Oxygen-Enhanced MRI in Cystic Fibrosis

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Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

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Conference Abstract: OE-MRI in Cystic Fibrosis

Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Katharina Martini, Thomas Frauenfelder, Geoff JM Parker


British Chapter of ISMRM Meeting 2019

Abstract

Introduction:

Oxygen Enhanced MRI (OE-MRI) exploits the paramagnetic properties of molecular oxygen to modify local T1 values to explore local lung function. During a dynamic OE-MRI experiment, the subject breaths varying concentrations of O2. Various parameters can be extracted, such as the ventilated volume fraction (VVF), defined as is the fraction of lung tissue showing O2 enhancement, and the oxygen wash-in time (Tup) [1]. In this work, we calculated τup, VVF, VVF-masked Tup and compared them with pulmonary function tests in a population of healthy volunteers (HV) and cystic fibrosis (CF) subjects.

Methods:

Analysis was applied retrospectively to OE-MRI data acquired from a previously published study [1]. 20 patients with CF (20 - 40 years, 13 male) and 4 HV (27-37 y, 2 male) underwent dynamic OE-MRI on a 1.5 T Philips Achieva MRI scanner. A free-breathing protocol based on an inversion-prepared centric ordered single shot 3D-turbo field echo sequence was used. The dynamic acquisition lasted 15 min (90 volumes), during which gas was delivered at 15 l/min via a disposable non-rebreathing mask and switched at minute 2 from medical air to 100% O2, and back to air at minute 10. All images were registered to correct for breathing motion using a non-linear registration algorithm [4]. Maps of Tup were derived from the signal intensity curves for each pixel by fitting to a mono-exponential recovery function. VVF was considered positive where the Akaike information criterion favours an exponential fit over a constant function. VVF fraction, median Tu and median Tup calculated only within VVF positive pixels (masked Tup) were extracted and compared to the results from conventional spirometry (FEV1, FVC and FEV1/FVC corrected for age, height and gender). Relationships between variables were evaluated with Pearson correlation with p < 0.05 considered to indicate the presence of a statistically significant correlations.

Results:

The table present the R2 and p-values of correlation between calculated parameters and corrected spirometry results.

                         FVC pred [%]     FEV1 pred [%]   FEV1/FVC pred [%]

VVF                   0.54 (p<0.001)   0.70 (p<0.001)    0.24 (p=0.02)

Tup [s]                0.00 (p=0.89)     0.01 (p=0.59)      0.12 (p=0.12)

Masked Tup [s]  0.03 (p=0.38)     0.11 (p=0.11)       0.27 (p=0.01)

Discussion:

VVF highly correlates with measurements of lung function derived from spirometry, particularly with FEV1. Oxygen wash-in time correlated significantly with FEV1/FVC pred [%] only when non-enhancing voxels are excluded.

Conclusion:

Parameters calculated from dynamic OE-MRI are highly correlated with measurement of lung function derived from spirometry.

Reference: [1] Martini K, et al. European Radiology:1-11 (2018)

CONFERENCE ABSTRACT: OE-MRI IN CYSTIC FIBROSIS
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Ga-NODAGA-IL2 for imaging activated T-cells

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[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

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Conference Abstract: 68Ga-NODAGA-IL2 for T-cell imaging

[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

Antunes, I., van der Veen, E. L., Suurs, F. V., Dierckx, R. A. J. O., Lub-de Hooge, M. N., de Vries, E. G. E. & de Vries, E. F. J.


Oct-2019, In : European Journal of Nuclear Medicine and Molecular Imaging. 46, SUPPL 1, p. S702 1 p.

32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) - Barcelona, Spain Duration: 12-Oct-2019 - 16-Oct-2019

CONFERENCE ABSTRACT: 68GA-NODAGA-IL2 FOR T-CELL IMAGING
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Tracers for non-invasive radionuclide imaging of immune

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Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

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PET tracers for immune checkpoint imaging

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Peter Wierstra, Gerwin Sandker, Erik Aarntzen, Martin Gotthardt, Gosse Adema, Johan Bussink, René Raavé & Sandra Heskamp.


EJNMMI Radiopharmacy and Chemistry volume 4,29 (2019). doi: 10.1186/s41181-019-0078-z.

Abstract

Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by non-invasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyte-associated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers..

PET TRACERS FOR IMMUNE CHECKPOINT IMAGING
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Physiologically-based pharmacokinetic modelling of transporter

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Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

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Conference Abstract: PBPK modelling of transporter-mediated hepatic disposition

Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

Daniel Scotcher, Sirisha Tadimalla, Adam Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, Aleksandra Galetin


ISSX conference 2019.

