Interstitial Volume Fraction Research Articles

Abstract 15511: A Novel Mitochondrial Targeted DNA Repair Enzyme Attenuates Maladaptive Myocardial Remodeling and Preserves Cardiac Function in Heart Failure

Background: Sustained increases in mitochondrial oxidative stress results in mitochondrial DNA (mtDNA) damage further worsening oxidative damage and cellular injury. These cellular events are pivotal in development and progression of myocardial damage and heart failure. We investigated the effects of a novel mitochondrial targeted fusion protein that traffics endonuclease III (Exscien1-III) and repairs mtDNA in the setting of pressure overload heart failure. Methods: Male C57/BL6J mice (n=10) were subjected to transverse aortic constriction (TAC; 27 g needle) and Exscien1-III (4 mg/kg/d, i.p.) or VEH were administered daily starting at 3 wks post TAC. Left ventricular (LV) function (Vevo 2100) was assessed at baseline and biweekly for 12 weeks post TAC. At the 12 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment of cellular injury. Results: Exscien1-III significantly attenuated TAC-induced LV dilation at 12 wks post TAC (LVEDD: 3.9 ± 0.1 vs. 4.6 ± 0.1 mm, p < 0.05; LVESD: 3.1 ± 0.2 vs. 3.9 ± 0.1 mm, p < 0.05) compared to VEH. Exscien1-III displayed a reduced LV wall thickness (LVPWd: 1.1 ± 0.1 vs. 1.4 ± 0.1 mm, p < 0.05) at 8 wks post TAC compared to VEH. In comparison to VEH, LV ejection fraction (LVEF) was preserved in the Exscien1-III treated mice at 8-12 weeks post TAC compared to VEH (*p < 0.05; **p < 0.01). Treatment with Exscien1-III resulted in a reduction in heart weights (9.7 ± 0.4 vs. 12.15 ± 1.2 mg/mm, p < 0.05) compared to VEH. Picrosirius Red staining of LV collagen revealed that Exscien1-III significantly decreased myocardial interstitial collagen volume fraction by 55% (p < 0.05 vs. VEH). Conclusion: Delayed treatment with Exscien1-III attenuated interstitial myocardial collagen deposition and preserved LVEF following the onset of TAC-induced cardiac hypertrophy and heart failure. Current studies are underway to further investigate the mechanisms by which this novel mtDNA repair enzyme protects the failing heart.

Evaluation of Tumor-associated Stroma and Its Relationship with Tumor Hypoxia Using Dynamic Contrast-enhanced CT and (18)F Misonidazole PET in Murine Tumor Models.

To determine the relationship between the fractional interstitial volume (Fis), as calculated at dynamic contrast material-enhanced (DCE) computed tomography (CT), and tumor-associated stroma and to analyze its spatial relationship with tumor hypoxia in several xenograft tumor models. All animal experiments were approved by the animal research committee. Mice with three different xenograft tumors (U251, CFPAC-1, and BxPC-3; n = 6, n = 8, and n = 6, respectively) underwent DCE CT then hypoxia imaging with fluorine 18 ((18)F) fluoromisonidazole (FMISO) positron emission tomography (PET) within 24 hours. Immunohistochemical analysis was performed in harvested tumors to detect hypoxia markers and to quantify microvascular and stromal density. Two DCE CT parameters (amount of interstitial space associated with the amount of stroma [Fis] and flow velocity [Fv]) were identified and quantitatively validated by using immunohistochemistry. FMISO uptake within the tumor was also assessed in relation to DCE CT parameters. Imaging and immunohistochemical parameters were assessed by using the Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni correction, and Pearson correlation coefficient. Almost no α-smooth muscle actin-positive cells were found in the U251 xenograft, while abundant stroma was found in the entire BxPC-3 xenograft and in the periphery of the CFPAC-1 xenograft. Quantitative analysis showed a significant correlation (R = 0.83, P < .0001) between Fis and stromal density. FMISO uptake had a negative correlation with Fis (R = -0.58, P < .0001) and Fv (R = -0.53, P < .0001). DCE CT can be used to quantify parameters associated with tumor-associated stroma. Tumor hypoxia was Complementarily localized in tumor-associated stroma in these models.

Water-Exchange-Modified Kinetic Parameters from Dynamic Contrast-Enhanced MRI as Prognostic Biomarkers of Survival in Advanced Hepatocellular Carcinoma Treated with Antiangiogenic Monotherapy.

