Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and ...metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-(18)Ffluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ((11)Cacetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.
Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial ...metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-18Ffluoro-6-thia-heptadecanoic acid (FTHA) and 18FFDG in patients with stable New York Heart Association functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%.
Twelve fasting patients underwent dynamic PET studies using 18FFTHA and FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for 18FFTHA and FDG. Subsequently, serum free fatty acid and glucose concentrations were used to calculate the myocardial free fatty acid and glucose uptake rates, respectively. Uptake rates were compared with reported values for 18FFTHA and FDG in subjects with normal left ventricular function.
The average Ki for 18FFTHA was 19.7 +/- 9.3 mL/100 g/min (range, 7.2-36.0 ml/100 g/min). The average myocardial fatty acid use was 19.3 +/- 2.3 mmol/100 g/min. The average Ki for FDG was 1.5 +/- 0.37 mL/100 g/min (range, 0.1-3.3 mL/100 g/min), and the average myocardial glucose use was 12.3 +/- 2.3 mmol/100 g/min.
Myocardial free fatty acid and glucose use in heart failure can be quantitatively assessed using PET with 18FFTHA and FDG. Myocardial fatty acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.
Use of beta-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One ...potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation.
We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction </=35%) using myocardial positron emission tomography studies and resting echocardiograms before and 3 months after carvedilol treatment. Myocardial uptake of the novel long chain fatty acid metabolic tracer 14(R, S)-(18)Ffluoro-6-thia-heptadecanoic acid ((18)F-FTHA) was used to determine myocardial FFA use, and (18)Ffluoro-2-deoxy-glucose ((18)F-FDG) was used to determine myocardial glucose use. After carvedilol treatment, the mean myocardial uptake rate for (18)F-FTHA decreased (from 20.4+/-8.6 to 9.7+/-2.3 mL. 100 g(-1). min(-1); P<0.005), mean fatty acid use decreased (from 19.3+/-7.0 to 8.2+/-1.8 micromoL. 100 g(-1). min(-1); P<0.005), the mean myocardial uptake rate for (18)F-FDG was unchanged (from 1.4+/-0.4 to 2.4+/-0.8 mL. 100 g(-1). min(-1); P=0.14), and mean glucose use was unchanged (from 11.1+/-3.1 to 18.7+/-6.0 micromoL. 100 g(-1). min(-1); P=0.12). Serum FFA and glucose concentrations were unchanged, and mean left ventricular ejection fraction improved (from 26+/-2% to 37+/-4%; P<0.05).
Carvedilol treatment in patients with heart failure results in a 57% decrease in myocardial FFA use without a significant change in glucose use. These metabolic changes could contribute to the observed improvements in energy efficiency seen in patients with heart failure.
Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive ...detection of cancer using PET. The aim of this study was to further evaluate (18)Ffluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium FCH) as an oncologic probe in comparison with several other closely related molecules.
FCH, (18)Ffluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), (18)Ffluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and (18)Ffluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through (18)Ffluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and methyl-(14)Ccholine (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor.
FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues.
The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.
Although de novo protein design is an important endeavor with implications for understanding protein folding, until now, structures have been determined for only a few 25- to 30-residue designed ...miniproteins. Here, the NMR solution structure of a complex 73-residue three-helix bundle protein, α 3D, is reported. The structure of α 3D was not based on any natural protein, and yet it shows thermodynamic and spectroscopic properties typical of native proteins. A variety of features contribute to its unique structure, including electrostatics, the packing of a diverse set of hydrophobic side chains, and a loop that incorporates common capping motifs. Thus, it is now possible to design a complex protein with a well defined and predictable three-dimensional structure.
Osteosarcoma (OS) is the most common primary bone tumor affecting children and young adults, and development of metastatic disease is associated with poor prognosis. The purpose of this study was to ...evaluate the antitumor efficacy of virotherapy with engineered measles virus (MV) vaccine strains in the treatment of OS. Cell lines derived from pediatric patients with OS (HOS, MG63, 143B, KHOS-312H, U2-OS and SJSA1) were infected with MV expressing green fluorescent protein (MV-GFP) and MV-expressing sodium iodide symporter (MV-NIS) strains. Viral gene expression and cytotoxicity as defined by syncytial formation, cell death and eradication of cell monolayers were demonstrated. Findings were correlated with in vivo efficacy in subcutaneous, orthotopic (tibial bone) and lung metastatic OS xenografts treated with the MV derivative MV-NIS via the intratumoral or intravenous route. Following treatment, we observed decrease in tumor growth of subcutaneous xenografts (P=0.0374) and prolongation of survival in mice with orthotopic (P<0.0001) and pulmonary metastatic OS tumors (P=0.0207). Expression of the NIS transgene in MV-NIS infected tumors allowed for single photon emission computed tomography and positron emission tomography-computed tomography imaging of virus infected tumors in vivo. Our data support the translational potential of MV-based virotherapy approaches in the treatment of recurrent and metastatic OS.
