OncoLog Volume 46, Number 05, May 2001

Antiangiogenic Agents: Changing the Nature of Cancer Treatment DiaLog: Angiogenesis Research: Looking for New Ways to Measure Success, by Roy S. Herbst, MD, PhD, Assistant Professor, Department of Thoracic/Head and Neck Medical Oncology House Call: Overcome Fears of Cancer Recurrence by Taking Action Recognition Spurs Prevention of Osteoporosis in Patients with Cancer Protocols: Clinical Trials of Antiangiogenic Agentshttps://openworks.mdanderson.org/oncolog/1097/thumbnail.jp

Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin

Warfarin (Coumadin) is a potent drug that when used judiciously and monitored closely, leads to substantial reductions in morbidity and mortality from thromboembolic events. However, even with careful monitoring, initiation of warfarin dosing is associated with highly variable responses between individuals and challenges achieving and maintaining levels within the narrow therapeutic range that can lead to adverse drug events. Variants of two genes, CYP2C9 and VKORC1, account for 30 -50% of the variability in dosing of warfarin; thus, many believe that testing of these genes will aid in warfarin dosing recommendations. Evidence about this test is evolving rapidly, as is its translation into clinical practice. In an effort to address this situation, a multidisciplinary expert group was organized in November 2006 to evaluate the role of CYP2C9 and VKORC1 testing in altering warfarin-related therapeutic goals and reduction of adverse drug events. A recently completed Rapid-ACCE (Analytical, Clinical Validity, Clinical Utility, and Ethical, Legal, and Social Implications) Review, commissioned to inform this work group, was the foundation for this analysis. From this effort, specific recommendations for the appropriate use of CYP2C9 and VKORC1 testing were developed and are presented here. The group determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin. However, there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients. Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing. Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in There is perhaps no drug whose therapeutic range is functionally as narrow as that of warfarin. Warfarin has a very large marketplace with over 30 million prescriptions in the United States in 2004, including up to a million new patients initiated on therapy each year. Although effective in reducing thrombotic events, warfarin's use is associated with 800 reports to the From th

Evaluation of Errors Associated with Cutting-Induced Plasticity in Residual Stress Measurements Using the Contour Method

Cutting-induced plasticity can lead to elevated uncertainties in residual stress measurements made by the contour method. In this study plasticity-induced stress errors are numerically evaluated for a benchmark edge-welded beam to understand the underlying mechanism. Welding and cutting are sequentially simulated by finite element models which have been validated by previous experimental results. It is found that a cutting direction normal to the symmetry plane of the residual stress distribution can lead to a substantially asymmetrical back-calculated stress distribution, owing to cutting-induced plasticity. In general, the stresses at sample edges are most susceptible to error, particularly when the sample is restrained during cutting. Inadequate clamping (far from the plane of cut) can lead to highly concentrated plastic deformation in local regions, and consequently the back-calculated stresses have exceptionally high values and gradients at these locations. Furthermore, the overall stress distribution is skewed towards the end-of-cut side. Adequate clamping (close to the plane of cut) minimises errors in back-calculated stress which becomes insensitive to the cutting direction. For minimal constraint (i.e. solely preventing rigid body motion), the plastic deformation is relatively smoothly distributed, and an optimal cutting direction (i.e. cutting from the base material towards the weld region in a direction that falls within the residual stress symmetry plane) is identified by evaluating the magnitude of stress errors. These findings suggest that cutting process information is important for the evaluation of potential plasticity-induced errors in contour method results, and that the cutting direction and clamping strategy can be optimised with an understanding of their effects on plasticity and hence the back-calculated stresses

Investigation on the direct and bystander effects in HeLa cells exposed to very low α-radiation using electrical impedance measurement

