Publications by authors named "Benjamin Guillet"

66 Publications

Comparison of a New Ga-Radiolabelled PET Imaging Agent sCD146 and RGD Peptide for In Vivo Evaluation of Angiogenesis in Mouse Model of Myocardial Infarction.

Cells 2021 09 3;10(9). Epub 2021 Sep 3.

Pharmacological Faculty, Aix Marseille University, INSERM 1263, INRAE 1260, C2VN, 13385 Marseille, France.

Ischemic vascular diseases are associated with elevated tissue expression of angiomotin (AMOT), a promising molecular target for PET imaging. On that basis, we developed an AMOT-targeting radiotracer, Ga-sCD146 and performed the first in vivo evaluation on a myocardial infarction mice model and then, compared AMOT expression and αβ-integrin expression with Ga-sCD146 and Ga-RGD imaging. After myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery, myocardial perfusion was evaluated by Doppler ultrasound and by F-FDG PET imaging. Ga-sCD146 and Ga-RGD PET imaging were performed. In myocardial infarction model, heart-to-muscle ratio of Ga-sCD146 imaging showed a significantly higher radiotracer uptake in the infarcted area of MI animals than in sham (* = 0.04). Interestingly, we also observed significant correlations between Ga-sCD146 imaging and delayed residual perfusion assessed by F-FDG (* = 0.04), with lowest tissue fibrosis assessed by histological staining (* = 0.04) and with functional recovery assessed by ultrasound imaging (** = 0.01). Ga-sCD146 demonstrated an increase in AMOT expression after MI. Altogether, significant correlations of early post-ischemic Ga-sCD146 uptake with late heart perfusion, lower tissue fibrosis and better functional recovery, make Ga-sCD146 a promising radiotracer for tissue angiogenesis assessment after MI.
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http://dx.doi.org/10.3390/cells10092305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466330PMC
September 2021

Long-term administration of resveratrol at low doses improves neurocognitive performance as well as cerebral blood flow and modulates the inflammatory pathways in the brain.

J Nutr Biochem 2021 Nov 1;97:108786. Epub 2021 Jun 1.

Aix Marseille Univ, INSERM, INRAE, C2VN, 13005 Marseille, France. Electronic address:

There is an increasing prevalence of coincident cerebrovascular deficiency and cognitive dysfunction with aging. Increased oxidative stress as well as inflammation that occurs with aging are associated with the impairment of cerebral vascularization. Interestingly, Resveratrol (RSV), a natural phytoalexin, is known to be a strong antioxidant and possesses anti-inflammatory properties. Collectively, these observations strongly suggest that RSV could protect against cerebral vascularization defect and then improves the decline cognitive function associated with aging. In order to test this hypothesis, we investigated the effect of a long-term RSV treatment (1.25 mg/day for 5 months) on cognitive performances of animals that we have allowed to age normally. Then, we further analyzed the gene expression profile and the cerebral blood flow in the brain. By means of novel object recognition (NOR) test, we observed that RSV enhanced NOR performances of aged rats. In addition, RSV enhanced cerebral blood flow during NOR task in aged rats. Using microarrays experiments, we also showed that several pathways related to inflammation and oxidative stress (Eicosanoid signaling, MIF-mediated innate immunity, NF-kB signaling, TNFR2 signaling, IL6 signaling, Production of nitric oxide and ROS) were down-regulated in the brain of RSV treatments rats compared to control rats. In conclusion, these results support that a long-term treatment with RSV improves cognitive performance in the elderly male rat model. This effect is associated with an increase in cerebral blood flow and a decrease in the expression of several pro-inflammatory pathways in the brain.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108786DOI Listing
November 2021

Development of a multi-functional preclinical device for the treatment of glioblastoma.

Biomed Opt Express 2021 Apr 23;12(4):2264-2279. Epub 2021 Mar 23.

Aix Marseille Univ, CNRS, Centrale Marseille, Institut Fresnel, Marseille, France.

