bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Small-Molecule Inhibitor of Glucose Transporter 1 Downregulates Glycolysis, Induces Cell-Cycle Arrest, and Inhibits Cancer Cell Growth In Vitro and In Vivo
Authors: Liu Yi , Cao Yanyan , Zhang Weihe , Bergmeier Stephen , Qian Yanrong , Akbar Huzoor , Colvin Robert , Ding Juan , Tong Lingying , Wu Shiyong , Hines Jennifer , Chen Xiaozhuo 
Published: June 2012

Abstract
The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation–like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor–treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism. Mol Cancer Ther; 11(8); 1672–82. ©2012 AACR.
The Your Disease Risk Index for Colorectal Cancer Is an Inaccurate Risk Stratification Tool for Advanced Colorectal Neoplasia at Screening Colonoscopy
Authors: Schroy Paul C. , Coe Alison M. , Mylvaganam Shamini R. , Ahn Lynne B. , Lydotes Maria A. , Robinson Patricia A. , Davis Julie T. , Chen Clara A. , Ashba Jacqueline , Atkinson Michael L. , Colditz Graham A. , Heeren Timothy C. 
Published: June 2012

Abstract
Tailoring the use of screening colonoscopy based on the risk of advanced colorectal neoplasia (ACN) could optimize the cost-effectiveness of colorectal cancer (CRC) screening. Our goal was to assess the accuracy of the Your Disease Risk (YDR) CRC risk index for stratifying average risk patients into low- versus intermediate/high-risk categories for ACN. The YDR risk assessment tool was administered to 3,317 asymptomatic average risk patients 50 to 79 years of age just before their screening colonoscopy. Associations between YDR-derived relative risk (RR) scores and ACN prevalence were examined using logistic regression and χ2 analyses. ACN was defined as a tubular adenoma ≥1 cm, tubulovillous or villous adenoma of any size, and the presence of high-grade dysplasia or cancer. The overall prevalence of ACN was 5.6%. Although YDR-derived RR scores were linearly associated with ACN after adjusting for age and gender (P = 0.033), the index was unable to discriminate “below average” from “above/average” risk patients [OR, 1.01; 95% confidence interval (CI), 0.75–1.37]. Considerable overlap in rates of ACN was also observed between the different YDR risk categories in our age- and gender-stratified analyses. The YDR index lacks accuracy for stratifying average risk patients into low- versus intermediate/high-risk categories for ACN. Cancer Prev Res; 5(8); 1044–52. ©2012 AACR.
Contractility and stiffness of noninfarcted myocardium after coronary ligation in rats. Effects of chronic angiotensin converting enzyme inhibition.
Authors: Litwin S E , Litwin C M , Raya T E , Warner A L , Goldman S 
Published: June 2012

BACKGROUND
Previous studies have shown that global left ventricular function is depressed after myocardial infarction. However, little is known about the effects of myocardial infarction on contractility and the passive-elastic properties of residual myocardium.

METHODS AND RESULTS
We evaluated isometric function and passive myocardial stiffness in isolated, noninfarcted left ventricular papillary muscle from rats 6 weeks after sham operation or myocardial infarction. Maximal developed tension and peak rate of tension rise (+dT/dt) were significantly decreased in untreated rats with large myocardial infarction compared with controls (3.3 +/- 1.1 versus 4.3 +/- 0.6 g/mm2 and 49.5 +/- 17.5 versus 72.5 +/- 10.5 g/mm2/sec, respectively). Time to peak tension was prolonged (120 +/- 8 versus 102 +/- 4 msec) and myocardial stiffness was increased in untreated myocardial infarction rats compared with controls (35.2 +/- 4.9 versus 24.2 +/- 3.7). Rats with smaller myocardial infarctions differed from controls only with respect to a prolongation of time to peak tension. Papillary muscle myocyte cross-sectional area was increased by 44% (p less than 0.05), and myocardial hydroxyproline content was increased by 160% (p less than 0.05) in rats with large myocardial infarctions compared with controls. To determine whether treatment that improves left ventricular function after myocardial infarction also improves myocardial function, rats were treated with captopril beginning 3 weeks after myocardial infarction and continuing for 3 weeks. Treatment with captopril attenuated the prolongation in time to peak tension in the myocardial infarction rats; however, developed tension, +dT/dt, and muscle stiffness remained abnormal. Compared with untreated myocardial infarction rats, captopril-treated myocardial infarction rats had a 9% decrease in myocyte cross-sectional area (p = 0.1) but a persistent increase in myocardial collagen content. In summary, large myocardial infarction in rats causes contractile dysfunction, increased stiffness, myocyte hypertrophy, and increased collagen content in the residual noninfarcted myocardium. Treatment with captopril alters the process of cardiac remodeling and hypertrophy and improves one parameter of contractility in noninfarcted myocardium; however, myocardial collagen content and myocardial stiffness remain abnormal.

