The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 mu mol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(II) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(II) and ZAP-70(-) CLL cells but not in unmutated IgV(II) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.

Distinct poor prognostic subgroups of acute myeloid leukaemia, FLT3-ITD and P-glycoprotein-positive, have contrasting levels of FOXO1

Regulation of ABCB1 (P-glycoprotein/Pgp) in AML was investigated. In a historical cohort with Pgp and transcriptional regulator expression profiling data available (n=141), FOXO1 correlated with Pgp protein expression. This was confirmed in an independent cohort (n=204). Down-regulation (siRNA) or hyperactivation (nicotinamide) of FOXO1 led to corresponding changes in Pgp. Low FOXO1 expression correlated with FLT3-ITDs (p

DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: a comprehensive profiling approach

BACKGROUND: Methylation-induced silencing of promoter CpG islands in tumor suppressor genes plays an important role in human carcinogenesis. In colorectal cancer, the CpG island methylator phenotype (CIMP) is defined as widespread and elevated levels of DNA methylation and CIMP+ tumors have distinctive clinicopathological and molecular features. In contrast, the existence of a comparable CIMP subtype in gastric cancer (GC) has not been clearly established. To further investigate this issue, in the present study we performed comprehensive DNA methylation profiling of a well-characterised series of primary GC.

METHODS: The methylation status of 1,421 autosomal CpG sites located within 768 cancer-related genes was investigated using the Illumina GoldenGate Methylation Panel I assay on DNA extracted from 60 gastric tumors and matched tumor-adjacent gastric tissue pairs. Methylation data was analysed using a recursively partitioned mixture model and investigated for associations with clinicopathological and molecular features including age, Helicobacter pylori status, tumor site, patient survival, microsatellite instability and BRAF and KRAS mutations.

RESULTS: A total of 147 genes were differentially methylated between tumor and matched tumor-adjacent gastric tissue, with HOXA5 and hedgehog signalling being the top-ranked gene and signalling pathway, respectively. Unsupervised clustering of methylation data revealed the existence of 6 subgroups under two main clusters, referred to as L (low methylation; 28% of cases) and H (high methylation; 72%). Female patients were over-represented in the H tumor group compared to L group (36% vs 6%; P = 0.024), however no other significant differences in clinicopathological or molecular features were apparent. CpG sites that were hypermethylated in group H were more frequently located in CpG islands and marked for polycomb occupancy.

CONCLUSIONS: High-throughput methylation analysis implicates genes involved in embryonic development and hedgehog signaling in gastric tumorigenesis. GC is comprised of two major methylation subtypes, with the highly methylated group showing some features consistent with a CpG island methylator phenotype.

Discovering subgroups of patients from DNA copy number data using NMF on compacted matrices

In the study of complex genetic diseases, the identification of subgroups of patients sharing similar genetic characteristics represents a challenging task, for example, to improve treatment decision. One type of genetic lesion, frequently investigated in such disorders, is the change of the DNA copy number (CN) at specific genomic traits. Non-negative Matrix Factorization (NMF) is a standard technique to reduce the dimensionality of a data set and to cluster data samples, while keeping its most relevant information in meaningful components. Thus, it can be used to discover subgroups of patients from CN profiles. It is however computationally impractical for very high dimensional data, such as CN microarray data. Deciding the most suitable number of subgroups is also a challenging problem. The aim of this work is to derive a procedure to compact high dimensional data, in order to improve NMF applicability without compromising the quality of the clustering. This is particularly important for analyzing high-resolution microarray data. Many commonly used quality measures, as well as our own measures, are employed to decide the number of subgroups and to assess the quality of the results. Our measures are based on the idea of identifying robust subgroups, inspired by biologically/clinically relevance instead of simply aiming at well-separated clusters. We evaluate our procedure using four real independent data sets. In these data sets, our method was able to find accurate subgroups with individual molecular and clinical features and outperformed the standard NMF in terms of accuracy in the factorization fitness function. Hence, it can be useful for the discovery of subgroups of patients with similar CN profiles in the study of heterogeneous diseases.

Intake of total and subgroups of fat minimally affect the associations between selected single nucleotide polymorphisms in the PPARγ pathway and changes in anthropometry among European adults from cohorts of the DiOGenes study