BackgroundTo find prognostic biomarkers in pretreatment dynamic contrast-enhanced MRI (DCE-MRI) water-exchange-modified (WX) kinetic parameters for advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy.MethodsTwenty patients with advanced HCC underwent DCE-MRI and were subsequently treated with sunitinib. Pretreatment DCE-MRI data on advanced HCC were analyzed using five different WX kinetic models: the Tofts-Kety (WX-TK), extended TK (WX-ETK), two compartment exchange, adiabatic approximation to tissue homogeneity (WX-AATH), and distributed parameter (WX-DP) models. The total hepatic blood flow, arterial flow fraction (γ), arterial blood flow (BF A), portal blood flow, blood volume, mean transit time, permeability-surface area product, fractional interstitial volume (v I), extraction fraction, mean intracellular water molecule lifetime (τ C), and fractional intracellular volume (v C) were calculated. After receiver operating characteristic analysis with leave-one-out cross-validation, individual parameters for each model were assessed in terms of 1-year-survival (1YS) discrimination using Kaplan-Meier analysis, and association with overall survival (OS) using univariate Cox regression analysis with permutation testing.ResultsThe WX-TK-model-derived γ (P = 0.022) and v I (P = 0.010), and WX-ETK-model-derived τ C (P = 0.023) and v C (P = 0.042) were statistically significant prognostic biomarkers for 1YS. Increase in the WX-DP-model-derived BF A (P = 0.025) and decrease in the WX-TK, WX-ETK, WX-AATH, and WX-DP-model-derived v C (P = 0.034, P = 0.038, P = 0.028, P = 0.041, respectively) were significantly associated with an increase in OS.ConclusionsThe WX-ETK-model-derived v C was an effective prognostic biomarker for advanced HCC treated with sunitinib.

Effect of T2* correction on contrast kinetic model analysis using a reference tissue arterial input function at 7 T.

We aimed to investigate the effect of T2* correction on estimation of kinetic parameters from T1-weighted dynamic contrast enhanced (DCE) MRI data when a reference-tissue arterial input function (AIF) is used. DCE-MRI data were acquired from seven mice with 4T1 mouse mammary tumors using a double gradient echo sequence at 7 T. The AIF was estimated from a region of interest in the muscle. The extended Tofts model was used to estimate pharmacokinetic parameters in the enhancing part of the tumor, with and without T2* correction of the lesion and AIF. The parameters estimated with T2* correction of both the AIF and lesion time-intensity curve were assumed to be the reference standard. For the whole population, there was significant difference (p < 0.05) in transfer constant (K(trans)) between T2* corrected and not corrected methods, but not in interstitial volume fraction (ve). Individually, no significant differences were found in K(trans) and ve of four and six tumors, respectively, between the T2* corrected and not corrected methods. In contrast, K(trans) was significantly underestimated, if the T2* correction was not used, in other tumors for which the median K(trans) was larger than 0.4 min(-1). T2* effect on tumors with high K(trans) may not be negligible in kinetic model analysis, even if AIF is estimated from reference tissue where the concentration of contrast agent is relatively low.

TVP1022

The current cornerstone treatment of myocardial infarction (MI) is restoration of coronary blood flow by means of thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion of ischemic myocardium can actually provoke tissue damage, defined as "ischemia-reperfusion (I/R) injury." TVP1022 [the S-isomer of rasagiline (Azilect), FDA-approved anti-Parkinson's drug] was found to exert cardioprotective activities against various cardiac insults, such as chronic heart failure and I/R, in rat models. Therefore, we tested the hypothesis that TVP1022 will provide cardioprotection against I/R injury and post-MI remodeling in a pig model. For inducing MI, we used an I/R model of midleft anterior descending artery occlusion for 90 minutes followed by follow-up for 8 weeks in 18 farm pigs (9 pigs in each group, MI + TVP1022 or MI + Vehicle). Echocardiographic measurements were performed and cardiac scar size was calculated using histopathological methods. For fibrosis evaluation, we measured the interstitial collagen volume fraction in the remote noninfarcted tissue. TVP1022 administration significantly decreased cardiac scar size, attenuated left ventricular dilation, and improved cardiac function assessed by segmental circumferential strain analysis. Furthermore, TVP1022 significantly reduced myocardial fibrosis 8 weeks post-MI. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R pig model.