CONCLUSIONS
These findings suggest that angiotensin converting enzyme inhibition in the rat infarct model of heart failure improves global cardiac performance via combined effects on myocardial function and the peripheral circulation.
Influence of coronary collateral vessels on myocardial infarct size in humans. Results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI Investigators.
Authors: Habib G B , Heibig J , Forman S A , Brown B G , Roberts R , Terrin M L , Bolli R 
Published: June 2012

BACKGROUND
The influence of coronary collateral vessels on infarct size in humans remains controversial, partly because no previous study has examined the impact of collaterals present at the onset of acute myocardial infarction on infarct size.

METHODS AND RESULTS
The present study used the data base of the Thrombolysis in Myocardial Infarction (TIMI) Phase I trial to correlate the presence or absence of angiographically documented collaterals in the initial hours of myocardial infarct evolution with the size of the infarct as assessed by serial measurements of serum creatine kinase (CK). To avoid the confounding effects of reperfusion on enzymatic estimates of infarct size, this report is limited to those 125 patients who failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A, n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B, n = 74) (1,877 +/- 216 versus 2,661 +/- 212 IU/l, respectively [mean +/- SEM], p = 0.004). Similarly, CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 +/- 2.5 versus 31.4 +/- 2.8 CK gram equivalents, p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus, the beneficial effects of collaterals were independent of the site of the infarct. In 65 of the 125 patients who failed to reperfuse, left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies, global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 +/- 1.8% to 53.4 +/- 1.8%, p = 0.10) but decreased in group B patients (from 50.3 +/- 1.8% to 47.8 +/- 1.7%, p = 0.02). At hospital discharge, global LVEF was greater in patients with coronary collaterals (53.5 +/- 1.7% versus 49.6 +/- 1.7%, p = 0.01).

CONCLUSIONS
The results demonstrate that, in patients in whom thrombolytic therapy fails to induce reperfusion, the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.
Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies.
Authors: Yarnell J W , Baker I A , Sweetnam P M , Bainton D , O'Brien J R , Whitehead P J , Elwood P C 
Published: June 2012

BACKGROUND
Recent studies have suggested that hemostatic factors and white blood cell count are predictive of ischemic heart disease (IHD). The relations of fibrinogen, viscosity, and white blood cell count to the incidence of IHD in the Caerphilly and Speedwell prospective studies are described.

METHODS AND RESULTS
The two studies have a common core protocol and are based on a combined cohort of 4,860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell; 251 major IHD events had occurred. Age-adjusted relative odds of IHD for men in the top 20% of the distribution compared with the bottom 20% were 4.1 (95% confidence interval, 2.6-6.5) for fibrinogen, 4.5 (95% confidence interval, 2.8-7.4) for viscosity, and 3.2 (95% confidence interval, 2.0-4.9) for white blood cell count. Associations with IHD were similar in men who had never smoked, exsmokers, and current smokers, and the results suggest that at least part of the effect of smoking on IHD is mediated through fibrinogen, viscosity, and white blood cell count. Multivariate analysis shows that white blood cell count is an independent risk factor for IHD as is either fibrinogen or viscosity, or possibly both. Jointly, these three variables significantly improve the fit of a logistic regression model containing all the main conventional risk factors. Further, a model including age, smoking habits, fibrinogen, viscosity, and white blood cell count predicts IHD as well as one in which the three hemostatic/rheological variables are replaced by total cholesterol, diastolic pressure, and body mass index.

