Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells.

Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.

Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97.

The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, a therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to proteasome inhibition. The ATPase valosin-containing protein (VCP; p97) is an essential regulator of protein degradation in multiple pathways and has emerged as a target for cancer therapy. We found that pharmacological depletion of VCP enzymatic activity with mechanistically different inhibitors robustly induced proteotoxic stress in solid cancer and multiple myeloma cells, including cells that were insensitive, adapted, or clinically resistant to proteasome inhibition. VCP inhibition had an impact on two key regulators of protein synthesis, eukaryotic initiation factor 2α (eIF2α) and mechanistic target of rapamycin complex 1 (mTORC1), and attenuated global protein synthesis. However, a block on protein translation that was itself cytotoxic alleviated stress signaling and reduced cell death triggered by VCP inhibition. Some of the proteotoxic effects of VCP depletion depended on the eIF2α phosphatase, protein phosphatase 1 regulatory subunit 15A (PPP1R15A)/PP1c, but not on mTORC1, although there appeared to be cross-talk between them. Thus, cancer cell death following VCP inhibition was linked to inadequate fine-tuning of protein synthesis and activity of PPP1R15A/PP1c. VCP inhibitors also perturbed intracellular amino acid levels, activated eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4), and enhanced cellular dependence on amino acid supplies, consistent with a failure of amino acid homeostasis. Many of the observed effects of VCP inhibition differed from the effects triggered by proteasome inhibition or by protein misfolding. Thus, depletion of VCP enzymatic activity triggers cancer cell death in part through inadequate regulation of protein synthesis and amino acid metabolism. The data provide novel insights into the maintenance of intracellular proteostasis by VCP and may have implications for the development of anti-cancer therapies.

Evaluación por parte del estudiante del programa de enseñanza empleado en la unidad curricular de Medicina Familiar de la Universidad del Zulia / Studentïs evaluation of teaching program in curricular unit of family medicine Zulia University

La unidad curricular de Medicina familiar implementó un nuevo programa en 1998 orientando a que el estudiante adquiera habilidades en atención médica primaria. Evaluar a través de la opinión de los estudiantes las estrategias de enseñanzas en el nuevo programa. Es una investigación Evaluativa-descriptiva, transversal, que evaluó el programa de medicina familiar a través de una encuesta anónima, con preguntas abiertas y cerradas usando una escala de 1 a 4 puntos, aplicada a los estudiantes al finalizar al progama. Se recibieron 78 (85 por ciento) encuestas de 92 estudiantes. En las preguntas cerradas se obtuvieron 1482 respuestas, 41 por ciento excelentes. Los aspectos administrativos resultaron buenos (41 por ciento), actividades prácticas, de aula y el docente fueron excelentes (40 por ciento) y las estrategias de evaluación buenas 837 por ciento). En general para el 47,4 por ciento el programa cumplió sus expectativas. En las preguntas abiertas se cuantificó más de una respuesta por estudiante, para el 96 por ciento el curso ofrece una experiencia positiva. Las actividades más valiosas fueron la discusión de casos (45 por ciento) y las consultas (35 por ciento). 58 por ciento definieron al docente entre bueno y excelente. El programa fue evaluado por los estudiantes de bueno a excelente. Se ofrecieron diferentes estrategias de aprendizaje considerando las más valiosas los casos clínicos y las consultas. Los estudiantes valoran los componentes educacionales en donde ellos se encontraban activamente involucrados

Utilization of LDH isoenzymes in the diagnosis of myocardial infarction.

With the arrival of managed care, increased pressure is being placed on the health-care system to reduce the use of laboratory services. When evaluating less expensive methods to measure CK-MB to help reduce costs of triaging patients suspected of having myocardial infarction (MI), we also had an opportunity to evaluate the ordering pattern of LDH isoenzymes for these same patients. We found that LDH isoenzymes were continuously ordered as a routine test at least 14% of the time. We worked with the Division of Cardiology to reduce the use of LDH isoenzymes in two ways: 1) by changing the protocol of triaging suspected MI patients and 2) by reporting the test result only after director approval. This article summarizes our approach to reducing the use of LDH isoenzymes, an expensive test in terms of reagent cost and technician time.

[Thermoactinomyces vulgaris as a cause of extrinsic allergic alveolitis]. / Thermoactinomyces vulgaris como productor de alveolitis alérgica extrínseca.