Glioblastoma multiforme (GBM) is one of the most common and aggressive malignant primary brain tumors in adults. The treatment of GBM is limited by the blood-brain barrier (BBB), which limits the diffusion of appropriate concentrations of therapeutic agents at the tumor site. Among experimental therapies, photo-thermal therapy (PTT) mediated by nanoparticles is a promising strategy. To propose a preclinical versatile research instrument for the development of new PTT for GBM, a multipurpose integrated preclinical device was developed. The setup is able to perform: i) BBB permeabilization by focused ultrasound sonication (FUS); ii) PTT with continuous wave laser; iii) temperature monitoring with photo-acoustic (PA) measurements. preliminary subcutaneous and transcranial experiments were conducted on healthy or tumor-bearing mice. Transcranial FUS-induced BBB permeabilization was validated using single photon emission computed tomography (SPECT) imaging. PTT capacities were monitored by PA thermometry, and are illustrated through subcutaneous and transcranial experiments. The results show the therapeutic possibilities and ergonomy of such integrated device as a tool for the validation of future treatments.
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http://dx.doi.org/10.1364/BOE.419412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086436PMC
April 2021

Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study.

Cells 2021 04 2;10(4). Epub 2021 Apr 2.

Aix Marseille University, INSERM 1263, INRAE 1260, C2VN, 13005 Marseille, France.

Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* = 0.0189). A microPET study using a radiolabeled integrin ligand ([Ga]Ga-RGD) showed an earlier angiogenic activation in the succinate arm compared to control mice (* = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.
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http://dx.doi.org/10.3390/cells10040795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066129PMC
April 2021

Systemic Administration of G-CSF Accelerates Bone Regeneration and Modulates Mobilization of Progenitor Cells in a Rat Model of Distraction Osteogenesis.

Int J Mol Sci 2021 Mar 28;22(7). Epub 2021 Mar 28.

ISM, CNRS, Aix Marseille University, 13009 Marseille, France.

Granulocyte colony-stimulating factor (G-CSF) was shown to promote bone regeneration and mobilization of vascular and osteogenic progenitor cells. In this study, we investigated the effects of a systemic low dose of G-CSF on both bone consolidation and mobilization of hematopoietic stem/progenitor cells (HSPCs), endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) in a rat model of distraction osteogenesis (DO). Neovascularization and mineralization were longitudinally monitored using positron emission tomography and planar scintigraphy. Histological analysis was performed and the number of circulating HSPCs, EPCs and MSCs was studied by flow cytometry. Contrary to control group, in the early phase of consolidation, a bony bridge with lower osteoclast activity and a trend of an increase in osteoblast activity were observed in the distracted callus in the G-CSF group, whereas, at the late phase of consolidation, a significantly lower neovascularization was observed. While no difference was observed in the number of circulating EPCs between control and G-CSF groups, the number of MSCs was significantly lower at the end of the latency phase and that of HSPCs was significantly higher 4 days after the bone lengthening. Our results indicate that G-CSF accelerates bone regeneration and modulates mobilization of progenitor cells during DO.
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http://dx.doi.org/10.3390/ijms22073505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037338PMC
March 2021

Pharmaceutical interviews to overcome digestive artefacts on [ Tc]Tc-tetrofosmin myocardial perfusion scintigraphy.

J Clin Pharm Ther 2021 Oct 22;46(5):1480-1483. Epub 2021 Mar 22.

Radiopharmacie, Hôpital Nord, APHM, INSERM 1263, INRAE 1260, C2VN, CERIMED, Aix-Marseille Univ, Marseille, France.

What Is Known And Objectives: Poor image quality was randomly seen in [ Tc]Tc-tetrofosmin myocardial perfusion scintigraphic imaging. The interference hampered or even precluded medical interpretation. Our objective was to identify the cause of the random interferences.

Methods: Out of 40 patients planned for [ Tc]Tc-tetrofosmin MPS, 36 presented normal tracer uptake and 4 exhibited subdiaphragmatic artefacts. Pharmaceutical interviews (P.I.) were set up to formally identify aetiologies of subdiaphragmatic uptake of [ Tc]Tc-tetrofosmin. Patients were questioned about their diet and current drug treatments.