CONCLUSION
Jointly, fibrinogen, viscosity, and white blood cell count are important risk factors for IHD.
Upward shift of the lower range of coronary flow autoregulation in hypertensive patients with hypertrophy of the left ventricle.
Authors: Polese A , De Cesare N , Montorsi P , Fabbiocchi F , Guazzi M , Loaldi A , Guazzi M D 
Published: June 2012

BACKGROUND
At any given perfusion pressure, coronary reserve is expressed by the difference between autoregulated and maximally vasodilated flow. In hypertension the raised coronary resistance reduces the steepness of the pressure-flow relationship at maximal vasodilatation. In the presence of cardiac hypertrophy the line of autoregulated flow becomes higher. For these reasons coronary reserve is reduced and the point at which baseline flow approaches the maximal achievable flow might be shifted to a higher perfusion pressure. Thus, any reduction below this elevated and critical value of pressure would lower the coronary flow.

METHODS AND RESULTS
The investigated patients were normotensive (controls, nine) and hypertensive with normal (group I, seven) or augmented LV mass index because of concentric LV hypertrophy (group II, eight). All had effort-induced angina and angiographically normal left epicardial branches. Flow in the great cardiac vein was measured by thermodilution in the baseline and during stepwise (5 mm Hg every 5 minutes) decrease of the coronary perfusion pressure with a titrated nitroprusside i.v. infusion; perfusion pressures of 60 mm Hg in the controls and 70 mm Hg in the hypertensives were taken as end points. Baseline flow averaged 102 ml/min in normotensives, 104 ml/min in hypertensive group I and 148 ml/min in hypertensive group II. At the end points flow was similar to baseline in the controls and group I. In group II coronary flow started to decline and myocardial O2 extraction started to slightly but significantly rise at perfusion pressures of 90-80 mm Hg; at the end point flow was reduced by 26% (p less than 0.01 from baseline). The perfusion patterns did not seem to be related to the changes in tension-time index and heart rate.

CONCLUSIONS
The association of high blood pressure (reduced ability of the coronary arterioles to dilate) and hypertrophy of the myocardium (augmented baseline coronary flow) may shift the point of exhaustion of coronary reserve to a higher perfusion pressure and make the myocardium vulnerable to treatment-induced relative hypertension.
Increased thrombin levels during thrombolytic therapy in acute myocardial infarction. Relevance for the success of therapy.
Authors: Gulba D C , Barthels M , Westhoff-Bleck M , Jost S , Rafflenbeul W , Daniel W G , Hecker H , Lichtlen P R 
Published: June 2012

BACKGROUND
It has been suggested that thrombolysis in a feedback reaction may generate pro-coagulant activities.

METHODS AND RESULTS
Fifty-five patients were treated with urokinase-preactivated prourokinase (n = 35) or tissue-type plasminogen activator (n = 20) for acute myocardial infarction and underwent coronary angiography at 90 minutes and at 24-36 hours into thrombolysis, and fibrinogen (Ratnoff-Menzie), D-dimer (ELISA) and thrombin-antithrombin III complex levels (ELISA) were measured. Primary patency was achieved in 39 patients (70.9%), 13 of whom (33.3%) suffered early reocclusion. Nonsignificant decreases in fibrinogen levels were observed while D-dimer levels increased +3,008 +/- 4,047 micrograms/l (p less than 0.01), differences not being significant in respect to the thrombolytic agents or to the clinical course. In contrast, while thrombin-antithrombin III complex levels decreased -4.4 +/- 13.0 micrograms/l in patients with persistent patency, they increased +7.5 +/- 13.6 micrograms/l in case of nonsuccessful thrombolysis (p less than 0.02) and +11.9 +/- 23.8 micrograms/l in case of early reocclusion (p less than 0.001). For patients with thrombin-antithrombin III complex levels greater than 6 ng/l 120 minutes into thrombolysis, the unfavorable clinical course was predicted with 96.2% sensitivity and 93.1% specificity.

CONCLUSION
Generation of thrombin, occurring during thrombolysis, is a major determinant for the success of therapy and thrombin-antithrombin III levels may serve as predictors for the short-term prognosis.
Baroreflex sensitivity and electrophysiological correlates in patients after acute myocardial infarction.
Authors: Farrell T G , Paul V , Cripps T R , Malik M , Bennett E D , Ward D , Camm A J 
Published: June 2012

BACKGROUND
Several studies have identified transient disturbances of autonomic function during the acute and recovery phases of myocardial infarction, and it has recently been suggested that survivors of acute myocardial infarction with depressed vagal tone may be at increased risk of sudden or arrhythmic death.

METHODS AND RESULTS
To investigate this hypothesis, parasympathetic function was assessed by arterial baroreflex sensitivity (BRS) testing (using the phenylephrine method) and by heart rate variability (HRV) analysis from 24-hour Holter recording in 68 patients at day 7-10 after infarction. The relation between autonomic tone and markers of arrhythmic propensity, including programmed ventricular stimulation (PVS) and late potentials in addition to other clinical variables, was examined. BRS for the whole group was 7.0 +/- 4.7 msec/mm Hg and was inversely correlated with age (r = 0.53, p less than 0.001) but not with left ventricular ejection fraction (r = 0.035, p = NS). In those patients in whom sustained monomorphic ventricular tachycardia (SMVT) was induced, BRS was significantly reduced (p = 0.001) as was HRV (p = 0.007) and left ventricular ejection fraction (p = 0.022). The strongest association between any variable (including HRV, BRS, late potentials, left ventricular ejection fraction, exercise testing, Q waves, and infarct site) and the induction of sustained monomorphic ventricular tachycardia was depressed BRS with a relative risk of 36.28 (95% confidence interval, 5-266).

CONCLUSIONS
This study confirms that depressed BRS identifies a subgroup at high risk for arrhythmic events after myocardial infarction and that programmed ventricular stimulation may be safely limited to this group without any loss of predictive accuracy.
Expected gains in life expectancy from various coronary heart disease risk factor modifications.
Authors: Tsevat J , Weinstein M C , Williams L W , Tosteson A N , Goldman L 
Published: June 2012

BACKGROUND
Despite much evidence that modifying risk factors for coronary heart disease can decrease morbidity and mortality, little is known about the impact of risk-factor modification on life expectancy.

METHODS AND RESULTS
We used the Coronary Heart Disease Policy Model, a state-transition computer simulation of the US population, to forecast potential gains in life expectancy from risk-factor modification for the cohort of Americans turning age 35 in 1990. Among 35-year-old men, we projected that the population-wide increase in life expectancy would be about 1.1 years from strict blood pressure control, 0.8 years from smoking cessation, 0.7 years from reduction of serum cholesterol to 200 mg/dl, and about 0.6 years from weight loss to ideal body weight. For women, reducing cholesterol to 200 mg/dl would have the greatest estimated impact-a gain of 0.8 years-whereas smoking cessation, blood pressure control, or weight loss would yield population-wide gains of 0.7, 0.4, and 0.4 years, respectively. Gains for 35-year-old individuals having a given risk factor are greater. We estimate that, on average, male smokers would gain 2.3 years from quitting smoking; males with hypertension would gain 1.1-5.3 years from reducing their diastolic blood pressure to 88 mm Hg; men with serum cholesterol levels exceeding 200 mg/dl would gain 0.5-4.2 years from lowering their serum cholesterol level to 200 mg/dl; and overweight men would gain an average of 0.7-1.7 years from achieving ideal body weight. Corresponding projected gains for at-risk women are 2.8 years from quitting smoking, 0.9-5.7 years from lowering blood pressure, 0.4-6.3 years from decreasing serum cholesterol, and 0.5-1.1 years from losing weight. Eliminating coronary heart disease mortality is estimated to extend the average life expectancy of a 35-year-old man by 3.1 years and a 35-year-old woman by 3.3 years.