BACKGROUND: Although the peroxisome proliferator-activated receptor γ (PPARγ) pathway is central in adipogenesis, it remains unknown whether it influences change in body weight (BW) and whether dietary fat has a modifying effect on the association. OBJECTIVES: We examined whether 27 single nucleotide polymorphisms (SNPs) within 4 genes in the PPARγ pathway are associated with the OR of being a BW gainer or with annual changes in anthropometry and whether intake of total fat, monounsaturated fat, polyunsaturated fat, or saturated fat has a modifying effect on these associations. METHODS: A case-noncase study included 11,048 men and women from cohorts in the European Diet, Obesity and Genes study; 5552 were cases, defined as individuals with the greatest BW gain during follow-up, and 6548 were randomly selected, including 5496 noncases. We selected 4 genes [CCAAT/enhancer binding protein β (CEBPB), phosphoenolpyruvate carboxykinase 2, PPARγ gene (PPARG), and sterol regulatory element binding transcription factor 1] according to evidence about biologic plausibility for interactions with dietary fat in weight regulation. Diet was assessed at baseline, and anthropometry was followed for 7 y. RESULTS: The ORs for being a BW gainer for the 27 genetic variants ranged from 0.87 (95% CI: 0.79, 1.03) to 1.12 (95% CI: 0.96, 1.22) per additional minor allele. Uncorrected, CEBPB rs4253449 had a significant interaction with the intake of total fat and subgroups of fat. The OR for being a BW gainer for each additional rs4253449 minor allele per 100 kcal higher total fat intake was 1.07 (95% CI: 1.02, 1.12; P = 0.008), and similar associations were found for subgroups of fat. CONCLUSIONS: Among European men and women, the influence of dietary fat on associations between SNPs in the PPARγ pathway and anthropometry is likely to be absent or marginal. The observed interaction between rs4253449 and dietary fat needs confirmation.

The three-dimensional structure of bothropasin, the main hemorrhagic factor from Bothrops jararaca venom: Insights for a new classification of snake venom metalloprotease subgroups

Bothropasin is a 48 kDa hemorrhagic PIII snake venom metalloprotease (SVMP) isolated from Bothrops jararaca, containing disintegrin/cysteine-rich adhesive domains. Here we present the crystal structure of bothropasin complexed with the inhibitor POL647. The catalytic domain consists of a scaffold of two subdomains organized similarly to those described for other SVMPs, including the zinc and calcium-binding sites. The free cysteine residue Cys(189) is located within a hydrophobic core and it is not available for disulfide bonding or other interactions. There is no identifiable secondary structure for the disintegrin domain, but instead it is composed mostly of loops stabilized by seven disulfide bonds and by two calcium ions. The ECD region is in a loop and is structurally related to the RGD region of RGD disintegrins, which are derived from I`ll SVMPs. The ECD motif is stabilized by the Cys(117)_Cys(310) disulfide bond (between the disintegrin and cysteine-rich domains) and by one calcium ion. The side chain of Glu(276) of the ECD motif is exposed to solvent and free to make interactions. In bothropasin, the HVR (hyper-variable region) described for other Pill SVMPs in the cysteine-rich domain, presents a well-conserved sequence with respect to several other Pill members from different species. We propose that this subset be referred to as PIII-HCR (highly conserved region) SVMPs. The differences in the disintegrin-like, cysteine-rich or disintegrin-like cysteine-rich domains may be involved in selecting target binding, which in turn could generate substrate diversity or specificity for the catalytic domain. (C) 2008 Elsevier Ltd. All rights reserved.

The classification and the conjugacy classes of the finite subgroups of the sphere braid groups

Let n >= 3. We classify the finite groups which are realised as subgroups of the sphere braid group B(n)(S(2)). Such groups must be of cohomological period 2 or 4. Depending on the value of n, we show that the following are the maximal finite subgroups of B(n)(S(2)): Z(2(n-1)); the dicyclic groups of order 4n and 4(n - 2); the binary tetrahedral group T*; the binary octahedral group O*; and the binary icosahedral group I(*). We give geometric as well as some explicit algebraic constructions of these groups in B(n)(S(2)) and determine the number of conjugacy classes of such finite subgroups. We also reprove Murasugi`s classification of the torsion elements of B(n)(S(2)) and explain how the finite subgroups of B(n)(S(2)) are related to this classification, as well as to the lower central and derived series of B(n)(S(2)).

On Groups Whose Maximal Cyclic Subgroups Are Maximal

We consider the problem of classifying those groups whose maximal cyclic subgroups are maximal. We give a complete classification of those groups with this property and which are either soluble or residually finite.

Classification of the virtually cyclic subgroups of the pure braid groups of the projective plane

We classify the ( finite and infinite) virtually cyclic subgroups of the pure braid groups P(n)(RP(2)) of the projective plane. The maximal finite subgroups of P(n)(RP(2)) are isomorphic to the quaternion group of order 8 if n = 3, and to Z(4) if n >= 4. Further, for all n >= 3, the following groups are, up to isomorphism, the infinite virtually cyclic subgroups of P(n)(RP(2)): Z, Z(2) x Z and the amalgamated product Z(4)*(Z2)Z(4).

Identifying subgroups of U.S. adults at risk for prolonged television viewing to inform program development

Background
Although adverse health effects of prolonged TV viewing have been increasingly recognized, little population-wide information is available concerning subgroups at greatest risk for this behavior.

Purpose
This study sought to identify, in a U.S. population–derived sample, combinations of variables that defined subgroups with higher versus lower levels of usual TV-viewing time.

