Characterisation of high throughput screening outputs for small molecule degrader discovery.

Targeted protein degradation is an important mechanism carried out by the cellular machinery, one that is gaining momentum as an exploitable strategy for the development of drug-like compounds. Molecules which are able to induce proximity between elusive therapeutic targets of interest and E3 ligases which subsequently leads to proteasomal degradation of the target are beginning to decrease the percentage of the human proteome described as undruggable. Therefore, having the ability to screen for, and understand the mechanism of, such molecules is becoming an increasingly attractive scientific focus. We have established a number of cascade experiments including cell-based assays and orthogonal triage steps to provide annotation to the selectivity and mechanism of action for compounds identified as putative degraders from a primary high throughput screen against a high value oncology target. We will describe our current position, using PROTACs as proof-of-concept, on the analysis of these novel outputs and highlight challenges encountered.

Utility of social media and crowd-sourced data for pharmacovigilance: a scoping review protocol

: Adverse events associated with medications are under-reported in postmarketing surveillance systems. A systematic review of published data from 37 studies worldwide (including Canada) found the median under-reporting rate of adverse events to be 94% in spontaneous reporting systems. This scoping review aims to assess the utility of social media and crowd-sourced data to detect and monitor adverse events related to health products including pharmaceuticals, medical devices, biologics and natural health products.

Disposición del conducto dentario inferior en el cuerpo mandibular: estudio anatómico y tomográfico / Location of the inferior dental canal within the mandibular body: anatomical and tomographic study

El objetivo del presente estudio fue determinar la distancia entre el conducto dentario inferior (CDI) y las tablas óseas lingual (TL), vestibular (TV) y basal (RB) en cuatro sectores del cuerpo mandibular. Se utilizaron diez mandíbulas que presentaban la región premolar y molar edéntula. Se evaluaron a través de tomografía espiral convencional (Cranex TOME multifuctional unit, Soredex, Finlandia) y en examen visual directo posterior a la osteotomía. Se realizaron mediciones desde el CDI hasta TL, TV y RB; a nivel del segundo premolar, primer molar, segunda molar y tercer molar. Los resultados obtenidos se evaluaron con las pruebas ANOVA, Kolmogorov-Smirnov y test de Levene que demostraron homogeneidad entre las medidas de los especimenes y las tomografías (p>0,05). Para referir las medidas se utilizó ANOVA y Kruskal-Wallis donde se encontró que el diámetro del CDI y la distancia hacia la TL eran constantes en los cuatro sectores del cuerpo mandibular (p>0,05). El diámetro del CDI presentó un rango de 2,3 mm a 2,6 mm y la distancia a TL de 2,5 mm a 2,8 mm. Las distancias a RB y TV presentaban diferencias estadísticamente significativas (p<0,05). El presente estudio demuestra que el diámetro del CDI en el cuerpo mandibular tiende ha ser constante y el CDI recorre el cuerpo mandibular con mayor proximidad a la TL.

The aim of the current study was determine the distance between mandibular canal (CDI) and the lingual (TL), labial (V) and basal cortical bone (RB) in four mandibular body areas. Ten mandibular bones showing premolar and molar edentulous region were used. They were assessedby Conventional Spiral Tomography (Cranex TOME multifuctional unit, Soredex, Finland) and a direct visual exam following osteotomy. Measures were made from CDI to TL, TV and RB? at second premolar, first molar, second molar and third molar level. The results were assessed by ANOVA, Kolmogorov-Smirnov and Levene tests that showed homogeneity among specimens measures and Tomographies (p>0.05). ANOVA and Kruskal-Wallis were used to refer measures where CDI diameter and the distance to TL were constant in the four mandibular body areas (p>0.05). CDI diameter showed a rank from 2.3mm to 2.6mm and a distance of 2.5mm a 2.8mm to TL. The distances to RB and TV showed statistically significant differences (p<0.05). The current study shows that CDI diameter remains constant and that CDI runs throught the mandibular body close to the TL.

Profile of health-related quality of life outcomes after liver transplantation: univariate effects and multivariate models.

AIM: To test the effects of pre- and post-transplant clinical covariates on post-transplant health-related quality of life (HRQOL) score profiles in liver transplant recipients. MATERIAL AND METHODS: HRQOL was measured before and after transplantation using the SF-36 Health Survey. Clinical data [diagnosis, model of end-stage liver disease (MELD) score, post-transplant rejection and infection episodes], pre-transplant functional performance (FP), and demographics were collected. Multivariate models for the eight SF-36 scales and two summary components were developed using multiple regression. Discriminant analysis was used to test whether the score profiles differentiated among recipients with and without hepatitis C virus (HCV) infection. RESULTS: 104 adults reported pre- and post-transplant HRQOL. Time post-transplant averaged 9+/-8 months (range 1-39). Scores on all SF-36 measures improved from pre- to post-transplant (p<0.001), and 7 of 10 models were significant (p<0.05). After controlling for pre-transplant HRQOL and time post-transplant, HCV infection had a negative effect on the role physical, bodily pain, and role emotional scales. History of a rejection episode had a negative effect on the bodily pain and vitality scales. MELD scores > or = 18 had a positive effect on the role physical scale. Pre-transplant FP and post-transplant infection episodes did not affect post-transplant HRQOL. HCV infection had a significant effect on the SF-36 score profile (canonical correlation=0.50; p<0.001). CONCLUSIONS: Pre-transplant HCV infection, MELD score, and post-transplant rejection episodes have significant independent effects on HRQOL after liver transplantation. Their specific effects vary among the individual SF-36 scales, and HRQOL score profiles differ among HCV+ and HCV- recipients.

