ABSTRACT
Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of coexpressed genes correlate with disease stage, tumor clonality and early progression. We validated CDC42BPA and CLEC11A as novel regulators and candidate therapeutic targets of MMSET-related myeloma. We then used MMNet to discover novel genes associated with high-risk myeloma and identified a novel four-gene prognostic signature. We identified new patient classes defined by network features and enriched for clinically relevant genetic events, pathways and deregulated genes. Finally, we demonstrated the ability of deep sequencing techniques to detect relevant structural rearrangements, providing evidence that encourages wider use of such technologies in clinical practice. An integrative network analysis of CoMMpass data identified new insights into multiple myeloma disease biology and provided improved molecular features for diagnosing and stratifying patients, as well as additional molecular targets for therapeutic alternatives.
Subject(s)
Multiple Myeloma/genetics , Multiple Myeloma/pathology , Bone Marrow/pathology , Cell Line, Tumor , Disease Progression , Gene Expression Regulation, Neoplastic/physiology , Genome/genetics , Genomics/methods , High-Throughput Nucleotide Sequencing/methods , Humans , PrognosisABSTRACT
BACKGROUND: In previous studies, surfactant-containing Hypochlor brands of sodium hypochlorite showed better tissue solubilizing abilities than Milton; differences not explained by original active chlorine content or presence of surfactant. It was postulated that exhaustion of active chlorine content could explain differences. This study aimed to assess whether Milton's poorer performance was due to exhaustion of active chlorine. Parallel experiments assessed the influence of titration methods, and the presence of chlorates, on active chlorine measurements. METHODS: Time required to dissolve one or groups of 10 samples of porcine incisor pulp samples in Milton was determined. Residual active chlorine was assessed by thermometric titration. Iodometric and thermometric titration was carried out on samples of Milton. Chlorate content was also measured. RESULTS: Dissolution of single and 10 pulp samples caused a mean loss of 1% and 3% respectively of active chlorine, not being proportional to tissue dissolved. Thermometric ammonium ion titration resulted in 10% lower values than iodometric titration. Chlorate accounted for much of this difference. CONCLUSIONS: Depletion of active chlorine is not the reason for differences in tissue dissolving capabilities of Milton. Thermometric ammonium ion titration gives more accurate measurement of active chlorine content than iodometric titration.
Subject(s)
Chlorine/analysis , Dental Pulp/drug effects , Root Canal Irrigants/chemistry , Sodium Hypochlorite/chemistry , Animals , Incisor , Swine , Titrimetry/methodsABSTRACT
A census is described which examined Glasgow General Practitioners (GPs) current practice in the treatment of Intravenous (IV) Drug Users, their expectations of specialist drug services and what aspects of care they are willing to provide.
