We are recruiting an Early Stage Researcher to work on the implementation of high-resolution MRSI methods in a pre-clinical scanner as part of the INSPiRE-MED European project.
We seek a highly motivated and qualified individual as Early Stage Researcher for a three-year applied research project. The successful candidate will contribute to the development of advanced biomedical research tools in the field of Magnetic Resonance Spectroscopy and Imaging, and its application to the clinical day-to-day practice.
The main aim of the PhD project (ESR4) will be the implementation of innovative high spatial resolution MRSI methods in a pre-clinical scanner. The ultimate goal will be the validation of optimal methods for improving imaging biomarker development of brain tumour in longitudinal studies of therapy response in mouse glioblastoma models. The project will involve evaluation of the methodology performance limits, repeatability and reproducibility compared to stock Bruker Biospec MRSI sequences and the assessment of speed-up MRSI methods in a 7-Tesla pre-clinical scanner.
Integrating Magnetic Resonance Spectroscopy and Multimodal Imaging for Research and Education in MEDicine (INSPiRE-MED) is an European research project awarded in the call H2020-MSCA-ITN-2018, of the MSCA-ITN-ETN – European Training Networks, to a consortium of partners including the GABRMN and SeRMN at UAB. The project is coordinated by Prof. Dominique Sappey-Marinier, of the Université Lyon-1 Claude-Bernard, Lyon, France. The scientist-in-charge at UAB will be Prof. Carles Arús (GABRMN), and Silvia Lope-Piedrafita (SeRMN) and Miquel Cabañas (SeRMN) will participate as senior scientists in the project.
Starting 1st of January 2019, the INSPiRE-MED Initial Training Network will investigate the theoretical and practical aspects of in vivo Magnetic Resonance Spectroscopy (MRS) and Spectroscopic Imaging (MRSI) with applications in oncology and neurology.
The network will host 15 Early Stage Researchers in the field of biomedical imaging, particularly in the field of Magnetic Resonance Spectroscopy (MRS) and MR Spectroscopic Imaging (MRSI) combined with Positron Emission Tomography (PET) and enhanced by machine learning techniques. The research training is supervised by a consortium of 12 academic partners with an established collaborative track record in R&D and 9 industrial partners from the broad and competitive preclinical and clinical imaging sector.
The main research topic to be carried at UAB —in close collaboration with other project members— will be the implementation of innovative high spatial resolution MRSI methods in a pre-clinical scanner. The ultimate goal will be the validation of optimal methods for improving imaging biomarker development of brain tumour in longitudinal studies of therapy response in mouse glioblastoma models.
Jiménez-Xarrié, Elena, Belén Pérez, Ana Paula Dantas, Lídia Puertas-Umbert, Joan Martí-Fabregas, Ángel Chamorro, Anna Maria Planas, Elisabet Vila, Francesc Jiménez-Altayó. 2018. Uric Acid Treatment After Stroke Prevents Long-Term Middle Cerebral Artery Remodelling and Attenuates Brain Damage in Spontaneously Hypertensive Rats. Translational Stroke Research. DOI: 10.1007/s12975-018-0661-8
Hypertension is the most important modifiable risk factor for stroke and is associated with poorer post-stroke outcomes. The antioxidant uric acid is protective in experimental normotensive ischaemic stroke. However, it is unknown whether this treatment exerts long-term protection in hypertension. The authors aimed to evaluate the impact of transient intraluminal middle cerebral artery (MCA) occlusion (90min)/reperfusion (1–15 days) on brain and vascular damage progression in adult and spontaneously hypertensive rats (SHR) treated with uric acid. Ischaemic brain damage was assessed longitudinally with magnetic resonance imaging at the Nuclear Magnetic Resonance Service of the Universitat Autònoma de Barcelona.
In SHR rats, more severe brain damage and poorer neurofunctional outcomes were coupled to higher cortical cerebral blood flow at the onset of reperfusion, a transient increase in oxidative stress and long-lasting stroke-induced MCA hypertrophic remodelling. Thus, stroke promotes larger brain and vascular damage in hypertensive rats that persists for long-time. Uric acid administered during early reperfusion attenuated short- and long-term brain injuries in both normotensive and hypertensive rats, an effect that was associated with abolishment of the acute oxidative stress response and prevention of stroke-induced long lasting MCA remodelling in hypertension. These results suggest that uric acid might be an effective strategy to improve stroke outcomes in hypertensive subjects.
