67 research outputs found

    Tuning a Polar Molecule for Selective Cytoplasmic Delivery by a pH (Low) Insertion Peptide

    Get PDF
    Drug molecules are typically hydrophobic and small in order to traverse membranes to reach cytoplasmic targets, but we have discovered that more polar molecules can be delivered across membranes using water-soluble, moderately hydrophobic membrane peptides of the pHLIP (pH low insertion peptide) family. Delivery of polar cargo molecules could expand the chemical landscape for pharmacological agents that have useful activity but are too polar by normal drug criteria. The spontaneous insertion and folding of the pHLIP peptide across a lipid bilayer seeks a free energy minimum, and insertion is accompanied by a release of energy that can be used to translocate cell-impermeable cargo molecules. In this study, we report our first attempt to tune the hydrophobicity of a polar cargo, phallacidin, in a systematic manner. We present the design, synthesis, and characterization of three phallacidin cargoes, where the hydrophobicity of the cargo was tuned by the attachment of diamines of various lengths of hydrophobic chains. The phallacidin cargoes were conjugated to pHLIP and shown to selectively inhibit the proliferation of cancer cells in a concentration-dependent manner at low pH

    Nuclear stress perfusion imaging versus computed tomography coronary angiography for identifying patients with obstructive coronary artery disease as defined by conventional angiography: insights from the CorE-64 multicenter study

    No full text
    We investigated the diagnostic accuracy of computed tomography angiography (CTA) versus myocardial perfusion imaging (MPI) for detecting obstructive coronary artery disease (CAD) as defined by conventional quantitative coronary angiography (QCA). Sixty-three patients who were enrolled in the CorE-64 multicenter study underwent CTA, MPI, and QCA imaging. All subjects were referred for cardiac catheterization with suspected or known coronary artery disease. The diagnostic accuracy of quantitative CTA and MPI for identifying patients with 50% or greater coronary arterial stenosis by QCA was evaluated using receiver operating characteristic (ROC) analysis. Pre-defined subgroups were patients with known CAD and those with a calcium score of 400 or over. Diagnostic accuracy by ROC analysis revealed greater area under the curve (AUC) for CTA than MPI for all 63 patients: 0.95 [95% confidence interval (CI): 0.89-0.100] vs 0.65 (95%CI: 0.53-0.77), respectively (P<0.01). Sensitivity, specificity, positive and negative predictive values were 0.93, 0.95, 0.97, 0.88, respectively, for CTA and 0.85, 0.45, 0.74, 0.63, respectively, for MPI. In 48 patients without known CAD, AUC was 0.96 for CTA and to 0.67 for SPECT (P<0.01). There was no significant difference in AUC for CTA in patients with calcium score below 400 versus over 400 (0.93 vs 0.95), but AUC was different for SPECT (0.61 vs 0.95; P<0.01). In a direct comparison, CTA is markedly superior to MPI for detecting obstructive coronary artery disease in patients. Even in subgroups traditionally more challenging for CTA, SPECT does not offer similarly good diagnostic accuracy. CTA may be considered the non-invasive test of choice if diagnosis of obstructive CAD is the purpose of imaging

    Patient Characteristics as Predictors of Image Quality and Diagnostic Accuracy of MDCT Compared With Conventional Coronary Angiography for Detecting Coronary Artery Stenoses: CORE-64 Multicenter International Trial

    No full text
    OBJECTIVE. The purpose of the study was to investigate patient characteristics associated with image quality and their impact on the diagnostic accuracy of MDCT for the detection of coronary artery stenosis. MATERIALS AND METHODS. Two hundred ninety-one patients with a coronary artery calcification (CAC) score of <= 600 Agatston units (214 men and 77 women; mean age, 59.3 +/- 10.0 years [SD]) were analyzed. An overall image quality score was derived using an ordinal scale. The accuracy of quantitative MDCT to detect significant (>= 50%) stenoses was assessed using quantitative coronary angiography (QCA) per patient and per vessel using a modified 19-segment model. The effect of CAC, obesity, heart rate, and heart rate variability on image quality and accuracy were evaluated by multiple logistic regression. Image quality and accuracy were further analyzed in subgroups of significant predictor variables. Diagnostic analysis was determined for image quality strata using receiver operating characteristic (ROC) curves. RESULTS. Increasing body mass index (BMI) (odds ratio [OR] = 0.89, p < 0.001), increasing heart rate (OR = 0.90, p < 0.001), and the presence of breathing artifact (OR = 4.97, p = 0.001) were associated with poorer image quality whereas sex, CAC score, and heart rate variability were not. Compared with examinations of white patients, studies of black patients had significantly poorer image quality (OR = 0.58, p = 0.04). At a vessel level, CAC score (10 Agatston units) (OR = 1.03, p = 0.012) and patient age (OR = 1.02, p = 0.04) were significantly associated with the diagnostic accuracy of quantitative MDCT compared with QCA. A trend was observed in differences in the areas under the ROC curves across image quality strata at the vessel level (p = 0.08). CONCLUSION. Image quality is significantly associated with patient ethnicity, BMI, mean scan heart rate, and the presence of breathing artifact but not with CAC score at a patient level. At a vessel level, CAC score and age were associated with reduced diagnostic accuracy

