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Gottlieb H.E.,Bar - Ilan University | Graczyk-Millbrandt G.,GSK | Inglis G.G.A.,Medicines Research Center | Nudelman A.,Bar - Ilan University | And 5 more authors.
Green Chemistry | Year: 2016

Residual solvents often appear as nuisance signals in experimental NMR spectra, and many chemists turn to well-known literature sources to quickly identify such peaks. While these publications are very useful, they do not currently include many solvents exemplified in green chemistry-related literature. This work provides a single compiled reference for NMR chemical shifts of 80 solvents in each of 6 deuterated NMR solvents. The overall green chemistry assessments, as reached via the methodology of the GSK Solvent Sustainability Guide, are displayed on these charts. ©2016 The Royal Society of Chemistry.

Amonkar M.M.,1250 South Collegeville Road | Chastek B.,Health Economic and Outcomes Research | Samant N.,Health Economic and Outcomes Research | Teitelbaum A.,Medical and Scientific Affairs
Journal of Medical Economics | Year: 2011

Background: Squamous cell carcinoma of the head and neck (SCCHN) places a high burden on society and poses complex challenges to healthcare providers. Methods: Retrospective claims-based analysis of commercially insured patients identified between 01-31-04 and 12-31-07 with diagnostic evidence of cancer of the lip, tongue, oral cavity, pharynx, or larynx who underwent surgical resection during identification period. Outcomes included treatment patterns, healthcare utilization, and costs. All study variables were analyzed descriptively. Results: Among the 1104 patients in the final study sample, 71.9% were male, with mean age 56.6 years. On average, patients were followed for 830 days (range of mean days: 805 for lip or tongue cancer to 847 for pharyngeal cancer). About half received radiation therapy during follow-up, whereas only 16.2% received chemotherapy. Patients with pharyngeal cancer were most likely to undergo chemotherapy. After their index surgery, 57.9% of patients had ≥1 inpatient stay, 44.9% had ≥1 ER visit, and all had ≥1 ambulatory visit. The percentage with ≥1 inpatient stay post-index was highest among patients with pharyngeal cancer (73.0%) and lowest in the laryngeal cancer cohort (49.5%). Mean number of hospitalized days, ER visits, and ambulatory visits was 0.45, 0.69, and 27.4, respectively, per-patient per-year. Overall, patients incurred ∼$94 million in cost following index surgery ($85,000 per-person, on average). Mean total healthcare cost was $34,450 per-patient per-year, the bulk of which comprised medical expenses ($32,401). The highest mean healthcare cost was incurred by the pharyngeal cancer cohort ($40,214). Conclusions: Patients with resected SCCHN incur substantial healthcare costs and have high utilization rates. Results of this analysis are primarily applicable to resected SCCHN in a managed-care setting, and therefore may not be generalizable to the entire US population. Furthermore, disease stage is an important factor impacting outcomes, but these analyses did not stratify patients according to disease stage. © 2011 Informa UK Ltd All rights reserved.

Disantostefano R.L.,Moore Research | Hinds D.,1250 South Collegeville Road | Van Le H.,Moore Research | Van Le H.,Parexel International | And 2 more authors.
Respiratory Medicine | Year: 2016

Background Current evidence suggests that blood eosinophil levels (Eos) are associated with chronic obstructive pulmonary disease (COPD) treatment response and natural history. This analysis investigated the relationship between Eos levels and clinical characteristics in a representative cohort of US subjects with spirometry-defined COPD. Methods Cross-sectional data from the National Health And Nutrition Examination Survey (NHANES 2007-2010) of subjects ≥40 years with spirometry-defined COPD and Eos data (n = 948) were analyzed. Differences in clinical characteristics by Eos level (≤2%, >2%) were compared using chi-square tests. Characteristics associated with Eos >2% were identified using multivariate logistic regression modeling. Characteristics associated with Eos >2% among subjects with normal lung function, plus other cut-points among the COPD population, were evaluated post hoc. Findings Most participants had Eos >2%; 70.7% with spirometry-defined COPD and 65.5% with normal lung function. Older age, male gender, and severe current asthma were significantly associated with Eos >2% in COPD subjects. The Eos ≤2% COPD group had higher reported rates of previous heart attack and anemia. Among participants with normal lung function, Eos >2% was associated with being male, being overweight/obese, older age, hay fever, and congestive heart failure. Interpretation In this large US-based cohort, Eos >2% was prevalent in participants with COPD and normal lung function. Among participants with COPD, Eos >2% was associated with specific characteristics including lower rates of some co-morbidities; however, the clinical implications and relationships between Eos levels, COPD mechanisms, and risk of outcomes require further evaluation. © 2016 The Authors.

Adams J.P.,Medicines Research Center | Alder C.M.,Medicines Research Center | Andrews I.,Medicines Research Center | Bullion A.M.,GSK | And 10 more authors.
Green Chemistry | Year: 2013

Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations of atom efficiency, stoichiometry, work-up and other issues. Guides covering alkene reduction, amide formation, C-H bromination, C-H chlorination, deoxychlorination, epoxidation, ester formation, ether formation, fluorination, iodination, ketone reduction, nitro reduction, oxidation of alcohols to aldehydes and ketones, reductive amination and sulfur oxidation are shared, with an explanation of the methodology behind their generation. © 2013 The Royal Society of Chemistry.

Ma J.,Glaxosmithkline | Martin J.D.,1250 South Collegeville Road | Xue Y.,Glaxosmithkline | Lor L.A.,1250 South Collegeville Road | And 7 more authors.
Archives of Biochemistry and Biophysics | Year: 2010

USP7, also known as the hepes simplex virus associated ubiquitin-specific protease (HAUSP), deubiquitinates both mdm2 and p53, and plays an important role in regulating the level and activity of p53. Here, we report that deletion of the TRAF-like domain at the N-terminus of USP7, previously reported to contain the mdm2/p53 binding site, has no effect on USP7 mediated deubiquitination of Ubn-mdm2 and Ubn-p53. Amino acids 208-1102 were identified to be the minimal length of USP7 that retains proteolytic activity, similar to full length enzyme, towards not only a truncated model substrate Ub-AFC, but also Ubn-mdm2, Ubn-p53. In contrast, the catalytic domain of USP7 (amino acids 208-560) has 50-700 fold less proteolytic activity towards different substrates. Moreover, inhibition of the catalytic domain of USP7 by Ubal is also different from the full length or TRAF-like domain deleted proteins. Using glutathione pull-down methods, we demonstrate that the C-terminal domain of USP7 contains additional binding sites, a.a. 801-1050 and a.a. 880-1050 for mdm2 and p53, respectively. The additional USP7 binding site on mdm2 is mapped to be the C-terminal RING finger domain (a.a. 425-491). We propose that the C-terminal domain of USP7 is responsible for maintaining the active conformation for catalysis and inhibitor binding, and contains the prime side of the proteolytic active site. © 2010 Elsevier Inc.

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