National Cheng Kung University

About: National Cheng Kung University is a education organization based out in Tainan City, Taiwan. It is known for research contribution in the topics: Population & Thin film. The organization has 49723 authors who have published 69799 publications receiving 1437420 citations. The organization is also known as: NCKU.

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions

Abstract: Importance The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. Objective To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. Design, Setting, and Participants Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. Main Outcomes and Measures Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. Results The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 ( CYP2C9*3 ) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P =1.1 × 10 −17 ). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z =8.58; P CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. Conclusions and Relevance This study identified CYP2C variants, including CYP2C9*3 , known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Expression Profiles of ErbB Family Receptors and Prognosis in Primary Transitional Cell Carcinoma of the Urinary Bladder

Abstract: In vitro experiments have demonstrated that epidermal growth factor (EGF)-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. The implications of cross-talk among ErbB family receptors in human cancer, however, remain to be clarified. This cohort study was performed to examine the expression patterns of ErbB receptors by immunohistochemistry in primary human bladder cancer (n = 245) and compared with conventional biological indicators for their prognostic significance. Expression of individual EGF receptor (EGFR) and ErbB2, ErbB3, or ErbB4 receptors was detected in 72.2, 44.5, 56.3, and 29.8% of bladder cancer cases, respectively. Expression of two of the receptors varied from 14.7 to 42.4%, of three of the receptors between 11.0 and 22.0%, and of all four of the ErbB receptors by 8.6%. Important indicators in association with patient survival were tumor staging (P = 0.017), ErbB2 (P = 0.018), EGFR-ErbB2 (P = 0.023), and ErbB2-ErbB3 (P = 0.042). In the subset of grade-2 tumors, EGFR-ErbB2-ErbB3 and EGFR-ErbB2 predicted the development of second recurrence (P = 0.026 and 0.039, respectively), and ErbB2-ErbB3 tended to correlate with patient survival (P = 0.09). The results indicate that a combination of EGFR, ErbB2, and ErbB3 expression profile may be a better prognostic indicator than any family member alone. Given that ErbB2 is the preferred coexpression partner of ErbB family members, expression of other ErbB receptors may significantly affect the prognostic implication of ErbB2 for bladder cancer patients.