Disposición del conducto dentario inferior en el cuerpo mandibular: estudio anatómico y tomográfico / Inferior alveolar nerve disposition in the mandibular body: an anatomical and tomographic study

El objetivo del presente estudio fue determinar la distancia entre el conducto dentario inferior (CDI) y las tablas óseas lingual (TL), vestibular (TV) y basal (RB) en cuatro sectores del cuerpo mandibular. Se utilizaron diez mandíbulas que presentaban la región premolar y molar edéntula. Se evaluaron mediante tomografía espiral convencional (Cranex TOME multifuctional unit, Soredex, Finlandia) y examen visual directo, posterior a la osteotomía. Se realizaron mediciones desde el CDI hasta TL, TV y RB; a nivel del segundo premolar, primer molar, segunda molar y tercer molar. Los resultados obtenidos se evaluaron estadísticamente con las pruebas Kolmogorov-Smirnov, ANOVA y test de Levene; las cuales demostraron homogeneidad y distribución normal entre las medidas de los especímenes y las tomografías (p>0.05). Al analizar las medidas mediante ANOVA y Kruskal-Wallis se encontró que el diámetro del CDI y la distancia hacia la TL eran constantes en los cuatro sectores del cuerpo mandibular (p>0.05). El diámetro del CDI presentó un rango de 2.3mm a 2.6mm y la distancia a TL de 2.5mm a 2.8mm. Las distancias a RB y TV presentaban diferencias estadísticamente significativas (p<0.05). El presente estudio demuestra que el diámetro del CDI en el cuerpo mandibular es constante y recorre el cuerpo mandibular con mayor proximidad a la TL.

The aim of the current study was determine the distance between mandibular canal (CDI) and lingual (TL), labial (V) and basal cortical bone (RB) in four mandibular body areas. Ten mandibular bones showing premolar and molar edentulous region was used. They were assessed by Conventional Spiral Tomography (Cranex TOME multifuctional unit, Soredex, Finland) and a direct visual exam following osteotomy. Measures were made from CDI to TL, TV and RB; at second premolar, first molar, second molar and third molar level. Gotten results were assessed by ANOVA, Kolmogorov-Smirnov and Levene tests that showed homogeneity among specimens measures and Tomographies (p>0.05). ANOVA and Kruskal-Wallis were used to refer measures where CDI diameter and the distance to TL were constant in the four mandibular body areas (p>0.05). CDI diameter showed a rank from 2.3mm to 2.6mm and a distance of 2.5mm a 2.8mm to TL. The distances to RB and TV showed statistically significant differences (p<0.05). The current study shows that CDI diameter remains constant and CDI runs mandibular body near to TL.

Contributions of the sympathetic nervous system, glutathione, body mass and gender to blood pressure increase with normal aging: influence of heredity.

Body mass and sympathetic activity increase with aging and might underlie blood pressure (BP) elevation. Increased body mass index (BMI) may elevate BP by increasing sympathetic activity. Glutathione (GSH) can decrease BP, and declines with aging. We measured systolic (SBP) and diastolic BP, BMI, plasma (NE(pl)) and urine norepinephrine (NEu), and plasma GSH in n=204 twins across the age spectrum. BP correlated directly with BMI, NEpl, and NEu, but inversely with GSH. Age correlated with BP, BMI, NEpl, and NEu. BP, BMI, NEpl, and NEu were higher in older subjects than younger subjects, whereas GSH was lower with aging. In older subjects with high (above median) NEpl, SBP was 8 mmHg higher than in those of comparable age with low NE. In younger subjects with high GSH, BP was significantly lower than in younger subjects having low GSH. NEu was significantly reduced in young high-BMI subjects vs young low-BMI subjects. The heritability (h2) of NEpl, NEu, and GSH ranged from approximately 50 to approximately 70%, and these biochemical quantities were considerably more heritable than BP. We conclude that increases in sympathetic activity contribute to aging-induced SBP elevations, especially in older females. GSH reductions apparently participate in aging-induced BP elevations, most strongly in males. BMI increases contribute to BP elevations, particularly in younger subjects. BMI elevations apparently raise BP mainly by peripheral mechanisms, with generally little sympathetic activation. Substantial h(2) for plasma GSH, NE, and urine NE suggests that such traits may be useful 'intermediate phenotypes' in the search for genetic determinants of BP.