    Diagnostic Performance of Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-MDCT: The CT Angiography and Perfusion Methods of the CORE320 Multicenter Multinational Diagnostic Study

    No full text
    OBJECTIVE. Coronary MDCT angiography has been shown to be an accurate noninvasive tool for the diagnosis of obstructive coronary artery disease (CAD). Its sensitivity and negative predictive value for diagnosing percentage of stenosis are unsurpassed compared with those of other noninvasive testing methods. However, in its current form, it provides no information regarding the physiologic impact of CAD and is a poor predictor of myocardial ischemia. CORE320 is a multicenter multinational diagnostic study with the primary objective to evaluate the diagnostic accuracy of 320-MDCT for detecting coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected CAD compared with the reference standard of conventional coronary angiography and SPECT myocardial perfusion imaging. CONCLUSION. We aim to describe the CT acquisition, reconstruction, and analysis methods of the CORE320 study.Toshiba Medical System

    The Absence of Coronary Calcification Does Not Exclude Obstructive Coronary Artery Disease or the Need for Revascularization in Patients Referred for Conventional Coronary Angiography

    Get PDF
    Objectives This study was designed to evaluate whether the absence of coronary calcium could rule out >= 50% coronary stenosis or the need for revascularization. Background The latest American Heart Association guidelines suggest that a calcium score (CS) of zero might exclude the need for coronary angiography among symptomatic patients. Methods A substudy was made of the CORE64 (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors) multicenter trial comparing the diagnostic performance of 64-detector computed tomography to conventional angiography. Patients clinically referred for conventional angiography were asked to undergo a CS scan up to 30 days before. Results In all, 291 patients were included, of whom 214 (73%) were male, and the mean age was 59.3 +/- 10.0 years. A total of 14 (5%) patients had low, 218 (75%) had intermediate, and 59 (20%) had high pre-test probability of obstructive coronary artery disease. The overall prevalence of >= 50% stenosis was 56%. A total of 72 patients had CS = 0, among whom 14 (19%) had at least 1 >= 50% stenosis. The overall sensitivity for CS = 0 to predict the absence of >= 50% stenosis was 45%, specificity was 91%, negative predictive value was 68%, and positive predictive value was 81%. Additionally, revascularization was performed in 9 (12.5%) CS = 0 patients within 30 days of the CS. From a total of 383 vessels without any coronary calcification, 47 (12%) presented with >= 50% stenosis; and from a total of 64 totally occluded vessels, 13 (20%) had no calcium. Conclusions The absence of coronary calcification does not exclude obstructive stenosis or the need for revascularization among patients with high enough suspicion of coronary artery disease to be referred for coronary angiography, in contrast with the published recommendations. Total coronary occlusion frequently occurs in the absence of any detectable calcification. (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218) (J Am Coll Cardiol 2010;55:627-34) (C) 2010 by the American College of Cardiology Foundatio

    Characterization of Peri-Infarct Zone Heterogeneity by Contrast-Enhanced Multidetector Computed Tomography: A Comparison With Magnetic Resonance Imaging

    Get PDF
    ObjectivesThis study examined whether multidetector computed tomography (MDCT) improves the ability to define peri-infarct zone (PIZ) heterogeneity relative to magnetic resonance imaging (MRI).BackgroundThe PIZ as characterized by delayed contrast-enhancement (DE)-MRI identifies patients susceptible to ventricular arrhythmias and predicts outcome after myocardial infarction (MI).MethodsFifteen mini-pigs underwent coronary artery occlusion followed by reperfusion. Both MDCT and MRI were performed on the same day approximately 6 months after MI induction, followed by animal euthanization and ex vivo MRI (n = 5). Signal density threshold algorithms were applied to MRI and MDCT datasets reconstructed at various slice thicknesses (1 to 8 mm) to define the PIZ and to quantify partial volume effects.ResultsThe DE-MDCT reconstructed at 8-mm slice thickness showed excellent correlation of infarct size with post-mortem pathology (r2= 0.97; p < 0.0001) and MRI (r2= 0.92; p < 0.0001). The DE-MDCT and -MRI were able to detect a PIZ in all animals, which correlates to a mixture of viable and nonviable myocytes at the PIZ by histology. The ex vivo DE-MRI PIZ volume decreased with slice thickness from 0.9 ± 0.2 ml at 8 mm to 0.2 ± 0.1 ml at 1 mm (p = 0.01). The PIZ volume/mass by DE-MDCT increased with decreasing slice thickness because of declining partial volume averaging in the PIZ, but was susceptible to increased image noise.ConclusionsA DE-MDCT provides a more detailed assessment of the PIZ in chronic MI and is less susceptible to partial volume effects than MRI. This increased resolution best reflects the extent of tissue mixture by histopathology and has the potential to further enhance the ability to define the substrate of malignant arrhythmia in ischemic heart disease noninvasively
    corecore