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Abstract The objective of this study is to provide a positron emission tomography (PET) imaging modality targeting vascular endothelial growth factor receptors (VEGFR) for the early noninvasive detection and assessment of pulmonary arterial hypertension (PAH) severity. To validate the effectiveness of the [18F]VEGFR PET tracer, we utilized a monocrotaline (MCT)‐induced PAH rat model. Molecular optical imaging, using a Cy5.5‐conjugated VEGFR targeting agent, was employed to demonstrate the uptake of the agent at pulmonary arterioles, correlating with the onset and progression of PAH. Histological examinations of the MCT‐PAH rat lung revealed a significant correlation between VEGFR2 expression and the pathogenesis of PAH. Molecular optical imaging demonstrated heightened uptake of the Cy5.5‐conjugated VEGFR targeting agent at pulmonary arterioles, corresponding with the onset and progression of PAH. [18F]VEGFR PET showed increased lung uptake detectable in early‐stage PAH before increase in pulmonary artery pressures, and this uptake correlated with increased PAH severity. Moreover, when compared to [18F]FDG PET, [18F]VEGFR PET exhibited markedly lower background cardiac signal, enhancing imaging sensitivity for lung abnormalities. Our study provides a compelling evidence for the potential utility of the innovative [18F]VEGFR PET tracer, in non‐invasively detecting early signs of PAH, and monitoring its progression. The observed correlations between VEGFR2 expression, molecular optical imaging results, and [18F]VEGFR PET findings support the use of this tracer for early detection, and assessment of PAH severity. The lower background cardiac signal observed with [18F]VEGFR PET further enhances its imaging sensitivity, emphasizing its potential clinical significance.

Myocardial infarction (MI) triggers adverse ventricular remodeling (VR), cardiac fibrosis, and subsequent heart failure. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is postulated to play a significant role in VR processing via activation of the TLR4 inflammatory pathway. We hypothesized that an eNAMPT specific monoclonal antibody (mAb) could target and neutralize overexpressed eNAMPT post-MI and attenuate chronic cardiac inflammation and fibrosis. We investigated humanized ALT-100 and ALT-300 mAb with high eNAMPT-neutralizing capacity in an infarct rat model to test our hypothesis. ALT-300 was 99mTc-labeled to generate 99mTc-ALT-300 for imaging myocardial eNAMPT expression at 2 hours, 1 week, and 4 weeks post-IRI. The eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg) or saline was administered intraperitoneally at 1 hour and 24 hours post-reperfusion and twice a week for 4 weeks. Cardiac function changes were determined by echocardiography at 3 days and 4 weeks post-IRI. 99mTc-ALT-300 uptake was initially localized to the ischemic area at risk (IAR) of the left ventricle (LV) and subsequently extended to adjacent non-ischemic areas 2 hours to 4 weeks post-IRI. Radioactive uptake (%ID/g) of 99mTc-ALT-300 in the IAR increased from 1 week to 4 weeks (0.54 ± 0.16 vs. 0.78 ± 0.13, P

It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with 99mTc and 125I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury.

Background: Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury.Methods/Results: Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS.Conclusions: These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.

Abstract Background Double inversion recovery (DIR) fast spin-echo (FSE) cardiovascular magnetic resonance (CMR) sequences are used clinically for black-blood T2-weighted imaging. However, these sequences suffer from slice inefficiency due to the non-selective inversion pulses. We propose a multi-band (MB) encoded DIR radial FSE (MB-DIR-RADFSE) technique to simultaneously excite two slices. This sequence has improved signal-to-noise ratio per unit time compared to a single slice excitation. It is also motion robust and enables the reconstruction of high-resolution black-blood T2-weighted images and T2 maps for the excited slices. Methods Hadamard encoded MB pulses were used in MB-DIR-RADFSE to simultaneously excite two slices. A principal component based iterative reconstruction was used to jointly reconstruct black-blood T2-weighted images and T2 maps. Phantom and in vivo experiments were performed to evaluate T2 mapping performance and results were compared to a T2-prepared balanced steady state free precession (bSSFP) method. The inter-segment variability of the T2 maps were assessed using data acquired on healthy subjects. A reproducibility study was performed to evaluate reproducibility of the proposed technique. Results Phantom experiments show that the T2 values estimated from MB-DIR-RADFSE are comparable to the spin-echo based reference, while T2-prepared bSSFP over-estimated T2 values. The relative contrast of the black-blood images from the multi-band scheme was comparable to those from a single slice acquisition. The myocardial segment analysis on 8 healthy subjects indicated a significant difference (p-value