Dynamic Contrast-Enhanced MRI Kinetic Parameters as Prognostic Biomarkers for Prediction of Survival of Patient with Advanced Hepatocellular Carcinoma: A Pilot Comparative Study

Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data analysis influences its use as a prognostic biomarker. Our aim was to find DCE-MRI parameters that predict 1-year survival (1YS) and overall survival (OS) among patients with advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy by conducting a proof-of-concept comparative study of five different kinetic models. Twenty patients with advanced HCC underwent DCE-MRI and subsequently received sunitinib. Pretreatment DCE-MRI data were analyzed retrospectively by using the Tofts-Kety (TK), extended TK, two compartment exchange, adiabatic approximation to the tissue homogeneity (AATH), and distributed parameter (DP) models. Arterial flow fraction (γ), arterial blood flow (BFA), permeability-surface area product (PS), fractional interstitial volume (vI), and other five parameters were calculated for each model. Individual parameters were evaluated for 1YS prediction using cross-validated Kaplan-Meier analysis, and for association with OS using univariate Cox regression analysis, with additional permutation testing. For 1YS prediction, the TK model-derived γ (P = .007) and vI (P = .029) and the AATH model-derived PS (P = .005) were significant; all these parameters were lower in the high-risk group. Increase in the AATH model-derived PS and the DP model-derived BFA was associated with significant increase in OS with hazard ratios of 0.766 (P = .023) and 0.809 (P = .025), respectively. The AATH model-derived PS was an effective prognostic biomarker for both 1YS and OS.

MRI-Tracked Tumor Vascular Changes in the Hours after Single-Fraction Irradiation.

The purpose of this study was to characterize changes in tumor vascular parameters hours after a single radiation exposure in an orthotopic brain tumor model. U-251 human brain tumors were established intracerebrally in rat brains, and tumor blood flow, forward volume transfer constant (K(trans)) and interstitial volume fraction (v(e)) were measured using magnetic resonance imaging (MRI). Tumors were exposure to a single stereotactic radiation treatment of 20 Gy. Vascular parameters were assessed one additional time between 2 and 24 h after irradiation. After the second MRI session, brain tissue histology was examined for gross changes and apoptosis. In separate studies, cerebral blood flow was measured in nonimplanted controls before radiation exposure and 2 and 24 h after 20 Gy irradiation, and in implanted rats before radiation exposure and at 2 and 24 h after 6 Gy irradiation. Significant changes were observed in tumor-bearing rat brains in the hours after 20 Gy irradiation. Two hours after 20 Gy irradiation, tumor blood flow decreased nearly 80% and ve decreased by 30%. At 4 h, the K(trans) increased by 30% over preirradiation values. Extensive vacuolization and an increase in apoptosis were evident histologically in rats imaged 2 h after irradiation. Between 8 and 12 h after irradiation, all vascular parameters including blood flow returned to near preirradiation values. One day after irradiation, tumor blood flow was elevated 40% over preirradiation values, and other vascular parameters, including K(trans) and ve, were 20-40% below preirradiation values. In contrast, changes in vascular parameters observed in the normal brain 2 or 24 h after 20 Gy irradiation were not significantly different from preirradiation values. Also, tumor blood flow appeared to be unchanged at 2 h after 6 Gy irradiation, with a small increase observed at 24 h, unlike the tumor blood flow changes after 20 Gy irradiation. Large and significant changes in vascular parameters were observed hours after 20 Gy irradiation using noninvasive MRI techniques. It is hypothesized that cellular swelling hours after a high dose of radiation, coinciding with vacuolization, led to a decrease in tumor blood flow and v(e). Four hours after radiation exposure, K(trans) increased in concert with an increase in tumor blood flow. Vascular permeability normalized, 24 h after 20 Gy irradiation, as characterized by a decrease in K(trans). Vascular parameters did not change significantly in the normal brain after 20 Gy irradiation or in the tumor-bearing brain after 6 Gy irradiation.

Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus.

Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/√2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Baseline mean age was 24.6 years, mean duration of T1D 11.2 years, median AER 6.4 µg/min and mean iohexol GFR 129 mL/min/1.73 m(2). No associations were found between hepcidin/Cr and morphometric variables. Higher MCP-1/Cr was associated with higher interstitial fractional volume at baseline and after 5 years in women (baseline partial r = 0.244, P = 0.024; 5-year partial r = 0.299, P = 0.005), but not in men (baseline partial r = -0.049, P = 0.678; 5-year partial r = 0.026, P = 0.830). MCP-1 was not associated with glomerular lesions in either sex. Elevated urinary MCP-1 concentration measured before clinical findings of DN in women with T1D was associated with changes in kidney interstitial volume, suggesting that inflammatory processes may be involved in the pathogenesis of early interstitial changes in DN.

Effects of Pre-Existing Defects on Nanoimprint Process Investigated by Molecular Dynamics Simulation

In current study molecular dynamics (MD) simulations are performed to reveal effects of pre-existing defects on nanoimprint of single crystal aluminum ( Al ) thin films. Simulation results suggest that critical force required for plastic deformation initiation decreases with the increase of vacancy volume fraction, but increases with the interstitial volume fraction. It is found that adsorption phenomenon is affected by pre-existing defects, as adsorption phenomenon weakens with the increasing interstitial volume fraction. Pre-existing defects have significant influence on the deformation mechanisms and imprint forces during the nanoimprint processes. Simulation results also show that surface deformation is strongly affected by pre-existing defects.

Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma

There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy.

Intratumor distribution and test-retest comparisons of physiological parameters quantified by dynamic contrast-enhanced MRI in rat U251 glioma.

The distribution of dynamic contrast-enhanced MRI (DCE-MRI) parametric estimates in a rat U251 glioma model was analyzed. Using Magnevist as contrast agent (CA), 17 nude rats implanted with U251 cerebral glioma were studied by DCE-MRI twice in a 24 h interval. A data-driven analysis selected one of three models to estimate either (1) plasma volume (vp), (2) vp and forward volume transfer constant (K(trans)) or (3) vp, K(trans) and interstitial volume fraction (ve), constituting Models 1, 2 and 3, respectively. CA distribution volume (VD) was estimated in Model 3 regions by Logan plots. Regions of interest (ROIs) were selected by model. In the Model 3 ROI, descriptors of parameter distributions--mean, median, variance and skewness--were calculated and compared between the two time points for repeatability. All distributions of parametric estimates in Model 3 ROIs were positively skewed. Test-retest differences between population summaries for any parameter were not significant (p ≥ 0.10; Wilcoxon signed-rank and paired t tests). These and similar measures of parametric distribution and test-retest variance from other tumor models can be used to inform the choice of biomarkers that best summarize tumor status and treatment effects.

A Review Study on the efficacy of Quantitative DCE-MRI in Adnexal Lesion Diagnosis

: Ovarian cancer is a leading indication for gynecological surgery. The conventional and widely-accepted imaging modalities, such as ultrasonography (US), fall short of specificity. Thus, advanced imaging modalities such as anatomical along with physiological magnetic resonance imaging, specifically dynamic contrast enhanced (DCE-) MRI could be used successfully as an adjunct to morphological assessment findings. The specificity of diagnosis could benefit from DCE-MRI analysis approach, either semi- or fully quantitative. The aim of this abstract is to give a review on the available scholarly works, in order to investigate the role of quantitative DCE-MRI in ovarian cancer diagnosis and differentiation. US is considered as the primary imaging modality for confirmation of the ovarian origin of the mass and characterization of the nature of the mass as benign or malignant. In a study on 72 patients, Sohaib et al. showed that the sensitivity and specificity of US for differentiating malignant from benign lesions are 100% and 39.5%, respectively. MRI has proved to be most predictive of malignancy. The sensitivity and specificity of anatomical MRI in detecting malignancy are 96.6% and 83.7%, respectively. DCE-MRI has been introduced as a beneficial functional MR imaging technique for improving the tumor diagnosis. In Bernardin et al. study, MRI features of 70 complex adnexal masses with enhancing components in 63 patients were reviewed and correlated with histopathology or radiological follow-up results. Their results showed a significant difference in maximum absolute enhancement of signal intensities (SImax), maximum relative enhancement (SIrel) and wash-in rate (WIR) between benign and borderline/invasive malignant groups. A cut-off of WIR?9.5 l/s had a specificity of 88% and positive predictive value of 86% for predicting malignancy, which was significantly higher than conventional MRI (62%). On the other hand, the pharmacokinetic (or model-based) analysis of DCE-MRI is a feasible and accurate technique to differentiate malignant from benign adnexal tumors. Thomassin-Naggara et al. managed to obtain diagnostic evaluation in 56 women. Microvascular parameters were extracted from high temporal resolution DCE-MRI series, using a two-compartmental model in the solid tissue of adnexal tumors. Malignant tumors displayed higher blood flow (FT), blood volume fraction (Vb), area under the enhancing curve (rAUC) and lower interstitial volume fraction (Ve) than benign tumors. FT was the most relevant factor for discriminating malignant from benign tumors. A tissue blood flow had a high sensitivity of 88.9% for predicting benignity. Diffusion weighted magnetic resonance imaging (DW-MRI) is an alternative functional MR imaging technique. In their study of DW-MRI, Nakayama et al. reported no significant difference in the ADC-values between the benign and malignant cystic ovarian lesions; however, there was a wide variation within the ADC-values of malignant ovarian tumors, which is related to complex morphology of ovarian cancer. DWI can improve characterization of adnexal lesions, especially benign lesions. Ovarian cancer is a genetically heterogeneous disease with a poor prognosis. US is less accurate for complex or indeterminate masses, even when combined with color Doppler imaging. Most MRI studies had higher prevalence of complex (solid, solid/cysts) ovarian lesions than that of US. Semi-quantitative parameters extracted from DCE-MRI are shown to produce promising results for differentiating benign, borderline, and invasive ovarian epithelial tumors and found to correlate with tumor antigenic status, as determined with immunohistochemical staining. Although semi-quantitative DCE-MRI analysis shows rather high sensitivity and specificity (88% and 86%), it lacks reproducibility, because they work based on signal intensity and do not take into account the individual variability of the arterial input function. On the other hand, quantitative DCE-MRI is rather accurate for differentiating borderline from primary invasive ovarian tumors (88.9% of sensitivity). It can be concluded that in order to increase sensitivity and specificity of quantitative DCE-MRI, it seems reasonable to use DWI as an adjunct to PW imaging in combination to conventional MRI, to improve the characterization of complex adnexal masses.

