Biomedical subjects

David M Shames

Publications and source records attributed to David M Shames.

At least 19 recordsLinked to original sources

PubMed2005

Magnetic resonance characterization of tumor microvessels in experimental breast tumors using a slow clearance blood pool contrast agent (carboxymethyldextran-A2-Gd-DOTA) with histopathological correlation.

Carboxymethyldextran (CMD)-A2-Gd-DOTA, a slow clearance blood pool contrast agent with a molecular weight of 52.1 kDa, designed to have intravascular residence for more than 1 h, was evaluated for its potential to characterize and differentiate the microvessels of malignant and benign breast tumors. Precontrast single-slice inversion-recovery snapshot FLASH and dynamic contrast-enhanced MRI using an axial T1-weighted three-dimensional spoiled gradient recalled sequence was performed in 30 Sprague-Dawley rats with chemically induced breast tumors. Endothelial transfer coefficient and fractional plasma volume of the breast tumors were estimated from MRI data acquired with CMD-A2-Gd-DOTA enhancement injected at a dose of 0.1 mmol Gd/kg body weight using a two-compartment bidirectional model of the tumor tissue. The correlation between MRI microvessel characteristics and histopathological tumor grade was determined using the Scarff-Bloom-Richardson method. Using CMD-A2-Gd-DOTA, no significant correlations were found between the MR-estimated endothelial transfer coefficient or plasma volumes with histological tumor grade. Analysis of CMD-A2-Gd-DOTA-enhanced MR kinetic data failed to demonstrate feasibility for the differentiation of benign from malignant tumors or for image-based tumor grading.

Animals↗

PubMed2005

Mixture model approach to tumor classification based on pharmacokinetic measures of tumor permeability.

PURPOSE: To categorize the disease severity of mammary tumors in an animal model through the application of a novel tumor permeability mixture model within a hierarchical modeling framework. MATERIALS AND METHODS: Thirty-six rats with mammary tumors of varying grade were imaged via dynamic contrast-enhanced (CE) MRI using albumin-(Gd-DTPA)30. Time-dependent contrast agent concentration curves for blood and tumor tissue were obtained and a mathematical model of microvascular blood-tissue exchange was developed under the hypothesis that endothelial integrity is disrupted in a manner proportional to the degree of malignancy, with benign tumors showing no disruption of the vasculature endothelium. This permeability model was incorporated into a statistical model for the benign and malignant tumor subgroups that enabled automatic subject classification. The structural and statistical models were implemented using the software Nonlinear Mixed Effects Modeling (NONMEM) to statistically separate subjects into the two subgroups. RESULTS: Individual tumor classifications (as benign or malignant) were evaluated against the Scarff-Bloom-Richardson microscopic scoring method as applied to the tumor histology of each subject. The model-based classification resulted in 90.9% sensitivity, 92.9% specificity, and 91.7% accuracy. CONCLUSION: Mixture model analysis provides a robust method for subject classification without user intervention and bias. Although the present results are promising, additional research is needed to further evaluate this technique for diagnostic purposes.

Animals↗

PubMed2005

Zinc absorption and kinetics during pregnancy and lactation in Brazilian women.

BACKGROUND: Adjustments in zinc absorption and endogenous excretion maintain zinc homeostasis in nonpregnant adults fed low-zinc diets. The effects on zinc homeostasis of a low zinc intake during pregnancy and lactation have not been described in a longitudinal study. OBJECTIVE: We examined longitudinal changes in fractional zinc absorption (FZA) and zinc kinetics in 10 healthy Brazilian women who habitually consumed a marginal zinc diet ( approximately 9 mg Zn/d). DESIGN: Zinc status was measured at 10-12 (early pregnancy; EP) and 34-36 (late pregnancy; LP) wk of pregnancy and at 7-8 wk after delivery (early lactation; EL). Zinc kinetics and FZA were studied by using stable isotopic tracers. RESULTS: Zinc intake averaged 9 +/- 3 mg/d throughout the study. FZA increased from 29 +/- 6% at EP to 43 +/- 10% at LP and to 39 +/- 13% at EL (P < 0.05). FZA was inversely related to plasma zinc at EL (r = -0.73, P = 0.02) and LP (r = -0.72, P = 0.07). Plasma zinc mass was 23% greater at LP than at EP or EL (P < 0.05). The amount of zinc (mg/d) that fluxed between plasma and the most-rapidly-turning-over extravascular pool was 53% greater at LP than at EP or EL (P < 0.05). The zinc flux between plasma and the less-rapidly-turning-over zinc pool at EL was 27% greater than that at EP or LP, but this difference was not significant. CONCLUSIONS: FZA increased significantly in women with marginal zinc intakes during pregnancy and lactation; the increase was higher in women with low plasma zinc. Plasma zinc was distributed into a different exchangeable pool at LP than at EL.

Adult↗

PubMed2005

The choice of region of interest measures in contrast-enhanced magnetic resonance image characterization of experimental breast tumors.