Nonalcoholic fatty liver disease (NAFLD) is now thought to be the most common liver disease worldwide. Cardiovascular complications are a leading cause of mortality in NAFLD. Fructose, a common nutrient in the westernized diet, has been reported to be associated with increased cardiovascular risk, but its impact on adolescents with NAFLD is not well understood. We designed a 4-week randomized, controlled, double-blinded beverage intervention study. Twenty-four overweight Hispanic-American adolescents who had hepatic fat >8% on imaging and who were regular consumers of sweet beverages were enrolled and randomized to calorie-matched study-provided fructose only or glucose only beverages. After 4 weeks, there was no significant change in hepatic fat or body weight in either group. In the glucose beverage group there was significantly improved adipose insulin sensitivity, high sensitivity C-reactive protein (hs-CRP), and low-density lipoprotein (LDL) oxidation. These findings demonstrate that reduction of fructose improves several important factors related to cardiovascular disease despite a lack of measurable improvement in hepatic steatosis. Reducing dietary fructose may be an effective intervention to blunt atherosclerosis progression among NAFLD patients and should be evaluated in longer term clinical trials.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and liver transplantation is the optimal treatment for selected patients with HCC and chronic liver disease (CLD). Accurate selection of patients for transplantation is essential to maximize patient outcomes and ensure optimized allocation of donor organs. Magnetic resonance imaging (MRI) is a powerful tool for the detection, characterization, and staging of HCC. In patients with CLD, the MRI findings of an arterial-enhancing mass with subsequent washout and enhancing capsule on delayed interstitial phase images are diagnostic for HCC. Major organizations with oversight for organ donor distribution, such as The Organ Procurement and Transplantation Network (OPTN), accept an imaging diagnosis of HCC, no longer requiring tissue biopsy. In patients that are awaiting transplantation, or are not candidates for liver transplantation, localized therapies such as transarterial chemoembolization and radiofrequency ablation may be offered. MRI can be used to monitor treatment response. The purpose of this review article is to describe the role of imaging methods in the diagnosis, staging, and follow-up of HCC, with particular emphasis on established and evolving MRI techniques employing nonspecific gadolinium chelates, hepatobiliary contrast agents, and diffusion weighted imaging. We also briefly review the recently developed Liver Imaging Reporting and Data System (LI-RADS) formulating a standardized terminology and reporting structure for evaluation of lesions detected in patients with CLD.

Diffuse liver disease, including chronic liver disease, affects tens of millions of people worldwide, and there is a growing need for diagnostic evaluation as treatments become more readily available, particularly for viral liver diseases. Magnetic resonance imaging (MRI) provides unique capabilities for noninvasive characterization of the liver tissue that rival or surpass the diagnostic utility of liver biopsies. There has been incremental improvement in the use of standardized MRI sequences, acquired before and after administration of a contrast agent, for the evaluation of diffuse liver disease and the study of the liver parenchyma and blood supply. More recent developments have led to methods for quantifying important liver metabolites, including lipids and iron, and liver fibrosis, the hallmark of chronic liver disease. Here, we review the MRI techniques and diagnostic features associated with acute and chronic liver disease.

Diffuse liver disease is a widespread global healthcare burden, and the abnormal accumulation of lipid and/or iron is common to important disease processes. Developing the improved methods for detecting and quantifying liver lipid and iron is an important clinical need. The inherent risk, invasiveness, and sampling error of liver biopsy have prompted the development of noninvasive imaging methods for lipid and iron assessment. Ultrasonography and computed tomography have the ability to detect diffuse liver disease, but with limited accuracy. The purpose of this review is to describe the current state-of-the-art methods for quantifying liver lipid and iron using magnetic resonance imaging and spectroscopy, including their implementation, benefits, and potential pitfalls. Imaging- and spectroscopy-based methods are naturally suited for lipid and iron quantification. Lipid can be detected and decomposed from the inherent chemical shift between lipid and water signals, whereas iron imparts significant paramagnetic susceptibility to tissue, which accelerates proton relaxation. However, measurements of these biomarkers are confounded by technical and biological effects. Current methods must address these factors to allow a precise correlation between the lipid fraction and iron concentration. Although this correlation becomes increasingly challenging in the presence of combined lipid and iron accumulation, advanced techniques show promise for delineating these quantities through multi-lipid peak analysis, T2 water mapping, and fast single-voxel water-lipid spectroscopy.

