All posts by Silvia

Metronomic treatment in immunocompetent preclinical glioblastoma

“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.

Multi-Slice MRSI Analysis of Therapy Response in Preclinical Glioblastoma

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.

 

Neonatal handling enduringly decreases anxiety and stress responses

“Neonatal handling enduringly decreases anxiety and stress responses and reduces hippocampus and amygdala volume in agenetic model of differential anxiety: Behavioral-volumetric associations in the Roman rats trains” by C. Río-Álamos, I. Oliveras, M. A. Piludu, C. Gerbolés, T. Cañete, G. Blázquez, S. Lope-Piedrafita, E. Martínez-Membrives, R. Torrubia, A. Tobeña, and A. Fernández-Teruel. European Neuropsychopharmacology, 2017,  27: 146–158. DOI: 10.1016/j.euroneuro.2016.12.003

The hippocampus and amygdala have been proposed as key neural structures related to anxiety. A more active hippocampus/amygdala system has been related to greater anxious responses in situations involving conflict/novelty. The Roman Low- (RLA) and High-avoidance (RHA) rat strains constitute a genetic model of differential anxiety. Relative to RHA rats, RLA rats exhibit enhanced anxiety/fearfulness, augmented hippocampal/amygdala c-Fos expression following exposure to novelty/conflict, increased hippocampal neuronal density and higher endocrine responses to stress. Neonatal handling (NH) is an environmental treatment with long-lasting anxiety/stress-reducing effects in rodents. Since hippocampus and amygdala volume are supposed to be related to anxiety/fear, it was hypothesized  a greater volume of both areas in RLA than in RHA rats, as well as that NH treatment would reduce anxiety and the volume of both structures. Adult untreated and NH-treated RHA and RLA rats were tested for anxiety, sensorimotor gating (PPI), stress-induced corticosterone and prolactin responses, two-way active avoidance acquisition and in vivo 7 T 1H-Magnetic resonance image.

As expected, untreated RLA rats showed higher anxiety and post-stress hormone responses, as well as greater hippocampus and amygdala volumes than untreated RHA rats. NH decreased anxiety/stress responses, especially in RLA rats, and significantly reduced hippocampus and amygdala volumes in this strain. Dorsal striatum volume was not different between the strains nor it was affected by NH. Finally, there were positive associations (as shown by correlations, factor analysis and multiple regression) between anxiety and PPI and hippocampus/amygdala volumes.

Transgenic mouse model of schizophrenia

“Mutation of the 3-Phosphoinositide-Dependent Protein Kinase 1
(PDK1) Substrate-Docking Site in the Developing Brain Causes
Microcephaly with Abnormal Brain Morphogenesis Independently of
Akt, Leading to Impaired Cognition and Disruptive Behaviors”
by Lluís Cordón-Barris, Sònia Pascual-Guiral, Shaobin Yang, Lydia Giménez-Llort, Silvia Lope-Piedrafita, Carlota Niemeyer, Enrique Claro, Jose M. Lizcano, and Jose R. Bayascas. Mol Cell Biol (2016), 36:2967–2982. DOI:10.1128/MCB.00230-16.

This report shows the involvement of PDK1 downstream effectors other than Akt in mouse neuropsychiatric-like disorders, with potential face and construct validity for negative and cognitive symptoms of schizophrenia. Results point to a prominent function for PIF pocket-dependent kinases as major effectors of this signaling hub downstream of Akt in the etiopathogenesis of schizophrenia that might provide construct validity to the PDK1 L155E mutants.

The phosphoinositide (PI) 3-kinase/Akt signaling pathway plays essential roles during neuronal development. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) coordinates the PI 3-kinase signals by activating 23 kinases of the AGC family, includingAkt. Phosphorylation of a conserved docking site in the substrate is a requisite for PDK1 to recognize, phosphorylate, and activate most of these kinases, with the exception of Akt. This differential mechanism of regulation it has been exploited by generating neuron-specific conditional knock-in mice expressing a mutant form of PDK1, L155E, in which the substrate-docking site binding motif, termed the PIF pocket, was disrupted. As a consequence, activation of all the PDK1 substrates tested except Akt was abolished. The mice exhibited microcephaly, altered cortical layering, and reduced circuitry, leading to cognitive deficits and exacerbated disruptive behavior combined with diminished motivation. The abnormal patterning of the adult brain arises from the reduced ability of the embryonic neurons to polarize and extend their axons, highlighting the essential roles that the PDK1 signaling beyond Akt plays in mediating the neuronal responses that regulate brain development.

10th Workshop on Magnetic Resonance Spectroscopy and Imaging (MRI/MRS) Applied to Laboratory Animals

Workshop dates: November 29th – December 2nd, 2016
Registration deadline: November 14th, 2016
Registration: REGISTRATION CLOSED  online
Capacity: Workshop limited to 4 participants (first come, first served)
Contact person: Silvia Lope-Piedrafita, PhD (silvia.lope@uab.es)

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.20161001_10cursomrimrs

See the workshop brochure for more information or contact Dra. Silvia Lope via email.

