Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotypeselective HDAC inhibitor. We have developed an isotypeselective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted. [Mol Cancer Ther 2008;7(4):759 -68]

Exemplar E Transformed E′ Isometric synthesis Anisometric synthesis Synthesis in atlas domain Textured surface Radiance-transfer syn. Figure 1: Transforming an exemplar into an 8D appearance space E′ improves synthesis quality and enables new real-time functionalities. Abstract Exemplar E Color space E ′ Appearance space E ′ dim. red. Transformed exemplar S texture synthesis [ ] E S appearance vectors Synthesized coordinates Synthesized textureFigure 2: Overview of synthesis using exemplar transformation.The traditional approach in texture synthesis is to compare color neighborhoods with those of an exemplar. We show that quality is greatly improved if pointwise colors are replaced by appearance vectors that incorporate nonlocal information such as feature and radiance-transfer data. We perform dimensionality reduction on these vectors prior to synthesis, to create a new appearance-space exemplar. Unlike a texton space, our appearance space is lowdimensional and Euclidean. Synthesis in this information-rich space lets us reduce runtime neighborhood vectors from 5×5 grids to just 4 locations. Building on this unifying framework, we introduce novel techniques for coherent anisometric synthesis, surface texture synthesis directly in an ordinary atlas, and texture advection. Remarkably, we achieve all these functionalities in real-time, or 3 to 4 orders of magnitude faster than prior work.

Exemplar Synthesized deterministic windowsMultiscale randomness Spatial modulation Feature drag-and-drop Figure 1: Given a small exemplar image, our parallel synthesis algorithm computes windows of spatially deterministic texture from an infinite landscape in real-time. Synthesis variation is obtained using a novel jittering technique that enables several intuitive controls. AbstractWe present a texture synthesis scheme based on neighborhood matching, with contributions in two areas: parallelism and control. Our scheme defines an infinite, deterministic, aperiodic texture, from which windows can be computed in real-time on a GPU. We attain high-quality synthesis using a new analysis structure called the Gaussian stack, together with a coordinate upsampling step and a subpass correction approach. Texture variation is achieved by multiresolution jittering of exemplar coordinates. Combined with the local support of parallel synthesis, the jitter enables intuitive user controls including multiscale randomness, spatial modulation over both exemplar and output, feature dragand-drop, and periodicity constraints. We also introduce synthesis magnification, a fast method for amplifying coarse synthesis results to higher resolution.

Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.

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Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhône-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.

Procedural noise functions are widely used in computer graphics, from off-line rendering in movie production to interactive video games. The ability to add complex and intricate details at low memory and authoring cost is one of its main attractions. This survey is motivated by the inherent importance of noise in graphics, the widespread use of noise in industry and the fact that many recent research developments justify the need for an up-to-date survey. Our goal is to provide both a valuable entry point into the field of procedural noise functions, as well as a comprehensive view of the field to the informed reader. In this report, we cover procedural noise functions in all their aspects. We outline recent advances in research on this topic, discussing and comparing recent and well-established methods. We first formally define procedural noise functions based on stochastic processes and then classify and review existing procedural noise functions. We discuss how procedural noise functions are used for modelling and how they are applied to surfaces. We then introduce analysis tools and apply them to evaluate and compare the major approaches to noise generation. We finally identify several directions for future work.

Exemplar Synthesized deterministic windowsMultiscale randomness Spatial modulation Feature drag-and-drop Figure 1: Given a small exemplar image, our parallel synthesis algorithm computes windows of spatially deterministic texture from an infinite landscape in real-time. Synthesis variation is obtained using a novel jittering technique that enables several intuitive controls. AbstractWe present a texture synthesis scheme based on neighborhood matching, with contributions in two areas: parallelism and control. Our scheme defines an infinite, deterministic, aperiodic texture, from which windows can be computed in real-time on a GPU. We attain high-quality synthesis using a new analysis structure called the Gaussian stack, together with a coordinate upsampling step and a subpass correction approach. Texture variation is achieved by multiresolution jittering of exemplar coordinates. Combined with the local support of parallel synthesis, the jitter enables intuitive user controls including multiscale randomness, spatial modulation over both exemplar and output, feature dragand-drop, and periodicity constraints. We also introduce synthesis magnification, a fast method for amplifying coarse synthesis results to higher resolution.