Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Mammography as screening for coronary artery disease.

Coronary artery disease (CAD) is the leading cause of death in American women. Screening mammograms are recommended for women starting at age 40 for the early detection of breast cancer. An additional benefit of this routine screening tool may be to detect breast arterial calcifications (BAC) as a possible sign of CAD. The purpose of this study was to determine further the relationship between mammographically detected BAC and CAD. The medical records of 44 women who had undergone coronary artery bypass grafting at our institution over 5 years were reviewed. These mammograms were examined for evidence of BAC. For all women included in the study, 18 of 44 (41%) had evidence of BAC on screening mammogram. This was statistically significant (P < 0.0001) compared with the prevalence of BAC reported in the general population in previous studies. Most were also overweight (61.1%), had hypertension (88.8%), and hypercholesterolemia (55.5%). This is the first study to look at the direct correlation between patients with known CAD requiring revascularization and BAC. Perhaps women with BAC seen on screening mammography should undergo further workup for CAD, with the potential benefit of early intervention.

Rapamycin inhibits release of tumor necrosis factor-alpha from human vascular smooth muscle cells.

Neointimal proliferation with plaque formation is the principal cause of coronary artery disease. In the neointima, inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) are expressed by vascular smooth muscle cells (VSMCs). These cytokines stimulate proliferation and migration of VSMCs, events that are crucial to neointima formation. Stents, liberating rapamycin, have been shown to reduce neointima formation in human coronary arteries. The purpose of this study was to determine if rapamycin could inhibit the production of TNF-alpha by VSMCs. With institutional review board approval, VSMCs were cultured from saphenous vein segments obtained from five patients. Cells were identified as VSMC by immunostaining for smooth muscle alpha-actin. Cells were exposed to bacterial lipopolysaccharide (LPS), LPS plus rapamycin, or LPS plus isoproterenol for 24 hours. Cells with no treatment served as controls. The culture medium was then removed and analyzed for TNF-alpha. Additionally, the effect of treatment on viability was determined by assay of mitochondrial activity. TNF-alpha released into the culture medium is expressed as pg TNF-alpha/mg cell protein. Statistical analysis was by ANOVA. In control cells, TNF-alpha was undetectable in the culture medium. The addition of LPS (10 microg/mL) increased TNF-alpha release to 4312 +/- 705 pg/mg at 24 hours. The addition of 1 ng/mL rapamycin with LPS reduced TNF-alpha production 50 per cent (P < 0.01 vs LPS alone). A similar reduction of TNF-alpha release was seen with 1 microM isoproterenol. LPS, rapamycin, or isoproterenol did not affect cell viability. These data show that rapamycin effectively inhibits the release of TNF-alpha from VSMCs stimulated with inflammatory mediators like LPS. Rapamycin is as effective as agents that raise intracellular cyclic AMP (e.g., isoproterenol). Therefore, a potential mechanism for the effectiveness of rapamycin-releasing stents is reduction of inflammatory cytokine expression by VSMCs.

Norepinephrine is a more potent inhibitor of tumor necrosis factor over a range of doses than dopamine.

In the current study, we test the hypothesis that norepinephrine has greater anti-inflammatory effects versus dopamine over a range of doses in a model of lipopolysaccharide (LPS)-stimulated cytokine release in human saphenous vein. Segments of saphenous vein were cut and separated into 1 mm x 1 mm squares and placed into two 24-well plates. These small segments of vessels were incubated in the presence of 20 microg/mL bacterial LPS, alone as a control or with 10x-6, 10x-5, 10x-4, 10x-3 concentration of dopamine or norepinephrine and LPS. The general linear models (GLM) statistical analysis for least squares means and adjustment for multiple comparisons was chosen to analyze the data. Both norepinephrine and dopamine were able to suppress the production of tumor necrosis factor (TNF) in a dose-dependent fashion. Over the range of doses, norepinephrine is a more potent inhibitor of TNF production than dopamine. This is a statistically significant linear trend (P < .0001). Both norepinephrine and dopamine are powerful anti-inflammatory agents. Norepinephrine is a more potent inhibitor of TNF than dopamine.