The second edition of An Introduction to Efficiency and Productivity Analysis is designed to be a general introduction for those who wish to study efficiency and productivity analysis. The book ...provides an accessible, well-written introduction to the four principal methods involved: econometric estimation of average response models, index numbers, data envelopment analysis (DEA), and stochastic frontier analysis (SFA). For each method, a detailed introduction to the basic concepts is presented, numerical examples are provided, and some of the more important extensions to the basic methods are discussed. Of special interest is the systematic use of detailed empirical applications using real-world data throughout the book. In recent years, there have been a number of excellent advance-level books published on performance measurement. This book, however, is the first systematic survey of performance measurement with the express purpose of introducing the field to a wide audience of students, researchers, and practitioners. Indeed, the 2nd Edition maintains its uniqueness: (1) It is a well-written introduction to the field. (2) It outlines, discusses and compares the four principal methods for efficiency and productivity analysis in a well-motivated presentation. (3) It provides detailed advice on computer programs that can be used to implement these performance measurement methods. The book contains computer instructions and output listings for the SHAZAM, LIMDEP, TFPIP, DEAP and FRONTIER computer programs. More extensive listings of data and computer instruction files are available on the book's website: (www.uq.edu.au/economics/cepa/crob2005).
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic ...determination of the two diseases.
Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.
Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).
Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
A key challenge in natural products drug discovery is compound supply. Hundreds of grams of purified material are needed to advance a natural product lead through preclinical development. ...Spliceostatins are polyketide-nonribosomal peptide natural products that bind to the spliceosome, an emerging target in cancer therapy. The wild-type bacterium Burkholderia sp. FERM BP-3421 produces a suite of spliceostatin congeners with varying biological activities and physiological stabilities. Hemiketal compounds such as FR901464 were the first to be described. Due to its improved properties, we were particularly interested in a carboxylic acid precursor analog that was first reported from Burkholderia sp. MSMB 43 and termed thailanstatin A. Inactivation of the iron/α-ketoglutarate-dependent dioxygenase gene fr9P had been shown to block hemiketal biosynthesis. However, a 4-deoxy congener of thailanstatin A was the main product seen in the dioxygenase mutant. We show here that expression of the cytochrome P450 gene fr9R is a metabolic bottle neck, as use of an l-arabinose inducible system led to nearly complete conversion of the 4-deoxy analog to the target molecule. By integrating fermentation media development approaches with biosynthetic engineering, we were able to improve production titers of the target compound >40-fold, going from the starting ~60mg/L to 2.5g/L, and to achieve what is predominantly a single component production profile. These improvements were instrumental in enabling preclinical development of spliceostatin analogs as chemotherapy.
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•Thailanstatin A is an anticancer, bacterial metabolite from the spliceostatin class.•Expression of the cytochrome P450 gene fr9R was shown to be a metabolic bottle neck.•Use of PBAD/araC led to what is predominantly a single component production profile.•Strain engineering and bioprocess development yielded 2.5g/L thailanstatin A.•Pre-clinical development of thailanstatin A as antibody drug conjugates was enabled.
Synthetic approaches to the 2009 new drugs Liu, Kevin K.-C.; Sakya, Subas M.; O’Donnell, Christopher J. ...
Bioorganic & medicinal chemistry,
02/2011, Letnik:
19, Številka:
3
Journal Article
Recenzirano
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into ...molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.
