Differential metabolism of deoxyribonucleosides by leukaemic T cells of immature and mature phenotype

Experimental evidence has indicated that T lymphoblasts are more sensitive to deoxynucleoside toxicity than are B lymphoblasts. These data have led to the use of purine enzyme inhibitors as selective chemotherapeutic drugs in the treatment of T cell malignancies ranging from T cell acute lymphoblastic leukaemia to cutaneous T cell lymphomas. We have compared the toxicities of 2′-deoxyadenosine, 2′-deoxyguanosine, and thymidine for T cell lines derived from patients with T cell acute lymphoblastic leukaemia with those for mature T cell lines derived from patients with cutaneous T cell leukaemia/lymphoma. We have found that both deoxynucleosides are far less toxic to the mature T cell lies than to T lymphoblasts and that the mature cells accumulate much lower amounts of dATP and dGTP when exposed to deoxyadenosine and deoxyguanosine, respectively. Similar studies performed on peripheral blood cells from patients with T cell leukaemias of mature phenotype and on peripheral blood T cells demonstrate similar low amounts of deoxynucleotide accumulation. Measurements of the activities of several purine metabolizing enzymes that participate in deoxynucleoside phosphorylation or degradation do not reveal differences which would explain the toxicity of deoxynucleosides for immature, as compared to mature, T cells. We conclude that deoxynucleoside metabolism in leukaemic T cells varies with their degree of differentiation. These observations may be relevant to the design of chemotherapeutic regimes for T cell malignancies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72479/1/j.1365-2141.1985.tb04067.x.pd

O risco do diabetes em uma comunidade rural no México: um estudo observacional

Introduction: The rapid transition from rural to urban eating habits, sedentary lifestyles and poor access to healthcare put people at higher risk of getting diabetes. However, only a few studies focus on this phenomenon at the rural level. Understanding risks allow identifying problem areas and reversing the situation by using healthcare models in this population. This study is aimed to describe risk factors found in a rural community in Guanajuato. Material and Methods: A descriptive observational cross-sectional study was conducted with a non-probabilistic sample of 164 individuals without diabetes, which was calculated using Epidat 3.1, 95% Confidence Interval and 3% accuracy. Type 2 diabetes risk assessment questionnaire was implemented. Results: 71% (117) of the population were women at an average age of 43; 85% of individuals were at a high risk for diabetes. The three main risk factors were 57.9% (95) were overweight and obese, 77.4% (127) had their waist circumference above suggested parameters and 75.6% (124) had a family history. As for gender, women were three times more likely to develop diabetes (p=<.05). Conclution: Rural environments, unlike previous observations, are at high risk of developing diabetes, which probably goes in parallel with changes in community habits, given that industrialization has already invaded them, including all aspects that it entails, as Moreno L points out. How to cite this article: Avila Sansores Grever María, Vega Argote Ma. Gloria, Ruvalcaba Palacios Gerardo, Barreto Arias Ma. Eugenia, Gomez Aguilar Patricia Isolina, Yam Sosa Antonio Vicente.  Riesgo de diabetes de una comunidad rural en México: un estudio observacional. Revista Cuidarte. 2020; 11(3): e797. http://dx.doi.org/10.15649/cuidarte.797   Introducción. La rápida transición del medio rural a la adopción de hábitos alimenticios de zonas urbanas, el sedentarismo, las dificultades de acceso a la salud, ponen a la población en mayor riesgo de desarrollo de diabetes, sin embargo, son pocos los estudios que se enfocan en este fenómeno a nivel rural. Conocer el riesgo permite identificar las áreas problemáticas y revertir la situación a través de modelos de atención para esta población. El objetivo de este estudio fue describir los factores de riesgo presentes en una comunidad rural de Guanajuato. Material y Métodos: Estudio descriptivo, observacional, transversal; muestra no probabilística de 164 personas sin diabetes, se calculó con Epidat 3.1, intervalo de confianza al 95%, precisión del 3%; se aplicó el Cuestionario de Factores de Riesgo para la Diabetes Mellitus. Para la colecta se hizo un recorrido de casa por casa hasta completar la muestra, para el análisis estadístico se utilizó la chi cuadrada y cálculo de odds ratio. Resultados: El 71%(117)  de la población fueron mujeres; el promedio para la edad fue de 43 años; el 85% de los sujetos presentaron un alto riesgo de padecer diabetes; los tres principales factores de riesgo fueron: 57.9% (95) con sobrepeso y obesidad, el 77.4%(127) de la muestra con cintura superior al parámetro recomendado, 75.6% (124) de la muestra presentó antecedentes heredofamiliares; en cuestión de género las mujeres presentaron 3 veces más riesgo de diabetes (p=<.05). Conclusión: Los entornos rurales muy contrario a lo que se observaba, tienen alto riesgo de desarrollo de diabetes, probablemente va de la mano con los cambios de hábitos de las comunidades, pues la industrialización las ha invadido, con todo lo que conlleva, como lo señala Moreno L. Como citar este artículo: Avila Sansores Grever María, Vega Argote Ma. Gloria, Ruvalcaba Palacios Gerardo, Barreto Arias Ma. Eugenia, Gomez Aguilar Patricia Isolina, Yam Sosa Antonio Vicente.  Riesgo de diabetes de una comunidad rural en México: un estudio observacional. Revista Cuidarte. 2020; 11(3): e797. http://dx.doi.org/10.15649/cuidarte.797   Introdução: A rápida transição dos hábitos alimentares rurais para os urbanos, os estilos de vida sedentários e as dificuldades de acesso aos serviços de saúde põem a população em maior risco de contrair diabetes. No entanto, poucos estudos se concentram neste fenômeno no âmbito rural. O conhecimento do risco nos permite identificar as áreas problemáticas e reverter a situação através de modelos de atenção a esta população. O objetivo deste estudo foi descrever os fatores de risco presentes em uma comunidade rural de Guanajuato. Material e Métodos: Estudo observacional transversal descritivo; amostra não probabilística de 164 pessoas sem diabetes, calculada com Epidat 3.1, intervalo de confiança de 95%, precisão de 3%; Questionário de Fatores de Risco para Diabetes Mellitus foi aplicado. Para a coleta de dados, foi feita uma pesquisa casa a casa até a conclusão da amostra; para a análise estatística, foram utilizados o chi quadrado e cálculo dos odds ratios. Resultados: 71% (117) da população eram mulheres; a média de idade foi de 43 anos; 85% dos indivíduos apresentaram alto risco de diabetes; os três principais fatores de risco foram: 57,9% (95) com sobrepeso e obesidade, 77,4% (127) da amostra com a cintura acima do parâmetro recomendado, 75,6% (124) da amostra apresentou histórico familiar; em termos de gênero, as mulheres apresentaram 3 vezes o risco de diabetes (p=<,05). Conclusão: Os ambientes rurais, ao contrário do que foi observado, têm alto risco de desenvolver diabetes, o que provavelmente vai junto com as mudanças de hábitos em comunidades, já que a industrialização as invadiu, com tudo o que isso implica, como aponta Moreno L. Como citar este artigo: Avila Sansores Grever María, Vega Argote Ma. Gloria, Ruvalcaba Palacios Gerardo, Barreto Arias Ma. Eugenia, Gomez Aguilar Patricia Isolina, Yam Sosa Antonio Vicente.  Riesgo de diabetes de una comunidad rural en México: un estudio observacional. Revista Cuidarte. 2020; 11(3): e797. http://dx.doi.org/10.15649/cuidarte.797&nbsp

Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition

Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

Respiración para el tratamiento de trastornos crónicos: ¿entrenar la mecánica o la química respiratoria?

One basic assumption of breathe training-based interventions is that respiration’s control provides patients with better emotional and health states. This assumption considers the existence of relationships between respiratory mechanisms, hearth activity and related parasympathetic activity. Therefore, it is common that these interventions are oriented only to control respiratory mechanisms. However, control of respiratory chemistry has equal or even more importance than control the mechanism, because alterations on O2 - CO2 interchange are related with chronic syndromes onset, as well as with development of negative emotional states. In this paper, a review about mechanism and chemistry of respiration is shown with the aim of emphasize necessity to consider the latter as an important element in chronic syndromes’ breathingmodulation treatments. Finally, we offer some recommendations for develop training programs to modulate respiratory chemistry

Riesgo de diabetes de una comunidad rural en México: un estudio observacional

Introducción. La rápida transición del medio rural a la adopción de hábitos alimenticios de zonas urbanas, el sedentarismo, las dificultades de acceso a la salud, ponen a la población en mayor riesgo de desarrollo de diabetes, sin embargo, son pocos los estudios que se enfocan en este fenómeno a nivel rural. Conocer el riesgo permite identificar las áreas problemáticas y revertir la situación a través de modelos de atención para esta población. El objetivo de este estudio fue describir los factores de riesgo presentes en una comunidad rural de Guanajuato. Material y Métodos: Estudio descriptivo, observacional, transversal; muestra no probabilística de 164 personas sin diabetes, se calculó con Epidat 3.1, intervalo de confianza al 95%, precisión del 3%; se aplicó el Cuestionario de Factores de Riesgo para la Diabetes Mellitus. Para la colecta se hizo un recorrido de casa por casa hasta completar la muestra, para el análisis estadístico se utilizó la chi cuadrada y cálculo de odds ratio. Resultados: El 71%(117) de la población fueron mujeres; el promedio para la edad fue de 43 años; el 85% de los sujetos presentaron un alto riesgo de padecer diabetes; los tres principales factores de riesgo fueron: 57.9% (95) con sobrepeso y obesidad, el 77.4%(127) de la muestra con cintura superior al parámetro recomendado, 75.6% (124) de la muestra presentó antecedentes heredofamiliares; en cuestión de género las mujeres presentaron 3 veces más riesgo de diabetes (p=&lt;.05). Conclusión: Los entornos rurales muy contrario a lo que se observaba, tienen alto riesgo de desarrollo de diabetes, probablemente va de la mano con los cambios de hábitos de las comunidades, pues la industrialización las ha invadido, con todo lo que conlleva, como lo señala Moreno L.</jats:p