CONCLUSIONS
Population-wide gains in life expectancy from single risk-factor modifications are modest, but gains to individuals at risk can be more substantial.
Short-term effect of dynamic exercise on arterial blood pressure.
Authors: Pescatello L S , Fargo A E , Leach C N , Scherzer H H 
Published: June 2012

BACKGROUND
To quantify the duration of postexercise hypotension at different exercise intensities, we studied six unmedicated, mildly hypertensive men matched with six normotensive controls.

METHODS AND RESULTS
Each subject wore a 24-hour ambulatory blood pressure monitor at the same time of day for 13 consecutive hours on 3 different days. On each of the 3 days, subjects either cycled for 30 minutes at 40% or 70% maximum VO2 or performed activities of daily living. There was no intensity effect on the postexercise reduction in blood pressure, so blood pressure data were combined for the different exercise intensities. Postexercise diastolic blood pressure and mean arterial pressure were lower by 8 +/- 1 (p less than 0.001) and 7 +/- 1 mm Hg (p less than 0.05), respectively, than the preexercise values for 12.7 hours in the hypertensive group. These variables were not different before and after exercise in the normotensive group. Systolic blood pressure was reduced by 5 +/- 1 mm Hg (p less than 0.05) for 8.7 hours after exercise in the hypertensive group. In contrast, systolic blood pressure was 5 +/- 1 mm Hg (p less than 0.001) higher for 12.7 hours after exercise in the normotensive group. When the blood pressure response on the exercise days was compared with that on the nonexercise day, systolic blood pressure (135 +/- 1 versus 145 +/- 1 mm Hg) and mean arterial pressure (100 +/- 1 versus 106 +/- 1 mm Hg) were lower (p less than 0.05) on the exercise days in the hypertensive but not in the normotensive group. We found a postexercise reduction in mean arterial pressure for 12.7 hours independent of the exercise intensity in the hypertensive group. Furthermore, mean arterial pressure was lower on exercise than on nonexercise days in the hypertensive but not in the normotensive group.

CONCLUSION
These findings indicate that dynamic exercise may be an important adjunct in the treatment of mild hypertension.
A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex.
Authors: Brugada P , Brugada J , Mont L , Smeets J , Andries E W 
Published: June 2012

BACKGROUND
In the differential diagnosis of a tachycardia with a wide QRS complex (greater than or equal to 0.12 second) diagnostic mistakes are frequent. Therefore, we investigated the reasons for failure of presently available criteria, and we identified new, simpler criteria and incorporated them in a stepwise approach that provides better sensitivity and specificity for making a correct diagnosis.

METHODS AND RESULTS
A prospective analysis revealed that current criteria had a poor specificity for the differential diagnosis. The value of four new criteria incorporated in a stepwise approach was prospectively analyzed in a total of 554 tachycardias with a widened QRS complex (384 ventricular and 170 supraventricular). The sensitivity of the four consecutive steps was 0.987, and the specificity was 0.965.

CONCLUSIONS
Current criteria for the differential diagnosis between supraventricular tachycardia with aberrant conduction and ventricular tachycardia are frequently absent or suggest the wrong diagnosis. The absence of an RS complex in all precordial leads is easily recognizable and highly specific for the diagnosis of ventricular tachycardia. When an RS complex is present in one or more precordial leads, an RS interval of more than 100 msec is highly specific for ventricular tachycardia. This new stepwise approach may prevent diagnostic mistakes.