Human Anti-Human PTPRJ monoclonal Antibody, clone SFB305 [PE]

Background: Palliative radiotherapy (RT) is effective in patients with painful bone metastases. Genetic factors may identify subgroup of patients who responded to RT. To identify DNA biomarkers associated with response to palliative RT. Methods: Patients who received a single 8 Gy dose of RT for painful bone metastases were categorised into responders (n=36), non-responders (NR) (n=71). Saliva samples were sequenced to identify single-nucleotide variants (SNVs) in genes with known disease-causing variants from inflammation, radiation response, and DNA damage pathways. In univariate analysis, Cochran-Armitage trend tests were used to identify SNVs that associated with pain response (P<0.005), and the Penalized LASSO method with minimum Bayesian Information Criterion was used to identify multi-SNVs that jointly predict pain response to RT. The corresponding estimated effect of the multi- SNVs were used to drive the prognostic score for each patient. Based on it, patients were divided into 3 equal size risk groups. Results: Forty-one significant variants were identified in univariate analysis. Multivariable analysis selected 14 variants to generate prognostic scores, adjusting for gender and primary cancer site. Eighty-nine percent of patients in the high prognostic group responded to palliative radiation therapy (P=0.0001). Estimated effect sizes of the variants ranged from 0.108-2.551. The most statistically significant variant was a deletion at position 111992032 in the ataxin gene ATXN2 (P=0.0001). Five variants were non-synonymous, including AOAH rs7986 (P=0.0017), ZAN rs539445 (P=0.00078) and rs542137 (P=0.00078), RAG1 rs3740955 (P=0.0014), and GBGT1 rs75765336 (P=0.0026). Conclusions: SNVs involved in mechanisms including DNA repair, inflammation, cellular adhesion, and cell signalling have significant associations with radiation response. SNVs with predictive power may stratify patient populations according to likelihood of responding to treatment, therefore enabling more efficient identification of beneficial strategies for pain management and improved resource utilisation.

In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation, including the promotion of leukemic cell proliferation and migration, as well as DNA damage and accumulation of mutations. Work reviewed in this article has revealed the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein tyrosine kinases in both processes, and the related pathways have been partially identified. FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITD), an important oncoprotein in a subset of acute myeloid leuke-mias, causes activation of AKT and, subsequently, stabilization of p22(phox), a regulatory subunit for NOX1-4. This process is linked to ROS formation and DNA damage. Moreover, FLT3-ITD signaling through STAT5 enhances expression of NOX4, ROS formation, and inactivation of the protein tyrosine phosphatase DEP-1/PTPRJ, a negative regulator of FLT3 signaling, by reversible oxidation of its catalytic cysteine residue. Genetic inactivation of NOX4 restores DEP-1 activity and attenuates cell transformation by FLT3-ITD in vitro and in vivo. Future work is required to further explore these mechanisms and their causal involvement in leukemic cell transformation, which may result in the identification of novel candidate targets for therapy. Copyright (C) 2016 ISEH-International Society for Experimental Hematology. Published by Elsevier Inc.