Role for glucose transporter 1 protein in human breast cancer

Glycolysis is increased in cancer cells compared with normal cells. It has been shown that glucose enters cells via a family of five functional glucose transporters (GLUT). However, GLUT expression appears to be altered in human breast cancer, which may serve as a selective advantage and facilitate the metastatic potential of these cells. The relationship of GLUT isoform expression and breast cancer cell invasiveness has not been adequately addressed. Thus, the purpose of this study was to investigate whether an association exists between GLUT expression and human breast cancer cell invasiveness. Invasiveness of the human breast cancer lines MCF-7, MDA-MB-435 and MDA-MB-231 was measured using anin vitro assay and compared with cellular GLUT isoform expression, assessed by Western blot analysis and verified by immunohistochemistry in a poorly differentiated human ductal breast cancer. Cell surface GLUT-1 expression was associated with the invasive ability of MCF-7 (2.0 ± 0.02%), MDA-MB-435 (6.4 ±0.4%), and MDA-MB-231 (19.3 ± 2.0%). However, GLUT-2 and GLUT-5 were inversely associated with invasiveness; GLUT-3 expression was variable; and GLUT-4 was undetected. In a poorly differentiated human ductal breast cancer,in situ GLUT-1 staining was intense. GLUT-1 expression was associated with the in vitro invasive ability of human breast cancer cells which was validatedin situ. If this relationship is found to exist in a larger number of human breast cancer tissues, it may be possible to develop diagnostic and therapeutic strategies based on targeted GLUT isoform expression.     

Quantitation of the extent of acute myocardial infarction by phosphorus-31 nuclear magnetic resonance spectroscopy

Phosphorus-31 nuclear magnetic resonance (P-31 NMR) spectroscopy is able to identify alterations in myocardial high energy phosphate metabolism associated with acute infarction. It was hypothesized that the extent of acute myocardial infarction could be quantitated from changes in the tissue content of inorganic phosphate (Pi), phosphocreatine (PCr) and adenosine triphosphate (ATP) derived from P-31 NMR spectra. Nine isolated, perfused rat hearts were studied at 121.5 MHz. After baseline spectra were obtained, varying locations of either the right or the left coronary artery were occluded without removing the heart from the spectrometer. Spectra were then collected during regional ischemia at 15 and 45 min after occlusion. Phosphate metabolites were quantitated from the baseline and 45-min regional ischemia spectra, times at which the metabolites are at steady state for the normal and ischemic conditions. The heart was removed from the spectrometer, perfused for a total duration of 2 h and sectioned into 2-mm thick slices for triphenyltetrazolium chloride staining. Percent infarct was determined by manual tracing of magnified, digitized images of the stained sections. Coronary blood flow, heart rate and blood pressure were monitored throughout the experiment. Significant linear relations were found between percent infarct (by triphenyltetrazolium chloride staining) and the percent change of beta-ATP (r = -0.74), Pi (r = 0.83) and the PCr/Pi ratio (r = -0.71) at 45 min after coronary occlusion. Coronary flow was also found to correlate significantly with percent infarct (r = -0.70). These results are applicable to in vivo P-31 NMR studies of acute infarction where the volume of interest may include both normal and acutely infarcted myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial collagen concentration and nuclear magnetic resonance relaxation times in the spontaneously hypertensive rat.

In order to test the hypothesis that the increased myocardial collagen concentration in the older, spontaneously hypertensive (SH) rat is associated with altered T2 and T1, we performed in vitro studies of 70 left ventricles from 8-, 22-, and 33-week-old SH and Wistar-Kyoto (WKY) rats. We also measured the left ventricle/body weight (LV/BW) ratio (as a measure of hypertrophy), left ventricular water and fat content, and hydroxyproline concentration (as a measure of collagen). The LV/BW ration was not significantly different between 8-week-old SH rats and WKY rats but was significantly greater in SH rats than in WKY rats at 22 and 33 weeks of age. Comparing SH rats with WKY rats at 22 weeks of age, no significant difference existed in T1, T2, water content, or hydroxyproline concentration. However, at 33 weeks of age in SH rats compared with WKY rats, hydroxyproline concentration was significantly greater (4.3 +/- 0.6 mg/g, respectively; P less than .0005), water content was significantly greater (77.1% +/- 0.3% vs. 76.2% +/- 0.3%, respectively; P less than .0001), and T2 and T1 were significantly longer (T2: 52.6 +/- 2.1 msec vs. 48.6 +/- 2.2 msec, respectively; P less than .0001; T1: 656 +/- 14 msec vs. 619 +/- 12 msec, respectively; P less than .0001). In all SH rats combined, T2 and hydroxyproline concentration were significantly correlated (r = .63; P less than .0001). Thus, in SH rats, myocardial hypertrophy precedes increased collagen deposition. These data suggest that estimation of magnetic resonance relaxation times may permit noninvasive identification of increased myocardial collagen deposition independent from changes in myocardial hypertrophy.     