The renin–aldosterone axis in kidney transplant recipients and its association with allograft function and structure

The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with GFR change, interstitial expansion and end-stage renal disease (ESRD) we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria or interstitial expansion. Losartan use, [HR 0.48 (95% CI 0.21–1.0), insignificant], and Caucasian donor, [HR 0.18 (95% CI 0.07–0.4), significant] were associated with less doubling of serum creatinine, death or ESRD. Hypertension, less than 3 HLA-matches, the combination of tacrolimus-rapamycin and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD, [HR 1.01 (95% CI 1.00–1.02)]. Thus, systemic RAAS is not overly activated in kidney transplant recipients but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.

Cilengitide-Induced Temporal Variations in Transvascular Transfer Parameters of Tumor Vasculature in a Rat Glioma Model: Identifying Potential MRI Biomarkers of Acute Effects

Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v p), forward volume transfer constant (K trans) and interstitial volume fraction (v e) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K trans (p = 0.0001 and v e (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.

Uncertainty in MR tracer kinetic parameters and water exchange rates estimated from T1‐weighted dynamic contrast enhanced MRI

The aim of this study was to assess the uncertainty in estimation of MR tracer kinetic parameters and water exchange rates in T1-weighted dynamic contrast enhanced (DCE) MRI. Simulated DCE-MRI data were used to assess four kinetic models; general kinetic model with a vascular compartment (GKM2), GKM2 combined with water exchange (SSM2), adiabatic approximation of the tissue homogeneity model (ATH), and ATH combined with water exchange (ATHX). In GKM2 and SSM2, increase in transfer constant (K(trans)) led to underestimation of vascular volume fraction (vb), and increase in vb led to overestimation of K(trans). Such coupling between K(trans) and vb was not observed in ATH and ATHX. The precision of estimated intracellular water lifetime (τi) was substantially improved in both SSM2 and ATHX when K(trans) > 0.3 min(-1). K(trans) and vb from ATHX model had significantly smaller errors than those from ATH model (P < 0.05). The results of this study demonstrated the feasibility of measuring τi from DCE-MRI data albeit low precision. While the inclusion of water exchange improved the accuracy of K(trans), vb, and the interstitial volume fraction estimation (ve), it lowered the precision of other kinetic model parameters within the conditions investigated in this study.

Myocardial Tissue Remodeling in Adolescent Obesity

BackgroundChildhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described.Methods and ResultsWe studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum.ConclusionsObese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function.

