A randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density.

PURPOSE: Obesity is a known risk factor for post-menopausal breast cancer and may increase risk for triple negative breast cancer in premenopausal women. Intervention strategies are clearly needed to reduce obesity-associated breast cancer risk. METHODS: We conducted a Phase II double-blind, randomized, placebo-controlled trial of metformin in overweight/obese premenopausal women with components of metabolic syndrome to assess the potential of metformin for primary breast cancer prevention. Eligible participants were randomized to receive metformin (850 mg BID, n = 76) or placebo (n = 75) for 12 months. Outcomes included breast density, assessed by fat/water MRI with change in percent breast density as the primary endpoint, anthropometric measures, and intervention feasibility. RESULTS: Seventy-six percent in the metformin arm and 83% in the placebo arm (p = 0.182) completed the 12-month intervention. Adherence to study agent was high with more than 80% of participants taking ≥ 80% assigned pills. The most common adverse events reported in the metformin arm were gastrointestinal in nature and subsided over time. Compared to placebo, metformin intervention led to a significant reduction in waist circumference (p < 0.001) and waist-to-hip ratio (p = 0.019). Compared to placebo, metformin did not change percent breast density and dense breast volume but led to a numerical but not significant decrease in non-dense breast volume (p = 0.070). CONCLUSION: We conclude that metformin intervention resulted in favorable changes in anthropometric measures of adiposity and a borderline decrease in non-dense breast volume in women with metabolic dysregulation. More research is needed to understand the impact of metformin on breast cancer risk reduction. TRIAL REGISTRATION: ClinicalTrials.gov NCT02028221. Registered January 7, 2014, https://clinicaltrials.gov/ct2/show/NCT02028221.

Mycoplasma hyopneumoniae Surveillance in Pig Populations: Establishing Sampling Guidelines for Detection in Growing Pigs.

Antemortem detection of Mycoplasma hyopneumoniae infection in swine production systems has relied on antibody testing, but the availability of tests based on DNA detection and novel diagnostic specimens, e.g., tracheal swabs and oral fluids, has the potential to improve M. hyopneumoniae surveillance. A field study was performed over a 14-week period during which 10 pigs in one pen at the center of a room with 1,250 6-week-old pigs housed in 46 pens were intratracheally inoculated with M. hyopneumoniae Thereafter, one tracheal sample, four serum samples, and one oral fluid sample were collected from every pen at 2-week intervals. Tracheal and oral fluid samples were tested for M. hyopneumoniae DNA and serum samples for M. hyopneumoniae antibody. Test results were modeled using a hierarchical Bayesian model, based on a latent spatial piecewise exponential survival model, to estimate the probability of detection by within-pen prevalence, number of positive pens in the barn, sample allocation, sample size, and sample type over time. Analysis showed that tracheal samples provided the earliest detection, especially at large sample sizes. While serum samples are more commonly collected and are less expensive to test, high probability of detection estimates were only obtained 30 days postexposure at large sample sizes. In all scenarios, probability of detection estimates for oral fluids within 30 days were significantly lower than those for tracheal and serum samples. Ultimately, the choice of specimen type, sample number, and assay will depend on testing objectives and economics, but the estimates provided here will assist in the design of M. hyopneumoniae surveillance and monitoring programs for different situations.

TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors.

The anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.

Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors.

The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and ∼70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ∼10 months. Kinase domain mutations are detectable in 25% to 37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications.

Correlación entre nivel de conocimientos sobre posturas odontológicas ergonómicas, posturas de trabajo y dolor postural según zonas de respuesta, durante las prácticas clínicas de estudiantes en una Facultad de Estomatología / Correlation between knowledge on dental ergonomics postures, positions of work and postural pain according to response of anatomic zones during clinical practices of dental students

En el presente estudio se investigaron los aspectos ergonómicos y dolor postural aplicados a la actividad odontológica, además de proporcionar información en busca de una buena calidad de vida y capacidad productiva en el campo de la salud ocupacional del Odontólogo. El objetivo fue determinar la correlación entre nivel de conocimientos sobre posturas odontológicas ergonómicas, posturas de trabajo y presencia de dolor postural según zonas anatómicas de respuesta durante las prácticas clínicas del estudiante del quinto año de la Facultad de Estomatología de la Universidad Peruana Cayetano Heredia. Se utilizaron: cuestionario de conocimientos en relación a posturas de trabajo ergonómicas, lista de verificación postural que comprobó la postura de trabajo clínico del estudiante, apoyada por fotografías digitales analizadas por medio de los programas de computación Autocad y Corel Draw. La Escala Analógica Visual (EAV) de percepción e intensidad del dolor postural según zonas anatómicas de respuesta. Para el análisis estadístico se utilizó el coeficiente de correlación de rangos de Spearman. En cuanto a las observaciones posturales de trabajo odontológico, sólo el 22,3 por ciento fueron correctas. Del universo de preguntas sobre posturas odontológicas, sólo 90 (37,5 por ciento) fueron respondidas correctamente. La percepción de dolor postural fue mayor en la zona cervical (75 por ciento) y menor en antebrazos (15 por ciento). Se encontró correlación entre nivel de conocimientos sobre posturas odontológicas ergonómicas y la aplicación de posturas de trabajo odontológico. Se concluye que existe relación directa entre las variables estudiadas.

Influencia de la ingestión de fibra contenida en la Cañihua (Chenopodium Pallidicaule Aellen) sobre el Lipidograma de pacientes hipercolesterolemicos primarios

Con el efecto de evaluar el efecto de la cañihua, planta oriunda del altiplano peruano, sobre los niveles de lípidos sanguíneos sometímos a 20 pacientes voluntarios (8 varones, 12 mujeres, entre 26 y 65 años) con hipercolesterolemia primaria a suplementos dietarios de 100 g. de cañihua diarios durante 28 días. Se determinaron los niveles de Colesterol total (Ct), HDL-C, LDL-C, Triglicéridos (TG) y porcentaje de Ct unido a HDL-C (por ciento Ct-HDL) 14 días antes del inicio del estudio, al inicio, 7 y 28 días después. Los resultados fueron procesados por análisis de varianza de bloques randomizados y prueba t de Student pareada con ajustes de Bonferroni, técnicas de regresión y correlación lineal simple y múltiple permitieron establecer asociación entre variables y se determinó el riesgo cardiovascular en el programa de computadora CYBERLOG 1:3. Los pesos de los pacientes no difirieron significativamente durante el estudio, se observó una disminución altamente significativa el Ct y LDL-C, aumento altamente significativo del HDL-C y por ciento Ct-HDL, mientras los TG permanecieron sin variación significativa (p>0.05). Los efectos fueron más pronunciados en hombres que en mujeres y más significativos en personas con mayor edad y Ct (Coeficiente Correl. = 0.1299), el riesgo cardiovascular de acuerdo a los criterios de Framinghan disminuyó en ambos sexos. Estos resultados sugieren que el consumo de cañihuaco puede ser una alternativa económica y útil en el manejo de la hipercolesterolemias, ejerciendo un efecto protector al incrementar de modo altamente significativo los niveles de HDL-C. El efecto observado fue evidente ya desde la primera semana de consumo aunque levemente, lo que puede considerarse como un efecto más rápido sobre los lípidos sanguíneos que el que cabría esperar de los fármacos convencionales utilizados para este fin