Conventional imaging (CI) is known to have limitations with respect to staging of patients with primary or relapsed prostate cancer. Positron emission tomography/computed tomography (PET/CT) with ...(18)F-flurodeoxyglucose (FDG) is also often suboptimal because of low tracer avidity, but (18)F-fluorocholine (FCH) appears to be a promising alternative molecular imaging probe. We report a prospective pilot study of PET/CT comparing both tracers for staging and restaging of patients with prostate cancer.
Sixteen prostate cancer patients were evaluated (7 for staging and 9 for restaging). All patients also underwent CI, comprising at least an abdominopelvic CT and a bone scan. All imaging results and other relevant data were extracted from the imaging reports and medical charts.
Based on all imaging-detected disease sites, both FCH-PET/CT and FDG-PET/CT (79%) were more sensitive than CI (14%), with the highest number of sites of nodal and distant disease on FCH PET/CT. FCH-PET/CT alone would have provided sufficient clinical information to form an appropriate management plan in 88% of cases, as compared with 56% for CI.
FCH-PET/CT has the potential to impact on the management of patients with prostate cancer significantly more often than CI.
Acute myocardial ischemia is accompanied by an increase in glucose uptake and metabolism, which appears to be important in protecting myocardial cells from irreversible ischemic injury. Because ...insulin augments myocardial glucose uptake by inducing the translocation of glucose transporters from an intracellular compartment to the plasma membrane, we hypothesized that acute ischemia would trigger a similar translocation.
We used a subcellular fractionation method to separate intracellular membrane and plasma membranes from control, ischemic, and hypoxic Langendorff-isolated perfused rat hearts and determined the expression of the major myocardial glucose transporter, GLUT4, in these separated membrane fractions. We found that translocation of GLUT4 molecules occurred in ischemic, hypoxic, and insulin-treated hearts and in hearts that underwent ischemia plus insulin treatment. The percentages of GLUT4 molecules present on the plasma membrane in the different conditions were as follows: control, 18.0 +/- 2.8%; ischemia, 41.3 +/- 9.4%; hypoxia, 31.1 +/- 2.9%; insulin, 61.1 +/- 2.6%; and ischemia plus insulin, 66.8 +/- 5.7%. Among the statistically significant differences in these values were the difference between control and ischemia and the difference between ischemia alone and insulin plus ischemia.
Ischemia causes substantial translocation of GLUT4 molecules to the plasma membrane of cardiac myocytes. A combination of insulin plus ischemia stimulates an even greater degree of GLUT4 translocation. GLUT4 translocation is likely to mediate at least part of the increased glucose uptake of ischemic myocardium and may be a mechanism for the cardioprotective effect of insulin during acute myocardial ischemia.
The aim of this study was to examine the relationship between depersonalization induced by tetrahydrocannabinol (THC), and regional brain activation.
Cerebral blood flow (CBF) was measured by means ...of positron emission tomography (PET) in 59 normal right-handed volunteers before and following intravenous infusions of THC.
After THC, CBF showed a global increase which was more marked in the right hemisphere, frontal lobes and anterior cingulate.
Regression analyses showed positive correlations between the right frontal and anterior cingulate and depersonalization.
Positron emission tomography (PET) imaging is used for the metabolic evaluation of cancer.
18Ffluorodeoxyglucose (FDG) is commonly used as a radiotracer but its low cellular uptake rate in prostate ...cancer limits its usefulness. We evaluated the novel choline analog
18Ffluorocholine (FCH) for detecting androgen dependent and androgen independent prostate cancer, and its metastases.
The cellular uptake of FCH and FDG was compared in cultured prostate cancer cells (LNCaP and PC-3). FCH and FDG were injected into nude mice xenografts (CWR-22 and PC-3) and radiotracer uptake in various organs were evaluated. Patients with androgen dependent (9) and independent (9) prostate cancer were studied by FCH and FDG PET.
FCH uptake was 849% and 60% greater than FDG uptake in androgen dependent (LNCaP) and independent (PC-3) cells, respectively. The addition of hemicholinium-3 (5 mM.) 30 minutes before radiotracer administration inhibited FCH uptake by 79% and 70% in LNCaP and PC-3 cells, respectively, whereas FDG uptake was not significantly affected. Although nude mice xenografts showed that FDG uptake was equal to or greater than FCH uptake, clinical imaging in patients demonstrated 2 to 4-fold higher uptake of FCH in those with androgen and androgen independent prostate carcinoma (p <0.001). More lesions were detected by FCH than by FDG in primary tumors, osseous metastases and soft tissue metastases.
In vitro data demonstrated greater FCH than FDG uptake in androgen dependent (LNCaP) and androgen independent (PC-3) prostate cancer cells. Although the murine xenograft data showed greater accumulation of FDG than FCH in PC-3 tumors, PET in humans showed that FCH was better than FDG for detecting primary and metastatic prostate cancer. Overall the data from this study suggest that FCH is preferable to FDG for PET of prostate carcinoma and support the need for future validation studies in a larger number of subjects.
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