OBJECTIVES: The objectives of this study were to determine if magnetic resonance (MR) estimates of quantitative tissue microvascular characteristics from regions of interest (ROI) limited to the tumor periphery provided a better correlation with tumor histologic grade than ROI defined for the whole tumor in cross-section. METHODS: A metaanalysis was based on 98 quantitative MR image breast tumor characterizations acquired in 3 separate experimental studies using identical methods for tumor induction and contrast enhancement. RESULTS: The endothelial transfer coefficient (K) of albumin (Gd-DTPA)30 from the tumor periphery correlated (r = 0.784) significantly more strongly (P < 0.001) with the pathologic tumor grade than K derived from the whole tumor (r = 0.604). K estimates, either from the tumor periphery or from the whole tumor, correlated significantly more strongly with histologic grade (P < 0.01) than MR image estimates of fractional plasma volume (fPV) from either tumor periphery (r = 0.368) or whole tumor (r = 0.323). CONCLUSIONS: K estimates from the tumor periphery were the best of these measurable MR image microvascular characteristics for predicting the histologic grade.

Animals↗

PubMed2005

Initial computed tomography imaging experience using a new macromolecular iodinated contrast medium in experimental breast cancer.

OBJECTIVE: The objective of this study was to evaluate computed tomography (CT) enhancement characteristics for a new iodinated macromolecular contrast medium (MMCM), PEG12000-Gen4-triiodo, for angiographic effect and for assessment of abnormal vascular permeability in cancer. MATERIALS AND METHODS: Time persistence of angiographic effect was evaluated on rat CT images acquired over 30 minutes using the iodinated polyethyleneglycol- (PEG) based macromolecule. Dynamic CT imaging after PEG12000-Gen4-triiodo-enhancement in tumor-bearing rats was used to quantitatively estimate plasma volume and microvascular transendothelial permeability for both tumor and normal soft tissue. Using identical doses of iodine, 300 mg iodine/kg, blood curves for this MMCM and iohexol were compared. RESULTS: Serial whole-body CT angiograms using PEG12000-Gen4-triiodo showed diagnostic vascular detail through 20 minutes, and the blood enhancement curve was higher and more persistent than with small-molecular iohexol. Permeability estimates were significantly (P<0.02; paired t test) higher in tumors (48.2+/-18.1 microL/min-1 100 mL) than in muscle (2.5+/-5.7 microL/min-1 100 mL). CONCLUSIONS: Use of PEG-based MMCM for experimental CT allowed for a persistent angiographic enhancement and for quantitative estimation of tumor microvascular characteristics.

Animals↗

PubMed2004

MRI monitoring of Avastin antiangiogenesis therapy using B22956/1, a new blood pool contrast agent, in an experimental model of human cancer.

PURPOSE: To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. MATERIALS AND METHODS: Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (KPS) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI. RESULTS: Tumors grew more slowly, although not significantly (P=0.07), in the drug-treated group. The KPS determined for B22956/1 decreased significantly in the drug-treated group compared to baseline (P <0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). CONCLUSION: With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.

Angiogenesis Inhibitors↗

PubMed2004

Plasma clearance of human low-density lipoprotein in human apolipoprotein B transgenic mice is related to particle diameter.

To test for intrinsic differences in metabolic properties of low-density lipoprotein (LDL) as a function of particle size, we examined the kinetic behavior of 6 human LDL fractions ranging in size from 251 to 265 A injected intravenously into human apolipoprotein (apo) B transgenic mice. A multicompartmental model was formulated and fitted to the data by standard nonlinear regression using the Simulation, Analysis and Modeling (SAAM II) program. Smaller sized LDL particles (251 to 257 A) demonstrated a significantly slower fractional catabolic rate (FCR) (0.050 +/- 0.045 h(-1)) compared with particles of larger size (262 to 265 A) (0.134 +/- -0.015 h(-1), P <.03), and there was a significant correlation between FCR and the peak LDL diameter of the injected fractions (R(2) =.71, P <.034). The sum of the equilibration parameters, k(2,1) and k(1,2), for smaller LDL (0.255 h(-1) and 0.105 h(-1), respectively) was significantly smaller than that for larger LDL (0.277 h(-1) and 0.248 h(-1), respectively; P <.01), indicative of slower intravascular-extravascular exchange for smaller LDL. Therefore in this mouse model, smaller LDL particles are cleared more slowly from plasma than larger LDL and are exchanged more slowly with the extravascular space. This might be due to compositional or structural features of smaller LDL that lead to retarded clearance.

Adult↗

PubMed2004

Kinetic parameters and plasma zinc concentration correlate well with net loss and gain of zinc from men.

