Small molecule inhibition of CBP/catenin interactions eliminates drug resistant clones in acute lymphoblastic leukemia

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia, however little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CBP) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300, leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using ChIP assay, we demonstrate occupancy by CBP of the survivin promoter, which is decreased by ICG-001 in primary ALL. CBP-mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL

The formation of massive black holes through collision runaway in dense young star clusters

A luminous X-ray source is associated with a cluster (MGG-11) of young stars \~200pc from the center of the starburst galaxy M82. The properties of the X-ray source are best explained by a black hole with a mass of at least 350Msun, which is intermediate between stellar-mass and supermassive black holes. A nearby but somewhat more massive star cluster (MGG-9) shows no evidence of such an intermediate mass black hole, raising the issue of just what physical characteristics of the clusters can account for this difference. Here we report numerical simulations of the evolution and the motions of stars within the clusters, where stars are allowed to mergers with each other. We find that for MGG-11 dynamical friction leads to the massive stars sinking rapidly to the center of the cluster to participate in a runaway collision, thereby producing a star of 800-3000Msun, which ultimately collapses to an black hole of intermediate mass. No such runaway occurs in the cluster MGG-9 because the larger cluster radius leads to a mass-segregation timescale a factor of five longer than for MGG-11.Comment: Accepted for publication in Nature (Including supplementary information

Effects of a school-based intervention on active commuting to school and health-related fitness

Background: Active commuting to school has declined over time, and interventions are needed to reverse this trend. The main objective was to investigate the effects of a school-based intervention on active commuting to school and health-related fitness in school-age children of Southern Spain. Methods: A total of 494 children aged 8 to 11 years were invited to participate in the study. The schools were non-randomly allocated (i.e., school level allocation) into the experimental group (EG) or the control group (CG). The EG received an intervention program for 6 months (a monthly activity) focused on increasing the level of active commuting to school and mainly targeting children’s perceptions and attitudes. Active commuting to school and health-related fitness (i.e., cardiorespiratory fitness, muscular fitness and speed-agility), were measured at baseline and at the end of the intervention. Children with valid data on commuting to school at baseline and follow-up, sex, age and distance from home to school were included in the final analysis (n = 251). Data was analyzed through a factorial ANOVA and the Bonferroni post-hoc test. Results: At follow up, the EG had higher rates of cycling to school than CG for boys only (p = 0.04), but not for walking to school for boys or girls. The EG avoided increases in the rates of passive commuting at follow up, which increased in the CG among girls for car (MD = 1.77; SE = 0.714; p = 0.010) and bus (MD = 1.77; SE = 0.714; p = 0.010) modes. Moreover, we observed significant interactions and main effects between independent variables (study group, sex and assessment time point) on health-related fitness (p < 0.05) over the 6-month period between groups, with higher values in the control group (mainly in boys). Conclusion: A school-based intervention focused on increasing active commuting to school was associated with increases in rates of cycling to school among boys, but not for walking to school or health-related fitness. However, the school-based intervention avoided increases in rates of passive commuting in the experimental group, which were significantly increased in girls of the control group

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

The potential for inhibitors of nuclear factor-κB (NF-κB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-κB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-κB inhibitor SN50 (18 μM) attenuated the expression of 205 proteasome α-subunits, two subunits of the 195 regulator MSSI and p42, and the ubiquitin-conjugating enzyme, E214k, as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-κB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 μM) and resveratrol (30 μM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2 14k. However, curcumin (150 and 300 mg kg-1) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg-1) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-κB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-κB may prove useful for the treatment of muscle wasting in cancer cachexia

Mode shifting in school travel mode: examining the prevalence and correlates of active school transport in Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>Studies examining the correlates of school transport commonly fail to make the distinction between morning and afternoon school trips. The purpose of this study was to examine the prevalence and correlates of mode shift from passive in the morning to active in the afternoon among elementary and secondary school students in Ontario, Canada.</p> <p>Methods</p> <p>Data were derived from the 2009 cycle of the Ontario Student Drug Use and Health Survey (OSDUHS). 3,633 students in grades 7 through 12 completed self-administered questionnaires. Socio-demographic, behavioural, psychological, and environmental predictors of active school transport (AST) were assessed using logistic regression.</p> <p>Results</p> <p>Overall, 47% and 38% of elementary school students reported AST to and from school, respectively. The corresponding figures were 23% and 32% for secondary school students. The prevalence of AST varied temporarily and spatially. There was a higher prevalence of walking/biking found for elementary school students than for secondary school students, and there was an approximate 10% increase in AST in the afternoon. Different correlates of active school transport were also found across elementary and secondary school students. For all ages, students living in urban areas, with a shorter travel time between home and school, and having some input to the decision making process, were more likely to walk to and from school.</p> <p>Conclusions</p> <p>Future research examining AST should continue to make the analytic distinction between the morning and afternoon trip, and control for the moderating effect of age and geography in predicting mode choice. In terms of practice, these variations highlight the need for school-specific travel plans rather than 'one size fits all' interventions in promoting active school transport.</p

Antipsychotic prescribing for vulnerable populations: a clinical audit at an acute Australian mental health unit at two-time points

Background: Antipsychotics are recognised as a critical intervention for schizophrenia and bipolar disorder. Guidelines globally endorse the routine practice of antipsychotic monotherapy, at the minimum effective dose. Even in treatmentresistant schizophrenia, clozapine use is endorsed before combining antipsychotics. This aim of this study was to review antipsychotic polytherapy alone, high-dose therapy alone, polytherapy and highdose prescribing patterns in adults discharged from an inpatient mental health unit at two time-points, and the alignment of this prescribing with clinical guideline recommendations. Additionally, associations with polytherapy and high-dose antipsychotic prescribing, including patient and clinical characteristics, were explored. Methods: A retrospective clinical audit of 400 adults (200 patients at two different time-points) discharged with at least one antipsychotic. Preliminary findings and education sessions were provided to physicians between Cohorts. Outcomes (polytherapy alone, high-dose therapy alone, polytherapy and high-dose therapy) were compared between study Cohorts using chi-squared and rank-sum tests. Associations between outcomes and covariates were assessed using multivariable logistic regression. Results: Most patients (62.5%) were discharged on a single antipsychotic within the recommended dose range. There was a clear preference for prescribing second generation antipsychotics, and in this respect, prescribing is aligned with current evidence-based guidelines. However, sub-optimal prescribing practices were identified for both Cohorts in relation to polytherapy and high-dose antipsychotic rates. Involuntary treatment, frequent hospitalisations and previous clozapine use significantly increased the risk of all three prescribing outcomes at discharge. Conclusions: In a significant minority, antipsychotic prescribing did not align with clinical guidelines despite increased training, indicating that the education program alone was ineffective at positively influencing antipsychotic prescribing practices. Further consideration should be given when prescribing antipsychotics for involuntary patients, people with frequent hospitalisations, and those who have previously trialled clozapine

A Superconducting Instability in the Infinite-U Anderson Lattice in the Presence of Crystal Electric Fields

We report evidence of a superconducting instability (of $T_{1g}$ symmetry) in the infinite-U Anderson lattice in the presence of crystal fields of cubic symmetry. We assume a lattice of $4f$ sites, each with a total angular momentum of $J=5/2$ that is split by crystal fields into a low-lying doublet of $\Gamma_7$ symmetry and an excited quartet of $\Gamma_8$ symmetry. Slave Bosons on the $4f$ sites create and destroy $4f^0$ configurations and Lagrange multipliers at each $4f$ site enforce the occupancy constraint due to the infinite Coulomb repulsion. Quasiparticle interactions are due to exchange of $4f$ density fluctuations, which are represented by fluctuations in the slave Bosons and Lagrange multipliers. We use the so-called analytic tetrahedron method to calculate the dressed (to order 1/N) Boson Green functions. In weak couping, the exchange of the dressed Bosons gives rise to a superconducting instability of $T_{1g}$, $xy(x^2-y^2)$, symmetry. The $A_{1g}$, ``s-wave'', channel has strongly repulsive interactions and hence no pairing instability. The $T_{2g}$ channel exhibits weakly repulsive interactions. Average quasiparticle interactions in the $E_g$, $x^2-y^2$, $3z^2-r^2$, channel fluctuate strongly as a function of the number of tetrahedra used to calculate the Bosonic Green functions,Comment: 66 pages+ 17 postscript figures, LATE

Directional genetic selection by pulp mill effluent on multiple natural populations of three-spined stickleback (Gasterosteus aculeatus)

Contamination can cause a rapid environmental change which may require populations to respond with evolutionary changes. To evaluate the effects of pulp mill effluents on population genetics, we sampled three-spined sticklebacks (Gasterosteus aculeatus) near four pulp mills and four adjacent reference sites and analyzed Amplified Fragment Length Polymorphism (AFLP) to compare genetic variability. A fine scale genetic structure was detected and samples from polluted sites separated from reference sites in multidimensional scaling plots (P < 0.005, 1000 permutations) and locus-by-locus Analysis of Molecular Variance (AMOVA) further confirmed that habitats are significantly separated (FST = 0.021, P < 0.01, 1023 permutations). The amount of genetic variation between populations did not differ between habitats, and populations from both habitats had similar levels of heterozygosity (polluted sites Nei’s Hs = 0.11, reference sites Nei’s Hs = 0.11). Still, pairwise FST: s between three, out of four, pairs of polluted-reference sites were significant. A FST-outlier analysis showed that 21 (8.4%) loci were statistically different from a neutral distribution at the P < 0.05 level and therefore indicated to be under divergent selection. When removing 13 FST-outlier loci, significant at the P < 0.01 level, differentiation between habitats disappeared in a multidimensional scaling plot. In conclusion, pulp mill effluence has acted as a selective agent on natural populations of G. aculeatus, causing a convergence in genotype composition change at multiple sites in an open environment