Identification of impaired metabolic reserve by atrial pacing in patients with significant coronary artery stenosis

We investigated myocardial 11C-palmitate clearance kinetics at a resting heart rate (control) and during pacing using positron-emission tomography in 10 patients with significant coronary artery stenosis (greater than 70%) and evidence of exercise-induced ischemia. Serial 11C-palmitate images acquired at control and during pacing revealed biexponential myocardial 11C clearance both in myocardium supplied by a stenotic coronary artery (myocardium "at risk") and in myocardium supplied by a normal coronary artery (normal myocardium). At control, the average rate of myocardial 11C clearance from the early rapid curve component (the clearance half-time) was similar in normal myocardium and in that at risk (22.2 +/- 5.2 vs 21.0 +/- 5.4 min, NS), as was the amount of myocardial 11C activity at the end of the early rapid phase (residual fraction 56.3 +/- 7.2% vs 54.7 +/- 7.3%, NS). Thus, myocardial clearance was homogeneous at control, suggesting a similar rate and amount of 11C-palmitate oxidation in normal myocardium and in that at risk. Pacing shortened clearance half-times and decreased residual fraction in both normal myocardium and that at risk compared with control. However, clearance half-times were 17% longer and residual fractions 14% higher in myocardium at risk compared with normal myocardium (p less than .005 and p less than .01, respectively). Therefore, during pacing myocardial 11C clearance became heterogeneous, suggesting impaired 11C-palmitate oxidation in myocardium at risk compared with normal myocardium. Increased substrate utilization in response to increased workload can be thought of as a measure of metabolic reserve. Our data suggest metabolic reserve for free fatty acid oxidation is impaired in myocardium supplied by a significantly stenosed coronary artery and that this impairment can be detected by analysis of myocardial 11C-palmitate clearance.     

Validation of PET-acquired input functions for cardiac studies

To validate the determination of the arterial input function by noninvasive dynamic PET imaging, measurements of blood-pool activity in canine LV by PET were compared to beta probe measurements of arterial blood withdrawn directly from the LV. PET scans were done during intravenous bolus injections of [13N]ammonia or 82Rb, while the activity of blood withdrawn continuously from a catheter inserted in the LV was measured with a beta probe. PET determinations of LV blood-pool activity were compared with dispersion-corrected beta probe time-activity curves. In 15 experiments involving four dogs under a wide range of physiologic conditions, LV time-activity curves obtained with PET matched well in shape with those obtained with the beta probe. Linear regression yielded slopes within 10% of unity (95% confidence interval) and high correlation (r greater than 0.968, p less than 0.001). We conclude that noninvasive measurement of the arterial input function by dynamic PET imaging is valid.     

Positron emission tomography detects tissue metabolic activity in myocardial segments with persistent thallium perfusion defects

Positron emission tomography with 13N-ammonia and 18F-2-deoxyglucose was used to assess myocardial perfusion and glucose utilization in 51 myocardial segments with a stress thallium defect in 12 patients. Myocardial infarction was defined by a concordant reduction in segmental perfusion and glucose utilization, and myocardial ischemia was identified by preservation of glucose utilization in segments with rest hypoperfusion. Of the 51 segments studied, 36 had a fixed thallium defect, 11 had a partially reversible defect and 4 had a completely reversible defect. Only 15 (42%) of the 36 segments with a fixed defect and 4 (36%) of the 11 segments with a partially reversible defect exhibited myocardial infarction on study with positron tomography. In contrast, residual myocardial glucose utilization was identified in the majority of segments with a fixed (58%) or a partially reversible (64%) thallium defect. All of the segments with a completely reversible defect appeared normal on positron tomography. Apparent improvement in the thallium defect on delayed images did not distinguish segments with ischemia from infarction. Thus, positron emission tomography reveals evidence of persistent tissue metabolism in the majority of segments with a fixed or partially resolving stress thallium defect, implying that markers of perfusion alone may underestimate the extent of viable tissue in hypoperfused myocardial segments.     