Results And Discussion: P.I. led to identification of dipyridamole as the cause of the artefacts. The systematic ingestion of a solid 25-gram high-fat snack bar and a glass of fresh water was introduced immediately after the injection of dipyridamole in 12 other patients undergoing [ Tc]Tc-tetrofosmin MPS. None of the 12 patients presented subdiaphragmatic artefacts.

What Is New And Conclusion: P.I. identified the cause of poor scintigraphic images to allow improved diagnoses.
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http://dx.doi.org/10.1111/jcpt.13418DOI Listing
October 2021

Renal SPECT/CT with 99mTc-dimercaptosuccinic acid is a non-invasive predictive marker for the development of interstitial fibrosis in a rat model of renal insufficiency.

Nephrol Dial Transplant 2021 04;36(5):804-810

Centre Européen de Recherche en Imagerie Médicale, Aix-Marseille Université, Marseille, France.

Background: Chronic kidney disease (CKD) increases cardiovascular risk and mortality. Renal fibrosis plays a major role in the progression of CKD but, to date, histology remains the gold standard to assess fibrosis. Non-invasive techniques are needed to assess renal parenchymal impairment and to perform the longitudinal evaluation of renal structure. Thus we evaluated renal isotopic imaging by single-photon emission computed tomography/computed tomography (SPECT/CT) with technetium-99m (99mTc)-dimercaptosuccinic acid (DMSA) to monitor renal impairment during renal insufficiency in rats.

Methods: Renal insufficiency was induced by an adenine-rich diet (ARD) at 0.25 and 0.5% for 28 days. Renal dysfunction was evaluated by assaying biochemical markers and renal histology. Renal parenchymal impairment was assessed by SPECT/CT isotopic imaging with 99mTc-DMSA on Days 0, 7, 14, 21, 28, 35 and 49.

Results: Compared with controls, ARD rats developed renal dysfunction characterized by increased serum creatinine and blood urea nitrogen, fibrosis and tubulointerstitial damage in the kidneys, with a dose-dependent effect of the adenine concentration. 99mTc-DMSA SPECT-CT imaging showed a significant decrease in renal uptake over time in 0.25 and 0.5% ARD rats compared with control rats (P = 0.011 and P = 0.0004, respectively). 99mTc-DMSA uptake on Day 28 was significantly inversely correlated with Sirius red staining evaluated on Day 49 (r = 0.89, P < 0.0001, R2 = 0.67).

Conclusions: 99mTc-DMSA renal scintigraphy allows a longitudinal follow-up of risk of renal fibrosis in rats. We found that the reduction of renal parenchyma in ARD rats is inversely proportional to newly formed fibrous tissue in the kidney. Our results suggest that 99mTc-DMSA renal scintigraphy may be a useful non-invasive prognostic marker of the development of renal fibrosis in animals and should be tested in humans.
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http://dx.doi.org/10.1093/ndt/gfaa374DOI Listing
April 2021

Combination of Alcohol and EVOH as a New Embolic Agent: Midterm Tissue and Inflammatory Effects in a Swine Model.

Radiol Res Pract 2020 23;2020:8831060. Epub 2020 Oct 23.

Diagnostic and Interventional Radiology Section, Department of Medical Imaging, University Hospital Timone APHM, 278 Rue Saint-Pierre, Marseille 13005, France.

Objective: To evaluate the vascular occlusion and midterm tissue toxicity properties of a combination of ethylene-vinyl alcohol (EVOH) (Squid 18®) (75%) and alcohol (25%)-Alco-Squid 18-in a swine model.

Materials And Methods: Alco-Squid 18 (75% Squid 18® mixed with 25% alcohol) (AS18) was compared to embolization with 96% alcohol alone and to embolization with Squid 18® (S18®) alone. An arteriovenous malformation (AVM) model was created in group 1 ( = 2). Each AVM model was then embolized with AS18 or S18® alone with evaluation of a ratio between the volume of embolic agent divided by the volume of the AVM (evaluated by CT). For group 2 ( = 5), each agent was tested on three different kidneys (upper pole kidney artery). Pre- and postinterventional CTs, angiographies, blood alcohol content dosages, and histological studies (3 months postintervention) were performed.