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. However, prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent used clinically for hepatic lesion characterisation. As a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2), gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury [1]. The current study aimed to characterise uptake kinetics of gadoxetate in plated rat hepatocytes and develop a PBPK model to predict gadoxetate in vivo plasma and liver exposure. In vitro uptake was measured by incubating rat hepatocytes with 0.01 – 10mM gadoxetate for 0.5 – 150 min. Relevant in vitro transporter kinetic parameters were derived using a mechanistic cell model [2]. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence (n=9) and absence (n=27) of a single 10 mg/kg intravenous dose of rifampicin [3] were used for PBPK model validation/refinement. In vitro gadoxetate uptake affinity constant (Km) obtained in rat hepatocytes was 0.106 mM (n=4 rats), with saturable active transport accounting for 94% of gadoxetate cellular uptake; bidirectional transport, not saturable under current experimental conditions, was minor. The fraction unbound in hepatocytes was estimated to be 0.65. The total (Kp,u) and unbound (Kp,uu) hepatocyte:media partition coefficients were 26.0 and 16.9, respectively. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding 2-fold increase in gadoxetate systemic exposure in the presence of rifampicin. In contrast, liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile, assuming complete and partial inhibition of hepatic uptake and biliary efflux by rifampicin, respectively. The current study demonstrates utility of imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition; considerations of interpretation of quantitative DCE-MRI data to inform PBPK models are discussed.

CONFERENCE ABSTRACT: PBPK MODELLING OF TRANSPORTER-MEDIATED HEPATIC DISPOSITION
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Synthesis and Evaluation of Zirconium-89 Labelled

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Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

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89Zr labeled long lived GLP-1 receptor agonist

Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

Christian Borch Jacobsen, René Raavé, Marie Østergaard Pedersen, Pierre Adumeau, Mathieu Moreau, Ibai Valverde, Inga Bjørnsdottir, Jesper Bøggild Kristensen, Mette Finderup Grove, Kirsten Raun, James McGuire, Victor Goncalves, Sandra Heskamp, Franck Denat, Magnus Gustafsson


Nuclear Medicine and Biology 2019 Dec 4. doi: 10.1016/j.nucmedbio.2019.11.006.

Abstract

Introduction

Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution.

Methods

The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging.

Results

The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats show high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels.

Conclusions and advances in knowledge

This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET.

89ZR LABELED LONG LIVED GLP-1 RECEPTOR AGONIST
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How consistently do physicians diagnose and manage drug-induced

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How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians

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Survey: How Consistently do Physicians Diagnose DI-ILD?

How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians

James A. Eaden, Sarah Skeoch, John C. Waterton, Nazia Chaudhuri, Stephen M. Bianchi on behalf of the TRISTAN investigators


ERJ Open Research 2020 6: 00286-2019 doi: 10.1183/23120541.00286-2019.

Abstract

Introduction

Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD.

Methods

Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater.

Results

When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer.

Conclusion

The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed.

SURVEY: HOW CONSISTENTLY DO PHYSICIANS DIAGNOSE DI-ILD?
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Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease

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Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease (Conference Abstract)

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Conference Abstract: OE-MRI biomarkers of lung function in ILD

Oxygen enhanced MRI biomarkers of lung function in interstitial lung disease (Conference Abstract)

Tibiletti M, Naish JH, Heaton MJ, Waterton JC, Hughes PJC, Eaden JA, Skeoch S, Chaudhuri N, Bruce I, Stephen SM, Wild JM, Parker GJM


Abstract OA4330 - ERS 30th International Congress held virtually 7–9 September, 2020.

CONFERENCE ABSTRACT: OE-MRI BIOMARKERS OF LUNG FUNCTION IN ILD
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Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

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Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

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Gadoxetate Relaxivity in Different Liver Compartments

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

Sabina Ziemian, Claudia Green, Steven Sourbron, Gregor Jost, Gunnar Schütz, Catherine D.G. Hines


NMR in Biomedicine, 26 August 2020, e4401; doi:10.1002/nbm.4401

 

Abstract

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild‐type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small‐animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol−1 s−1) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well‐known bias in gadoxetate rate constants. This will promote the clinical translation of MR‐based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.

