Pharmacogenomics: Challenges and Opportunities

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients

Desainer Grafis yang Menciptakan dan Menjual Produk Berupa Barang

Graphic designers in their economic activities are more widely known simply as seller of the product in the form of services. Whereas in reality it is not so since the days of Art and Craft movement spearheaded by William Morris at the end of the 19th century. William Morris, a graphic designer, had created products with good design for sale. Many reasons are behind it, starting from desires to break free from pressures of the clients, expanding spaces to express creativity to economic motives. Discussion of graphic designers crossing border of disciplines by creating products is very interesting. They do not just perform the profession on the basis of orders (client-based), but they are able to read the market that will absorb the products they created. Even, they create market trend (as a trendsetter). At this level, a designer does not just make value-added work, but already at the level of creating new value (value creation)

Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.

Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform in arrhythmia susceptibility. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO). Chronic exposure (10-100 nM; 5-48 hours) to PI3K-α-specific subunit inhibitors BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased INaL in SCN5A-transfected CHO cells and mouse cardiomyocytes. The specific inhibitors (10-100 nM for 5 hours) markedly prolonged APs and generated triggered activity in mouse cardiomyocytes (9/12) but not in controls (0/6), and BKM120 caused similar effects (3/6). The inclusion of water-soluble PIP3, a downstream effector of the PI3K signaling pathway, in the pipette solution reversed these arrhythmogenic effects. By contrast, inhibition of PI3K-β, -γ, and -δ isoforms did not alter INaL or APs. We conclude that inhibition of cardiac PI3K-α is arrhythmogenic by increasing INaL and this effect is not seen with inhibition of other PI3K isoforms. These results highlight a mechanism underlying potential cardiotoxicity of PI3K-α inhibitors

Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

<p>Abstract</p> <p>Background</p> <p>Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost <it>Danio rerio </it>(zebrafish).</p> <p>Results</p> <p>We identified and cloned single zebrafish gene homologs for beta1-beta3 (<it>zbeta1-zbeta3</it>) and duplicate genes for beta4 (<it>zbeta4.1, zbeta4.2</it>). Sodium channel beta subunit loci are similarly organized in fish and mammalian genomes. Unlike their mammalian counterparts, <it>zbeta1 </it>and <it>zbeta2 </it>subunit genes display extensive alternative splicing. Zebrafish beta subunit genes and their splice variants are differentially-expressed in excitable tissues, indicating tissue-specific regulation of <it>zbeta1-4 </it>expression and splicing. Co-expression of the genes encoding zbeta1 and the zebrafish sodium channel alpha subunit Na_v1.5 in Chinese Hamster Ovary cells increased sodium current and altered channel gating, demonstrating functional interactions between zebrafish alpha and beta subunits. Analysis of the synteny and phylogeny of mammalian, teleost, amphibian, and avian beta subunit and related genes indicated that all extant vertebrate beta subunits are orthologous, that beta2/beta4 and beta1/beta3 share common ancestry, and that beta subunits are closely related to other proteins sharing the V-type immunoglobulin domain structure. Vertebrate sodium channel beta subunit genes were not identified in the genomes of invertebrate chordates and are unrelated to known subunits of the <it>para </it>sodium channel in <it>Drosophila</it>.</p> <p>Conclusion</p> <p>The identification of conserved orthologs to all 4 voltage-gated sodium channel beta subunit genes in zebrafish and the lack of evidence for beta subunit genes in invertebrate chordates together indicate that this gene family emerged early in vertebrate evolution, prior to the divergence of teleosts and tetrapods. The evolutionary history of sodium channel beta subunits suggests that these genes may have played a key role in the diversification and specialization of electrical signaling in early vertebrates.</p

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from &lt;1x10-3 to &lt;1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Pharmacological Properties and Functional Role of Kslow Current in Mouse Pancreatic β-Cells: SK Channels Contribute to Kslow Tail Current and Modulate Insulin Secretion

The pharmacological properties of slow Ca2+-activated K+ current (Kslow) were investigated in mouse pancreatic β-cells and islets to understand how Kslow contributes to the control of islet bursting, [Ca2+]i oscillations, and insulin secretion. Kslow was insensitive to apamin or the KATP channel inhibitor tolbutamide, but UCL 1684, a potent and selective nonpeptide SK channel blocker reduced the amplitude of Kslow tail current in voltage-clamped mouse β-cells. Kslow was also selectively and reversibly inhibited by the class III antiarrythmic agent azimilide (AZ). In isolated β-cells or islets, pharmacologic inhibition of Kslow by UCL 1684 or AZ depolarized β-cell silent phase potential, increased action potential firing, raised [Ca2+]i, and enhanced glucose-dependent insulin secretion. AZ inhibition of Kslow also supported mediation by SK, rather than cardiac-like slow delayed rectifier channels since bath application of AZ to HEK 293 cells expressing SK3 cDNA reduced SK current. Further, AZ-sensitive Kslow current was extant in β-cells from KCNQ1 or KCNE1 null mice lacking cardiac slow delayed rectifier currents. These results strongly support a functional role for SK channel-mediated Kslow current in β-cells, and suggest that drugs that target SK channels may represent a new approach for increasing glucose-dependent insulin secretion. The apamin insensitivity of β-cell SK current suggests that β-cells express a unique SK splice variant or a novel heteromultimer consisting of different SK subunits

Veratridine Can Bind to a Site at the Mouth of the Channel Pore at Human Cardiac Sodium Channel NaV1.5

The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we perform docking calculations and high-throughput electrophysiology experiments in the present study. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.