The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models.

The Wnt/ß-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).

Daily Walking among Commuters: A Cross-Sectional Study of Associations with Residential, Work, and Regional Accessibility in Melbourne, Australia (2012-2014).

BACKGROUND: Most research on walking for transport has focused on the walkability of residential neighborhoods, overlooking the contribution of places of work/study and the ease with which destinations outside the immediate neighborhood can be accessed, referred to as regional accessibility. OBJECTIVES: We aimed to examine if local accessibility/walkability around place of work/study and regional accessibility are independently and interactively associated with walking. METHODS: A sample of 4,913 adult commuters was derived from a household travel survey in Melbourne, Australia (2012-2014). Local accessibility was measured as the availability of destinations within an 800-m pedestrian network from homes and places of work/education using a local living index [LLI; 0-3 (low), 4-6, 7-9, and 10-12 (high) destinations]. Regional accessibility was estimated using employment opportunity, commute travel time by mode, and public transport accessibility. Every individual's potential minutes of walking for each level of exposure (observed and counter to fact) were predicted using multivariable regression models including confounders and interaction terms. For each contrast of exposure levels of interest, the corresponding within-individual differences in predicted walking were averaged across individuals to estimate marginal effects. RESULTS: High LLI at home and work/education was associated with more minutes walking than low LLI by 3.9 [95% confidence interval (CI): 2.3, 5.5] and 8.3 (95% CI: 7.3, 9.3) min, respectively, in mutually adjusted models. Across regional accessibility measures, an independent association with walking and an interactive association with LLI at work/education was observed. To take one example, the regional accessibility measure of "Jobs within 30 min by public transport" was associated with 4.3 (95% CI: 2.9, 5.7) more mins walking for high (≥30,000 jobs) compared with low (<4,000 jobs) accessibility in adjusted models. The estimated difference for high vs. low LLI (work/education) (among those with low regional accessibility) was 3.6 min (95% CI: 2.3, 4.8), while the difference for high vs. low regional accessibility (among those with low LLI) was negligible (-0.01; 95% CI: -1.2, 1.2). However, the combined effect estimate for high LLI and high regional accessibility, compared with low on both, was 12.8 min (95% CI: 11.1, 14.5), or 9.3 (95% CI: 6.7, 11.8) min/d walking more than expected based on the separate effect estimates. CONCLUSIONS: High local living (work/education) and regional accessibility, regardless of the regional accessibility measure used, are positively associated with physical activity. High exposure to both is associated with greater benefit than exposure to one or the other alone. https://doi.org/10.1289/EHP3395.

Evaluation of the Efficacy of a Onetime Injectable Dexamethasone Administered Orally in the Pediatric Emergency Department for Asthma Exacerbation.

OBJECTIVE: This study assessed the efficacy of injectable dexamethasone administered orally in pediatric patients who presented to the emergency department with asthma exacerbation. METHODS: This was a retrospective study of patients 0 to 18 years of age who presented to and who were directly discharged from the emergency department at Moses H. Cone Memorial Hospital between September 1, 2012, and September 30, 2015, for the diagnosis of asthma or asthma exacerbation. Patients had to receive a onetime dose of injectable dexamethasone orally prior to discharge. Patients were followed for a 30-day period to identify the number of asthma relapses. RESULTS: Ninety-nine patients were included in this study. The average weight-based dose ± SD of dexamethasone was 0.35 ± 0.18 mg/kg (range, 0.08-0.62 mg/kg) and the actual dose ± SD was 10.58 ± 1.92 mg (range, 5-16 mg). Over a 30-day period, 6 patients (6%) had one repeated emergency department visit, 6 patients (6%) were admitted to the hospital, and 3 patients (3%) presented to an outpatient clinic for asthma-related symptoms. CONCLUSIONS: Injectable dexamethasone administered orally may be an efficacious treatment for asthma exacerbation in pediatric patients. A randomized control trial comparing injectable dexamethasone administered orally to other dexamethasone formulations/routes of administration should be performed to adequately assess the bioequivalence and effectiveness of the former formulation.