Model selection in measures of vascular parameters using dynamic contrast‐enhanced MRI: experimental and clinical applications

A review of the selection of models in dynamic contrast-enhanced MRI (DCE-MRI) is conducted, with emphasis on the balance between the bias and variance required to produce stable and accurate estimates of vascular parameters. The vascular parameters considered as a first-order model are the forward volume transfer constant K(trans) , the plasma volume fraction vp and the interstitial volume fraction ve . To illustrate the critical issues in model selection, a data-driven selection of models in an animal model of cerebral glioma is followed. Systematic errors and extended models are considered. Studies with nested and non-nested pharmacokinetic models are reviewed; models considering water exchange are considered.

Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7 T

To test the hypothesis that a noninvasive dynamic contrast enhanced MRI (DCE-MRI) derived interstitial volume fraction (ve ) and/or distribution volume (VD ) were correlated with tumor cellularity in cerebral tumor. T1 -weighted DCE-MRI studies were performed in 18 athymic rats implanted with U251 xenografts. After DCE-MRI, sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Using a Standard Model analysis and Logan graphical plot, DCE-MRI image sets during and after the injection of a gadolinium contrast agent were used to estimate the parameters plasma volume (vp ), forward transfer constant (K(trans) ), ve , and VD . Parameter values in regions where the standard model was selected as the best model were: (mean ± S.D.): vp = (0.81 ± 0.40)%, K(trans) = (2.09 ± 0.65) × 10(-2) min(-1) , ve = (6.65 ± 1.86)%, and VD = (7.21 ± 1.98)%. The Logan-estimated VD was strongly correlated with the standard model's vp + ve (r = 0.91, P < 0.001). The parameters, ve and/or VD , were significantly correlated with tumor cellularity (r ≥ -0.75, P < 0.001 for both). These data suggest that tumor cellularity can be estimated noninvasively by DCE-MRI, thus supporting its utility in assessing tumor pathophysiology.

Sang-qi Granula Reduces Blood Pressure and Myocardial Fibrosis by Suppressing Inflammatory Responses Associated with the Peroxisome Proliferator-Activated Receptors and Nuclear FactorκB Protein in Spontaneously Hypertensive Rats

Aim. Sang-qi Granula (SQ) is a compound prepared from Chinese herbs and is currently used for treatment of hypertension in China. Given its protective effects on cardial function in decreasing blood pressure, we investigated the mechanism of protective effects of SQ on myocardium. Methods. 16 male normal Wistar-Kyoto rats and 16 spontaneous hypertension rats (SHR) were employed without medical treatment. 16 SHR were employed with SQ treatment. Rats in each group were sacrificed at two time points (8-week treatment and 16-week treatment). Blood pressure (BP), and heart weight/body weight (HW/BW) were measured. The expression of myeloperoxidase (MCP-1), ICAM-1, TNF-α, and CD68-positive cells was assessed. The interstitial collagen volume fraction (CVF), perivascular collagen volume area (PVCA), and the expression of TGF-β, Smad-3, PPARα, γ, and NF-κB (P65 and P50) were observed. Results. SQ significantly inhibited the elevation of the blood pressure and HW/BW of SHR. Next, SQ prevented myocardial fibrosis. Finally, a proinflammatory mediator associated with NF-κB (TNF-α, ICAM-1, MCP-1, CD68), TGF-β, and Smad-3 related to collagen deposition, which is upregulated in SHR group, was significantly suppressed by SQ. Expression of NF-κB was decreased in SHQ+SQ group compared to PPARα, and γ expression was increased by SQ. Conclusion. Treatment with SQ ameliorates cardial fibrosis induced by hypertension by attenuating the upregulation of ICAM-1, TNF-α, MCP-1, TGF-β, Smad-3, P65, and P50 expression and improving PPARα and PPARγ expression level. The results suggest that SQ may be an option for preventing cardial fibrosis through PPAR signalling pathway.

Don’t Lose Sleep Over Neurodegeneration-It Helps Clear Amyloid Beta

Xie et al. in their article entitled “sleep drives metabolite clearance from the adult brain” in Science (342: 373–377) (1), provide an important insight into the potential physiology behind the restorative and homeostatic nature of sleep, a basic requirement for normal brain function. This study, utilizing a mouse model explores the clearance of peptides such as amyloid beta, which is implicated in the pathogenesis of Alzheimer’s disease (2) and may offer a platform for the investigation of other forms of neurodegeneration associated with other putative neurotoxic proteins.