi-square or exact Fisher''s tests. Non-parametric continuous variables were compared using the Mann-Whitney U test. P-value less than 0.05 were considered significant. RESULTS: The 10, 548 cases studied had a mean age of 38.41 (±22.07) years, being significantly higher in women (p=0.0001). 67.7% of the poisonings occurred at home, and the most frequent routes of exposure were respiratory (48.3%), digestive (35.3%) and ocular (13.1%). The most frequent toxic groups were toxic gases (31%), caustics (25.6%) and irritant gases (12.1%). Of the patients that required treatment (76.2%), antidotes were used in 27.2%. 20.6% of the patients were admitted at Hospital, with a median stay of 32 (±151.94) days, with significant differences for pesticides and solvents (p=0.02). Sequelae were presented at discharge in 2.1% of patients. Mortality was 1.4% (146 patients) with a mean age of 62.08 years (±19.58) (p=0.0001). CONCLUSIONS: The reduction of chemical poisonings should be prevented in the domestic environment, taking into account the sources of exposure to carbon monoxide and the handling of household cleaning products, both caustic liquids and the generation of irritating gases when mixed. OBJETIVO: Existen pocos estudios epidemiológicos, sobre todo de tipo multicéntrico, sobre las intoxicaciones agudas a causa de productos químicos agroindustriales y del hogar en España. El objetivo de este trabajo fue describir el perfil epidemiológico y clínico de estas intoxicaciones en nuestro país, y analizar su evolución temporal. METODOS: El Sistema Español de Toxicovigilancia (SETv) es un registro prospectivo que incluye a 32 Servicios de Urgencias y Unidades de Cuidados intensivos de España. Se realizó un estudio descriptivo observacional de las intoxicaciones agudas por agentes químicos (excluyendo drogas y fármacos) en sus primeros 15 años de funcionamiento (1999-2014). Las comparaciones de proporciones se realizaron mediante las pruebas de Chi-cuadrado o exacta de Fisher, y entre pares de grupos independientes con la prueba de Mann-Whitney. Se consideraron significativos los valores de probabilidad menores de 0, 05. RESULTADOS: Los 10.548 casos estudiados presentaban una edad media de 38, 41 (±22, 07) años, siendo significativamente superior en las mujeres (p=0, 0001). El 67, 7% de las intoxicaciones ocurrieron en el hogar, y las vías de entrada más frecuentes fueron la respiratoria (48, 3%), la digestiva (35, 3%) y la ocular (13, 1%). Los grupos tóxicos más frecuentes fueron los gases tóxicos (31%), los cáusticos (25, 6%) y los gases irritantes (12, 1%). Un 76, 2% de los casos requirieron tratamiento (27, 2% con antídotos). Ingresó en un centro hospitalario un 20, 6% de las personas, con una estancia media de 32 (±151, 94) días, con diferencias significativas para los plaguicidas y disolventes (p=0, 02). Presentaron secuelas al alta un 2, 1%. La mortalidad fue del 1, 4% (146 pacientes), con una edad media de 62, 08 años (±19, 58; p=0, 0001). CONCLUSIONES: En las intoxicaciones por productos químicos, las medidas preventivas deben centrarse fundamentalmente en el ámbito doméstico, controlando las fuentes de exposición al monóxido de carbono y la manipulación de los productos de limpieza, fundamentalmente los líquidos cáusticos y la generación de gases irritantes al mezclarlos

Fusion of 8He with 206Pb around Coulomb barrier energies

The experimental study of the fusion of light neutron-rich nucleus 8He with 206Pb is reported in this work. A fusion stack of 206Pb targets has been used for this study. The most prominent evaporation residue (210Po), which has half-life of 138 days and decays by alpha emission, is populated in the reaction. Radiochemical analysis technique is used to extract the yield of this evaporation residue.Ministerio de Ciencia e Innovavión FPA2007-63074European Union 21269

Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations : Overlap of TWNK-related recessive disorders

Altres ajuts: This research was supported with cofounding from the European Regional Development Fund (ERDF), "A way to make Europe") (to IdC); S2017/BMD‑3721‑RAREGENOMICS‑CM from the Consejería de Educación e Investigación de la Comunidad de Madrid (to MAMP).Background: Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. Methods: Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Results: Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29∗), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Conclusions: Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome