ABSTRACT
Genome-wide expression data from tumors and cell lines in breast cancer, together with drug response of cell lines, open prospects for integrative analyses that can lead to better personalized therapy. Drug responses and expression data collected from cell lines and tumors were used to generate tripartite networks connecting clusters of patients to cell lines and cell lines to drugs, to connect drugs to patients. Various approaches were applied to connect cell lines to tumor clusters: a standard method that uses a biomarker gene set, and new methods that compute metasignatures for transcription factors and histone modifications given upregulated genes in cell lines or tumors. The results from the metasignature analysis identify two major clusters of patients: one enriched for active histone marks and one for repressive marks. The tumors enriched for activation marks are correlated with poor prognosis. Overall, the analyses suggest new patient clustering, discover dysregulated pathways, and recommend individualized use of drugs to treat subsets of patients.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e35; doi:10.1038/psp.2013.11; advance online publication 27 March 2013.
ABSTRACT
OBJECTIVES: This study was designed to validate strain measurements obtained using magnetic resonance tagging with spatial modulation of magnetization (SPAMM). We compared circumferential segment shortening measurements (%S) obtained using SPAMM to sonomicrometry %S in a canine model with (n = 28) and without (n = 3) coronary artery ligation. BACKGROUND: Magnetic resonance tagging enables noninvasive measurement of myocardial strain, but such strain measurements have not yet been validated in vivo. METHODS: Circumferential sonomicrometry crystal pairs were placed in apical myocardium at ischemic risk in ligation studies and in adjacent and remote myocardium. The %S was obtained from closely juxtaposed sonomicrometry and SPAMM sites. RESULTS: Paired data were available from 19 of 31 studies. Both methods distinguished remote from ischemic function effectively (p = 0.014 for SPAMM and p = 0.002 for sonomicrometry). SPAMM %S was similar to sonomicrometry %S in ischemic myocardium (2 +/- 3 vs. 0 +/- 3 p = 0.067) but was slightly higher than sonomicrometry %S in remote myocardium (11 +/- 10 vs. 7 +/- 5, p = 0.033). End-systolic (n = 30) and late systolic (n = 34) SPAMM %S correlated well with sonomicrometry %S (r = 0.84, p < 0.0001 and r = 0.88, p < 0.0001). CONCLUSIONS: Magnetic resonance tagging using SPAMM can quantitate myocardial strain in ischemic and remote myocardium. This study validates its application in scientific investigation and clinical assessment of patients with myocardial ischemia.
Subject(s)
Echocardiography/methods , Magnetic Resonance Imaging/methods , Myocardial Ischemia/diagnosis , Animals , Dogs , Myocardial Ischemia/diagnostic imagingSubject(s)
Child Abuse/diagnosis , Child , Denial, Psychological , Female , Humans , Male , Obstetric Nursing , Parents , PregnancyABSTRACT
BACKGROUND: In hypertensive left ventricular hypertrophy (LVH), intrinsic myocardial systolic function may be normal or depressed. Magnetic resonance tagging can depict intramural myocardial shortening in vivo. METHODS AND RESULTS: Tagged left ventricular magnetic resonance images were obtained in 30 hypertensive subjects with LVH (mean LV mass index, 142 +/- 41 g/m) and normal ejection fraction (mean, 64 +/- 9%) using spatial modulation of magnetization. In 26 subjects, circumferential myocardial shortening (%S) was compared with results obtained in 10 normal subjects at endocardium, midwall, and epicardium on up to 4 short-axis slices each. Similarly, in 10 subjects, midwall long-axis shortening at basal, midventricular, and apical sites was compared with results obtained in 12 normal volunteers. Circumferential %S was reduced in hypertensive subjects. Mean shortening was 29 +/- 6% at the endocardium in hypertensive subjects versus 44 +/- 6% in normal subjects (P = .0001); 20 +/- 6% at the midwall versus 30 +/- 6% (P = .0001); and 13 +/- 5% at the epicardium versus 21 +/- 5% (P = .0002). However, the transmural gradient in percent shortening from endocardium to epicardium in hypertensive subjects paralleled that in normal subjects. The normal base-to-apex gradient in circumferential %S was absent in LVH. In contrast to normal subjects, circumferential %S showed regional heterogeneity in hypertensive subjects, being maximal in the lateral wall and least in the inferior wall. Longitudinal shortening was also uniformly depressed in hypertensive subjects: 10 +/- 9% at the base versus 21 +/- 6% in normal subjects (P = .0001); 14 +/- 8% at the midventricle versus 18 +/- 3% (P = .03); and 14 +/- 8% at the apex versus 18 +/- 4% (P = .04). CONCLUSIONS: In hypertensive LVH with normal pump function, intramural circumferential and longitudinal myocardial shortening are depressed.
