Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor.

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. METHODS: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. RESULTS: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. CONCLUSIONS: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. TRIAL REGISTRATION: NCT02674152 and NCT02689505.

Tryptophan catabolites and depression in the general population: results from the Gutenberg Health Study.

Previous studies reported significantly altered tryptophan catabolite concentrations in major depression. Thus, tryptophan catabolites were considered as potential biomarkers of depression and their modulators as potential targets for psychopharmacotherapy. However, the results were based mainly on studies with small sample sizes limiting their generalizability. Against this background, we investigated the relationship of peripheral tryptophan catabolites with depression in a population-based sample with n = 3,389 participants (with fasting status ≥ 8 h and C-reactive protein < 10 mg/L). N = 248 had clinically significant depression according to a PHQ-9 score of ≥ 10, n = 1,101 subjects had mild depressive symptoms with PHQ-9 scores between 5 and 9, and n = 2,040 had no depression. After multivariable adjustment, clinically significant depression was associated with lower kynurenine and kynurenic acid. Spearman correlation coefficients of the tryptophan catabolites with the severity of depression were very small (rho ≤ 0.080, p ≤ 0.015). None of the tryptophan catabolites could diagnostically separate depressed from not depressed persons. Concerning linear associations, kynurenine and kynurenic acid were associated only with the severity and the cognitive dimension of depression but not its somatic dimension. Tryptophan catabolites were not associated with persistence or recurrence of depression at the 5 year follow-up. The results replicated the association between kynurenine and kynurenic acid with depression. However, the associations were small raising doubts about their clinical utility. Findings underline the complexity of the relationships between depression and tryptophan catabolites. The search for subgroups of depression with a potentially higher impact of depression might be warranted.

The Combination of MR Elastography and Proton Density Fat Fraction Improves Diagnosis of Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide. It is subdivided into nonalcoholic fatty liver (NAFL) and the more aggressive form, nonalcoholic steatohepatitis (NASH), which carries a higher risk of developing fibrosis and cirrhosis. There is currently no reliable non-invasive method for differentiating NASH from NAFL. PURPOSE: To investigate the ability of magnetic resonance imaging (MRI)-based imaging biomarkers to diagnose NASH and moderate fibrosis as well as assess their repeatability. STUDY TYPE: Prospective. SUBJECTS: Sixty-eight participants (41% women) with biopsy-proven NAFLD (53 NASH and 15 NAFL). Thirty participants underwent a second MRI in order to assess repeatability. FIELD STRENGTH/SEQUENCE: 3.0 T; MR elastography (MRE) (a spin-echo echo-planar imaging [SE-EPI] sequence with motion-encoding gradients), MR proton density fat fraction (PDFF) and R2* mapping (a multi-echo three-dimensional gradient-echo sequence), T1 mapping (a single-point saturation-recovery technique), and diffusion-weighted imaging (SE-EPI sequence). ASSESSMENT: Quantitative MRI measurements were obtained and assessed alone and in combination with biochemical markers (cytokeratin-18 [CK18] M30, alanine transaminase [ALT], and aspartate transaminase [AST]) using logistic regression models. Models that could differentiate between NASH and NAFL and between moderate to advanced fibrosis (F2-4) and no or mild fibrosis (F0-1), based on the histopathological results, were identified. STATISTICAL TESTS: Independent samples t-test, Pearson's chi-squared test, area under the receiver operating characteristic curve (AUROC), Spearman's correlation, intra-individual coefficient of variation, and intraclass correlation coefficient (ICC). Statistical significance was set at P < 0.05. RESULTS: There was a significant difference between the NASH and NAFL groups with liver stiffness assessed with MRE, CK18 M30, and ALT, with an AUROC of 0.74, 0.76, and 0.70, respectively. Both MRE and PDFF contributed significantly to a bivariate model for diagnosing NASH (AUROC = 0.84). MRE could significantly differentiate between F2-4 and F0-1 (AUROC = 0.74). A model combining MRE with AST improved the diagnosis of F2-4 (AUROC = 0.83). The ICC for repeatability was 0.94 and 0.99 for MRE and PDFF, respectively. DATA CONCLUSION: MRE can potentially diagnose NASH and differentiate between fibrosis stages. Combining MRE with PDFF improves the diagnosis of NASH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

The association between plasma tryptophan catabolites and depression: The role of symptom profiles and inflammation.