The search for a reliable, convenient indicator of Zn status was the focus of research for several decades. Plasma Zn concentration is still the most widely used clinical measurement, despite the known problems of interpretation. More recently, researchers suggested that isotopically determined kinetic parameters, such as the exchangeable Zn pool (EZP), may more accurately and reliably reflect body Zn status. The objective of this study was to examine the relationship between net body Zn loss and gain during acute changes in dietary Zn intake with biochemical and kinetic indices of Zn status. Five men participated in an 85-d Zn depletion/repletion study. Net body Zn loss and gain were determined from the difference between dietary plus intravenously administered Zn and Zn excretion. Biochemical indicators of Zn status included plasma Zn, plasma alkaline phosphatase activity, and plasma retinol binding protein concentration. Following intravenous administration of (70)Zn or (67)Zn, a compartmental model was used to determine EZP mass, fractional Zn absorption, endogenous zinc excretion (EZE), and plasma Zn flux. The changes in total body zinc correlated best with changes in plasma Zn (r(2) = 0.826, P < 0.001), EZE (r(2) = 0.773, P < 0.001), and plasma Zn flux (r(2) = 0.766, P < 0.001). This study confirms that plasma Zn concentration is a valid indicator of whole-body Zn status in the absence of confounding factors; however, further research is needed to determine how kinetic parameters respond to conditions where plasma Zn concentration is known to be unreliable.

Absorption↗

PubMed2004

Magnetic resonance imaging detects early changes in microvascular permeability in xenograft tumors after treatment with the matrix metalloprotease inhibitor Prinomastat.

Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10(th) day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.

Animals↗

PubMed2003

Iron and zinc absorption from two bean (Phaseolus vulgaris L.) genotypes in young women.

Extrinsic and intrinsic iron and zinc labels were used to test iron and zinc absorption from two bean (Phaseolus vulgaris) genotypes, containing normal (common beans, CB) or higher (HFeZnB) iron and zinc concentrations, fed in single meals to young women with low iron reserves. The women were divided into two groups, with one receiving a CB test meal (n = 12) and the other, an HFeZnB test meal (n = 11). The beans were intrinsically labeled hydroponically with (55)Fe (CB and HFeZnB) and with (70)Zn (HFeZnB). Concentrations of zinc and iron were 98 and 65% higher, respectively, in HFeZnB as compared to CB, but phytic acid contents were similar. Extrinsic labels were (59)Fe (CB and HFeZnB), (67)Zn (CB), and (68)Zn (HFeZnB). Iron and zinc percent absorption levels were calculated from radio-iron activity in red blood cells and from urinary excretion of zinc isotopes. Intrinsic and extrinsic iron absorption measures were highly correlated (R (2) = 0.986) (average extrinsic/intrinsic ratio was 1.00). Iron absorption was low (geometric mean < 2%) in both bean types, and total iron absorbed was not different between types. Intrinsic zinc absorption from the HFeZn beans was higher than extrinsic absorption (15.2% vs 13.4%, p < 0.05) (average extrinsic/intrinsic was 0.90). The correlation between intrinsic and extrinsic zinc measures was not as high as that for iron (R (2) = 0.719). Percent zinc absorption levels were similar in both bean types, but total extrinsic zinc absorbed was 90% higher (p < 0.05) from the HFeZnB meal. Thus, the less expensive and time-consuming extrinsic labeling may be used to screen various varieties of beans for iron bioavailability in humans, but it underestimates zinc absorption by approximately 10%. Selective breeding for high-zinc bean genotypes may improve zinc status. However, high-iron genotypes appear to have little effect on iron status when fed alone in single meals to women with low iron reserves.

Adult↗

PubMed2003

MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model.

The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (approximately 30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K(PS)) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (K(PS)) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and K(PS) values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (K(PS)), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy.

Angiogenesis Inhibitors↗

PubMed2002

Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme.

PURPOSE: To evaluate the effects of a neutralizing anti-vascular endothelial growth factor (anti-VEGF) antibody on tumor microvascular permeability, a proposed indicator of angiogenesis, and tumor growth in a rodent malignant glioma model. MATERIALS AND METHODS: A dynamic contrast-enhanced magnetic resonance imaging (MRI) technique, permitting noninvasive in vivo and in situ assessment of potential therapeutic effects, was used to measure tumor microvascular characteristics and volumes. U-87, a cell line derived from a human glioblastoma multiforme, was implanted orthotopically into brains of athymic homozygous nude rats. RESULTS: Treatment with the monoclonal antibody A4.6.1, specific for VEGF, significantly inhibited tumor microvascular permeability (6.1 +/- 3.6 mL min(-1)100 cc(-1)), compared to the control, saline-treated tumors (28.6 +/- 8.6 mL min(-1)100 cc(-1)), and significantly suppressed tumor growth (P <.05). CONCLUSION: Findings demonstrate that tumor vascular permeability and tumor growth can be inhibited by neutralization of endogenous VEGF and suggest that angiogenesis with the maintenance of endothelial hyperpermeability requires the presence of VEGF within the tissue microenvironment. Changes in tumor vessel permeability and tumor volumes as measured by contrast-enhanced MRI provide an assay that could prove useful for clinical monitoring of anti-angiogenic therapies in brain tumors.

Animals↗

PubMed2002