The impact of radiation-induced bystander effect (RIBE) is still not well understood in radiotherapy. RIBEs are biological effects expressed by nonirradiated cells near or far from the irradiated cells. Most radiological studies on cancer cells have been based on biochemical characterization. However, biophysical investigation with label-free techniques to analyze and compare the direct irradiation effect and RIBE has lagged. In this work, we employed an electrical cell-indium tin oxide (ITO) substrate impedance system (ECIIS) as a bioimpedance sensor to evaluate the HeLa cells’ response. The bioimpedance of untreated/nonirradiated HeLa (N-HeLa) cells, α-particle (Am-241)-irradiated HeLa (I-HeLa) cells, and bystander HeLa (B-HeLa) cells exposed to media from I-HeLa cells was monitored with a sampling interval of 8 s over a period of 24 h. Also, we imaged the cells at times where impedance changes were observed. Different radiation doses (0.5 cGy, 1.2 cGy, and 1.7 cGy) were used to investigate I-HeLa and B-HeLa cells’ radiation-dose-dependence. By analyzing the changes in absolute impedance and cell size/number with time, compared to N-HeLa cells, B-HeLa cells mimicked the I-HeLa cells’ damage and modification of proliferation rate. Contrary to the irradiated cells, the bystander cells’ damage rate and proliferation rate enhancements have an inverse radiation-dose-response. Also, we report multiple RIBEs in HeLa cells in a single measurement and provide crucial insights into the RIBE mechanism without any labeling procedure. Unambiguously, our results have shown that the time-dependent control of RIBE is important during α-radiation-based radiotherapy of HeLa cells

Revisiting the Glick-Rogoff Current Account Model: An Application to the Current Accounts of BRICS Countries

Understanding what drives the changes in current accounts is one of the most important macroeconomic issues for developing countries. Excessive surpluses in current accounts can trigger trade wars, and excessive deficits in current accounts can, on the other hand, induce currency crises. The Glick-Rogoff (1995, Journal of Monetary Economics) model, which emphasizes productivity shocks at home and in the world, fit well with developed economies in the 1970s and 1980s. However, the Glick-Rogoff model fits poorly when it is applied to fast-growing BRICS countries for the period including the global financial crisis. We conclude that different mechanisms of current accounts work for developed and developing countries

Nonthermal Emission from Star-Forming Galaxies

The detections of high-energy gamma-ray emission from the nearby starburst galaxies M82 & NGC253, and other local group galaxies, broaden our knowledge of star-driven nonthermal processes and phenomena in non-AGN star-forming galaxies. We review basic aspects of the related processes and their modeling in starburst galaxies. Since these processes involve both energetic electrons and protons accelerated by SN shocks, their respective radiative yields can be used to explore the SN-particle-radiation connection. Specifically, the relation between SN activity, energetic particles, and their radiative yields, is assessed through respective measures of the particle energy density in several star-forming galaxies. The deduced energy densities range from O(0.1) eV/cm^3 in very quiet environments to O(100) eV/cm^3 in regions with very high star-formation rates.Comment: 17 pages, 5 figures, to be published in Astrophysics and Space Science Proceeding

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

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Acyl-Protein Thioesterase 2 Catalizes the Deacylation of Peripheral Membrane-Associated GAP-43

An acylation/deacylation cycle is necessary to maintain the steady-state subcellular distribution and biological activity of S-acylated peripheral proteins. Despite the progress that has been made in identifying and characterizing palmitoyltransferases (PATs), much less is known about the thioesterases involved in protein deacylation. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Using fluorescent fusion constructs, we measured in vivo the rate of deacylation of GAP-43 and its single acylated mutants in Chinese hamster ovary (CHO)-K1 and human HeLa cells. Biochemical and live cell imaging experiments demonstrated that single acylated mutants were completely deacylated with similar kinetic in both cell types. By RT-PCR we observed that acyl-protein thioesterase 1 (APT-1), the only bona fide thioesterase shown to mediate deacylation in vivo, is expressed in HeLa cells, but not in CHO-K1 cells. However, APT-1 overexpression neither increased the deacylation rate of single acylated GAP-43 nor affected the steady-state subcellular distribution of dually acylated GAP-43 both in CHO-K1 and HeLa cells, indicating that GAP-43 deacylation is not mediated by APT-1. Accordingly, we performed a bioinformatic search to identify putative candidates with acyl-protein thioesterase activity. Among several candidates, we found that APT-2 is expressed both in CHO-K1 and HeLa cells and its overexpression increased the deacylation rate of single acylated GAP-43 and affected the steady-state localization of diacylated GAP-43 and H-Ras. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure