Publications by authors named "Monique Bernard"

111 Publications

The rs6942067 genotype is associated with a worse overall survival in young or non-smoking HPV-negative patients with positive nodal status in head and neck squamous cell carcinoma.

Oral Oncol 2022 Jan 10;125:105696. Epub 2022 Jan 10.

Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada; Otolaryngology-Head and Neck Surgery Service, Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2021.105696DOI Listing
January 2022

Male and Female Rats Have Different Physiological Response to High-Fat High-Sucrose Diet but Similar Myocardial Sensitivity to Ischemia-Reperfusion Injury.

Nutrients 2021 Aug 24;13(9). Epub 2021 Aug 24.

Aix Marseille University, CNRS, CRMBM, 13005 Marseille, France.

Prediabetes is a strong predictor of type 2 diabetes and its associated cardiovascular complications, but few studies explore sexual dimorphism in this context. Here, we aim to determine whether sex influences physiological response to high-fat high-sucrose diet (HFS) and myocardial tolerance to ischemia-reperfusion injury. Male and female Wistar rats were subjected to standard (CTRL) or HFS diet for 5 months. Then, ex-vivo experiments on isolated perfused heart model were performed to evaluate tolerance to ischemia-reperfusion injury. HFS diet induced fasting hyperglycemia and increased body fat percent to a similar level in both sexes. However, glucose intolerance was more pronounced in female HFS. Cholesterol was increased only in female while male displayed higher level of plasmatic leptin. We observed increased heart weight to tibia length ratio only in males, but we showed a similar decrease in tolerance to ischemia-reperfusion injury in female and male HFS compared with respective controls, characterized by impaired cardiac function, energy metabolism and coronary flow during reperfusion. In conclusion, as soon as glucose intolerance and hyperglycemia develop, we observe higher sensitivity of hearts to ischemia-reperfusion injury without difference between males and females.
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http://dx.doi.org/10.3390/nu13092914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472056PMC
August 2021

Medical image segmentation automatic quality control: A multi-dimensional approach.

Med Image Anal 2021 Dec 12;74:102213. Epub 2021 Aug 12.

Aix Marseille Univ, CNRS, I2M, Marseille, France.

In clinical applications, using erroneous segmentations of medical images can have dramatic consequences. Current approaches dedicated to medical image segmentation automatic quality control do not predict segmentation quality at slice-level (2D), resulting in sub-optimal evaluations. Our 2D-based deep learning method simultaneously performs quality control at 2D-level and 3D-level for cardiovascular MR image segmentations. We compared it with 3D approaches by training both on 36,540 (2D) / 3842 (3D) samples to predict Dice Similarity Coefficients (DSC) for 4 different structures from the left ventricle, i.e., trabeculations (LVT), myocardium (LVM), papillary muscles (LVPM) and blood (LVC). The 2D-based method outperformed the 3D method. At the 2D-level, the mean absolute errors (MAEs) of the DSC predictions for 3823 samples, were 0.02, 0.02, 0.05 and 0.02 for LVM, LVC, LVT and LVPM, respectively. At the 3D-level, for 402 samples, the corresponding MAEs were 0.02, 0.01, 0.02 and 0.04. The method was validated in a clinical practice evaluation against semi-qualitative scores provided by expert cardiologists for 1016 subjects of the UK BioBank. Finally, we provided evidence that a multi-level QC could be used to enhance clinical measurements derived from image segmentations.
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http://dx.doi.org/10.1016/j.media.2021.102213DOI Listing
December 2021

Impaired aerobic capacity and premature fatigue preceding muscle weakness in the skeletal muscle Tfam-knockout mouse model.

Dis Model Mech 2021 09 15;14(9). Epub 2021 Sep 15.

Aix-Marseille Université, CRMBM UMR CNRS 7339, 13385 Marseille, France.

Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.
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http://dx.doi.org/10.1242/dmm.048981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461820PMC
September 2021

DCBLD1 is associated with the integrin signaling pathway and has prognostic value in non-small cell lung and invasive breast carcinoma.

Sci Rep 2021 06 17;11(1):12753. Epub 2021 Jun 17.

Centre de recherche du Centre hospitalier de l'université de Montréal, Montreal, QC, Canada.

Germline single nucleotide polymorphisms in the promoter region of the DCBLD1 gene are associated with non-smoking cases of both non-small cell lung carcinoma (NSCLC) and human papillomavirus-negative head and neck cancer. However the clinical relevance and function of DCBLD1 remain unclear. This multicenter retrospective study was designed to evaluate the prognostic value and function of DCBLD1 in the four main solid cancers: NSCLC, invasive breast carcinoma, colorectal adenocarcinoma and prostate adenocarcinoma. We included the following cohorts: GSE81089 NSCLC, METABRIC invasive breast carcinoma, GSE14333 colorectal adenocarcinoma, GSE70770 prostate adenocarcinoma and The Cancer Genome Atlas (TCGA) Firehose Legacy cohorts of all four cancers. DCBLD1 gene expression was associated with a worse overall survival in multivariate analyses for both NSCLC cohorts (TCGA: P = 0.03 and GSE81089: P = 0.04) and both invasive breast carcinoma cohorts (TCGA: P = 0.02 and METABRIC: P < 0.001). Patients with high DCBLD1 expression showed an upregulation of the integrin signaling pathway in comparison to those with low DCBLD1 expression in the TCGA NSCLC cohort (FDR = 5.16 × 10) and TCGA invasive breast carcinoma cohort (FDR = 1.94 × 10).
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http://dx.doi.org/10.1038/s41598-021-92090-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211811PMC
June 2021

Sex Differences of the Diabetic Heart.

Front Physiol 2021 27;12:661297. Epub 2021 May 27.

Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

Type 2 diabetes is a chronic disease associated with micro- and macro-vascular complications, including myocardial ischemia, and also with a specific and intrinsic cardiac dysfunction called diabetic cardiomyopathy (DCM). Both clinical and animal studies demonstrate significant sex differences in prevalence, pathophysiology, and outcomes of cardiovascular diseases (CVDs), including those associated with diabetes. The increased risk of CVDs with diabetes is higher in women compared to men with 50% higher risk of coronary artery diseases and increased mortality when exposed to acute myocardial infarction. Clinical studies also reveal a sexual dimorphism in the incidence and outcomes of DCM. Based on these clinical findings, growing experimental research was initiated to understand the impact of sex on CVDs associated with diabetes and to identify the molecular mechanisms involved. Endothelial dysfunction, atherosclerosis, coagulation, and fibrosis are mechanisms found to be sex-differentially modulated in the diabetic cardiovascular system. Recently, impairment of energy metabolism also emerged as a determinant of multiple CVDs associated with diabetes. Therefore, future studies should thoroughly analyze the sex-specific metabolic determinants to propose new therapeutic targets. With current medicine tending toward more personalized care of patients, we finally propose to discuss the importance of sex as determinant in the treatment of diabetes-associated cardiac diseases to promote a more systemic inclusion of both males and females in clinical and preclinical studies.
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http://dx.doi.org/10.3389/fphys.2021.661297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192974PMC
May 2021

Comparison of single-voxel H-cardiovascular magnetic resonance spectroscopy techniques for in vivo measurement of myocardial creatine and triglycerides at 3T.

J Cardiovasc Magn Reson 2021 05 13;23(1):53. Epub 2021 May 13.

Aix-Marseille Univ, CNRS, CRMBM UMR 7339, Marseille, France.

Background: Single-voxel proton cardiovascular magnetic resonance spectroscopy (H-CMRS) benefits from 3 T to detect metabolic abnormalities with the quantification of intramyocardial fatty acids (FA) and creatine (Cr). Conventional point resolved spectroscopy (PRESS) sequence remains the preferred choice for CMRS, despite its chemical shift displacement error (CSDE) at high field (≥ 3 T). Alternative candidate sequences are the semi-adiabatic Localization by Adiabatic SElective Refocusing (sLASER) recommended for brain and musculoskeletal applications and the localized stimulated echo acquisition mode (STEAM). In this study, we aim to compare these three single-voxel H-CMRS techniques: PRESS, sLASER and STEAM for reproducible quantification of myocardial FA and Cr at 3 T. Sequences are compared both using breath-hold (BH) and free-breathing (FB) acquisitions.

Methods: CMRS accuracy and theoretical CSDE were verified on a purposely-designed fat-water phantom. FA and Cr CMRS data quality and reliability were evaluated in the interventricular septum of 10 healthy subjects, comparing repeated BH and free-breathing with retrospective gating.

Results: Measured FA/W ratio deviated from expected phantom ratio due to CSDE with all sequences. sLASER supplied the lowest bias (10%, vs -28% and 27% for PRESS and STEAM). In vivo, PRESS provided the highest signal-to-noise ratio (SNR) in FB scans (27.5 for Cr and 103.2 for FA). Nevertheless, a linear regression analysis between the two BH showed a better correlation between myocardial Cr content measured with sLASER compared to PRESS (r = 0.46; p = 0.03 vs. r = 0.35; p = 0.07) and similar slopes of regression lines for FA measurements (r = 0.94; p < 0.001 vs. r = 0.87; p < 0.001). STEAM was unable to perform Cr measurement and was the method with the lowest correlation (r = 0.59; p = 0.07) for FA. No difference was found between measurements done either during BH or FB for Cr, FA and triglycerides using PRESS, sLASER and STEAM.

Conclusion: When quantifying myocardial lipids and creatine with CMR proton spectroscopy at 3 T, PRESS provided higher SNR, while sLASER was more reproducible both with single BH and FB scans.
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http://dx.doi.org/10.1186/s12968-021-00748-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117273PMC
May 2021

Deep Learning-based Automated Segmentation of Left Ventricular Trabeculations and Myocardium on Cardiac MR Images: A Feasibility Study.

Radiol Artif Intell 2021 Jan 25;3(1):e200021. Epub 2020 Nov 25.

Departments of Radiology (A.B., A.J.) and Cardiology (G.H.), Hôpital de la Timone Adultes, AP-HM, 264, rue Saint-Pierre 13385 Marseille Cedex 05, France; CRMBM-UMR CNRS 7339, Medical Faculty, Aix-Marseille University, Marseille, France (A.B., J.F., Z.B., M.B., A.J.); I2M-UMR CNRS 7373, Aix-Marseille University, Centrale Marseille, Marseille, France (J.F., B.G.); ImVia Laboratory and University Hospital of Dijon, Bourgogne-Franche Comté University, Dijon, France (A.L.); Department of Radiology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France (L.B.); Department of Cardiovascular Imaging, Lille University Hospital, Lille, France (F.P.); and Department of Diagnostic Imaging, Rouen University Hospital, Rouen, France (J.N.D.).

Purpose: To develop and evaluate a complete deep learning pipeline that allows fully automated end-diastolic left ventricle (LV) cardiac MRI segmentation, including trabeculations and automatic quality control of the predicted segmentation.

Materials And Methods: This multicenter retrospective study includes training, validation, and testing datasets of 272, 27, and 150 cardiac MR images, respectively, collected between 2012 and 2018. The reference standard was the manual segmentation of four LV anatomic structures performed on end-diastolic short-axis cine cardiac MRI: LV trabeculations, LV myocardium, LV papillary muscles, and the LV blood cavity. The automatic pipeline was composed of five steps with a DenseNet architecture. Intraobserver agreement, interobserver agreement, and interaction time were recorded. The analysis includes the correlation between the manual and automated segmentation, a reproducibility comparison, and Bland-Altman plots.

Results: The automated method achieved mean Dice coefficients of 0.96 ± 0.01 (standard deviation) for LV blood cavity, 0.89 ± 0.03 for LV myocardium, and 0.62 ± 0.08 for LV trabeculation (mean absolute error, 3.63 g ± 3.4). Automatic quantification of LV end-diastolic volume, LV myocardium mass, LV trabeculation, and trabeculation mass-to-total myocardial mass (TMM) ratio showed a significant correlation with the manual measures ( = 0.99, 0.99, 0.90, and 0.83, respectively; all < .01). On a subset of 48 patients, the mean Dice value for LV trabeculation was 0.63 ± 0.10 or higher compared with the human interobserver (0.44 ± 0.09; < .01) and intraobserver measures (0.58 ± 0.09; < .01). Automatic quantification of the trabeculation mass-to-TMM ratio had a higher correlation (0.92) compared with the intra- and interobserver measures (0.74 and 0.39, respectively; both < .01).

Conclusion: Automated deep learning framework can achieve reproducible and quality-controlled segmentation of cardiac trabeculations, outperforming inter- and intraobserver analyses.© RSNA, 2020.
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http://dx.doi.org/10.1148/ryai.2020200021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082330PMC
January 2021

Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice.

Hum Mol Genet 2021 06;30(14):1305-1320

Department of Physiology, Amsterdam UMC (location VUmc), Amsterdam 1081 HV, The Netherlands.

Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.
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http://dx.doi.org/10.1093/hmg/ddab112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255131PMC
June 2021

mTOR as a senescence manipulation target: A forked road.

Adv Cancer Res 2021 18;150:335-363. Epub 2021 Mar 18.

Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC, Canada; Institut du cancer de Montréal, Montreal, QC, Canada; Université de Montréal, Département de radiologie, radio-oncologie et médicine nucléaire, Montreal, QC, Canada. Electronic address:

Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.
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http://dx.doi.org/10.1016/bs.acr.2021.02.002DOI Listing
November 2021

Contactless Thermometry by MRI and MRS: Advanced Methods for Thermotherapy and Biomaterials.

iScience 2020 Oct 14;23(10):101561. Epub 2020 Sep 14.

Aix-Marseille University, CNRS, CRMBM, 27 Bd Jean Moulin, 13005 Marseille, France.

Control of temperature variation is of primordial importance in particular areas of biomedicine. In this context, medical treatments such as hyperthermia and cryotherapy, and also the development and use of hydrogel-based biomaterials, are of particular concern. To enable accurate temperature measurement without perturbing or even destroying the biological tissue or material to be monitored, contactless thermometry methods are preferred. Among these, the most suitable are based on magnetic resonance imaging and spectroscopy (MRI, MRS). Here, we address the latest developments in this field as well as their current and anticipated practical applications. We highlight recent progress aimed at rendering MR thermometry faster and more reproducible, versatile, and sophisticated and provide our perspective on how these new techniques broaden the range of applications in medical treatments and biomaterial development by enabling insight into finer details of thermal behavior. Thus, these methods facilitate optimization of clinical and industrial heating and cooling protocols.
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http://dx.doi.org/10.1016/j.isci.2020.101561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489251PMC
October 2020

Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2020 Aug 21;12(9). Epub 2020 Aug 21.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.

Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies.
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http://dx.doi.org/10.3390/cancers12092371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563873PMC
August 2020

Simultaneous multi-slice T1 mapping using MOLLI with blipped CAIPIRINHA bSSFP.

Magn Reson Imaging 2020 Apr 15. Epub 2020 Apr 15.

Aix Marseille Univ, CNRS, CRMBM, Marseille, France; APHM, Hôpital Universitaire Timone, CEMEREM, Marseille, France. Electronic address:

Background: This study evaluates the possibility for replacing conventional 3 slices, 3 breath-holds MOLLI cardiac T1 mapping with single breath-hold 3 simultaneous multi-slice (SMS3) T1 mapping using blipped-CAIPIRINHA SMS-bSSFP MOLLI sequence. As a major drawback, SMS-bSSFP presents unique artefacts arising from side-lobe slice excitations that are explained by imperfect RF modulation rendering and bSSFP low flip angle enhancement. Amplitude-only RF modulation (AM) is proposed to reduce these artefacts in SMS-MOLLI compared to conventional Wong multi-band RF modulation (WM).

Materials And Methods: Phantoms and ten healthy volunteers were imaged at 1.5 T using a modified blipped-CAIPIRINHA SMS-bSSFP MOLLI sequence with 3 simultaneous slices. WM-SMS3 and AM-SMS3 were compared to conventional single-slice (SMS1) MOLLI. First, SNR degradation and T1 accuracy were measured in phantoms. Second, artefacts from side-lobe excitations were evaluated in a phantom designed to reproduce fat presence near the heart. Third, the occurrence of these artefacts was observed in volunteers, and their impact on T1 quantification was compared between WM-SMS3 and AM-SMS3 with conventional MOLLI as a reference.

Results: In the phantom, larger slice gaps and slice thicknesses yielded higher SNR. There was no significant difference of T1 values between conventional MOLLI and SMS3-MOLLI (both WM and AM). Positive banding artefacts were identified from fat neighbouring the targeted FOV due to side-lobe excitations from WM and the unique bSSFP signal profile. AM RF pulses reduced these artefacts by 38%. In healthy volunteers, AM-SMS3-MOLLI showed similar artefact reduction compared to WM-SMS3-MOLLI (3 ± 2 vs 5 ± 3 corrupted LV segments out of 16). In-vivo native T1 values obtained from conventional MOLLI and AM-SMS3-MOLLI were equivalent in LV myocardium (SMS1-T1 = 935.5 ± 36.1 ms; AM-SMS3-T1 = 933.8 ± 50.2 ms; P = 0.436) and LV blood pool (SMS1-T1 = 1475.4 ± 35.9 ms; AM-SMS3-T1 = 1452.5 ± 70.3 ms; P = 0.515). Identically, no differences were found between SMS1 and SMS3 postcontrast T1 values in the myocardium (SMS1-T1 = 556.0 ± 19.7 ms; SMS3-T1 = 521.3 ± 28.1 ms; P = 0.626) and the blood (SMS1-T1 = 478 ± 65.1 ms; AM-SMS3-T1 = 447.8 ± 81.5; P = 0.085).

Conclusions: Compared to WM RF modulation, AM SMS-bSSFP MOLLI was able to reduce side-lobe artefacts considerably, providing promising results to image the three levels of the heart in a single breath hold. However, few artefacts remained even using AM-SMS-bSSFP due to residual RF imperfections. The proposed blipped-CAIPIRINHA MOLLI T1 mapping sequence provides accurate in vivo T1 quantification in line with those obtained with a single slice acquisition.
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http://dx.doi.org/10.1016/j.mri.2020.03.006DOI Listing
April 2020

Autophagy drives fibroblast senescence through MTORC2 regulation.

Autophagy 2020 11 13;16(11):2004-2016. Epub 2020 Jan 13.

Centre De Recherche, Centre Hospitalier De l'Université De Montréal (CRCHUM) and Université De Montréal , Montréal, QC, Canada.

Sustained macroautophagy/autophagy favors the differentiation of fibroblasts into myofibroblasts. Cellular senescence, another means of responding to long-term cellular stress, has also been linked to myofibroblast differentiation and fibrosis. Here, we evaluate the relationship between senescence and myofibroblast differentiation in the context of sustained autophagy. We analyzed markers of cell cycle arrest/senescence in fibroblasts , where autophagy was triggered by serum starvation (SS). Autophagic fibroblasts expressed the senescence biomarkers CDKN1A/p21 and CDKN2A/p16 and exhibited increased senescence-associated GLB1/beta-galactosidase activity. Inhibition of autophagy in serum-starved fibroblasts with 3-methyladenine, LY294002, or (autophagy related 7) silencing prevented the expression of senescence-associated markers. Similarly, suppressing MTORC2 activation using rapamycin or by silencing also prevented senescence hallmarks. Immunofluorescence microscopy showed that senescence and myofibroblast differentiation were induced in different cells, suggesting mutually exclusive activation of senescence and myofibroblast differentiation. Reactive oxygen species (ROS) are known inducers of senescence and exposing fibroblasts to ROS scavengers decreased ROS production during SS, inhibited autophagy, and significantly reduced the expression of senescence and myofibroblast differentiation markers. ROS scavengers also curbed the AKT1 phosphorylation at Ser473, an MTORC2 target, establishing the importance of ROS in fueling MTORC2 activation. Inhibition of senescence by shRNA to / and shRNA / increased myofibroblast differentiation, suggesting a negative feedback loop of senescence on autophagy-induced myofibroblast differentiation. Collectively, our results identify ROS as central inducers of MTORC2 activation during chronic autophagy, which in turn fuels senescence activation and myofibroblast differentiation in distinct cellular subpopulations. : 3-MA: 3-methyladenine; ACTA2: actin, alpha 2, smooth muscle, aorta; AKT1: AKT serine/threonine kinase 1; p-AKT1: AKT1 Ser473 phosphorylation; t-AKT1: total AKT serine/threonine kinase 1; ATG4A: autophagy related 4A cysteine peptidase; ATG7: autophagy gene 7; C12FDG: 5-dodecanoylaminofluorescein Di-β-D-Galactopyranoside; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; Ctl: control; DAPI: 4',6-diamidino-2-phenylindole, dilactate; ECM: extracellular matrix; GSH: L-glutathione reduced; HO: hydrogen peroxide; HLF: adult human lung fibroblasts; Ho: Hoechst 33342 (2'-[4-ethoxyphenyl]-5-[4-methyl-1-piperazinyl]-2.5'-bi-1-benzimidazole); HSC: hepatic stellate cells; LY: LY294002; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTORC1/2: mechanistic target of rapamycin kinase complex 1/2; N: normal growth medium; NAC: N-acetyl-L-cysteine; PBS: phosphate-buffered saline; PDGFA: platelet derived growth factor subunit A; PRKCA/PKCα: protein kinase C alpha; PtdIns3K: class III phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; R: rapamycin; RICTOR: RPTOR independent companion of MTOR complex 2; ROS: reactive oxygen species; RPTOR: regulatory associated protein of MTOR complex 1; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SGK1: serum/glucocorticoid regulated kinase 1; shRNA: short hairpin RNA; siCtl: control siRNA; siRNA: small interfering RNA; SQSTM1: sequestosome 1; SS: serum-free (serum starvation) medium; TP53: tumor protein p53; TUBA: tubulin alpha; V: vehicle.
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http://dx.doi.org/10.1080/15548627.2020.1713640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595590PMC
November 2020

In vivo characterization of skeletal muscle function in nebulin-deficient mice.

Muscle Nerve 2020 03 21;61(3):416-424. Epub 2020 Jan 21.

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

Introduction: The conditional nebulin knockout mouse is a new model mimicking nemaline myopathy, a rare disease characterized by muscle weakness and rods within muscle fibers. We investigated the impact of nebulin (NEB) deficiency on muscle function in vivo.

Methods: Conditional nebulin knockout mice and control littermates were studied at 10 to 12 months. Muscle function (force and fatigue) and anatomy (muscles volume and fat content) were measured in vivo. Myosin heavy chain (MHC) composition and nebulin (NEB) protein expression were assessed by protein electrophoresis.

Results: Conditional nebulin knockout mice displayed a lower NEB level (-90%) leading to a 40% and 45% reduction in specific maximal force production and muscles volume, respectively. Nebulin deficiency was also associated with higher resistance to fatigue and increased MHC I content.

Discussion: Adult nebulin-deficient mice displayed severe muscle atrophy and weakness in vivo related to a low NEB content but an improved fatigue resistance due to a slower contractile phenotype.
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http://dx.doi.org/10.1002/mus.26798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393679PMC
March 2020

Single Nucleotide Polymorphism rs6942067 Is a Risk Factor in Young and in Non-Smoking Patients with HPV Negative Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2019 Dec 24;12(1). Epub 2019 Dec 24.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0A9, Canada.

Genetic factors behind the increasing incidence of human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) in young non-smokers are suspected, but have not been identified. Recently, rs6942067, a single nucleotide polymorphism (SNP) located upstream of the DCBLD1 gene, was found associated with non-smoking lung adenocarcinoma. To validate if this SNP is also implicated in HNSCC, participants of The Cancer Genome Atlas HNSCC cohort were investigated for rs6942067 status, associated DCBLD1 expression, and clinical characteristics. Occurrence of the rs6942067 GG genotype is significantly higher in young and in HPV negative non-smoking HNSCC than in other HNSCC. Additionally, rs6942067 GG is associated with higher DCBLD1 expression in HNSCC and patients with high DCBLD1 expression have a worse overall survival at three years, both in univariate and multivariate analysis. Furthermore, high DCBLD1 expression is associated with activation of the integrin signaling pathway and its phosphorylation with EGFR and MET. Collectively, these findings suggest that DCBLD1 plays a critical role in HNSCC and demonstrate an association between rs6942067 and clinical characteristics of young age and HPV negative non-smoking status in HNSCC patients.
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http://dx.doi.org/10.3390/cancers12010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017251PMC
December 2019

Clinical and Preclinical Imaging of Hepatosplenic Schistosomiasis.

Trends Parasitol 2020 02 18;36(2):206-226. Epub 2019 Dec 18.

CNRS, Aix-Marseille Université, CRMBM, Faculté des Sciences Médicales et Paramédicales la Timone, Marseille, France. Electronic address:

Schistosomiasis, a neglected tropical disease, is a major cause of chronic morbidity and disability, and premature death. The hepatosplenic form of schistosomiasis is characterized by hepatosplenomegaly, liver fibrosis, portal hypertension, and esophageal varices, whose rupture may cause bleeding and death. We review currently available abdominal imaging modalities and describe their basic principles, strengths, weaknesses, and usefulness in the assessment of hepatosplenic schistosomiasis (HSS). Advanced imaging methods are presented that could be of interest for hepatosplenic schistosomiasis evaluation by yielding morphological, functional, and molecular parameters of disease progression. We also provide a comprehensive view of preclinical imaging studies and current research objectives such as parasite visualization in hosts, follow-up of the host's immune response, and development of noninvasive quantitative methods for liver fibrosis assessment.
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http://dx.doi.org/10.1016/j.pt.2019.11.007DOI Listing
February 2020

The Use of Higher Proportions of Platelet-Rich Plasma to Enrich Microfat Has Negative Effects: A Preclinical Study.

Plast Reconstr Surg 2020 01;145(1):130-140

From the Plastic Surgery Department and the Cell Therapy Department, Hôpital de la Conception, AP-HM; Public Health, Chronic Diseases and Quality of Life, Research Unit, INSERM, INRA, C2VN, CNRS, CRMBM, Massilia Pathologie; Aix Marseille University; and the Cell Therapy Department, Hôpital Hautepierre.

Background: Platelet-rich plasma improves engraftment after fat transfer. However, the effects of platelet dose have never been investigated. The authors used magnetic resonance imaging to compare surviving graft volumes in mice after administration of four different formulations (microfat alone, and three platelet-rich plasma-enriched microfat mixes).

Methods: The authors used a random, double-blinded, fat transfer protocol using three different platelet levels: 1 million (low-dose), 500 million (medium-dose), and 1000 million (high-dose) platelets/ml, and fat alone (control). The authors grafted 0.4 ml of the 70/30 platelet-rich plasma-enriched microfat mixtures (0.4 million, 200 million, and 400 million platelets per 0.12 ml for the low-dose, medium-dose, and high-dose mixtures, respectively) or 0.4 ml of microfat alone into 22 nude mice and monitored surviving graft volumes every month for 3 months. Then, the authors histologically analyzed all grafts to assess neoangiogenesis status and fat integrity.

Results: Three-dimensional magnetic resonance imaging showed that the median surviving graft volumes at 3 months were 9.5 percent (interquartile range, 0 to 25 percent; p = 0.003) (high-dose), 4.1 percent (interquartile range, 0 to 18 percent; p = 0.001) (medium-dose), and 18 percent (interquartile range, 8 to 38 percent; p = 0.41) (low-dose) compared to 36 percent (interquartile range, 28 to 53 percent) for the control value. The histologic integrity of microfat-alone grafts was significantly better than those of the other grafts, although the high-dose and low-dose grafts exhibited higher levels of neoangiogenesis.

Conclusion: Higher platelet levels in microfat grafts were associated with poor graft survival in nude mice; a clinical review would be appropriate.
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http://dx.doi.org/10.1097/PRS.0000000000006406DOI Listing
January 2020

Effect of landiolol on sex-related transcriptomic changes in the myocardium during sepsis.

Intensive Care Med Exp 2019 Aug 19;7(1):50. Epub 2019 Aug 19.

Aix-Marseille Univ, INSERM UMR 1090, TAGC, Campus de Luminy, Case 928, 13288, Marseille Cedex 9, France.

Objectives: The aims of this study are to better understand phenotypic differences between male and female rats during sepsis, to characterise the contribution of the beta1-adrenergic blocker landiolol to septic cardiomyopathy and to determine why landiolol induces divergent effects in males and females.

Methods: The myocardial transcriptional profiles in male and female Wistar rats were assessed after the induction of sepsis by cecal ligation and puncture and addition of landiolol.

Results: Our results showed major differences in the biological processes activated during sepsis in male and female rats. In particular, a significant decrease in processes related to cell organisation, contractile function, ionic transport and phosphoinositide-3-kinase/AKT (PI3K/AKT) signalling was observed only in males. The transcript of ATPase sarcoplasmic/endoplasmic reticulum Ca transporting 3 (SERCA3) was sex-differently regulated. In males, landiolol reversed several signalling pathways dysregulated during sepsis. The expression level of genes encoding tubulin alpha 8 (TUBA8) and myosin heavy chain 7B (MYH7) contractile proteins, phosphatase 2 catalytic subunit alpha (PPP2CA), G protein-coupled receptor kinase 5 (GRK5) and A-kinase anchoring protein 6 (AKAP6) returned to their basal levels. In contrast, in females, landiolol had limited effects.

Conclusion: In males, landiolol reversed the expression of many genes that were deregulated in sepsis. Conversely, sepsis-induced deregulation of gene expression was less pronounced in females than in males, and was maintained in the landiolol-treated females. These findings highlight important sex-related differences and confirm previous observations on the important benefit of landiolol intake on cardiac function in male rats.
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http://dx.doi.org/10.1186/s40635-019-0263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701793PMC
August 2019

Multiparametric statistical quantification of pH heterogeneity by H MRS and MRSI of extracellular pH markers: Proof of principle.

NMR Biomed 2019 11 17;32(11):e4134. Epub 2019 Jul 17.

Aix-Marseille University, CRMBM, Marseille, France.

Acid production and transport in numerous biological tissues and medical conditions are active areas of research. Heterogeneity of pH within a given homogeneous-appearing tissue volume has been reported, but none of the conventional methods currently available for measuring tissue pH provides quantitative parameters describing the frequency of occurrence of pH values within such a volume. We have previously presented a multiparametric noninvasive in vivo approach, providing at least 10 different statistical descriptors of pH heterogeneity based on a novel type of line shape analysis developed for pH-sensitive P MRS resonances. However, this method suffers from lack of sensitivity, thus making rapid and spatially resolved measurements difficult. We present here the proof of principle of a new, more sensitive approach to statistical characterization of extracellular pH heterogeneity based on H MRS, with the potential of being combined with spatial resolution. We experimentally study a range of test solutions of a reporter molecule that has previously been shown to possess a H MRS resonance whose chemical shift varies with pH, including when injected intravenously into experimental animals (imidazole ethoxycarbonylpropionic acid, [IEPA]). Statistical pH heterogeneity descriptors are determined for phantoms mimicking tissue pH heterogeneity. To this end, the pH-sensitive H MRS resonance is transformed into a pH curve. Subsequently, the digital points of this pH profile are used to build a histogram using dedicated algorithms. The following descriptors are computed from this histogram: weighted mean pH and median pH, pH standard deviation, pH range, pH mode(s), pH kurtosis, pH skewness and pH entropy. Our new method is also validated by analyzing previously published in vivo MRSI spectra. The proof of principle provided in this work should form the basis of further in vivo studies in physiology and medicine, eg in cancer research, but also in other fields such as kidney and muscle research.
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http://dx.doi.org/10.1002/nbm.4134DOI Listing
November 2019

A method for multiparametric statistical quantification of the heterogeneity of free Na concentration by F MR spectroscopy: Proof of principle in silico and in vitro.

NMR Biomed 2019 09 12;32(9):e4117. Epub 2019 Jul 12.

School of Medicine, CRMBM, Aix-Marseille University, Marseille, France.

Sodium(I) (Na ) is one of the most important cations in mammalian tissues. Since Na plays a key role in basic cell function, noninvasive methods for measuring intracellular concentrations of free sodium ions in biological tissue have been developed on the basis of F NMR spectroscopy. However, intracellular Na levels are often not uniform throughout a tissue volume (or voxel) being measured. In such cases, [Na ] heterogeneity is not reflected in results obtained by the classical technique, and may even result in biased average values. For this reason, we have designed an approach for quantifying [Na ] heterogeneity. First, the F MRS resonance from FCrown-1 serving as a "Na probe" is transformed into a [Na ] curve. Then the digital points of the resulting [Na ] profile are used to construct a histogram with specially developed algorithms. From each [Na ] histogram, at least eight quantitative parameters describing the underlying statistical [Na ] distribution were computed: weighted median, weighted mean, standard deviation, range, mode(s), kurtosis, skewness, and entropy. In addition to our new paradigm, we present a first validation based on (i) computer simulations and (ii) experimentally obtained F MR spectra of model solutions. This basic proof of principle warrants future in vivo experiments, in particular because of its ability to provide quantitative information complementary to that made available by commonly used Na MRI: (i) multiparametric statistical characterization of [Na ] distributions; (ii) total [Na ] heterogeneity analysis not intrinsically limited by the size of any MRI voxels; and (iii) analysis of unequivocally intracellular [Na ], as opposed to measurement of a combination of intra- and extracellular [Na ].
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http://dx.doi.org/10.1002/nbm.4117DOI Listing
September 2019

Tumor protein 53-induced nuclear protein 1 deficiency alters mouse gastrocnemius muscle function and bioenergetics in vivo.

Physiol Rep 2019 05;7(10):e14055

Aix Marseille Univ, CNRS, CRMBM, Marseille, France.

Tumor protein 53-induced nuclear protein 1 (TP53INP1) deficiency leads to oxidative stress-associated obesity and insulin resistance. Although skeletal muscle has a predominant role in the development of metabolic syndrome, the bioenergetics and functional consequences of TP53INP1 deficiency upon this tissue remain undocumented. To clarify this issue, gastrocnemius muscle mechanical performance, energy metabolism, and anatomy were investigated in TP53INP1-deficient and wild-type mice using a multidisciplinary approach implementing noninvasive multimodal-NMR techniques. TP53INP1 deficiency increased body adiposity but did not affect cytosolic oxidative stress, lipid content, and mitochondrial pool and capacity in myocyte. During a fatiguing bout of exercise, the in vivo oxidative ATP synthesis capacity was dramatically reduced in TP53INP1-deficient mice despite ADP level (the main in vivo stimulator of mitochondrial respiration) did not differ between both genotypes. Moreover, TP53INP1 deficiency did not alter fatigue resistance but paradoxically increased the contractile force, whereas there were no differences for muscle fiber-type distribution and calcium homeostasis between both genotypes. In addition, muscle proton efflux was decreased in TP53INP1-deficient mice, thereby indicating a reduced blood supply. In conclusion, TP53INP1 plays a role in muscle function and bioenergetics through oxidative capacity impairment possibly as the consequence of abnormal mitochondrial respiration regulation and/or defective blood supply.
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http://dx.doi.org/10.14814/phy2.14055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533175PMC
May 2019

Cardiac remodeling and higher sensitivity to ischemia-reperfusion injury in female rats submitted to high-fat high-sucrose diet: An in vivo/ex vivo longitudinal follow-up.

J Nutr Biochem 2019 07 8;69:139-150. Epub 2019 Apr 8.

Aix Marseille Univ, CNRS, CRMBM, Marseille, France. Electronic address:

Prediabetes is an important risk factor for Type 2 diabetes and cardiovascular complications, such as myocardial infarction. However, few studies explore female sex in this context. Here, we aim to investigate the effects of high-fat high-sucrose diet on cardiac parameters and sensitivity to ischemia-reperfusion injury of female Wistar rats. Female Wistar rats received for 5 months normal diet (CTRL group) or high-fat high-sucrose diet (HFS group). Every month, MRI was performed to follow myocardial morphology, function and perfusion; cardiac and hepatic triglyceride content; and amount of sub-cutaneous and visceral adipose tissues. Then, ex vivo experiments were performed on isolated perfused hearts to evaluate tolerance to ischemia-reperfusion, with simultaneous measurement of energy metabolism by P MRS and contractile function. Coronary flow was measured before and after ischemia. At the end of the experiments, hearts were freeze-clamped for biochemical assays. Five months of high-fat high-sucrose diet induced a prediabetic condition in female Wistar rats, associated with an increase in myocardial perfusion, systolic and diastolic wall thickness. HFS rats also exhibited higher sensitivity to ischemia-reperfusion injury in comparison to controls, characterized by impaired cardiac function, energy metabolism and endothelial function. Biochemical analyses in hearts highlighted eNOS uncoupling, higher malondialdehyde level and lower S-Glutathionylation of proteins in HFS rats, indicating higher oxidative stress. Prediabetes induced by energy-dense diet was associated with modification of cardiac morphology and higher myocardial sensitivity to ischemia-reperfusion injury. These results may be related to the high risk of cardiovascular complications among Type 2 diabetic women.
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http://dx.doi.org/10.1016/j.jnutbio.2019.03.022DOI Listing
July 2019

Lipodystrophy-like features after total body irradiation among survivors of childhood acute leukemia.

Endocr Connect 2019 Apr;8(4):349-359

Aix Marseille University, INSERM, INRA, C2VN, Marseille, France.

Background/objective: The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children's irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors.

Design: We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI.

Subjects/methods: Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture.

Results: Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation.

Conclusions: These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.
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http://dx.doi.org/10.1530/EC-18-0497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454302PMC
April 2019

Investigating heartbeat-related in-plane motion and stress levels induced at the aortic root.

Biomed Eng Online 2019 Feb 26;18(1):19. Epub 2019 Feb 26.

Laboratoire de Biomécanique Appliquée, Aix-Marseille Université, IFSTTAR, LBA, UMR T24, 51 Bd. P. Dramard, 13015, Marseille, France.

Background: The axial motion of aortic root (AR) due to ventricular traction was previously suggested to contribute to ascending aorta (AA) dissection by increasing its longitudinal stress, but AR in-plane motion effects on stresses have never been studied. The objective is to investigate the contribution of AR in-plane motion to AA stress levels.

Methods: The AR in-plane motion was assessed on magnetic resonance imagining data from 25 healthy volunteers as the movement of the AA section centroid. The measured movement was prescribed to the proximal AA end of an aortic finite element model to investigate its influences on aortic stresses. The finite element model was developed from a patient-specific geometry using LS-DYNA solver and validated against the aortic distensibility. Fluid-structure interaction (FSI) approach was also used to simulate blood hydrodynamic effects on aortic dilation and stresses.

Results: The AR in-plane motion was 5.5 ± 1.7 mm with the components of 3.1 ± 1.5 mm along the direction of proximal descending aorta (PDA) to AA centroid and 3.0 ± 1.3 mm perpendicularly under the PDA reference system. The AR axial motion elevated the longitudinal stress of proximal AA by 40% while the corresponding increase due to in-plane motion was always below 5%. The stresses at proximal AA resulted approximately 7% less in FSI simulation with blood flow.

Conclusions: The AR in-plane motion was comparable with the magnitude of axial motion. Neither axial nor in-plane motion could directly lead to AA dissection. It is necessary to consider the heterogeneous pressures related to blood hydrodynamics when studying aortic wall stress levels.
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http://dx.doi.org/10.1186/s12938-019-0632-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391796PMC
February 2019

Wireless coils based on resonant and nonresonant coupled-wire structure for small animal multinuclear imaging.

NMR Biomed 2019 05 17;32(5):e4079. Epub 2019 Feb 17.

Aix Marseille Univ, CNRS, CRMBM, Marseille, France.

Earlier work on RF metasurfaces for preclinical MRI has targeted applications such as whole-body imaging and dual-frequency coils. In these studies, a nonresonant loop was used to induce currents into a metasurface that was operated as a passive inductively powered resonator. However, as we show in this study, the strategy of using a resonant metasurface reduces the impact of the loop on the global performance of the assembled coil. To mitigate this deficiency, we developed a new approach that relies on the combination of a commercial surface coil and a coupled-wire structure operated away from its resonance. This strategy enables the extension of the sensitive volume of the surface coil while maintaining its local high sensitivity without any hardware modification. A wireless coil based on a two parallel coupled-wire structure was designed and electromagnetic field simulations were carried out with different levels of matching and coupling between both components of the coil. For experimental characterization, a prototype was built and tested at two frequencies, 300 MHz for H and 282.6 MHz for F at 7 T. Phantom and in vivo MRI experiments were conducted in different configurations to study signal and noise figures of the structure. The results showed that the proposed strategy improves the overall sensitive volume while simultaneously maintaining a high signal-to-noise ratio (SNR). Metasurfaces based on coupled wires are therefore shown here as promising and versatile elements in the MRI RF chain, as they allow customized adjustment of the sensitive volume as a function of SNR yield. In addition, they can be easily adapted to different Larmor frequencies without loss of performance.
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http://dx.doi.org/10.1002/nbm.4079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594360PMC
May 2019

Protective Effect of Resveratrol against Ischemia-Reperfusion Injury via Enhanced High Energy Compounds and eNOS-SIRT1 Expression in Type 2 Diabetic Female Rat Heart.

Nutrients 2019 Jan 6;11(1). Epub 2019 Jan 6.

Aix-Marseille University, CNRS, Centre de Résonance Magnétique Biologique et Médicale (CRMBM), Faculté de Médecine, 27 Boulevard Jean Moulin, 13385 Marseille, CEDEX 05, France.

Type 2 diabetic women have a high risk of mortality via myocardial infarction even with anti-diabetic treatments. Resveratrol (RSV) is a natural polyphenol, well-known for its antioxidant property, which has also shown interesting positive effects on mitochondrial function. Therefore, we aim to investigate the potential protective effect of 1 mg/kg/day of RSV on high energy compounds, during myocardial ischemia-reperfusion in type 2 diabetic female Goto-Kakizaki (GK) rats. For this purpose, we used P magnetic resonance spectroscopy in isolated perfused heart experiments, with a simultaneous measurement of myocardial function and coronary flow. RSV enhanced adenosine triphosphate (ATP) and phosphocreatine (PCr) contents in type 2 diabetic hearts during reperfusion, in combination with better functional recovery. Complementary biochemical analyses showed that RSV increased creatine, total adenine nucleotide heart contents and citrate synthase activity, which could be involved in better mitochondrial functioning. Moreover, improved coronary flow during reperfusion by RSV was associated with increased eNOS, SIRT1, and P-Akt protein expression in GK rat hearts. In conclusion, RSV induced cardioprotection against ischemia-reperfusion injury in type 2 diabetic female rats via increased high energy compound contents and expression of protein involved in NO pathway. Thus, RSV presents high potential to protect the heart of type 2 diabetic women from myocardial infarction.
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http://dx.doi.org/10.3390/nu11010105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356423PMC
January 2019

Exercise stress CMR reveals reduced aortic distensibility and impaired right-ventricular adaptation to exercise in patients with repaired tetralogy of Fallot.

PLoS One 2018 31;13(12):e0208749. Epub 2018 Dec 31.

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

Background: The aim of our study was to evaluate the feasibility of exercise cardiac magnetic resonance (CMR) in patients with repaired tetralogy of Fallot (RTOF) and to assess right and left ventricular adaptation and aortic wall response to exercise in comparison with volunteers.

Methods: 11 RTOF and 11 volunteers underwent prospective CMR at rest and during exercise. A supine bicycle ergometer was employed to reach twice the resting heart rate during continuous exercise, blood pressure and heart rate were recorded. Bi-ventricular parameters and aortic stiffness were assessed using accelerated cine sequences and flow-encoding CMR. A t-test was used to compare values between groups. A Mann Whitney test was used to compare values within groups.

Results: In RTOF both ventricles showed an impaired contractile reserve (RVEF rest 36.2±8.3%, +1.3±3.9% increase after exercise; LVEF rest 53.8±6.1%, +5.7±6.4% increase after exercise) compared to volunteers (RVEF rest 50.5±5.0%, +10.4±7.1% increase after exercise, p = 0.039; LVEF rest 61.9±3.1%, +12.2±4.7% increase after exercise, p = 0.014). RTOF showed a reduced distensibility of the ascending aorta during exercise compared to volunteers (RTOF: 3.4±1.9 10-3.mmHg-1 vs volunteers: 5.1±1.4 10-3.mmHg-1; p = 0.027). Ascending aorta distensibility was correlated to cardiac work in the volunteers but not in RTOF.

Conclusion: RTOF showed an impaired contractile reserve for both ventricles. The exercise unmasked a reduced distensibility of the ascending aorta in RTOF, which may be an early sign of increased aortic rigidity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312273PMC
May 2019

Ischaemia-induced muscle metabolic abnormalities are poorly alleviated by endurance training in a mouse model of sickle cell disease.

Exp Physiol 2019 03 15;104(3):398-406. Epub 2019 Jan 15.

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

New Findings: What is the central question of this study? The aim of this study was to evaluate the potential beneficial effects of endurance training during an ischaemia-reperfusion protocol in a mouse model of sickle cell disease (SCD). What is the main finding and its importance? Endurance training did not reverse the metabolic defects induced by a simulated vaso-occlusive crisis in SCD mice, with regard to intramuscular acidosis, mitochondrial dysfunction or anatomical properties. Our results suggest that endurance training would reduce the number of vaso-occlusive crises rather than the complications related to vaso-occlusive crises.

Abstract: The aim of this study was to investigate whether endurance training could limit the abnormalities described in a mouse model of sickle cell disease (SCD) in response to an ischaemia-reperfusion (I/R) protocol. Ten sedentary (HbSS-SED) and nine endurance-trained (HbSS-END) SCD mice were submitted to a standardized protocol of I/R of the leg, during which ATP, phosphocreatine and inorganic phosphate concentrations and intramuscular pH were measured using magnetic resonance spectroscopy. Forty-eight hours later, skeletal muscles were harvested. Oxidative stress markers were then measured. Although the time course of protons accumulation was slightly different between trained and sedentary mice (P < 0.05), the extent of acidosis was similar at the end of the ischaemic period. The initial rate of phosphocreatine resynthesis measured at blood flow restoration, illustrating mitochondrial function, was not altered in trained mice compared with sedentary mice. Although several oxidative stress markers were not different between groups (P > 0.05), the I/R-related increase of uric acid concentration observed in sedentary SCD mice (P < 0.05) was not present in the trained group. The spleen weight, generally used as a marker of the severity of the disease, was not different between groups (P > 0.05). In conclusion, endurance training did not limit the metabolic consequences of an I/R protocol in skeletal muscle of SCD mice, suggesting that the reduction in the severity of the disease previously demonstrated in the basal state would be attributable to a reduction of the occurrence of vaso-occlusive crises rather than a decrease of the deleterious effects of vaso-occlusive crises.
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http://dx.doi.org/10.1113/EP087430DOI Listing
March 2019

Simultaneous multi-slice cardiac cine with Fourier-encoded self-calibration at 7 Tesla.

Magn Reson Med 2019 04 19;81(4):2576-2587. Epub 2018 Nov 19.

Aix Marseille Univ, CNRS, CRMBM, Marseille, France.

Purpose: To accelerate cardiac cine at 7 tesla using simultaneous multi-slice (SMS) acquisition with self-calibration to resolve misalignment between calibration and imaging data due to breathing motion.

Methods: A spoiled-gradient echo cine sequence was modified with radiofrequency phase-cycled SMS excitations. A Fourier encoding strategy was applied along the cardiac phase dimension to allow for slice untangling and split-slice GRAPPA calibration. Split-slice GRAPPA was coupled with regular GRAPPA (SMS-GRAPPA) and L1-SPIRiT (SMS-L1SPIRiT) for image reconstruction. 3-slice SMS cine MRI was evaluated in ten subjects against single-slice cine MRI in terms of SNR and contrast-to-noise ratio and slice leakage.

Results: SNR decreased significantly from 10.1 ± 7.1 for single-slice cine to 7.4 ± 2.8 for SMS-GRAPPA (P = 0.02) and was recovered to 9.0 ± 4.5 with SMS-L1SPIRiT (P = 0.02). Contrast to noise ratio decreased significantly from 14.5 ± 8.1 for single-slice cine to 5.6 ± 3.6 for SMS-GRAPPA (P < 0.0001) and increased slightly but significantly back to 6.7 ± 4.4 for SMS-L1SPIRiT (P = 0.03). Specific absorption rate restrictions imposed a reduced nominal flip angle (-37 ± 7%, P = 0.02) for 3-slice SMS excitations compared to single-slice acquisitions. SMS slice leakage increased significantly from apex (8.6 ± 6.5 %) to base (13.1 ± 4.1 %, P = 0.03) in the left ventricle.

Conclusion: Three-fold acceleration of cine at 7T was achieved using the proposed SMS technique. Fourier encoding self-calibration and regularized image reconstruction enabled simultaneous acquisition of three slices without significant SNR decrease but significant CNR decrease linked to the reduced nominal excitation flip angle.
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http://dx.doi.org/10.1002/mrm.27593DOI Listing
April 2019
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