Results: AS18 has better distal distribution than S18® alone, both in the kidneys (mean capsule-S18® distance: 3.9 mm (±0.23) and mean capsule-AS18 distance: 2.3 mm (±0.11) (=0.029) and in the AVM model. Histological exploration found a higher rate of tubular necrosis with AS18 compared with S18® alone and alcohol alone (3.78 ± 0.44 compared to 2.33 ± 1.22 ( = 0.012) and 1.22 ± 0.67 (  < 0 .0001)). The blood alcohol content was negligible in all cases.

Conclusion: AS18 can suggest a better distal sclerotic and embolic character as compared with S18® alone without systemic toxicity.
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http://dx.doi.org/10.1155/2020/8831060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605951PMC
October 2020

FairEmbo Concept for Arterial Embolizations: In Vivo Feasibility and Safety Study with Suture-Based Microparticles Compared with Microspheres.

Cardiovasc Intervent Radiol 2021 Apr 25;44(4):625-632. Epub 2020 Oct 25.

Interventional Radiololy Section, Department of Medical Imaging, University Hospital Timone, APHM, Marseille, France.

Purpose: Microspheres are effective embolic agents, especially for the management of bleeding and oncologic lesions. The first FairEmbo study reported the effectiveness of embolization using suture fragments. The effectiveness and safety of arterial embolization with suture-based microparticles (SBM) were assessed in a swine model.

Materials And Methods: In this ethical-approved animal study, a polar artery in each kidney was embolized in four swine: one side with hand-cut non-absorbable SBM (Flexocrin 2®) and the contralateral side with Embozene® 900 for comparison. Swine were followed for 3 months (M3) to evaluate the effectiveness and the safety of SBM. Follow-up protocol included clinical monitoring, computed tomography (CT) control and digital subtraction angiography (DSA), followed by histological analyses. The SBM confection parameters were evaluated by automatic microscopic sizer. RStudio software and Mann-Whitney test (significance at P < 0.05) were used for statistics.

Results: The average size of SBM was 1002 μm (SD = 258). All targets were effectively embolized by SBM with an angiogram defect estimated at 45.6% (95% CI [35.9-55.2]), compared to 40.5% (95% CI [30.6-55.5]) for Embozene® group (P = 0.342). The average duration of SBM embolization procedure was significantly increased compared to Embozene® embolization (1202 s versus 222 s, P = 0.029). There were no statistical differences in M3 DSA and CT for SBM and Embozene®, with persistence of partial arterial occlusion and atrophic embolized area. No postoperative complications were observed on clinical and CT controls.

Conclusion: This experimental study suggests that embolization with SBM is feasible, safe and effective in short- and medium-term follow-up as compared to microspheres.
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http://dx.doi.org/10.1007/s00270-020-02678-0DOI Listing
April 2021

Development and Validation of a Fully GMP-Compliant Process for Manufacturing Stromal Vascular Fraction: A Cost-Effective Alternative to Automated Methods.

Cells 2020 09 24;9(10). Epub 2020 Sep 24.

Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, 13005 Marseille, France.

The therapeutic use of adipose-derived stromal vascular fraction (SVF) is expanding in multiple pathologies. Various processes have been proposed for manufacturing SVF but they must be revisited based on advanced therapy medicinal product (ATMP) regulations. We report here the development and validation of a fully good manufacturing practices (GMP)-compliant protocol for the isolation of SVF. Adipose tissue was collected from healthy volunteers undergoing lipoaspiration. The optimal conditions of collagenase digestion and washing were determined based on measurements of SVF cell viability, yield recovery, and cell subset distribution. Comparability of the SVF obtained using the newly developed manufacturing process (n = 6) and the Celution-based automated method (n = 33), used as a reference, was established using inter-donor analyses. Characteristics of SVF (n = 5) generated using both manufacturing protocols were analyzed for an intra-donor comparison. In addition, these comparisons also included the determination of colony-forming unit fibroblast frequency, in vitro angiogenic activity, and in vivo regenerative effects in a mouse ischemic cutaneous wound model. We successfully developed a process for the generation of SVF presenting higher cell viability and yield recovery compared to the Celution device-based protocol. Characteristics of the SVF including phenotype, capacity for angiogenesis, and wound-healing promotion attested to the comparability of the two manufacturing processes. We validated an optimized non-automated process that should allow for a GMP-compliant, more affordable, and reduced-cost strategy to exploit the potential of SVF-based regenerative therapies.
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http://dx.doi.org/10.3390/cells9102158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598595PMC
September 2020

Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS-Positive Tumors Imaging.

Bioconjug Chem 2020 10 18;31(10):2339-2349. Epub 2020 Sep 18.

Institut des Biomolécules Max Mousseron, IBMM, UMR-5247, CNRS, Université de Montpellier, ENSCM, Place Eugène Bataillon, Montpellier 34095 Cedex 5, France.

Several independent studies have demonstrated the overexpression of NTS in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [Ga]JMV6659 exhibits high hydrophilicity (log = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS ( = 6.29 ± 1.37 nM), good selectivity ( NTS/ NTS = 35.9), and high NTS-mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS-expressing tumors.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00419DOI Listing
October 2020

Surface Charge of Supramolecular Nanosystems for In Vivo Biodistribution: A MicroSPECT/CT Imaging Study.

Small 2020 09 14;16(37):e2003290. Epub 2020 Aug 14.

Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UMR 7325, Equipe Labellisée Ligue Contre le Cancer, Marseille, 13288, France.

Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology-based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self-assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid cage with the smaller 1,4,7-triazacyclononane-1,4,7-triacetic acid scaffold as the In chelator, the corresponding dendrimer exhibits neutral In -complex terminals in place of negatively charged In -complex terminals. This negative-to-neutral surface charge alteration completely reverses the zeta-potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought-after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.
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http://dx.doi.org/10.1002/smll.202003290DOI Listing
September 2020

Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.

J Am Soc Nephrol 2020 07 11;31(7):1509-1521. Epub 2020 Jun 11.

Centre Européen de recherche en Imagerie Médicale, Aix Marseille Université, Centre National de la Recherche Scientifique, Marseille, France

Background: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells.

Methods: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of Tc-DTPA, an imaging marker of blood-brain barrier permeability.

Results: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between Tc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment.

Conclusions: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.
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http://dx.doi.org/10.1681/ASN.2019070728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350986PMC
July 2020

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease.

Int J Mol Sci 2020 Apr 3;21(7). Epub 2020 Apr 3.

C2VN, Aix Marseille University, INSERM 1263, INRAe, 13005 Marseille, France.

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins-mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR males. AhR females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.
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http://dx.doi.org/10.3390/ijms21072483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177716PMC
April 2020

Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors.

Int J Cancer 2020 09 22;147(6):1666-1679. Epub 2020 Feb 22.

INSERM, INRAE, C2VN, UFR Pharmacie, Aix-Marseille University, Marseille, France.

Initially discovered in human melanoma, CD146/MCAM is expressed on many tumors and is correlated with cancer progression and metastasis. However, targeting CD146 remains challenging since it is also expressed on other cell types, as vessel cells, where it displays important physiological functions. We previously demonstrated that CD146 is shed as a soluble form (sCD146) that vectorizes the effects of membrane CD146 on tumor angiogenesis, growth and survival. We thus generated a novel monoclonal antibody, the M2J-1 mAb, which specifically targets sCD146, but not membrane CD146, and counteracts these effects. In our study, we analyzed the effects of sCD146 on the dissemination and the associated procoagulant phenotype in two highly invasive human CD146-positive cancer cell lines (ovarian and melanoma). Results show that sCD146 induced epithelial to mesenchymal transition, favored the generation of cancer stem cells and increased the membrane expression of tissue factor. Treatment of cancer cells with sCD146 in two experimental models (subcutaneous xenografting and intracardiac injection of cancer cells in nude mice) led to increased tumor dissemination and procoagulant activity. The M2J-1 mAb drastically reduced metastasis but also procoagulant activity, in particular by decreasing the number of circulating tumor microparticles, and blocked the relevant signaling pathways as demonstrated by RNA expression profiling experiments. Thus, our findings demonstrate that sCD146 mediates important pro-metastatic and procoagulant effects in two CD146-positive tumors. Targeting sCD146 with the newly generated M2J-1 mAb could constitute an innovative strategy for preventing dissemination and thromboembolism in many CD146-positive tumors.
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http://dx.doi.org/10.1002/ijc.32909DOI Listing
September 2020