Abstract Background and aims Fetuin-A has a plausible role in the inhibition of arterial calcification, but its association with risk of coronary heart disease (CHD) in the general population is ...unclear. We used two common genetic variants in the fetuin-A gene ( AHSG ) that are strongly associated with circulating fetuin-A levels to investigate the associations with risk of CHD and subclinical cardiovascular measures (intima-media thickness, ankle-arm index, and coronary artery calcification). Methods Genetic variation and fetuin-A levels were assessed in 3299 community-living individuals (2733 Caucasians and 566 African Americans) 65 years of age or older, free of previous cardiovascular disease, who participated in the Cardiovascular Health Study (CHS) in 1992–1993. Results Among Caucasians, both rs2248690 and rs4917 were associated with 12% lower fetuin-A concentrations per minor allele ( P < 0.0001). The hazard ratios (HRs) per minor allele for incident CHD were 1.12 (95% CI: 1.00–1.26) for rs2248690 and 1.02 (0.91–1.14) for rs4917. Using both genotypes as an instrumental variable for measured fetuin-A, the HRs for one standard deviation increase in genetically determined fetuin-A levels on CHD risk were 0.84 (95% CI: 0.70–1.00) for rs2248690 and 0.97 (95% CI: 0.82–1.14) for rs4917, respectively. However, in CHS neither of the genotypes were associated with subclinical cardiovascular measures and when CHS data were meta-analyzed with data from six other prospective studies (totaling 26,702 Caucasian participants and 3295 CHD cases), the meta-analyzed HRs for incident CHD were 1.12 (0.93–1.34) and 1.06 (0.93–1.20) for rs2248690 and rs4917, respectively ( p heterogeneity 0.005 and 0.0048). Conclusion Common variants in the AHSG gene are strongly associated with fetuin-A levels, but their concurrent association with CHD risk in current prospective studies is inconsistent. Further investigation in studies with measured fetuin-A and AHSG variants is needed to clarify the potential causal association of fetuin-A with CHD risk.
A delayed heart rate (HR) recovery after graded exercise testing has been associated with increased all-cause mortality in clinic-based samples. No prior study has examined the association of HR ...recovery after exercise with the incidence of coronary heart disease (CHD) and cardiovascular disease (CVD) events. We evaluated 2,967 Framingham study subjects (1,400 men, mean age 43 years) who were free of CVD and underwent a treadmill exercise test (Bruce protocol) at a routine examination. We examined the relations of HR recovery indexes (decrease in HR from peak exercise) to the incidence of a first CHD or CVD event and all-cause mortality, adjusting for established CVD risk factors. During follow-up (mean 15 years), 214 subjects experienced a CHD event (156 men), 312 developed a CVD event (207 men), and 167 died (105 men). In multivariable models, continuous HR recovery indexes were not associated with the incidence of CHD or CVD events, or with all-cause mortality. However, in models evaluating quintile-based cut points, the top quintile of HR recovery (greatest decline in HR) at 1-minute after exercise was associated with a lower risk of CHD (hazards ratio vs bottom 4 quintiles 0.54, 95% confidence interval CI, 0.32 to 0.93) and CVD (hazards ratio 0.61, 95% CI 0.41 to 0.93), but not all-cause mortality (hazards ratio 0.99, 95% CI 0.60 to 1.62). In our community-based sample, HR recovery indexes were not associated with all-cause mortality. A very rapid HR recovery immediately after exercise was associated with lower risk of CHD and CVD events. These findings should be confirmed in other settings.
Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks ...for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.
Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency > or = 0.10, call rate > or = 80%, Hardy-Weinberg p-value > or = 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).
Associations at p < 10(-3) were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10(-3); lowest p-value, rs6683968, p = 1 x 10(-4)) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.
In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.
Coronary artery calcium (CAC) predicts risk for coronary heart disease (CHD) events and perhaps CAC testing may further stratify risk in individuals at intermediate CHD risk. We sought to determine ...the percentage of participants at intermediate CHD risk who could potentially be reclassified as having a high CHD risk based on the presence of a high CAC score and the prevalence, treatment, and control of CHD risk factors in this group. Framingham Heart Study Offspring and Third Generation cohort participants underwent multidetector computed tomography (n = 3,529, mean age 51 years, 48% women). High CAC was defined as ≥90th age- and gender-specific percentiles based on a healthy reference group or by an absolute modified Agatston score of 100 HU. Prevalence of CHD risk factors (hypertension, hypercholesterolemia, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, smoking, and obesity), their treatment, and control was compared between nondiabetic participants with and without high CAC. Of the 595 participants at intermediate CHD risk, 22% had CAC ≥90th percentile and 39% had CAC ≥100 and could be eligible for reclassification as having a high CHD risk based on the presence of a high CAC score. There were no statistically significant differences in prevalence, treatment, and control of risk factors between those with and without high CAC. In conclusion, prevalence of CHD risk factors did not differ between intermediate-risk participants with and without high CAC. Approximately 25% of intermediate-risk individuals have high CAC scores and may be eligible for reclassification into a higher-risk category.
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