Glucose versus fructose metabolism in the liver measured with deuterium metabolic imaging

Chronic intake of high amounts of fructose has been linked to the development of metabolic disorders, which has been attributed to the almost complete clearance of fructose by the liver. However, direct measurement of hepatic fructose uptake is complicated by the fact that the portal vein is difficult to access. Here we present a new, non-invasive method to measure hepatic fructose uptake and metabolism with the use of deuterium metabolic imaging (DMI) upon administration of [6,6’-2H2]fructose. Using both [6,6’-2H2]glucose and [6,6’-2H2]fructose, we determined differences in the uptake and metabolism of glucose and fructose in the mouse liver with dynamic DMI. The deuterated compounds were administered either by fast intravenous (IV) bolus injection or by slow IV infusion. Directly after IV bolus injection of [6,6’-2H2]fructose, a more than two-fold higher initial uptake and subsequent 2.5-fold faster decay of fructose was observed in the mouse liver as compared to that of glucose after bolus injection of [6,6’-2H2]glucose. In contrast, after slow IV infusion of fructose, the 2H fructose/glucose signal maximum in liver spectra was lower compared to the 2H glucose signal maximum after slow infusion of glucose. With both bolus injection and slow infusion protocols, deuterium labeling of water was faster with fructose than with glucose. These observations are in line with a higher extraction and faster turnover of fructose in the liver, as compared with glucose. DMI with [6,6’-2H2]glucose and [6,6’-2H2]fructose could potentially contribute to a better understanding of healthy human liver metabolism and aberrations in metabolic diseases

Validation of In Vivo Nodal Assessment of Solid Malignancies with USPIO-Enhanced MRI: A Workflow Protocol

Background: In various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superpara-magnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented, which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology. Methods: In patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious of harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens. Results: Matching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology, which allowed for analyses on a nodal, or at least on a nodal station, basis. Conclusions: A workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed for the analysis at a nodal basis, or at least nodal station basis, of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced, MRI-detected lymph nodes

A consensus protocol for functional connectivity analysis in the rat brain

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience

In vivo 31P MRSI for metabolic profiling of human breast cancer xenografts

Purpose To study cancer associated with abnormal metabolism of phospholipids, of which several have been proposed as biomarkers for malignancy or to monitor response to anticancer therapy. We explored 3D 31P magnetic resonance spectroscopic imaging (MRSI) at high magnetic field for in vivo assessment of individual phospholipids in two patient-derived breast cancer xenografts representing good and poor prognosis (luminal- and basal-like tumors). Materials and Methods Metabolic profiles from luminal-like and basal-like xenograft tumors were obtained in vivo using 3D 31P MRSI at 11.7T and from tissue extracts in vitro at 14.1T. Gene expression analysis was performed in order to support metabolic differences between the two xenografts. Results In vivo 31P MR spectra were obtained in which the prominent resonances from phospholipid metabolites were detected at a high signal-to-noise ratio (SNR >7.5). Metabolic profiles obtained in vivo were in agreement with those obtained in vitro and could be used to discriminate between the two xenograft models, based on the levels of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine. The differences in phospholipid metabolite concentration could partly be explained by gene expression profiles. Conclusion Noninvasive metabolic profiling by 3D 31P MRSI can discriminate between subtypes of breast cancer based on different concentrations of choline- and ethanolamine-containing phospholipids

In vivo MR guided boiling histotripsy in a mouse tumor model evaluated by MRI and histopathology

Boiling histotripsy (BH) is a new high intensity focused ultrasound (HIFU) ablation technique to mechanically fragmentize soft tissue into submicrometer fragments. So far, ultrasound has been used for BH treatment guidance and evaluation. The in vivo histopathological effects of this treatment are largely unknown. Here, we report on an MR guided BH method to treat subcutaneous tumors in a mouse model. The treatment effects of BH were evaluated one hour and four days later with MRI and histopathology, and compared with the effects of thermal HIFU (T-HIFU). The lesions caused by BH were easily detected with T2w imaging as a hyper-intense signal area with a hypo-intense rim. Histopathological evaluation showed that the targeted tissue was completely disintegrated and that a narrow transition zone (2w imaging and H&E stained sections, making T2w imaging a suitable method for treatment evaluation during or directly after BH. After T-HIFU, contrast enhanced imaging was required for adequate detection of the ablation zone. On histopathology, an ablation zone with concentric layers was seen after T-HIFU. In line with histopathology, contrast enhanced MRI revealed that after BH or T-HIFU perfusion within the lesion was absent, while after BH in the transition zone some micro-hemorrhaging appeared. Four days after BH, the transition zone with apoptotic cells was histologically no longer detectable, corresponding to the absence of a hypo-intense rim around the lesion in T2w images. This study demonstrates the first results of in vivo BH on mouse tumor using MRI for treatment guidance and evaluation and opens the way for more detailed investigation of the in vivo effects of BH

Noninvasive magnetic resonance imaging of the development of individual colon cancer tumors in rat liver.