A self-assembling amphiphilic dendrimer nanotracer for SPECT imaging.

Chem Commun (Camb) 2019 Dec;56(2):301-304

Aix Marseille Univ, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (UMR 7325), Equipe Labellisée Ligue Contre le Cancer, Marseille, France.

Bioimaging has revolutionized modern medicine, and nanotechnology can offer further specific and sensitive imaging. We report here an amphiphilic dendrimer able to self-assemble into supramolecular nanomicelles for effective tumor detection using SPECT radioimaging. This highlights the promising potential of supramolecular dendrimer platforms for biomedical imaging.
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http://dx.doi.org/10.1039/c9cc07750bDOI Listing
December 2019

Have you looked for "stranger things" in your automated PET dose dispensing system? A process and operators qualification scheme.

EJNMMI Radiopharm Chem 2019 Jun 13;4(1):11. Epub 2019 Jun 13.

Radiopharmacie Hôpital Nord AP-HM, Marseille, France.

Background: Many nuclear medicine departments have equipped themselves with automated dispensing systems (ADS) for PET radiopharmaceuticals, in both the operators' and the patients' interests. Whether partially or fully automated, to date there is no marketed ADS representing a true "closed-system". Despite the sterile, injectable nature of ready-to-use radiopharmaceutical drug solutions manipulated by these systems, neither manufacturer's recommendation nor literature report was found about specific qualification of the process' sterility, or about operators' qualification on these dispensing systems. We set up a master plan validation in a radiopharmacy equipped with Trasis Unidose®, including: 1) monthly process-simulating media-fill tests and microbiological contamination assessments of the ADS surfaces; 2) initial and periodic qualification of the operators. The microbiological qualification consisted in surface biocontamination assessment on critical zones with Tryptic-Soy agar. The operator qualification consisted in the evaluation of the operators' knowledge and skills for using the ADS.

Results: This study highlighted a minor, handborne microbiological contamination on our first assessment, that corrective actions solved. We therefore decided to brief our operators once a month on microbiological control results, hygiene and good practices, with the support of the present case illustrating the biodecontamination efficiency.

Conclusions: As the automation of PET monodose conditioning process still implies human intervention for material preparation and manual biodecontamination, this study illustrates that initial and periodic qualification of the environment and the conditioning process of ADS, including microbiological qualification and operators' qualification, are needed to meet specifications.
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http://dx.doi.org/10.1186/s41181-019-0061-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565780PMC
June 2019

Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography.

iScience 2019 Nov 9;21:68-83. Epub 2019 Oct 9.

Aix-Marseille Univ, CNRS, IBDM (Developmental Biology Institute of Marseille), 163 Avenue de Luminy, case 907, Marseille 13009, France. Electronic address:

Computed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26 mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment.
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http://dx.doi.org/10.1016/j.isci.2019.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820243PMC
November 2019

A Comprehensive Review of Non-Covalent Radiofluorination Approaches Using Aluminum [F]fluoride: Will [F]AlF Replace Ga for Metal Chelate Labeling?

Molecules 2019 Aug 7;24(16). Epub 2019 Aug 7.

CERIMED, Aix-Marseille University, 13005 Marseille, France.

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the F chemical toolbox gave aluminum [F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [F][AlF] cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [F]AlF labeling applications through a description of the various [F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.
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http://dx.doi.org/10.3390/molecules24162866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719958PMC
August 2019

European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.

