Magic™ Anti-GSK3B monoclonal antibody

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. Grade > 2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (kappa = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

NOK (also known as STYK1) has been identified as an oncogene. However, its biochemical and biological activities as a molecular regulator are poorly defined. In the present study, we report that NOK overexpression led to enhanced phosphorylation of GSK-3 beta at its Ser9 residue via Akt phosphorylation at Thr308. NOK could make complexes with both Akt and GSK-3 beta. Moreover, the expression levels of NOK, p-Akt(Thr308) and p-GSK-3 beta(Ser9) were positively correlated in cancerous and non-cancerous breast cell lines. Thus, our data identified a novel functional molecular complex formed by NOK, Akt and GSK-3 beta that may relay a NOK-directed tumourigenic cascade. Structured summary of protein interactions: GSK3B physically interacts with NOK and Akt by anti tag coimmunoprecipitation (View interaction). GSK3B physically interacts with NOK by anti tag coimmunoprecipitation (View interaction). (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.