Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APC(Min/+) Mouse Model of Intestinal Tumorigenesis

Canadian Institutes of Health Research grant to JL

Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

Modeling macronuclear DNA regulation in two ciliates : Paramecium tetraurelia and Tetrahymena thermophila

A revision to existing models for regulating the macronuclear DNA content of the ciliates Paramecium tetraurelia and Tetrahymena thermophila explains previously unresolved observations. Using an independent parameter to regulate ciliate macronuclear DNA content allows the mass of P. tetraurelia to be linked with DNA regulation. A similar parameterization of the T. thermophila model accounts for observed generation-dependent variations. Introducing controlled selection rules on macronuclear DNA content in modeled populations of T. thermophila results in evolving periodic distributions. The amount of unequal macronuclear division in the population is then directly proportional to the frequency of the resulting oscillation. Unequal division acts to restore the distribution opposing the selection displacement. Another parameter related to the replication’s independence from macronucleus DNA content shows a critical value of the √2–1 such that higher values result in periodic variations while lower values do not.Science, Faculty ofUnreviewedUndergraduat

Colon-specific reduction/reversal of polyps.

<p>Initiation of treatment with ATB-346 (14.5 mg/kg once daily for 14 days) at week 12 had no effect on the small intestinal polyp score (assessed at week 14), but markedly reduced polyp formation in the colon (**p<0.01).</p

Treatment with ATB-346 reduced intestinal β-catenin and cMyc levels in APC^Min/+ mice.

<p>Expression of both β-catenin (panel A) and cMyc (panel B) were significantly elevated in colonic tissue from APC^Min/+ mice as compared to wild-type mice. Treatment of APC^Min/+ mice with ATB-346 (14.5 mg/kg) significantly reduced β-catenin and cMyc expression to levels comparable to those in wild-type mice, while naproxen treatment (10 mg/kg) reduced cMyc but not β-catenin. Tissue samples were collected from the mice at 14 weeks of age, while drug treatment occurred in the 6^th and 7^th weeks of age. Each bar represents the mean ± SEM for at least 4 mice (p<0.05 vs. wild-type mice; ^ψp<0.05 vs. wild type. *p<0.05 vs. naproxen-treated).</p

Dose-related preventative effects of oral treatment with ATB-346 or naproxen on intestinal polyp formation in APC^Min/+ mice.

<p>Groups of at least 6 mice each were treated daily with vehicle, naproxen (1 or 10 mg/kg), or equimolar doses of ATB-346 or of the hydrogen sulfide-releasing moiety of ATB-346 (TBZ; 4-hydroxythiobenzamide). Treatments were started at week 6 of life, and the numbers and areas (in mm²) of polyps in the small intestine and colon were blindly assessed at week 14 of life (panels A, B and C show examples; arrows indicate polyps). Panel D shows the ‘total polyp score’ data (the sum of the areas of all polyps in each mouse). Data are shown as the mean ± SEM. **p<0.01, ***p<0.001 versus the vehicle-treated group (one-way ANOVA and Dunnett’s test). ^Ψp<0.05 versus the group treated with naproxen at the same dose (Student’s t-test).</p

Summary of transcriptomics analysis.

<p>Genes altered by >1.5-fold in the colon of APC^Min/+ mice as compared to wild-type mice, and the effects of daily treatment for one week with naproxen or ATB-346. Fold-change values represent direction of change from the first listed condition to the second. During the 6^th week of age, mice were treated with vehicle, naproxen at a dose of 10 mg/kg, or ATB-346 at an equimolar dose. Tissue samples were harvested at the start of the 7^th week of age. *p<0.05 by one-way ANOVA with Student-Neuman-Keuls post-hoc test and Storey’s bootstrapping multiple comparison correction. n = 6-8/group.</p

Polyp formation in the small intestine and colon of APC^Min+ mice at 12 weeks of age.

<p>Panel A shows ileum from a wild-type (C57Bl/6) mouse, while panel B shows ileum from an APC^Min+ mouse (with numerous polyps visible in the latter). Panel C shows the Polyp Score for 12 APC^Min+ mice, illustrating the regional variation through the small intestine and colon. Each line represents the results from one mouse. The ileum exhibited the greatest polyp score, while the colon exhibited the lowest.</p