“Differential effects of apoE and apoJ mimetic peptides on the action of an anti-Aβ scFv in 3xTg-AD mice” by L. Montoliu-Gaya, J. Güell-Bosch, G. Esquerda-Canals, A.R. Roda, G. Serra-Mir, S. Lope-Piedrafita, J.L. Sánchez-Quesada, S. Villegas. Biochem Pharmacol. 2018, 155:380-392. DOI: 10.1016/j.bcp.2018.07.012.
Anti-Aβ immunotherapy has emerged as a promising approach to treat Alzheimer’s disease (AD). The single-chain variable fragment scFv-h3D6 is an anti-Aβ antibody fragment that lacks the Fc region, which is associated with the induction of microglial reactivity by the full-length monoclonal antibody bapineuzumab. ScFv-h3D6 was previously shown to restore the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ) in a tripletransgenic- AD (3xTg-AD) mouse model. Since apoE and apoJ play an important role in the development of AD, we aimed to study the in vivo effect of the combined therapy of scFv-h3D6 with apoE and apoJ mimetic peptides (MPs).
Magnetic Resonance Imaging showed a general tendency of the different treatments to protect against the reduction in brain volume. This protection was further suggested by MRS, since all the treatments tended to recover the levels of Ala, which is involved in the alanine-glucose cycle, and NAA, which is a marker for cell viability. All the treatments in the present work recovered the IL-33 levels, and apoE-MP showed a potent anti-inflammatory effect in terms of glial activation that was decreased in the presence of scFv-h3D6, whereas the combination of apoJ-MP and scFvh3D6 was not detrimental. Moreover, the endogenous apoE and apoJ levels were decreased by scFvh3D6, but the MPs induced a simultaneous increase in both apolipoproteins, which reflects a coordinated expression between them.
Workshop limited to 4 participants (first come, first served)
Silvia Lope-Piedrafita, PhD (firstname.lastname@example.org)
This course combines a comprehensive series of lectures on the technology of Magnetic resonance spectroscopy and imaging (MRS/MRI) with hands-on laboratory sessions to provide practical demonstrations of key concepts and procedures for preclinical studies.
Whether you are considering MRI as a research tool in your lab or just would like to learn more about MRI, this workshop addresses practical aspects of experimental MRI with laboratory animals and provide valuable hands-on experience on a 7 Tesla Bruker BioSpec spectrometer.
“Preclinical MRI: Methods and Protocols” by Maria Luisa Garcia Martin and Pilar Lopez Larrubia (Editors). Part of the Methods in Molecular Biology book series (MIMB, volume 1718). DOI: 10.1007/978-1-4939-7531-0.
This book was conceived with the idea of providing an update on a wide variety of preclinical MRI methods and protocols to help technicians and researchers interested in this technology. The basics of MRI physics are introduced, followed by chapters describing updated methodology and protocols for some standard and more advanced MRI techniques covering diffusion, perfusion, functional imaging, in-vivo spectroscopy (proton and heteronuclear), susceptibility contrast MRI… The book also contains some chapters where some applications of those methods are illustrated in animal models of several diseases including cancer, stroke and neurodegeneration. Protocols are described in a step-by-step approach, with interesting notes and tips at the end of each chapter, which -a priori- should allow the new worker to obtain successful results with the first attempt ;o) .
“Assessment of biodistribution using mesenchymal stromal cells: Algorithm for study design and challenges in detection methodologies” by Reyes B, Coca MI, Codinach M, López-Lucas MD, Del Mazo-Barbara A, Caminal M, Oliver-Vila I, Cabañas V, S. Lope-Piedrafita, García-López J, Moraleda JM, Fontecha CG, Vives J. Cytotherapy. 2017 :1060-1069. doi: 10.1016/j.jcyt.2017.06.004.
Biodistribution of candidate cell-based therapeutics is a critical safety concern that must be addressed in the preclinical development program. We aimed to design a decision tree based on a series of studies included in actual dossiers approved by competent regulatory authorities, noting that the design, execution and interpretation of pharmacokinetics studies using this type of therapy is not straightforward and presents a challenge for both developers and regulators. This work contributes to the standardization in the design of biodistribution studies by improving methods for accurate assessment of safety.
