The synthesis of a library of tetrahydro-β-carboline-containing compounds in milligram quantities is described. Among the unique heterocyclic frameworks are twelve tetrahydroindolizinoindoles, six ...tetrahydrocyclobutanindoloquinolizinones and three tetrahydrocyclopentenoneindolizinoindolones. These compounds were selected from a virtual combinatorial library of 11,478 compounds. Physical chemical properties were calculated and most of them are in accordance with Lipinski's rules. Virtual docking and ligand-based target evaluations were performed for the β-carboline library compounds and selected synthetic intermediates to assess the therapeutic potential of these small organic molecules. These compounds have been deposited into the NIH Molecular Repository (MLSMR) and may target proteins such as histone deacetylase 4, endothelial nitric oxide synthase, 5-hydroxytryptamine receptor 6 and mitogen-activated protein kinase 1. These in silico screening results aim to add value to the β-carboline library of compounds for those interested in probes of these targets.
Aminoacridines have a long history in the drug and dye industries and display a wide range of biological and physical properties. Despite the historical relevance of 9-aminoacridines, there have been ...few studies investigating their stability. 9-Aminoacridines are known to hydrolyze at the C9−N15 bond, yielding acridones. In this study, the pH-dependent hydrolysis rates of a series of 9-substituted aminoacridines are investigated. In addition, ground-state physical properties of the compounds are determined using ab initio quantum mechanics calculations to gain insight into the forces that drive hydrolysis. An analysis of the bond orders, bond dissociation energies, and conformational energies show that the rate of hydrolysis depends on two main factors: delocalization across the C9−N15 bond and steric effects. The computational results are applied to explain the change in experimental rates of hydrolysis going from primary to secondary and to tertiary substituted 9-aminoacridines. In the case of tertiary substituted amines, the calculations indicate the C9−N15 bond is forced into a more gauche-like conformation, greatly diminishing delocalization (as shown by reductions in bond orders and bond energy), which leads to rapid hydrolysis. A model of intramolecular hydrogen bonding is also presented, which explains the increased rate of hydrolysis observed for highly substituted compounds under acidic conditions.
To determine the incidence of bacteremia in dairy cows with naturally occurring acute coliform mastitis (ACM) with a wide range of disease severity.
Cohort study.
144 dairy cows with ACM from 6 ...herds.
Cows were examined at time of identification of ACM (time 0) and classified as having mild, moderate, or severe mastitis on the basis of rectal temperature, hydration status, rumen contraction rate, and attitude. Cows were reexamined at 24 or 48 hours. Bacteriologic culturing of milk and blood (30 ml), CBC, and serum biochemical analysis were performed at each time point. Appropriate samples were obtained at a single point from herdmates without mastitis (controls) that were closely matched for lactation number and days since parturition. Blood culture results were compared among severity groups and controls by use of chi2 tests, as was outcome of an ACM episode for cows grouped by blood bacterial isolates.
Bacteria were isolated from 52 blood samples from 46 of 144 (32%) cows with ACM, which was significantly more than control cows (11/156; 7.1%). Group-1 isolates (Escherichia coli, Pasteurella multocida, Mannheimia haemolytica, Klebsiella pneumoniae, Enterobacter agglomerans, and Salmonella enterica serotype Typhimurium) were identified in 20 of 144 (14%) cows with ACM and 0 of 156 control cows. Group-1 isolates were identified in 4.3, 9.1, and 42% of cows classified as having mild, moderate, and severe ACM, respectively. Escherichia coli and K pneumoniae milk and blood isolates obtained from the same cow were of the same genotype. Bacillus spp were identified in 21 of 144 (15%) cows with ACM, which was significantly more than control cows (3/156; 1.9%). Thirty-five percent of cows with a group-1 isolate died during the mastitis episode.
Results suggest that bacteremia develops in a substantial proportion of cows with ACM. Classification of severity of disease is important for establishment of effective treatment protocols; parenteral antimicrobial treatment may be indicated in cows with ACM.
Given the importance of financial intermediation and the rise of globalization, there is little prior research on how national preferences for financial intermediation (markets versus institutions) ...are determined by cultural, legal, and other national characteristics. Using panel analysis for data on a recent 8-year period for 30 countries, this paper documents that national preferences for market financing increase with political stability, societal openness, economic inequality, and equity market concentration, and decreases with regulatory quality and ambiguity aversion. We confirm with robustness tests that our result for regulatory quality is independent of differences in national wealth and that our result for political stability is independent of both wealth and political legitimacy. These results should be of much interest to managers, scholars, regulators, and policy makers.
While it is clear that some countries are bank oriented and others rely more on equity financing, there is little research on the degree to which the national architecture for financial ...intermediation is determined by legal, cultural, and other national characteristics. Using panel analysis of data for a recent eleven-year period for nineteen major European countries, this paper documents that the architecture of financial intermediation is influenced by national cultural, political, and economic factors. Specifically, we provide robust evidence that a greater predilection for market financing over bank financing is associated with higher levels of power distance, concentration in equity markets, control of corruption, efficiency of debt enforcement; and the adoption of the euro. Lower predilection for equity financing is associated with an English legal origin, greater uncertainty avoidance, and greater political legitimacy. Our results should be of great interest to managers and policy makers and to scholars interested in the relationship of culture, political economy, and financial intermediation.
Background.
The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic ...sequencing is critically important.
Methods.
A prospective clinical study was conducted on 100 patients with diverse‐histology, rare, or poor‐prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)‐certified, comprehensive genomic profiling assay (FoundationOne), using formalin‐fixed, paraffin‐embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board.
Results.
Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen‐activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol‐4,5‐bisphosphate 3‐kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing.
Conclusion.
Use of targeted next‐generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor‐prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early‐phase clinical trials and targeted agents may increase actionability.
Implications for Practice:
Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next‐generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.
To study the frequency with which targeted tumor sequencing results will lead to implemented change in care, this study assessed tumors from 100 patients for utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations.
PDF
