A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

BACKGROUND: Aberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy. METHODOLOGY: This was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. MAIN FINDINGS: 16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5(m)C content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively. CONCLUSIONS: Hydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy

DNA Methylation-Independent Reversion of Gemcitabine Resistance by Hydralazine in Cervical Cancer Cells

BACKGROUND: Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase

A study of the dry forest communities in the Dominican Republic

This paper is a floristic and phytosociological study of the dry forest communities of the Dominican Republic. A total of 69 relevés in dry forest biotopes were carried out. The samples were subsequently subjected to Detrended Correspondence Analysis for the determination and study of possible groupings. The study does not cover tree formations growing on serpentines, nor the so-called semideciduous forests, peculiar to areas with higher rainfall. A total of nine phytocoenoses were identified. The most significant results led to the description of six new phytosociological associations: Simaroubetum berteroani (thorny dry forest on coastal dunes), Phyllostylo rhamnoidis-Prosopidetum juliflorae (southern Dominican disturbed dry forest), Consoleo moniliformis-Camerarietum linearifoliae (dry forest on hard limestones), Lemaireocereo hystricis-Prosopidetum juliflorae (northern Dominican disturbed dry forest), Lycio americani-Prosopidetum juliflorae (disturbed dry forest on saline soils) and Guettardo ellipticae-Guapiretum discoloris (dry forest on flat-topped hillocks in Montecristi). This is an important step forward in the phytosociological and floristic studies of the Caribbean territories.Este trabalho apresenta um estudo florístico e fitossociológico das comunidades de florestas secas da República Dominicana. Um total de 69 amostras foram obtidas pelo método relevé em biótopos florestais secos. As amostras foram posteriormente submetidas à análise de correspondência destendenciada para a determinação e estudo de possíveis agrupamentos. O estudo não abrange formações arbóreas desenvolvidas sobre serpentinitos, nem as chamadas florestas semideciduais, peculiares às áreas de maior pluviosidade. Foram identificados nove fitocenoses. Os resultados mais significativos levaram à descrição de seis novas associações fitossociológicas: Simaroubetum berteroani (floresta espinhosa seca em dunas costeiras), Phyllostylo rhamnoidis-Prosopidetum juliflorae (floresta seca perturbada do sul da República Dominicana), Consoleo moniliformis-Camerarietum linearifoliae (floresta seca sobre calcários compactos), Lemaireocereo hystricis-Prosopidetum juliflorae (floresta seca perturbada do norte da República Dominicana), Lycio americani-Prosopidetum juliflorae (floresta seca perturbada desenvolvida em solos salinos) Guettardo ellipticae-Guapiretum discoloris (floresta seca em colinas de topo achatado em Montecristi). O trabalho realizado representa um importante avanço nos estudos fitossociológicos e florísticos dos territórios do Caribe.This research paper was possible thanks to the sponsorship of the Agencia Española de Cooperación Internacional para el Desarrollo (AECID), under the auspices of the Ministerio de Asuntos Exteriores y de Cooperación de España, which funded the project (cod. A/3499/05)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Propiedades psicométricas de la Escala de Motivación en el Deporte revisada (SMS-II) adaptada al español hablado en México

The aim of this study was to analyze the psychometric properties (factorial structure, reliability, construct validity) of a Mexican Spanish version of the revised Sport Motivation Scale (SMS-II), which is composed of 18 items that measure six factors of behavioral regulation. Such factors were suggested by the Self-determination Theory in order to prove a model that allows the assessment of Autonomous and Controlled Motivation. The study involved 279 high performance athletes with an average age of 23.15 years old (SD = 5.58), who answered the Mexican Spanish Version of the SMS-II. After eliminating one of the items, the results supported the six major factor model (intrinsic motivation, integrated regulation, identified regulation, introjected regulation, external regulation and amotivation); and the internal consistent data exceeded or were under the limit of the usage criteria in five of the factors. After the motivational regulations were combined in order to form a three-factor model, two of the minor factors (autonomous and controlled motivation) plus one major factor (amotivation), such model was supported and the internal consistency of the factors was appropriate. In conclusion, the Mexican Spanish version of the SMS-II offers factorial structure and construct validity, excluding one of the items. Thus, it can be used for assessing autonomous and controlled motivation in elite athletes, even though further research shall be conducted to improve this instrument.El objetivo de este estudio fue examinar las propiedades psicométricas (estructura factorial, fiabilidad, validez de constructo) de una versión en español hablado en México de la Escala de Motivación en el Deporte revisada (SMS-II) compuesta por 18 ítems que miden seis factores de regulación conductual planteados por la teoría de la autodeterminación, y probar un modelo que permitiese evaluar la motivación autónoma y la motivación controlada. Participaron 279 deportistas de alto rendimiento con una edad promedio de 23.15 años (DT = 5.58), quienes respondieron a una versión en español hablado en México de la SMS-II. Los resultados apoyaron el modelo de seis factores de primer orden (motivación intrínseca, regulación integrada, regulación identificada, regulación introyectada, regulación externa, y desmotivación) tras la eliminación de un ítem; y los datos de consistencia interna superaron o estuvieron al límite de los criterios de uso en cinco factores. Cuando las regulaciones motivacionales se combinaron para conformar un modelo trifactorial, dos de sus factores de segundo orden (motivación autónoma y motivación controlada) más un factor de primer orden (desmotivación), se soportó dicho modelo, y la consistencia interna de los factores fue adecuada. En conclusión se ofrece validez factorial y de constructo de esta versión en español hablado en México de la Escala de Motivación en el Deporte revisada con la exclusión un ítem, y puede utilizarse para la medición de la motivación controlada y autónoma en el deporte de alto rendimiento, aunque se requiere de mayor estudio para mejorar el instrumento