Diffuse liver disease, including all causes of chronic liver disease, affects tens of millions of people worldwide. There is a growing need for diagnostic evaluation as treatments become more readily available, particularly for viral liver disease. Magnetic resonance imaging (MRI) provides unique capabilities for noninvasive characterization of liver tissue that rival or surpass the diagnostic utility of liver biopsies. There has been incremental improvement in the use of standardized MRI sequences, acquired before and after administration of contrast for the evaluation of diffuse liver disease, and this includes study of the liver parenchyma and blood supply. More recent developments have led to methods for quantifying important liver metabolites, including fat and iron, and liver fibrosis, which is the hallmark for chronic liver disease. In this study, we review the MRI techniques and diagnostic features associated with common and uncommon etiologies of diffuse liver diseases, including processes that lead to abnormal perfusion (e.g. Budd-Chiari syndrome, congestive hepatomegaly), deposition diseases (e.g. fatty liver, hemochromatosis, Wilson’s disease), and abnormalities that are related to inflammation and fibrosis (e.g. primary sclerosing cholangitis, sarcoidosis).

Comprehensive bowel examination results from the combined use of T2-weighted single-shot and breath hold T1-weighted gradient echo, minus/plus fat suppression, and gadolinium-enhanced 3D gradient echo (3D VIBE, T1 FAME, 3D THRIVE). Gadolinium-enhanced imaging should be performed dynamically, but the venous 60- to 90-second delayed phase images with fat suppression are generally the most valuable. Removal of fat signal for detection of enhancing normal and abnormal structures is critical. Newly available True-FISP (FIESTA, BFFE) sequences obtained in the 2D form can be very helpful in delineation of bowel wall pathology and overall bowel anatomy, particularly when combined with a water-based intraluminal distending agent. Advantages include rapid acquisition, high signal-to-noise, and motion insensitivity. Generalized protocol for comprehensive evaluation of the entire abdomen and pelvis can be used for the following bowel indications: type and severity of inflammatory bowel disease (IBD); identifying enteric abscesses and fistulae; preoperative staging of malignant neoplasms, including rectal carcinoma; differentiating postoperative and radiation therapy changes from recurrent carcinoma; follow-up evaluation of metastases response to localized ablative or systemic chemotherapy. For improved visualization of bowel wall in dedicated examinations, bowel distension should be achieved using either orally or rectally delivered contrast agents to produce either bright or dark lumen. We have found 2D True-FISP without fat suppression superior to 3D True-FISP and to single-shot echo-train sequences to provide a T2-weighted image of bowel morphology. Strengths include: performed without fat suppression results in the very dark bowel wall being sandwiched between intermediate high signal fat adjacent to bowel serosa, and very high lumen signal from water-distending agent; 2D True-FISP provides motion insensitivity that is lost if 3D is used; True-FISP produces better edge sharpness than single-shot echo-train, higher contrast, and resists flow void artifacts commonly seen with single-shot echo-train imaging combined with a water distending agent. Drawbacks of this technique include: artifacts related to extreme sensitivity to field inhomogeneity, including air-soft tissue interfaces at the patient skin surface, and from retained bowel gas; retained bowel gas is dark against dark bowel wall, impairing bowel wall assessment; and True-FISP does not provide sensitivity for edema, which is superior on single-shot echo-train imaging. Small/large bowel indications for MRI include: inflammatory bowel disease, infectious disease including abscess evaluation or for appendicitis, inflammatory conditions including ischemia, and partial obstruction, malnutrition, and neoplasm search. [ABSTRACT FROM AUTHOR]

To evaluate peripancreatic signal changes on fat-suppressed T1-weighted spoiled gradient echo images associated with acute pancreatitis and investigate potential utility in regards to relationship to clinical outcome. The abdominal MR images in 31 patients with acute pancreatitis were reviewed, and evaluated for the presence of elevated signal intensity within the peripancreatic fat on fat-suppressed T1-weighted spoiled gradient echo images; the degree of signal changes was graded as mild, moderate, or severe. Ten of 31 patients demonstrated abnormal high signal intensity in the peripancreatic fat on fat-suppressed T1-weighted images. The degree of signal change was mild in three patients, moderate in one, and severe in six patients. All six patients with severe elevated peripancreatic soft tissue signal died within seven to 68 days (mean, 47 days) of their admission. All 21 patients without elevated peripancreatic fat signal survived without any complications. The correlation between the presence and severity of elevated peripancreatic MR signal and patient outcome was significant (P < 0.05). Elevated peripancreatic signal on fat-suppressed T1-weighted images is associated progressively with poor outcome in patients with acute pancreatitis, and may represent a simplified method for prognostic cross-sectional imaging. J. Magn. Reson. Imaging 2003;18:49–58. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]