Sickle cell disease causes severe pain. We examined pain-related behaviors, correlative neurochemical changes, and analgesic effects of morphine and cannabinoids in transgenic mice expressing human sickle hemoglobin (HbS). Paw withdrawal threshold and withdrawal latency (to mechanical and thermal stimuli, respectively) and grip force were lower in homozygous and hemizygous Berkley mice (BERK and hBERK1 ,

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Background Epidermal growth factor receptor (EGFR) is co-activated by the μ-opioid receptor (MOR), expressed on non-small cell lung cancer (NSCLC) cells and human lung cancer. We hypothesized that clinically used opioid analgesics that are MOR agonists co-activate EGFR, resulting in growth- and survival-promoting signaling. Methods We used H2009, a human adenocarcinoma NSCLC cell line, with constitutive EGFR phosphorylation, which showed increased expression of MOR and delta opioid receptor (DOR) by reverse transcriptase polymerase chain reaction. We used Western immunoblotting, magnetic bead-based Bio-plex cytokine assay, immunofluorescent staining, BrdU incorporation ELISA and BioCoat™ Matrigel™ invasion assay, to examine cell signaling, cytokine expression, co-localization of MOR and EGFR in human lung cancer, cell proliferation and invasion, respectively. Results Like epidermal growth factor (EGF), morphine stimulated phosphorylation of EGFR, Akt/protein kinase B (Akt), and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling in H2009 cells. Opioid receptor (OR) antagonist, naloxone, EGFR tyrosine kinase inhibitor, erlotinib, and silencing of MOR and DOR abrogated morphine- and EGF-induced phosphrylation of signaling, suggestive of OR mediated co-activation of EGFR. H2009 cells secreted significantly higher levels of cytokines as compared to control Beas2B epithelial cells. H2009 conditioned medium stimulated MOR expression in Beas2B cells, suggesting that cytokines secreted by H2009 may be associated with increased OR expression in H2009. We observed co-localization of EGFR and MOR, in human NSCLC tissue. Functionally, morphine and EGF-induced proliferation and invasion of H2009 cells was ameliorated by naloxone as well as erlotinib. Conclusion Morphine-induced phosphorylation of EGFR occurs via ORs, leading to downstream MAPK/ERK, Akt phosphorylation, cell proliferation and increased invasion. Notably, ORs are also associated with EGF-induced phosphorylation of EGFR. Increased co-expression of MOR and EGFR in human lung cancer suggests that morphine may have a growth-promoting effect in lung cancer.

The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a weeklong event - A Full Immersion Week of Bioanalysis for PK, Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on PK, biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This White Paper is published in 3 parts due to length. This part (Part 3) discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Parts 1 (small molecule bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in the Bioanalysis journal, issues 22 and 23, respectively.

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