Thermoactinomycetes are microorganisms similar to the aerobic actinomycetes that grow at temperatures between 32 65 degrees C and are usually found in soil, hay and warm environment. They are the agent of Extrinsic Allergy Alveolitis producing an interstitial process of immunologic, generated by the inhalation of the environmental dust that contain spores from these fungi. There is one case of a middle age man who works in a boiler of a foundry company of province de Buenos Aires in Argentina. The patient presents a clinical picture compatible with the above mentioned illness and he gets better in vacation periods. The Thermoactinomyces vulgaris was isolated from the dust accumulated in a ceiling light.

[Frequency of sickle-cell anemia in the population of "Cuatro Bocas," Parroquia Ricaurte, Mara municipality, Zulia state, Venezuela]. / Frecuencia de anemia falciforme en la población de "Cuatro Bocas", Parroquia Ricaurte, Municipio Mara, Estado Zulia, Venezuela.

Isla de Toas is an island on the north of the Maracaibo Lake, it is known in the scientific community, for the high frequency of sickle cell disease, in a population with caucasoid phenotype. The purpose of the present work was to determine the frequency of sickle cell anemia in the population of Cuatro Bocas, situated 35 km from the southwest of Isla de Toas. The town is the center of confluence of a rural population constituted mainly of farmers. The sample consisted of 870 persons of both sexes, aged from 8 months to 66 years. The presence of the sickling phenomenon was determined in all the individuals, and hemoglobin electrophoresis in agarose was performed in all the positive samples. The following results were obtained: fifty-six cases (6.4%), showed drepanocytic changes, and forty-six of them were haemoglobin A/S, 8 were S/S and 2 were S/C. The higher frequency of hemoglobin S was in adolescents and adults. The family backgrounds suggest an insular origin of the sickle cell gene. About 75% of the affected population was ignorant of this condition. The hemoglobin values were lower in the individuals with the sickle cell disease (p < 0.05), than in the normal persons. Iron deficiency in adolescents was suspected because or their low hemoglobin values. The results indicate that the sickle cell gen is expanding to the nearest communities of the Mara county. It is important to consider that the findings of the present work should serve as an alert to the Public Health authorities, and that education of the population is important in order to prevent the spreading of the disease.

Flora fungica en piel lampina / Fungal floral in beardless skin

Se realizo un estudio prospectivo correspondiente a cincuenta pacientes, cuyas edades oscilaron entre catorce y setenta anos, presentando lesiones en piel lisa, compatibles con dermatomicosis. Se realizaron estudios micologicos de las muestras obtenidas, con la finalidad de conocer la flora fungica en piel lampina y la prevalencia de los distintos agentes etiologicos, causantes de dermatomicosis, segun topografia. Para los examenes directos se utilizo HOK al 20%y los aislamientos se llevaron a cabo en Agar Glucosado de Saboraud con Cloramfenicol y Agar Selectivo para Hongos Patogenos. La identificacion fue basada en observacion macroscopica microscopica y pruebas adicionales. Los estudios revelaron: 14%de levaduras pertenecientes al genero Candida, 56%de dermatofitos, no habiendose demostrado el hallazgo del genero Malasezzia. En piel lisa predomino Microsporum canis y Trichopython rubrum, en grandes pliegues lo hicieron Epidemophyton flocccosum y Candida albicans y en pequenos pliegues Trichophyton rubrum coincidiendo esto con otras estadisticas realizadas con mayor numero de casos. Se destaca el aislamiento de Microsporum gypseum como causante de dermatoficia en grandes pliegues

Flora fungica en piel lampina / Fungal floral in beardless skin

Se realizo un estudio prospectivo correspondiente a cincuenta pacientes, cuyas edades oscilaron entre catorce y setenta anos, presentando lesiones en piel lisa, compatibles con dermatomicosis. Se realizaron estudios micologicos de las muestras obtenidas, con la finalidad de conocer la flora fungica en piel lampina y la prevalencia de los distintos agentes etiologicos, causantes de dermatomicosis, segun topografia. Para los examenes directos se utilizo HOK al 20%y los aislamientos se llevaron a cabo en Agar Glucosado de Saboraud con Cloramfenicol y Agar Selectivo para Hongos Patogenos. La identificacion fue basada en observacion macroscopica microscopica y pruebas adicionales. Los estudios revelaron: 14%de levaduras pertenecientes al genero Candida, 56%de dermatofitos, no habiendose demostrado el hallazgo del genero Malasezzia. En piel lisa predomino Microsporum canis y Trichopython rubrum, en grandes pliegues lo hicieron Epidemophyton flocccosum y Candida albicans y en pequenos pliegues Trichophyton rubrum coincidiendo esto con otras estadisticas realizadas con mayor numero de casos. Se destaca el aislamiento de Microsporum gypseum como causante de dermatoficia en grandes pliegues