Contains fulltext : 71195.pdf (publisher's version ) (Closed access)Monitoring tumor development is essential for the understanding of mechanisms involved in tumor progression and to determine efficacy of therapy. One of the evolving approaches is longitudinal noninvasive magnetic resonance imaging (MRI) of tumors in experimental models. We applied high-resolution MRI at 7 Tesla to study the development of colon cancer tumors in rat liver. MRI acquisition was triggered to the respiratory cycle to minimize motion artifacts. A special radio frequency (RF) coil was designed to acquire detailed T1-weighted and T2-weighted images of the liver. T2-weighted images identified hyperintense lesions representing tumors with a minimum diameter of 2 mm, enabling the determination of growth rates and morphological aspects of individual tumors. It is concluded that high-resolution MRI using a dedicated RF coil and triggering to the respiratory cycle is an excellent tool for quantitative and morphological analysis of individual diffusely distributed tumors throughout the liver. However, at present, MRI requires expensive equipment and expertise and is a time-consuming methodology. Therefore, it should preferably be used for dedicated applications rather than for high-throughput assessment of total tumor load in animals

Imatinib attenuates reperfusion injury in a rat model of acute myocardial infarction

Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by microvascular injury, leading to worse long-term prognosis. Experimental studies have revealed the potential of tyrosine-kinase inhibitor imatinib to reduce vascular leakage in various organs. Here, we examined the potential of imatinib to attenuate microvascular injury in a rat model of myocardial reperfusion injury. Isolated male Wistar rat hearts (n = 20) in a Langendorff system and male Wistar rats (n = 37) in an in vivo model were randomly assigned to imatinib or placebo and subjected to ischaemia and reperfusion. Evans-blue/Thioflavin-S/TTC staining and Cardiac Magnetic Resonance Imaging were performed to assess the extent of reperfusion injury. Subsequently, in vivo hearts were perfused ex vivo with a vascular leakage tracer and fluorescence and electron microscopy were performed. In isolated rat hearts, imatinib reduced global infarct size, improved end-diastolic pressure, and improved rate pressure product recovery compared to placebo. In vivo, imatinib reduced no-reflow and infarct size with no difference between imatinib and placebo for global cardiac function. In addition, imatinib showed lower vascular resistance, higher coronary flow, and less microvascular leakage in the affected myocardium. At the ultrastructural level, imatinib showed higher preserved microvascular integrity compared to placebo. We provide evidence that low-dose imatinib can reduce microvascular injury and accompanying myocardial infarct size in a rat model of acute myocardial infarction. These data warrant future work to examine the potential of imatinib to reduce reperfusion injury in patients with acute myocardial infarction

Perinatal exposure to the immune-suppressant di-n-octyltin dichloride affects brain development in rats.

Disruption of the immune system during embryonic brain development by environmental chemicals was proposed as a possible cause of neurodevelopmental disorders. We previously found adverse effects of di-n-octyltin dichloride (DOTC) on maternal and developing immune systems of rats in an extended one-generation reproductive toxicity study according to OECD 443 test guideline. We hypothesize that the DOTC-induced changes in the immune system can affect neurodevelopment. Therefore, we used in-vivo MRI and PET imaging and genomics, in addition to behavioral testing and neuropathology as proposed in OECD test guideline 443, to investigate the effect of DOTC on structural and functional brain development. Male rats were exposed to DOTC (0, 3, 10, or 30 mg/kg of diet) from 2 weeks prior to mating of the F0-generation until sacrifice of F1-animals. The brains of rats, exposed to DOTC showed a transiently enlarged volume of specific brain regions (MRI), altered specific gravity and transient hyper-metabolism ([18F]FDG PET). The alterations in brain development concurred with hyper-responsiveness in auditory startle response and slight hyperactivity in young adult animals. Genomics identified altered transcription of key regulators involved in neurodevelopment and neural function (e.g. Nrgrn, Shank3, Igf1r, Cck, Apba2, Foxp2); and regulators involved in cell size, cell proliferation and organ development, especially immune system development and functioning (e.g. LOC679869, Itga11, Arhgap5, Cd47, Dlg1, Gas6, Cml5, Mef2c). The results suggest involvement of immunotoxicity in the impairment of the nervous system by DOTC and support the hypothesis of a close connection between the immune and nervous systems in brain development