Thrombolytic-Associated Cholesterol Emboli Syndrome: Case Report and Literature Review

Thrombolytics can cause cholesterol embolization syndrome (CES). This adverse effect has received less attention than other risks of thrombolytic therapy, such as systemic bleeding and hemorrhage, with only sporadic reports of CES in the literature. Risk factors have not been consistently identified and emphasized; therefore, occurrence of CES after thrombolysis remains difficult to predict, it results in substantial morbidity and mortality, and it lacks effective pharmacologic treatment. Heightened awareness of the disorder can aid in its correct identification and reporting.     

An improved method for the quantification of left-to-right cardiac shunts.

We have investigated a technique for quantifying QP/QS in left-to-right cardiac shunts. In this method, the gamma variate, which is fitted to the first-pass portion of the lung curve, is used to generate a curve, which simulates the response of a normal lung curve with systemic recirculation. The difference between this curve and the observed lung curve is then used to calculate QP/QS. This method was evaluated on a set of simulated lung time-activity curves with precisely known QP/QS values on a group of 11 patients with no clinical suspicion of cardiac shunt and on a group of 30 patients referred for cardiac shunt studies. The QP/QS in each of these studies was determined by three individuals using both the Maltz-Treves method and the new method. This method yielded QP/QS values that were more accurate on the simulated lung data and had less interobserver variation on all the studies than those obtained from the Maltz-Treves method.     

Dissociation between regional myocardial dysfunction and subendocardial ST segment elevation during and after exercise-induced ischemia in dogs

The onset and resolution of electrical and functional measures of regional myocardial ischemia were examined in nine conscious dogs during control exercise and exercise after beta-receptor blockade. The dogs had been instrumented with an ameroid constrictor and were studied when no regional dysfunction was evident at rest, although severe coronary stenosis or coronary occlusion with collateral circulation development was present. ST segment elevation was measured on subendocardial electrograms, and regional wall motion was studied by sonomicrometry. During control exercise, subendocardial myocardial blood flow in the ischemic zone, normalized to blood flow in the nonischemic zone, decreased. Subendocardial ST elevation increased slowly, was significantly different from control standing values by 2.5 minutes of exercise and returned quickly to control values within 5 minutes after exercise. Percent systolic wall thickening decreased rapidly, was significantly depressed by 1 minute of exercise and did not return to control values until 30 minutes after exercise. A second, identical exercise stress was performed on the same day after a single oral dose (1 mg/kg body weight) of atenolol. In the ischemic zone during exercise after atenolol compared with control exercise, normalized subendocardial myocardial blood flow was improved and significantly less ST elevation occurred, but the onset and resolution of ST elevation were not altered. Systolic wall dysfunction during exercise was significantly less after atenolol, and function returned toward preexercise values by 1 minute after exercise, even more rapidly than ST segment resolution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary artery disease and cardiac events with asymptomatic and symptomatic cerebrovascular disease.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the prevalence of coronary artery disease and coronary events during follow-up in patients with asymptomatic carotid stenosis, transient ischemic attacks, or small strokes. METHODS: We prospectively studied 60 consecutive patients with thallium-201 scintigraphy followed by coronary arteriography according to an established protocol. RESULTS: The 201Tl testing was abnormal in seven of 15 patients (47%) with asymptomatic carotid stenosis and in 19 of 44 patients (43%) with transient ischemic attacks or small strokes (p greater than 0.05). In 33 patients with no history of coronary artery disease, 11 (33%) had reversible 201Tl defects. In 26 patients with a history of coronary artery disease, 15 (58%) had reversible and/or fixed defects (p = 0.054 compared with patients with no history). A history of peripheral vascular disease was the only risk factor significantly associated with an abnormal 201Tl test (p = 0.032). Coronary artery stenosis of greater than 50% was identified in one or more vessels in 14 of 15 patients undergoing coronary arteriography. Over a mean follow-up period of 311 days, four patients (7%) developed new onset of angina. There were four coronary events among 14 patients (29%) with both a reversible area on the 201Tl and abnormal coronary arteriography. In comparison, there were only four coronary events among 46 patients (9%) without reversible defects on the 201Tl studies (p = 0.055). CONCLUSIONS: Our study demonstrates that one third of patients with no history of coronary artery disease had an abnormal 201Tl test and that nearly one half of patients with either symptomatic or asymptomatic cerebrovascular disease had abnormal 201Tl tests. Patients with a reversible 201Tl defect and significant stenosis by coronary arteriography were at higher risk for subsequent cardiac events. These findings demonstrate the utility of screening patients with asymptomatic and symptomatic cerebrovascular disease for cardiac disease.