GADOXETATE RELAXIVITY IN DIFFERENT LIVER COMPARTMENTS
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PET of 89Zr-Pembrolizumab in Cynomolgus

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PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

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PET of 89Zr-Pembrolizumab in Cynomolgus

PET/CT Imaging of 89Zr-N-sucDf-Pembrolizumab in Healthy Cynomolgus Monkeys

Wenping Li, Yuchuan Wang, Daniel Rubins, Idriss Bennacef, Marie Holahan, Hyking Haley, Mona Purcell, Liza Gantert, SuChun Hseih, Michael Judo, Wolfgang Seghezzi, Shuli Zhang, Elly L. van der Veen, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Jeffrey L. Evelhoch, Michael Klimas, Eric D. Hostetler


Molecular Imaging and Biology 2020 Oct 26. doi: 10.1007/s11307-020-01558-w

Abstract

Purpose:

Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, the efficacy differs between patients. Factors contributing to this variability are PD-L1 expression levels and immune cells present in tumors. However, it is not well understood how PD-1 expression in the tumor microenvironment impacts immunotherapy response. Thus, imaging of PD-1-expressing immune cells is of interest. This study aims to evaluate the biodistribution of Zirconium-89 (89Zr)-labeled pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting PD-1, in healthy cynomolgus monkeys as a translational model of tracking PD-1- positive immune cells.

Procedures:

Pembrolizumab was conjugated with the tetrafluorophenol-N-succinyl desferal- Fe(III) ester (TFP-N-sucDf) and subsequently radiolabeled with 89Zr. Four cynomolgus monkeys with no previous exposure to humanized monoclonal antibodies received tracer only or tracer co-injected with pembrolizumab intravenously over 5 min. Thereafter, a static whole-body positron emission tomography (PET) scan was acquired with 10 min per bed position on days 0, 2, 5, and 7. Image-derived standardized uptake values (SUVmean) were quantified by region of interest (ROI) analysis.

Results:

89Zr-N-sucDf-pembrolizumab was synthesized with high radiochemical purity (>99 %) and acceptable molar activity (>7 MBq/nmol). In animals dosed with tracer only, 89Zr-N-sucDf-pembrolizumab distribution in lymphoid tissues such as mesenteric lymph nodes, spleen, and tonsils increased over time. Except for the liver, low radiotracer distribution was observed in all non-lymphoid tissue including the lung, muscle, brain, heart, and kidney. When a large excess of pembrolizumab was co-administered with a radiotracer, accumulation in the lymph nodes, spleen, and tonsils was reduced, suggestive of target-mediated accumulation.

Conclusions:

89Zr-N-sucDf-pembrolizumab shows preferential uptake in the lymphoid tissues including the lymph nodes, spleen, and tonsils. 89Zr-N-sucDf-pembrolizumab may be useful in tracking the distribution of a subset of immune cells in non-human primates and humans.

Trial registration:

ClinicalTrials.gov; Identifier: NCT02760225

PET of 89Zr-Pembrolizumab in Cynomolgus
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Collagen I-PET and MRI in a Rat Lung Injury Model

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Longitudinal Imaging Using PET/CT with Collagen-I PET-Tracer and MRI for Assessment of Fibrotic and Inflammatory Lesions in a Rat Lung Injury Model

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Collagen I-PET and MRI in a Rat Lung Injury Model

Longitudinal Imaging Using PET/CT with Collagen-I PET-Tracer and MRI for Assessment of Fibrotic and Inflammatory Lesions in a Rat Lung Injury Model

by Irma Mahmutovic Persson, Nina Fransén Pettersson, Jian Liu, Hanna Falk Håkansson, Anders Örbom, René In ’t Zandt, Ritha Gidlöf, Marie Sydoff, Karin von Wachenfeldt and Lars E. Olsson on behalf of the TRISTAN Consortium


J. Clin. Med. 2020, 9(11), 3706. doi: 10.3390/jcm9113706

Abstract

Non-invasive imaging biomarkers (IBs) are warranted to enable improved diagnostics and follow-up monitoring of interstitial lung disease (ILD) including drug-induced ILD (DIILD). Of special interest are IB, which can characterize and differentiate acute inflammation from fibrosis. The aim of the present study was to evaluate a PET-tracer specific for Collagen-I, combined with multi-echo MRI, in a rat model of DIILD. Rats were challenged intratracheally with bleomycin, and subsequently followed by MRI and PET/CT for four weeks. PET imaging demonstrated a significantly increased uptake of the collagen tracer in the lungs of challenged rats compared to controls. This was confirmed by MRI characterization of the lesions as edema or fibrotic tissue. The uptake of tracer did not show complete spatial overlap with the lesions identified by MRI. Instead, the tracer signal appeared at the borderline between lesion and healthy tissue. Histological tissue staining, fibrosis scoring, lysyl oxidase activity measurements, and gene expression markers all confirmed establishing fibrosis over time. In conclusion, the novel PET tracer for Collagen-I combined with multi-echo MRI, were successfully able to monitor fibrotic changes in bleomycin-induced lung injury. The translational approach of using non-invasive imaging techniques show potential also from a clinical perspective.

Collagen I-PET and MRI in a Rat Lung Injury Model
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