Eight studies were evaluated for the definition of a decision tree, in which mesenchymal stromal cells (MSCs) were administered to mouse, rat and sheep models using diverse routes (local or systemic), cell labeling (chemical or genetic) and detection methodologies (polymerase chain reaction (PCR), immunohistochemistry (IHC), fluorescence bioimaging, and magnetic resonance imaging (MRI). Moreover, labeling and detection methodologies were compared in terms of cost, throughput, speed, sensitivity and specificity.
“Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide” by by L. Ferrer-Font, N. Arias-Ramos, S. Lope-Piedrafita, M. Julià-Sapé , M. Pumarola, C. Arús and A. P. Candiota. NMR Biomed. 2017. DOI: 10.1002/nbm.3748.
Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. In preceding years, efforts have focused in new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, as for example the “metronomic” approaches.
We have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/Kg) or TMZ (range 140-240 mg/Kg) metronomic administration (every 6 days) were performed in tumor-bearing mice. Tumor evolution was monitored at 7T with T2-weighted MRI, Diffusion weighted imaging and MRSI-based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6+21.0 days, n=30) compared to control (19.4+2.4 days, n=18). Also, it was found a clear edema appearance during chemotherapeutic treatment suggesting inflammatory associated processes. The necropsy performed in mice cured from GBM after high TMZ cumulative dosage (980-1400 mg/Kg) revealed lymphoma incidence.
“Generation of a new model of patellar tendinopathy in rats which mimics the human sports pathology: A pilot study” by David Domínguez, Paola Contreras-Muñoz, Silvia Lope, Gil Rodas, G. and Mario Marotta. Apunts. Medicina de l’Esport, 2017, 52:194, 53-59. DOI: 10.1016/j.apunts.2017.01.002
Introduction: Patellar tendon pathophysiology is not still fully understood. The collection of clinical samples from athletes that could permit the analysis of the tendinopathy progression, especially in the early stages, is difficult. For that reason, the purpose of this study is to develop a new experimental animal model of patellar tendinopathy in rats which mimics the human tendinopathy by in vivo intratendinous collagenase injection in the proximal portion of the patellar tendon. Material and methods: The experimental model used was 8-week-old male Wistar rats (N = 4). The administration of collagenase was performed by ultrasound-guided puncture at the level of the proximal and deep portion of the patellar tendon in anesthetized animals. The tendon lesion was evaluated 48 h after injury by magnetic resonance and then, the animals were euthanized and the patellar tendons were collected for histological evaluation. Results: The collagenase-induced lesion model demonstrated important similarities with the human patellar tendinopathy in the region of the proximal insertion. Conclusions: The experimental model of patellar tendinopathy in rat model induces a degeneration and distortion of the patellar tendon architecture in its proximal portion, which closely mimics to that seen in human patellar tendinopathy, and could represent an excellent preclinical model for the study of new therapies focused on treatment of tendinopathy.
“Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment” by N. Arias-Ramos, L. Ferrer-Font, S. Lope-Piedrafita, V. Mocioiu, M. Julià-Sapé , M. Pumarola, C. Arús and A. P. Candiota. Metabolites, 2017, 18;7(2). pii: E20. DOI: 10.3390/metabo7020020.
Glioblastoma (GBM) is the most common and aggressive glial primary tumor with a survival average of 14-15 months, even after application of standard treatment. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Nosological images of therapy response using a semi-supervised source extraction approach in preclinical GBM based on single slice Magnetic Resonance Spectroscopic Imaging (MRSI) was previously describe by our group. However, because of GBM heterogeneity, relevant response information could be missed just by studying one slice. Therefore, the goal of this work was to acquire 3D-like information from preclinical GBM under a longitudinal treatment protocol, using a multi-slice MRSI approach.
Nosological maps were obtained based on semi-supervised convex Non-negative Matrix Factorization and each voxel was colored according to the contribution to the spectral pattern of each one of the three sources or characteristic spectral patterns: Normal brain, actively proliferating tumour or responding tumour.
Heterogeneous response levels were observed and three arbitrary groups of treated animals were defined as: high response, intermediate response, and low response. Histopathological studies showed an inverse correlation between the responding pattern level and Ki67 proliferation rate.