Raza, fobias e intolerancias. Num. 31 (2004) Vol. 11 mayo-agosto. Cuicuilco Revista de la Escuela Nacional de Antropología e Historia

- Presentación, por Pablo Yankelevich - Dossier: - La singularidad de Auschwitz. Un debate sobre el uso público de la historia, por Enzo Traverso - El científico frente a la “crisis” de la civilización. Una aproximación a La incógnita del hombre de Alexis Carrel, por Andrés H. Reggiani - ¿Quiénes deben procrear? Los médicos eugenistas bajo el signo social (México, 1931-1940), por Marta Saade Granados - Ni blancos ni negros: mexicanos. El papel de la Patrulla Fronteriza estadounidense en la definición de una nueva categoría racial. 1924-1940, por Kelly Lytle Hernández - Nación y extranjería en el México revolucionario, por Pablo Yankelevich - Miscelánea: - El indigenismo como antropología aplicada, algunos apuntes a contrapunto, por José Palacios Ramírez - Una aproximación teórica a James C. Scott, por Mercedes Henríquez y España - Paradojas de la historia ejidal: El Llanito, Dolores Hidalgo, Guanajuato, 1930-1960, por Manola Sepúlveda Garza - Presencia de esterilidad: actores o sujetos en la actualidad, por Mayra L. Chávez-Courtois - Homosexualidad y género, por Magali Díaz Álvarez - Mente, intencionalidad y autopoiesis. Una heurística antropológica, por Jorge H. Flores Trejo

The Mexican consensus on nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak.This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease. Resumen: La enfermedad por hígado graso no alcohólico (EHGNA) afecta prácticamente a un tercio de la población mundial. México es uno de los países cuya población reúne varios factores de riesgo para esta enfermedad y su prevalencia podría superar el 50%; es por eso que el panorama a mediano plazo es muy pesimista si no se toman acciones inmediatas para contrarrestar lo que ya se considera un problema de salud nacional.De ahí el interés de la Asociación Mexicana de Gastroenterología y de la Asociación Mexicana de Hepatología para realizar el Consenso mexicano de EHGNA, en el cual se hizo una revisión actualizada y a fondo de temas como epidemiología, fisiopatología, formas clínicas, diagnóstico y tratamiento, con el objetivo de ofrecer al médico mexicano una herramienta útil para la prevención y el manejo de esta enfermedad. Keywords: Nonalcoholic fatty liver disease, Mexican consensus, Palabras clave: Enfermedad por hígado graso no alcohólico, Consenso mexican

Consenso mexicano de la enfermedad por hígado graso no alcohólico

Resumen: La enfermedad por hígado graso no alcohólico (EHGNA) afecta prácticamente a un tercio de la población mundial. México es uno de los países cuya población reúne varios factores de riesgo para esta enfermedad y su prevalencia podría superar el 50%; es por eso que el panorama a mediano plazo es muy pesimista si no se toman acciones inmediatas para contrarrestar lo que ya se considera un problema de salud nacional.De ahí el interés de la Asociación Mexicana de Gastroenterología y de la Asociación Mexicana de Hepatología para realizar el Consenso mexicano de EHGNA, en el cual se hizo una revisión actualizada y a fondo de temas como epidemiología, fisiopatología, formas clínicas, diagnóstico y tratamiento, con el objetivo de ofrecer al médico mexicano una herramienta útil para la prevención y el manejo de esta enfermedad. Abstract: Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak.This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease. Palabras clave: Enfermedad por hígado graso no alcohólico, Consenso mexicano, Keywords: Nonalcoholic fatty liver disease, Mexican consensu