Pharmaceutical development and preclinical evaluation of a GMP-grade anti-inflammatory nanotherapy.

Unlabelled: The present study describes the development of a good manufacturing practice (GMP)-grade liposomal nanotherapy containing prednisolone phosphate for the treatment of inflammatory diseases. After formulation design, GMP production was commenced which yielded consistent, stable liposomes sized 100nm±10nm, with a prednisolone phosphate (PLP) incorporation efficiency of 3%-5%. Pharmacokinetics and toxicokinetics of GMP-grade liposomal nanoparticles were evaluated in healthy rats, which were compared to daily and weekly administration of free prednisolone phosphate, revealing a long circulatory half-life with minimal side effects.

A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.

Objective: Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET.

Enhanced identification of BOLD-like components with multi-echo simultaneous multi-slice (MESMS) fMRI and multi-echo ICA.

The recent introduction of simultaneous multi-slice (SMS) acquisitions has enabled the acquisition of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data with significantly higher temporal sampling rates. In a parallel development, the use of multi-echo fMRI acquisitions in conjunction with a multi-echo independent component analysis (ME-ICA) approach has been introduced as a means to automatically distinguish functionally-related BOLD signal components from signal artifacts, with significant gains in sensitivity, statistical power, and specificity. In this work, we examine the gains that can be achieved with a combined approach in which data obtained with a multi-echo simultaneous multi-slice (MESMS) acquisition are analyzed with ME-ICA.

Quantification of hepatic blood flow using a high-resolution phase-contrast MRI sequence with compressed sensing acceleration.

OBJECTIVE. The objective of our study was to evaluate the performance of a high-spatial-resolution 2D phase-contrast (PC) MRI technique accelerated with compressed sensing for portal vein (PV) and hepatic artery (HA) flow quantification in comparison with a standard PC MRI sequence. SUBJECTS AND METHODS.

Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?

Context: Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS.

Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder.

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions.

Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation.

Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease.

Atherosclerotic plaque targeting mechanism of long-circulating nanoparticles established by multimodal imaging.

Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model.

Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.

Objectives: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events.

Background: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk.

DCE-MRI of the liver: reconstruction of the arterial input function using a low dose pre-bolus contrast injection.

Purpose: To assess the quality of the arterial input function (AIF) reconstructed using a dedicated pre-bolus low-dose contrast material injection imaged with a high temporal resolution and the resulting estimated liver perfusion parameters.

Materials And Methods: In this IRB-approved prospective study, 24 DCE-MRI examinations were performed in 21 patients with liver disease (M/F 17/4, mean age 56 y). The examination consisted of 1.

Diffusion-weighted MR imaging of the pancreas: current status and recommendations.

Advances in image quality over the past few years, mainly due to refinements in hardware and coil systems, have made diffusion-weighted ( DW diffusion weighted ) magnetic resonance (MR) imaging a promising technique for the detection and characterization of pancreatic conditions. DW diffusion weighted MR imaging can be routinely implemented in clinical protocols, as it can be performed relatively quickly, does not require administration of gadolinium-based contrast agents, and enables qualitative and quantitative assessment of tissue diffusivity (diffusion coefficients). In this review, acquisition parameters, postprocessing, and quantification methods applied to pancreatic DW diffusion weighted MR imaging will be discussed.

Ultra-High-Field MR Neuroimaging.

At ultra-high magnetic fields, such as 7T, MR imaging can noninvasively visualize the brain in unprecedented detail and through enhanced contrast mechanisms. The increased SNR and enhanced contrast available at 7T enable higher resolution anatomic and vascular imaging. Greater spectral separation improves detection and characterization of metabolites in spectroscopic imaging.

Abdominal 4D flow MR imaging in a breath hold: combination of spiral sampling and dynamic compressed sensing for highly accelerated acquisition.

Purpose: To develop a highly accelerated phase-contrast cardiac-gated volume flow measurement (four-dimensional [4D] flow) magnetic resonance (MR) imaging technique based on spiral sampling and dynamic compressed sensing and to compare this technique with established phase-contrast imaging techniques for the quantification of blood flow in abdominal vessels.

Materials And Methods: This single-center prospective study was compliant with HIPAA and approved by the institutional review board. Ten subjects (nine men, one woman; mean age, 51 years; age range, 30-70 years) were enrolled.

Simultaneous measurement of hepatic and splenic stiffness using MR elastography: preliminary experience.

Purpose: To compare MR elastography (MRE) using a single and a dual driver excitation for the quantification of hepatic and splenic stiffness (HS and SS), and to investigate the performance of HS and SS measured with single or dual driver excitation for the detection of liver cirrhosis in subjects with liver disease.

