Ototoxicity is a debilitating side effect of platinating agents with substantial inter-patient variability. We sought to evaluate the association of TPMT and COMT genetic variations with cisplatin-related hearing damage in the context of frontline pediatric cancer treatment protocols. In 213 children from St. Jude Medulloblastoma-96 and -03 protocols, hearing loss was related to younger age (P=0.013) and craniospinal irradiation (P=0.001), but did not differ by TPMT or COMT variants. Results were similar in an independent cohort of 41 children from solid tumor frontline protocols. Functional hearing loss or hair cell damage was not different in TPMT knockout vs. wildtype mice following cisplatin treatment, and neither TPMT nor COMT variant was associated with cisplatin cytotoxicity in lymphoblastoid cell lines. In conclusion, our results indicated that TPMT or COMT genetic variation was not related to cisplatin ototoxicity in children with cancer and did not influence cisplatin-induced hearing damage in laboratory models.

Background: Lack of self-monitoring of blood glucose (SMBG) records in actual practice settings continues to create therapeutic challenges for clinicians, especially in adjusting insulin therapy. In order to overcome this clinical obstacle, a ''Symptom-based Insulin adjustment for Glucose Normalization'' (SIGN) algorithm was developed to guide clinicians in caring for patients with uncontrolled type 2 diabetes who have few to no SMBG records. This study examined the clinical outcome and safety of the SIGN algorithm. Subjects and Methods: Glycated hemoglobin (HbA1c), insulin usage, and insulin-related adverse effects of a total of 114 patients with uncontrolled type 2 diabetes who refused to use SMBG or performed SMBG once a day for less than three times per week were studied 3 months prior to the implementation of the algorithm and prospectively at every 3-month interval for a total of 6 months after the algorithm implementation. Patients with type 1 diabetes, nonadherence to diabetes medications, or who were not on insulin therapy at any time during the study period were excluded from this study. Results: Mean HbA1c improved by 0.29% at 3 months (P = 0.015) and 0.41% at 6 months (P = 0.006) after algorithm implementation. A slight increase in HbA1c was observed when the algorithm was not implemented. There were no major hypoglycemic episodes. The number of minor hypoglycemic episodes was minimal with the majority of the cases due to irregular meal habits. Conclusions: The SIGN algorithm appeared to offer a viable and safe approach when managing uncontrolled patients with type 2 diabetes who have few to no SMBG records.

Induction of the antioxidant and cytoprotective phase 2 enzymes via the Keap1/Nrf2/antioxidant response element (ARE) pathway is an accepted strategy for cancer prevention. Recent studies have identified inhibition of inflammatory response as a consistent attribute of chemicals with phase 2 enzymes-inducing properties. As chronic inflammation has been associated with the pathogenesis of cancer, compounds eliciting both phase 2 enzymes-inducing and anti-inflammatory properties may serve as potential candidates for cancer chemoprevention. In our previous study, we had found that trans-cinnamaldehyde (CA) and its analog 2-benzoyloxycinnamaldehyde (BCA) were able to induce phase 2 enzymes via the Keap1/Nrf2/ARE pathway. In this study, we investigated the chemopreventive and anti-inflammatory properties of CA, BCA, and a novel series of “supercinnamaldehydes”. In the ARE-luciferase reporter gene assay, compounds were screened for their chemopreventive potencies by determining their ability to induce ARE-mediated gene expression in human embryonic kidney cells (HEK293). All supercinnamaldehydes induced ARE transcriptional activity, with one compound showing an induction of almost nine fold at 20 µM as compared to that of around six fold induction for 40 µM CA. To evaluate the anti-inflammatory properties of supercinnamaldehydes, we induced inflammatory conditions in mouse macrophage-like cells (RAW264.7) with lipopolysachharide (LPS) and measured nitric oxide (NO) concentrations in presence of the compounds. Compounds with good ARE-fold induction also exhibited low IC50 values for NO generation. The most potent compound inhibited NO production with an IC50 of 4.63 µM, significantly lower than the IC50 (34.45 µM) for CA. We focused our subsequent studies on CA, BCA, and two supercinnamaldehydes with highest ARE-fold induction and lowest IC50 values for NO release. The selected compounds showed marked induction of Nrf2 and phase 2 enzyme levels in HEK293 cells and wild-type mouse embryonic fibroblasts (MEFs) as observed by immunoblotting. In contrast, little induction was observed in Keap1-knockout MEFs, suggesting that the compounds could, at least in part, be targeting Keap1/Nrf2/ARE pathway for phase 2 enzyme induction. Immunoblotting also revealed that these compounds inhibited the LPS-induced up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). A suppressive effect on the NFκB signaling pathway was also observed. In conclusion, we hereby introduce a new class of compounds with superior phase 2 enzyme inducing and anti-inflammatory properties than the naturally occurring CA, which may be potentially efficacious in cancer prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1639. doi:1538-7445.AM2012-1639