Lineage of origin in rhabdomyosarcoma informs pharmacological response.

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Behavioral support intervention for uncontrolled hypertension: a complier average causal effect (CACE) analysis.

BACKGROUND: The complier average causal effect (CACE) analysis addresses noncompliance with intervention and missing end-point measures in randomized controlled trials. OBJECTIVES: To conduct a CACE analysis for the Peer Coach and Office Staff Support Trial examining the intervention's effect among "compliers," defined as subjects who would have received an effective dose of the intervention had it been offered, and to compare with an intention-to-treat analysis. RESEARCH DESIGN AND SUBJECTS: A randomized controlled trial of 280 African American patients aged 40-75 with sustained uncontrolled hypertension from 2 general internal medicine practices. MEASURES: Change in 4-year coronary heart disease (CHD) risk (primary) and in systolic blood pressure (SBP) (secondary) from the baseline to the end of the 6-month intervention. RESULTS: Of 136 intervention subjects, 68% were compliers who had significantly more end points measured (86% vs. 34% for CHD risk; 99% vs. 57% for SBP) and lower baseline CHD risk (5% vs. 7.5%) and SBP (139 vs. 144 mm Hg) compared with noncompliers. In the intention-to-treat analysis, the effect of offering the intervention was nonsignificant for 4-year CHD risk (P=0.08) but significant for SBP (P=0.003). CACE analyses showed that receipt of an effective dose of the intervention resulted in a 1% greater reduction in 4-year CHD risk (P<0.05) and at least 8.1 mm Hg greater reduction in SBP compared with compliers in the control group (P<0.05). CONCLUSIONS: Among compliers, an effective dose of peer coach and office-based support resulted in significant reductions in 4-year CHD risk and SBP. More intensive interventions are likely to be required for noncompliers.

The mountain cedar model in clinical trials of seasonal allergic rhinoconjunctivitis.

BACKGROUND: Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar (Juniperus ashei) season as the predominate model. OBJECTIVE: To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. METHODS: The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. RESULTS: Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. CONCLUSION: Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis.

Proximal caries lesion detection using the Canary Caries Detection System: an in vitro study.

OBJECTIVE: This study investigated the accuracy of the Canary System (CS) to detect proximal caries lesions in vitro, and compared it with conventional methods: International Caries Detection and Assessment System (ICDAS) II and bitewing radiography (BW). METHODS: Visible proximal surfaces of extracted human teeth were assessed by ICDAS-II before setting them in five manikin mouth models. Then contacting proximal surfaces in mouth models were assessed by BW and CS. Histological validation with polarized-light microscopy served as a gold standard. Pairwise comparisons were performed on area under the curve (AUC), sensitivity, and specificity of the three methods, and corrected using Bonferroni's method. Sensitivities and specificities were compared using a test of proportions and AUC values were compared using DeLong's method. RESULTS: The CS presented significantly higher sensitivity (0.933) than ICDAS-II (0.733, P = 0.01) and BW (0.267, P < 0.001), and ICDAS-II higher sensitivity than BW (P < 0.001). There were no significant differences between their specificity values: 0.825 (CS), 0.65 (ICDAS-II), and 0.875 (BW). The AUC of CS (0.862) was significantly higher than of ICDAS-II (0.681, P < 0.001) and BW (0.577, P < 0.001). CONCLUSION: The CS demonstrated greater accuracy in detecting proximal lesions than ICDAS-II and BW, although without significantly higher specificity.