Subject(s)
Hypertension/physiopathology , Hypertrophy, Left Ventricular/physiopathology , Myocardial Contraction/physiology , Female , Humans , Hypertension/complications , Hypertrophy, Left Ventricular/diagnosis , Hypertrophy, Left Ventricular/etiology , Image Processing, Computer-Assisted , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myocardium/pathologyABSTRACT
BACKGROUND: Conventional cardiac imaging methods do not depict true segmental myocardial shortening, since they cannot determine segment length between fixed points in the myocardium. METHODS AND RESULTS: We used electrocardiographically gated magnetic resonance imaging with spatial modulation of magnetization to noninvasively "tag" the myocardium with dark stripes at uniform 7-mm intervals center to center at end diastole. We then determined end-systolic stripe separation and thereby calculated circumferential shortening. When end systole was not reached in the first image series, a second temporally overlapped series starting in late systole was used to determine late-systolic shortening. Septal, anterior, lateral, and inferior segments were assessed at endocardium, midwall, and epicardium on five midventricular short-axis sections each in 10 normal volunteers. A transmural gradient in circumferential shortening was observed, with the percentage of endocardial segment shortening consistently greater than epicardial segment shortening (epicardial, 22 +/- 5%; midwall, 30 +/- 6%; and endocardial, 44 +/- 6%; p less than 0.0001 by analysis of variance). Circumferential shortening varied from apex to base with slices closer to the base of the left ventricle showing less shortening at the midwall (28 +/- 9%) and endocardium (39 +/- 6%) than more apical slices at the midwall (34 +/- 13%) and endocardium (49 +/- 9%) (p less than 0.05 and p less than 0.01, respectively, by analysis of variance). CONCLUSIONS: Transmural and longitudinal heterogeneity of circumferential shortening is present in the normal human left ventricle. Magnetic resonance imaging with spatial modulation of magnetization is a powerful new tool for assessment of circumferential shortening and provides information unobtainable with conventional imaging methods.
Subject(s)
Magnetic Resonance Imaging/methods , Myocardial Contraction , Ventricular Function, Left , Adult , Diastole , Female , Humans , Male , SystoleABSTRACT
Ultrafast computed tomography (ultrafast-CT) is a minimally invasive imaging modality with very short acquisition time and excellent anatomic definition. It shows promise of providing precise measurement of right and left ventricular volumes, left ventricular mass, and left ventricular diastolic function with a single test. We expand on the knowledge regarding normal humans by studying ten normal volunteers in the short axis. Cardiac volumes and mass (mean +/- 1 S.D.) were as follows: 1) left ventricle: end-diastolic volume index (ml/m2) = 61 +/- 15, end-systolic volume index (ml/m2) = 19 +/- 7, stroke volume index (ml/m2) = 43 +/- 9, cardiac index (liters/min/m2) = 2.7 +/- .5, ejection fraction (%) = 70 +/- 7, end-diastolic mass (g/m2) = 95 +/- 15; 2) right ventricle: end-diastolic volume index (ml/m2) = 76 +/- 19, end-systolic volume index (ml/m2) = 35 +/- 13, stroke volume index (ml/m2) = 40 +/- 8, cardiac index (liters/min/m2) = 2.6 +/- .5, ejection fraction (%) = 55 +/- 6. Stroke volume index differed by 1.6 +/- 2.0 ml/m2 between ventricles. Measurement of global and segmental left ventricular diastolic function revealed: 1) Peak filling rate (end-diastolic volumes/second): global = 2.29 +/- .40, base = 1.78 +/- .49, midventricle = 2.49 +/- .57, apex = 3.13 +/- .39 (P less than .001, base vs. apex; P less than .01, base vs. midventricle and midventricle vs. apex); 2) time to peak filling rate (msec): global = 193 +/- 24, base = 192 +/- 20, midventricle = 194 +/- 26, apex = 190 +/- 19 (P = NS between levels).(ABSTRACT TRUNCATED AT 250 WORDS)