Methods
A total of 5556 adults from a national consumer panel participated in the mail survey in 2001 (55% women, 71% white, 13% black, and 11% Hispanic). Nonparametric risk classification analyses were conducted in 2008.

Results
Subgroups with the highest proportions of people watching >14 hours/week of TV were identified and described using a combination of demographic (i.e., lower household incomes, divorced/separated); health and mental health (i.e., poorer rated overall health, higher BMI, more depression); and behavioral (i.e., eating dinner in front of the TV, smoking, less physical activity) variables. The subgroup with the highest rates of TV viewing routinely ate dinner while watching TV and had lower income and poorer health. Prolonged TV viewing also was associated with perceived aspects of the neighborhood environment (i.e., heavy traffic and crime, lack of neighborhood lighting, and poor scenery).

Conclusions
The results can help inform intervention development in this increasingly important behavioral health area.

The value of impulsivity to define subgroups of addicted individuals differing in personality dysfunction, craving, psychosocial adjustment, and wellbeing: A latent class analysis

High impulsivity is common to substance and gambling addictions. Despite these commonalities, there is still substantial heterogeneity on impulsivity levels within these diagnostic groups, and variations in impulsive levels predict higher severity of symptoms and poorer outcomes. We addressed the question of whether impulsivity scores can yield empirically driven subgroups of addicted individuals that will exhibit different clinical presentations and outcomes. We applied latent class analysis (LCA) to trait (UPPS-P impulsive behavior scale) and cognitive impulsivity (Stroop and d2 tests) scores in three predominantly male addiction diagnostic groups: Cocaine with Personality Disorders, Cocaine Non-comorbid, and Gambling and analyzed the usefulness of the resulting subgroups to differentiate personality beliefs and relevant outcomes: Craving, psychosocial adjustment, and quality of life. In accordance with impulsivity scores, the three addiction diagnostic groups are best represented as two separate classes: Class 1 characterized by greater trait impulsivity and poorer cognitive impulsivity performance and Class 2 characterized by lower trait impulsivity and better cognitive impulsivity performance. The two empirically derived classes showed significant differences on personality features and outcome variables (Class 1 exhibited greater personality dysfunction and worse clinical outcomes), whereas conventional diagnostic groups showed non-significant differences on most of these measures. Trait and cognitive impulsivity scores differentiate subgroups of addicted individuals with more versus less severe personality features and clinical outcomes.

Nonparametric discovery of learning patterns and autism subgroups from therapeutic data

Autism Spectrum Disorder (ASD) is growing at a staggering rate, but, little is known about the cause of this condition. Inferring learning patterns from therapeutic performance data, and subsequently clustering ASD children into subgroups, is important to understand this domain, and more importantly to inform evidence-based intervention. However, this data-driven task was difficult in the past due to insufficiency of data to perform reliable analysis. For the first time, using data from a recent application for early intervention in autism (TOBY Play pad), whose download count is now exceeding 4500, we present in this paper the automatic discovery of learning patterns across 32 skills in sensory, imitation and language. We use unsupervised learning methods for this task, but a notorious problem with existing methods is the correct specification of number of patterns in advance, which in our case is even more difficult due to complexity of the data. To this end, we appeal to recent Bayesian nonparametric methods, in particular the use of Bayesian Nonparametric Factor Analysis. This model uses Indian Buffet Process (IBP) as prior on a binary matrix of infinite columns to allocate groups of intervention skills to children. The optimal number of learning patterns as well as subgroup assignments are inferred automatically from data. Our experimental results follow an exploratory approach, present different newly discovered learning patterns. To provide quantitative results, we also report the clustering evaluation against K-means and Nonnegative matrix factorization (NMF). In addition to the novelty of this new problem, we were able to demonstrate the suitability of Bayesian nonparametric models over parametric rivals.

On invariant Rings of Sylow subgroups of finite classical groups

In this thesis we study the invariant rings for the Sylow p-subgroups of the nite classical groups. We have successfully constructed presentations for the invariant rings for the Sylow p-subgroups of the unitary groups GU(3; Fq2) and GU(4; Fq2 ), the symplectic group Sp(4; Fq) and the orthogonal group O+(4; Fq) with q odd. In all cases, we obtained a minimal generating set which is also a SAGBI basis. Moreover, we computed the relations among the generators and showed that the invariant ring for these groups are a complete intersection. This shows that, even though the invariant rings of the Sylow p-subgroups of the general linear group are polynomial, the same is not true for Sylow p-subgroups of general classical groups. We also constructed the generators for the invariant elds for the Sylow p-subgroups of GU(n; Fq2 ), Sp(2n; Fq), O+(2n; Fq), O-(2n + 2; Fq) and O(2n + 1; Fq), for every n and q. This is an important step in order to obtain the generators and relations for the invariant rings of all these groups.