BACKGROUND: Tryptophan catabolites ("TRYCATs") produced by the kynurenine pathway (KP) may play a role in depression pathophysiology. Studies comparing TRYCATs levels in depressed subjects and controls provided mixed findings. We examined the association of TRYCATs levels with 1) the presence of Major Depressive Disorder (MDD), 2) depressive symptom profiles and 3) inflammatory markers. METHODS: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1100) or remitted (n = 753) MDD DSM-IV diagnosis and healthy controls (n = 642). Plasma levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KynA), quinolinic acid (QA), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured. Atypical/energy-related symptom (AES), melancholic symptom (MS) and anxious-distress symptom (ADS) profiles were derived from questionnaires. RESULTS: After adjustment for age, sex, education, smoking status, alcohol consumption and chronic diseases, no significant differences in TRYCATs were found comparing MDD cases versus controls. The MS profile was associated (q < 0.05) with lower KynA (ß = -0.05), while AES was associated with higher KYN (ß = 0.05), QA (ß = 0.06) and TRP (ß = 0.06). Inflammatory markers were associated with higher KYN (CRP ß = 0.12, IL-6 ß = 0.08, TNF ß = 0.10) and QA (CRP ß = 0.21, IL-6 ß = 0.12, TNF ß = 0.18). Significant differences against controls emerged after selecting MDD cases with high (top 30%) CRP (KYN d = 0.20, QA d = 0.33) and high TNF (KYN d = 0.24; QA d = 0.39). CONCLUSIONS: TRYCATs levels were related to specific clinical and biological features, such as atypical symptoms or a proinflammatory status. Modulation of KP may potentially benefit a specific subset of depressed patients. Clinical studies should focus on patients with clear evidence of KP dysregulations.

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

Background: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. Methods: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. Results: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. Conclusions: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders.

Animal models for the study of inflammatory bowel diseases: a meta-analysis on modalities for imaging inflammatory lesions.

Inflammatory bowel diseases are lifelong disorders affecting the gastrointestinal tract characterized by intermittent disease flares and periods of remission with a progressive and destructive nature. Unfortunately, the exact etiology is still not completely known, therefore a causal therapy to cure the disease is not yet available. Current treatment options mainly encompass the use of non-specific anti-inflammatory agents and immunosuppressive drugs that cause significant side effects that often have a negative impact on patients' quality of life. As the majority of patients need a long-term follow-up it would be ideal to rely on a non-invasive technique with good compliance. Currently, the gold standard diagnostic tools for managing IBD are represented by invasive procedures such as colonoscopy and histopathology. Nevertheless, recent advances in imaging technology continue to improve the ability of imaging techniques to non-invasively monitor disease activity and treatment response in preclinical models of IBD. Novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. Furthermore, molecular imaging advances allow us to increase our knowledge on the critical biological pathways involved in disease progression by characterizing in vivo processes at a cellular and molecular level and enabling significant improvements in the understanding of the etiology of IBD. This review presents a critical and updated overview on the imaging advances in animal models of IBD. Our aim is to highlight the potential beneficial impact and the range of applications that imaging techniques could offer for the improvement of the clinical monitoring and management of IBD patients: diagnosis, staging, determination of therapeutic targets, monitoring therapy and evaluation of the prognosis, personalized therapeutic approaches.

A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.

Fatty acids in multiple circulating lipid fractions reflects the composition of liver triglycerides in humans.

