Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.     

Predictors of non-compliance in autologous hematopoietic SCT patients undergoing out-patient transplants

Non-compliance has received significant attention in medicine, yet few studies have examined its correlates in autologous hematopoietic SCT (AHSCT) patients. This study examined predictors of non-compliance in a sample of 151 AHSCT patients treated in an outpatient setting. Before AHSCT, participants completed a validated measure of mood and retrospective chart reviews were conducted to assess non-compliance during AHSCT, defined as refusal of oral hygiene, prescribed exercise programs, oral nutrition and/or prescribed medications. We found 121 patients (80%) were non-compliant with an aspect of the AHSCT regimen on 1 or more days; mean percentage of non-compliant days was 16.6 (s.d. 15.6). Men were more likely than women to be non-compliant (P<0.05); as were participants with an elevated depression score (P<0.05). Stepwise regression models identified significant predictors of non-compliance: gender, depression, global distress and nausea and vomiting severity (P-values all <0.01). Further analysis revealed that the interaction of the psychological variables with gender was a more robust predictor of non-compliance (P<0.001). For outpatient AHSCT, our findings suggest the need to broaden conceptualizations of risk factors for non-compliance and the importance of assessing patient barriers to compliance to ensure optimal treatment outcome.     

Investigation of Ethylene Oxide-co-propylene Oxide for Dissolution Enhancement of Hot-Melt Extruded Solid Dispersions

The optimal design of amorphous solid dispersion formulations requires the use of excipients to maintain supersaturation and improve physical stability to ensure shelf-life stability and better absorption during intestinal transit, respectively. Blends of excipients (surfactants and polymers) are often used within pharmaceutical products to improve the oral delivery of Biopharmaceutical Classification System class II drugs. Therefore, in this study, a dissolution enhancer, poloxamer 407 (P407), was investigated to determine its effect on the dissolution properties and on the amorphous nature of the active pharmaceutical ingredient contained in the formulation. Phase solubility studies of indomethacin (INM) in aqueous solutions of P407 and poly(vinylpyrrolidone-vinyl acetate copolymer) showed an increase in the kinetic solubility of INM compared with the pure drug at 37°C with a K_a value of 0.041 μg/mL. The solid dispersions showed a higher dissolution rate when compared to pure and amorphous drugs when performed in pH buffer 1.2 with a kinetic solubility of 21 μg/mL. The stability data showed that the amorphous drug in solid solutions with poly(vinylpyrrolidone-vinyl acetate copolymer) and P407 remained amorphous, and the %P407 loading had no effect on the amorphous stability of INM. This study concluded that the amorphous solid dispersion contributed to the increased solubility of INM.