ABSTRACT
BACKGROUND: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. METHODS: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. RESULTS: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. CONCLUSIONS: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various 'high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions.
Subject(s)
Blood Chemical Analysis/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Early Detection of Cancer/methods , Lung Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Algorithms , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Case-Control Studies , Cohort Studies , Female , Humans , Lung Neoplasms/blood , Male , Middle Aged , Serum/chemistryABSTRACT
The mechanisms underlying desensitization of serotonin 2A (5-HT(2A)) receptor signaling by antagonists are unclear but may involve changes in gene expression mediated via signal transduction pathways. In cells in culture, olanzapine causes desensitization of 5-HT(2A) receptor signaling and increases the levels of regulators of G protein signaling (RGS) 7 protein dependent on phosphorylation/activation of the Janus kinase 2 (Jak2)/signal transducers and activators of transcription 3 (Stat3) signaling pathway. In the current study, the 5-HT(2A) receptor signaling system in rat frontal cortex was examined following 7 days of daily treatment with 0.5, 2.0 or 10.0 mg/kg i.p. olanzapine. Olanzapine increased phosphorylation of Stat3 in rats treated daily with 10 mg/kg olanzapine and caused a dose-dependent desensitization of 5-HT(2A) receptor-mediated phospholipase C activity. There were dose-dependent increases in the levels of membrane-associated 5-HT(2A) receptor, G(alpha11) and G(alphaq) protein levels but no changes in the G(beta) protein levels. With olanzapine treatment, RGS4 protein levels increase in the membrane-fraction and decrease in the cytosolic fraction by similar amounts suggesting a redistribution of RGS4 protein within neurons. RGS7 protein levels increase in both the membrane and cytosolic fractions in rats treated daily with 10mg/kg olanzapine. The olanzapine-induced increase in Stat3 activity could underlie the increase in RGS7 protein expression in vivo as previously demonstrated in cultured cells. Furthermore, the increases in membrane-associated RGS proteins could play a role in desensitization of signaling by terminating the activated G(alphaq/11) proteins more rapidly.