BACKGROUND AND AIMS: Fatty acids (e.g. 16:1n-7) and desaturase indices (e.g. stearoyl-CoA desaturase, SCD) in plasma cholesteryl esters (CE) and phospholipids (PL) are used as biomarkers of dietary fat quality and lipid metabolism and are associated with disease outcomes. Endogenously produced circulating fatty acids are believed to reflect composition of the liver, yet little data exist to support such relationship. We investigated associations between circulating fatty acids and fatty acids within the liver. METHODS: Liver biopsies and blood were collected from n = 60 patients with non-alcoholic fatty liver disease. Fatty acids in CE, PL and triglycerides (TG) in plasma and liver were analyzed using gas chromatography. Associations were assessed using Spearman rank correlations. RESULTS: Overall, fatty acids and desaturase indices in plasma PL and TG showed moderate-strong correlations with fatty acids and desaturase indices in corresponding lipid fractions in liver. For plasma CE, 16:1n-7 and SCD were correlated with 16:1n-7 and SCD in liver CE. Noteworthy, fatty acids in plasma CE and PL also showed moderate-strong correlations with fatty acids in liver TG (e.g. r = 0.82-0.87 for 16:1n-7 and r = 0.77 for SCD). CONCLUSION: We demonstrate that fatty acids in circulating lipid fractions, including CE, TG and PL, reflects the composition of liver TG in humans, suggesting that circulating fatty acids might be useful biomarkers for the fatty acid composition of the liver. As liver tissue is rarely available in cohort studies, our findings could enhance our understanding of plasma fatty acids as markers of hepatic lipid metabolism and their links to metabolic diseases.

Advanced magnetic resonance imaging to support clinical drug development for malignant glioma.

Even though the treatment options and survival of patients with glioblastoma multiforme (GBM), the most common type of malignant glioma, have improved over the past decade, there is still a high unmet medical need to develop novel therapies. Complexity in pathology and therapy require biomarkers to characterize tumors, to define malignant and active areas, to assess disease prognosis, and to quantify and monitor therapy response. While conventional magnetic resonance imaging (MRI) techniques have improved these assessments, limitations remain. In this review, we evaluate the role of various non-invasive biomarkers based on advanced structural and functional MRI techniques in the context of GBM drug development over the past 5 years.

Hepatic Unsaturated Fatty Acids Are Linked to Lower Degree of Fibrosis in Non-alcoholic Fatty Liver Disease.

Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited. Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0-1) or significant fibrosis (F2-4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions. Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis. Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.

Design and rationale of the EMPA-VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure.

AIMS: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS. CONCLUSIONS: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

Guidelines for preclinical animal research in ALS/MND: A consensus meeting.

The development of therapeutics for ALS/MND is largely based on work in experimental animals carrying human SOD mutations. However, translation of apparent therapeutic successes from in vivo to the human disease has proven difficult and a considerable amount of financial resources has been apparently wasted. Standard operating procedures (SOPs) for preclinical animal research in ALS/MND are urgently required. Such SOPs will help to establish SOPs for translational research for other neurological diseases within the next few years. To identify the challenges and to improve the research methodology, the European ALS/MND group held a meeting in 2006 and published guidelines in 2007 (1). A second international conference to improve the guidelines was held in 2009. These second and improved guidelines are dedicated to the memory of Sean F. Scott.

Inductively coupled Helmholtz coil on a dedicated imaging platform for the in vivo 1H-MRS measurement of intramyocellular lipids in the hind leg of rats.

Skeletal muscle triglycerides are markers for insulin resistance in type 2 diabetes. Recently, MR spectroscopy was adapted for in vivo measurement of triglycerides in animal models and for the characterization of new therapeutic approaches. Because of small MR spectroscopy voxel sizes used in skeletal muscles, surface coils are used for signal reception. Furthermore, to obtain well-resolved and undistorted lipid spectra, muscle fibers must be aligned parallel to the magnetic field. Consequently, to achieve a high signal-to-noise ratio and spectral quality, a coil setup must combine high sensitivity with a reliable and reproducible positioning of muscle and voxel. These demands are difficult to match using surface coils. Here, a coil platform is described, which uses inductively coupled Helmholtz coil setup combined with a leg retainer system for rats. The new system allows for measurement of intramyocellular lipids with high signal-to-noise ratio and for significantly improved animal handling, positioning, and throughput.

Morphological and metabolic changes in the cortex of mice lacking the functional presynaptic active zone protein bassoon: a combined 1H-NMR spectroscopy and histochemical study.