Patients And Methods: This prospective HIPAA compliant and IRB approved study involved 49 subjects who underwent MRE at 3.0T, comparing three different acquisition methods (single driver on the liver, single driver on the spleen and dual driver acoustic excitation).

Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.

Background: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk.

Objectives: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients.

Methods: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls.

Intravoxel incoherent motion diffusion imaging of the liver: optimal b-value subsampling and impact on parameter precision and reproducibility.

Purpose: To increase diffusion sampling efficiency in intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) of the liver by reducing the number of diffusion weightings (b-values).

Materials And Methods: In this IRB approved HIPAA compliant prospective study, 53 subjects (M/F 38/15, mean age 52 ± 13 y) underwent IVIM DWI at 1.5T using 16 b-values (0-800s/mm(2)), with 14 subjects having repeat exams to assess IVIM parameter reproducibility.

Efficient drug delivery and induction of apoptosis in colorectal tumors using a death receptor 5-targeted nanomedicine.

Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that is a potential therapeutic target in cancer. Despite the potency of DR5-targeting agents in preclinical models, the translation of these effects into the clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles.

In vivo imaging of enhanced leukocyte accumulation in atherosclerotic lesions in humans.

Background: Understanding how leukocytes impact atherogenesis contributes critically to our concept of atherosclerosis development and the identification of potential therapeutic targets.

Objectives: The study evaluates an in vivo imaging approach to visualize peripheral blood mononuclear cell (PBMC) accumulation in atherosclerotic lesions of cardiovascular (CV) patients using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT).

Methods: At baseline, CV patients and healthy controls underwent (18)fluorodeoxyglucose positron emission tomography-computed tomography and magnetic resonance imaging to assess arterial wall inflammation and dimensions, respectively.

Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of hypoxia-inducible factor-1α and vascular endothelial growth factor signaling.

Background: Alternatively spliced tissue factor (asTF) is a novel isoform of full-length tissue factor, which exhibits angiogenic activity. Although asTF has been detected in human plaques, it is unknown whether its expression in atherosclerosis causes increased neovascularization and an advanced plaque phenotype.

Methods And Results: Carotid (n=10) and coronary (n=8) specimens from patients with stable or unstable angina were classified as complicated or uncomplicated on the basis of plaque morphology.

Diffusion-weighted imaging of the liver: techniques and applications.

Diffusion-weighted imaging (DWI) is a technique that assesses the cellularity, tortuosity of the extracellular/extravascular space, and cell membrane density based on differences in water proton mobility in tissues. The strength of the diffusion weighting is reflected by the b value. DWI using several b values enables the quantification of the apparent diffusion coefficient.

A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting.

Unlabelled: Advances in preclinical molecular imaging have generated new opportunities to noninvasively visualize the biodistribution and tumor targeting of nanoparticle therapeutics. Capitalizing on recent achievements in this area, we sought to develop an (89)Zr-based labeling strategy for liposomal nanoparticles that accumulate in tumors via passive targeting mechanisms.

Methods: (89)Zr-labeled liposomes were prepared using 2 different approaches: click labeling and surface chelation.

White matter abnormalities in schizophrenia and schizotypal personality disorder.

Prior diffusion tensor imaging (DTI) studies examining schizotypal personality disorder (SPD) and schizophrenia, separately have shown that compared with healthy controls (HCs), patients show frontotemporal white matter (WM) abnormalities. This is the first DTI study to directly compare WM tract coherence with tractography and fractional anisotropy (FA) across the schizophrenia spectrum in a large sample of demographically matched HCs (n = 55), medication-naive SPD patients (n = 49), and unmedicated/never-medicated schizophrenia patients (n = 22) to determine whether (a) frontal-striatal-temporal WM tract abnormalities in schizophrenia are similar to, or distinct from those observed in SPD; and (b) WM tract abnormalities are associated with clinical symptom severity indicating a common underlying pathology across the spectrum. Compared with both the HC and SPD groups, schizophrenia patients showed WM abnormalities, as indexed by lower FA in the temporal lobe (inferior longitudinal fasciculus) and cingulum regions.

DCE-MRI of the liver: effect of linear and nonlinear conversions on hepatic perfusion quantification and reproducibility.

Purpose: To evaluate the effect of different methods to convert magnetic resonance (MR) signal intensity (SI) to gadolinium concentration ([Gd]) on estimation and reproducibility of model-free and modeled hepatic perfusion parameters measured with dynamic contrast-enhanced (DCE)-MRI.

Materials And Methods: In this Institutional Review Board (IRB)-approved prospective study, 23 DCE-MRI examinations of the liver were performed on 17 patients. SI was converted to [Gd] using linearity vs.