New Book Release: MORPHOLOGICAL MOUSE PHENOTYPING

“MORPHOLOGICAL MOUSE PHENOTYPING: Anatomy, Histology and Imaging” by Jesús Ruberte París, Ana Carretero Romay, and Marc Navarro Beltrán (2016). Editorial Médica Panamericana.

Morphologial Mouse Phenotypiong_BOOKAn extraordinary atlas of mouse anatomy which includes more than 2,200 original images over 600 pages to show the anatomy, histology and cellular structure of mouse organs. This book attempts to provide an overview of the different levels of morphology of the mouse, ranging from gross anatomy and topographical anatomy (to explain the relative position of the organs and structures of a particular body region) down to the microscopic anatomy. Imaging technologies used for that include magnetic resonance imaging (MRI), computed tomography (CT), ultrasonography, angiography, X-ray, and electron microscopy. Also, classical anatomical techniques such as conventional dissection, skeletal preparations, vascular injections, histology and immunohistochemistry have been employed to characterize the mouse morphology.

All MRI images included in this book were acquired at our NMR facility (SeRMN, Universitat Autònoma de Barcelona) in a 7 Tesla Bruker BioSpec spectrometer.

In vivo MRS and ex vivo HRMAS in an Ischemic Rat Stroke Model

JCBMcover“In vivo and ex vivo Magnetic Resonance Spectroscopy of the Infarct and the Subventricular Zone in Experimental Stroke” by E. Jiménez-Xarrié, M. Davila, S. Gil-Perotín, A. Jurado-Rodríguez, A.P. Candiota, R. Delgado-Mederos, S. Lope-Piedrafita, J.M. García-Verdugo, C. Arús, J. Martí-Fàbregas. Journal of Cerebral Blood Flow & Metabolism, 2015, 35:828–834. DOI: 10.1038/jcbfm.2014.257

Ischemic stroke changes the metabolic pattern in the infarct area and also in other regions such as the ipsilateral subventricular zone (SVZi) where neural progenitor cells (NPCs) proliferation is enhanced in the mammalian and human brains. Magnetic resonance spectroscopy (MRS) provides metabolic information in vivo. With regard to NPCs proliferation, a resonance at 1.28 ppm has been described as an in vivo MRS biomarker of NPCs in the hippocampus of rats and humans. Continue reading In vivo MRS and ex vivo HRMAS in an Ischemic Rat Stroke Model

9th Workshop on Magnetic Resonance Spectroscopy and Imaging (MRI/MRS) Applied to Laboratory Animals

Dates: February 3rd to 6th, 2015

Organized by the SeRMN of the Autonomous University of Barcelona (UAB).

This course cMRIombines 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. Continue reading 9th Workshop on Magnetic Resonance Spectroscopy and Imaging (MRI/MRS) Applied to Laboratory Animals

Hyperpolarized 13C Magnetic Resonance in Acute Liver Failure Rats

2014_coverNMinBiomedReal-time assessment of 13C metabolism  reveals an early lactate increase in the brain of rats with acute liver failure” by Laia Chavarria, Jordi Romero-Giménez, Eva Monteagudo, Silvia Lope-Piedrafita, Juan Cordoba. NMR in Biomedicine (2014) 28:17-23. DOI: 10.1002/nbm.3226

Intracranial hypertension is a severe complication of acute liver failure (ALF) secondary to brain edema. The pathogenesis of cerebral edema in ALF is not clear, but seems to be related to energy metabolism in which lactate may have an important role. The aim of this study was to follow the synthesis of brain lactate using a novel in vivo metabolic technology in a rat model of ALF. Continue reading Hyperpolarized 13C Magnetic Resonance in Acute Liver Failure Rats

Ex vivo method to evaluate MRI contrast agents

“A 2014_coverJnanobiotechnologynew ex vivo method to evaluate the performance of candidate MRI contrast agents: a proof-of-concept study” by Candiota A.P., Acosta M., Simões R.V., Delgado-Goñi T., Lope-Piedrafita S., Irure A., Marradi M., Bomatí-Miguel O., Miguel-Sancho N., Abasolo I., Schwartz S. Jr., Santamaría J., Penadés S., Arús C. J Nanobiotechnology 2014 12:12. DOI: 10.1186/1477-3155-12-12.

A new method has been developed for selecting MRI contrast agents with better expected in vivo performance. This method requires only a very small amount of contrast agent (e.g. 5 nmols/animal, 800 times less than the quantity necessary for in vivo administration) and allows to carry out a more rationally informed candidate selection, avoiding unnecessary in vivo and toxicology tests for the ex vivo poorly performing substances, consequently reducing animal needs, material consumption and overall costs. Continue reading Ex vivo method to evaluate MRI contrast agents