Mice lacking functional presynaptic active zone protein Bassoon are characterized by an enlarged cerebral cortex and an altered cortical activation pattern. This morphological and functional phenotype is associated with defined metabolic distortions as detected by a metabonomic approach using high-field (14.1 T) high-resolution 1H-nuclear magnetic resonance spectroscopy (MRS) in conjunction with statistical pattern recognition. Within the cortex but not in the cerebellum, concentrations of N-acetyl aspartate, glutamine, and glutamate are significantly reduced, whereas the majority of all other detectable low molecular metabolites are unchanged. The reduction of the neuron-specific metabolite N-acetyl aspartate in the cortex coincides with a significant decrease in neuronal density in cortical layer V. Comparing the neuron with glia cell densities across the cortex reveals cortex layer-dependent alterations in the ratio between both cell types. Whereas the ratio shifts significantly toward neurons in the cortical input layers IV, the ratio is reversed in cortical layer V. Consequently, the previously observed altered neuronal activation pattern in the cortex is reflected not only in defined cytoarchitectural anomalies but also in metabolic disturbances in the glutamine-glutamate and N-acetyl aspartate metabolism.

Challenges in IBD Research: Novel Technologies.

Novel technologies is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the novel technologies section is focused on prioritizing unmet clinical needs in IBD that will benefit from novel technologies applied to: 1) non-invasive detection and monitoring of active inflammation and assessment of treatment response; 2) mucosal targeted drug delivery systems; and 3) prevention of post-operative septic complications and treatment of fistulizing complications. Proposed approaches include development of multiparametric imaging modalities and biosensors, to enable non invasive or minimally invasive detection of pro-inflammatory signals to monitor disease activity and treatment responses. Additionally, technologies for local drug delivery to control unremitting disease and increase treatment efficacy while decreasing systemic exposure are also proposed. Finally, research on biopolymers and other sealant technologies to promote post-surgical healing; and devices to control anastomotic leakage and prevent post-surgical complications and recurrences are also needed.

Combined PET/DCE-MRI in a Rabbit Model of Atherosclerosis: Integrated Quantification of Plaque Inflammation, Permeability, and Burden During Treatment With a Leukotriene A4 Hydrolase Inhibitor.

OBJECTIVES: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis. BACKGROUND: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18F-fluorodeoxyglucose (18F-FDG) PET, DCE-MRI, and morphological MRI. The authors describe a novel, integrated PET-DCE/MRI protocol to noninvasively quantify these parameters in aortic plaques of a rabbit model of atherosclerosis. As proof-of-concept, the authors apply this protocol to assess the efficacy of the novel LTA4H inhibitor BI691751. METHODS: New Zealand White male rabbits (N = 49) were imaged with integrated PET-DCE/MRI after atherosclerosis induction and 1 and 3 months after randomization into 3 groups: 1) placebo; 2) high-dose BI691751; and 3) low-dose BI691751. All animals were euthanized at the end of the study. RESULTS: Among the several metrics that were quantified, only maximum standardized uptake value and target-to-background ratio by 18F-FDG PET showed a modest, but significant, reduction in plaque inflammation in rabbits treated with low-dose BI691751 (p = 0.03), whereas no difference was detected in the high-fat diet and in the high-dose BI691751 groups. No differences in vessel wall area by MRI and area under the curve by DCE-MRI were detected in any of the groups. No differences in neovessel and macrophage density were found at the end of study among groups. CONCLUSIONS: The authors present a comprehensive, integrated 18F-FDG PET and DCE-MRI imaging protocol to noninvasively quantify plaque inflammation, neovasculature, permeability, and burden in a rabbit model of atherosclerosis on a simultaneous PET/MRI scanner. A modest reduction was found in plaque inflammation by 18F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751.

Comparison of estimates for volumes of brain ablations derived from structural MRI and classical histology.

Estimates of auditory cortex ablation sizes in a rodent model as derived from classical histology (volume reconstructions from Nissl-stained brain sections) and structural magnetic resonance imaging (MRI) (T1-weighted whole-brain scans from a 4.7 T animal scanner) were compared in the same specimens (Mongolian gerbils). Estimates of lesion volumes obtained with the two methods were very similar, robust, highly correlated and not significantly different from each other. Hence, the general usefulness of structural MRI for the determination of brain lesion size in small animal models is demonstrated. MRI therefore seems to be well suited to determine proper size and location of an experimental brain ablation prior to (potentially extensive) behavioral testing.

