Right Internal Thoracic Artery with an Anteroaortic Course

Coronary artery bypass graft surgery remains the procedure of choice to revascularize patients with complex multivessel coronary artery disease. The left internal thoracic artery and saphenous vein are the most commonly utilized conduits in coronary artery bypass graft surgery. The left internal thoracic artery is widely accepted as the conduit of choice for coronary artery bypass grafting. Accumulated evidence in recent years has demonstrated the superiority of bilateral internal thoracic artery grafting over single internal thoracic artery grafting in terms of event-free survival, freedom from reintervention and survival. The survival benefit seen with bilateral internal thoracic artery grafting has been associated particularly with grafting the myocardium supplied by the left coronary artery system. Many surgical strategies have been tested in order to achieve left-sided myocardial revascularization with bilateral internal thoracic artery grafting. These include directing the right internal thoracic artery through the transverse sinus in a retroaortic course, free graft connected proximally either to the left internal thoracic artery (composite grafting) or to the ascending aorta. Another technical option is in situ right internal thoracic artery to the left anterior descending and left internal thoracic artery to circumflex marginal branches; in this chapter we will comment on this technique

Test bed ion engine development

A test bed ion (TBI) engine was developed to serve as a tool in exploring the limits of electrostatic ion thruster performance. A description of three key ion engine components, the decoupled extraction and amplified current (DE-AC) accelerator system, field enhanced refractory metal (FERM) hollow cathode and divergent line cusp (DLC) discharge chamber, whose designs and operating philosophies differ markedly from conventional thruster technology is given. Significant program achievements were: (1) high current density DE-AC accelerator system operation at low electric field stress with indicated feasibility of a 60 mA/sq cm argon ion beam; (2) reliable FERM cathode start up times of 1 to 2 secs. and demonstrated 35 ampere emission levels; (3) DLC discharge chamber plasma potentials negative of anode potential; and (4) identification of an efficient high plasma density engine operating mode. Using the performance projections of this program and reasonable estimates of other parameter values, a 1.0 Newton thrust ion engine is identified as a realizable technology goal. Calculations show that such an engine, comparable in beam area to a J series 30 cm thruster, could, operating on Xe or Hg, have thruster efficiencies as high as 0.76 and 0.78 respectively, with a 100 eV/ion discharge loss

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

A microcomputer-interfaced continuous flow toxicity test system

While continuous-flow tests for toxicity evaluation are preferable over static tests, their use has been limited due to problems associated with their operation. Fluctuations in toxicant concentrations during exposure periods requires frequent analyses and represent a drawback in conventional diluter systems. To reduce toxicant fluctuations and to maintain suitable water quality during long-term test periods, a low cost microcomputer-interfaced monitoring system (MIMS) was installed on a Benoit type serial diluter. The system monitored flow rates of test solutions and measured a number of water quality parameters.The MIMS system provided up-to-date information on whether the test was progressing well and indicated when diluter maintenance was needed. The MIMS interfaced diluter system performed well in long-term continuous-flow tests with minimal disruption and eliminated experimental failure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26564/1/0000103.pd

Application of tracer techniques to continuous-flow toxicity testing

Frequent toxicant analyses are essential for good quality data in long-term continuous-flow tests. Due to the time consuming and costly chemical analyses, exposure levels are measured at best on a daily basis. These infrequent determinations may not detect variability in toxicant concentrations that could result in test failures. To minimize repetitive testing and improve data quality, a dye tracer method was evaluated. Rhodamine WT was selected as a toxicant tracer because of easy detectability, low toxicity to aquatic organisms, and negligible transformation in the aquatic environment.Results over a 24 h period showed that rhodamine reliably predicted the toxicant (diquat) concentrations with an r value of 0.99. Based upon these data, two replicate long-term tests with and without tracer were carried out exposing fathead minnows Pimephales promelas to diquat (1:1'-ethylene-2:2'-dipiridium dibromide). The test results indicated that the added rhodamine WT did not alter the diquat toxicity to fathead minnows using LC50 and EC50 values for comparisons. From these findings it is concluded that dye tracers are suitable toxicant surrogates. Their use in flow-through tests allow more frequent analyses which result in better data and minimizes experimental failure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26566/1/0000105.pd

Estimation of a single probit line from multiple toxicity test data

LC50 values for the same compound and the same species may vary considerably within a laboratory and between laboratories. These differences are usually attributed to variable test conditions and response of the test organisms to the toxicant. Furthermore, the lack of standardization for aquatic toxicity testing may contribute to the variability in LC50 values.To employ toxicity data for regulatory purposes, it may be useful to report one single LC50 value and its associated confidence interval, instead of several LC50 values for each test substance. To accomplish this, a procedure for combining probit lines from several toxicity tests was developed by modifying the maximum likelihood probit method with inclusion of the technique for parallel line probit analysis. The resulting single probit line from this method is referred to as a "grand probit line' and takes into account separate test results. To ease the calculation a BASIC program was developed for an IBM PC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27381/1/0000411.pd

Dasatinib preferentially induces apoptosis by inhibiting Lyn kinase in nilotinib-resistant chronic myeloid leukemia cell line

Nilotinib is approved for treatment of newly diagnosed chronic myeloid leukemia (CML) and it is shown superiority over imatinib in first-line treatment for patients of CML. In this study, we established a nilotinib-resistant cell line, K562NR, and evaluated the resistance to nilotinib and efficacy of dasatinib. We found activation of Lyn plays a dominant role in survival of the nilotinib-resistant cell line. We found dasatinib induces the apoptosis of nilotinib-resistant cells and inhibits Lyn kinase activity. This novel nilotinib-resistant CML cell line may help to explore novel therapy for CML

Advances in the treatment of chronic myeloid leukemia

Although imatinib is firmly established as an effective therapy for newly diagnosed patients with chronic myeloid leukemia (CML), the field continues to advance on several fronts. In this minireview we cover recent results of second generation tyrosine kinase inhibitors in newly diagnosed patients, investigate the state of strategies to discontinue therapy and report on new small molecule inhibitors to tackle resistant disease, focusing on agents that target the T315I mutant of BCR-ABL. As a result of these advances, standard of care in frontline therapy has started to gravitate toward dasatinib and nilotinib, although more observation is needed to fully support this. Stopping therapy altogether remains a matter of clinical trials, and more must be learned about the mechanisms underlying the persistence of leukemic cells with treatment. However, there is good news for patients with the T315I mutation, as effective drugs such as ponatinib are on their way to regulatory approval. Despite these promising data, accelerated or blastic phase disease remains a challenge, possibly due to BCR-ABL-independent resistance

Characteristics of transposable element exonization within human and mouse

Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs) revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.Comment: 11 pages, 4 figure