Coarsening of axial segregation patterns of slurries in a horizontally rotating drum.

Segregation structures of granular mixtures in rotating drums represent classical examples of pattern formation in granular material. We investigate the coarsening of axial segregation patterns of slurries in a long horizontally rotating cylinder. The dynamics and the three-dimensional geometry of the segregation structures are analyzed with optical methods and nuclear magnetic resonance imaging. Previous studies have mainly considered global statistical features of the pattern dynamics. In order to get insight into driving mechanisms for the coarsening process, we focus on the details of the dissolution of individual bands. We treat the coarsening as a consequence of interactions of adjacent bands in the pattern, which are determined by their geometrical relations. In addition to initially homogeneous mixtures, which evolve to spontaneously formed patterns, we study the evolution of specially prepared simple initial states. The role of the three-dimensional geometry of the axial core in the dissolution process of segregation bands is demonstrated. Relations between geometry and dynamic processes are established, which may help to find the correct microscopic models for the coarsening mechanism.

Clinical imaging in anti-atherosclerosis drug development.

The development of novel drugs for the treatment of atherosclerosis faces many challenges, particularly caused by the need for large and costly outcome trials. When predictive biochemical biomarkers are not available, clinical imaging data can serve as intermediate Phase II endpoints to demonstrate mechanistic and anti-atherosclerotic activity of new compounds. These data can support risk mitigation before continuing development in large Phase III outcome trials. Imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT) and ultrasound [intima-media thickness (IMT) and intravascular ultrasound (IVUS)] can provide detailed information on vascular plaque volume and morphology, whereas functional changes can potentially be captured by positron emission tomography (PET) techniques in the vessel wall. We will review the application and operational aspects of clinical imaging methods and endpoints used in interventional atherosclerosis trials.

A comparative PET imaging study with the reversible and irreversible EGFR tyrosine kinase inhibitors [(11)C]erlotinib and [(18)F]afatinib in lung cancer-bearing mice.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have experienced a tremendous boost in the last decade, where more than 15 small molecule TKIs have been approved by the FDA. Unfortunately, despite their promising clinical successes, a large portion of patients remain unresponsive to these targeted drugs. For non-small cell lung cancer (NSCLC), the effectiveness of TKIs is dependent on the mutational status of epidermal growth factor receptor (EGFR). The exon 19 deletion as well as the L858R point mutation lead to excellent sensitivity to TKIs such as erlotinib and gefitinib; however, despite initial good response, most patients invariably develop resistance against these first-generation reversible TKIs, e.g., via T790M point mutation. Second-generation TKIs that irreversibly bind to EGFR wild-type and mutant isoforms have therefore been developed and one of these candidates, afatinib, has now reached the market. Whether irreversible TKIs differ from reversible TKIs in their in vivo tumor-targeting properties is, however, not known and is the subject of the present study. METHODS: Erlotinib was labeled with carbon-11 and afatinib with fluorine-18 without modifying the structure of these compounds. A preclinical positron emission tomography (PET) study was performed in mice bearing NSCLC xenografts with a representative panel of mutations: an EGFR-WT xenograft cell line (A549), an acquired treatment-resistant L858R/T790M mutant (H1975), and a treatment-sensitive exon 19 deleted mutant (HCC827). PET imaging was performed in these xenografts with both tracers. Additionally, the effect of drug efflux transporter permeability glycoprotein (P-gp) on the tumor uptake of tracers was explored by therapeutic blocking with tariquidar. RESULTS: Both tracers only demonstrated selective tumor uptake in the HCC827 xenograft line (tumor-to-background ratio, [(11)C]erlotinib 1.9 ± 0.5 and [(18)F]afatinib 2.3 ± 0.4), thereby showing the ability to distinguish sensitizing mutations in vivo. No major differences were observed in the kinetics of the reversible and the irreversible tracers in each of the xenograft models. Under P-gp blocking conditions, no significant changes in tumor-to-background ratio were observed; however, [(18)F]afatinib demonstrated better tumor retention in all xenograft models. CONCLUSIONS: TKI-PET provides a method to image sensitizing mutations and can be a valuable tool to compare the distinguished targeting properties of TKIs in vivo.