Eur J Nucl Med Mol Imaging 2019 Sep 29;46(10):2112-2137. Epub 2019 Jun 29.

Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.

Methods: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.

Conclusion: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (I)/iodine-131 (I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
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http://dx.doi.org/10.1007/s00259-019-04398-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446938PMC
September 2019

Probing the Cellular Size Distribution in Cell Samples Undergoing Cell Death.

Ultrasound Med Biol 2019 07 22;45(7):1787-1798. Epub 2019 Apr 22.

Aix-Marseille Université, INSERM, INRA, C2 VN, Marseille, France.

A polydisperse scattering model adapted for concentrated medium, namely the polydisperse structure factor model, was examined to explain the backscatter coefficients (BSCs) measured from packed cell samples undergoing cell death. Cell samples were scanned using high-frequency ultrasound in the 10-42 MHz bandwidth. A parameter estimation procedure was proposed to estimate the volume fraction and the relative impedance contrast that could explain the changes in BSC pattern by considering the actual change in cellular size distribution. Quantitative ultrasound parameters were estimated and related to the percentage of dead cells determined by flow cytometry. The standard deviation of scatterer size distribution extracted from the polydisperse structure factor model and the spectral intercept were found to be strongly correlated to the percentage of dead cells (r = 0.79 and r = 0.72, respectively). This study contributes to the understanding of ultrasonic scattering from cells undergoing cell death toward the monitoring of cancer therapy.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2019.01.006DOI Listing
July 2019

CD146 deficiency promotes plaque formation in a mouse model of atherosclerosis by enhancing RANTES secretion and leukocyte recruitment.

J Mol Cell Cardiol 2019 05 27;130:76-87. Epub 2019 Mar 27.

Aix-Marseille Univ., INSERM 1263, INRA 1260, C2VN, Marseille, France. Electronic address:

Aims: The progression of atherosclerosis is based on the continued recruitment of leukocytes in the vessel wall. The previously described role of CD146 in leukocyte infiltration suggests an involvement for this adhesion molecule in the inflammatory response. In this study, we investigated the role of CD146 in leukocyte recruitment by using an experimental model of atherogenesis.

Methods And Results: The role of CD146 was explored in atherosclerosis by crossing CD146-/- mice with ApoE-/- mice. CD146 -/-/ApoE -/- and ApoE -/- mice were fed a Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. The arterial wall was significantly thicker in CD146-deficient mice. After 24 weeks of Western diet, a significant increase of atheroma in both total aortic lesion and aortic sinus of CD146-null mice was observed. In addition, atherosclerotic lesions were more inflammatory since plaques from CD146-deficient mice contained more neutrophils and macrophages. This was due to up-regulation of RANTES secretion by macrophages in CD146-deficient atherosclerotic arteries. This prompted us to further address the function of CD146 in leukocyte recruitment during acute inflammation by using a second experimental model of peritonitis induced by thioglycollate. Neutrophil recruitment was significantly increased in CD146-deficient mice 12 h after peritonitis induction and associated with higher RANTES levels in the peritoneal cavity. In CD146-null macrophages, we also showed that increased RANTES production was dependent on constitutive inhibition of the p38-MAPK signaling pathway. Finally, Maraviroc, a RANTES receptor antagonist, was able to reduce atherosclerotic lesions and neutrophilia in CD146-deficient mice to the same level as that found in ApoE -/- mice.

Conclusions: Our data indicate that CD146 deficiency is associated with the upregulation of RANTES production and increased inflammation of atheroma, which could influence the atherosclerotic plaque fate. Thus, these data identify CD146 agonists as potential new therapeutic candidates for atherosclerosis treatment.
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http://dx.doi.org/10.1016/j.yjmcc.2019.03.017DOI Listing
May 2019

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats.

Crit Care 2019 Feb 11;23(1):42. Epub 2019 Feb 11.

Department of Anaesthesiology and Critical Care Medicine, INT (Institut de Neurosciences de la Timone), University Hospital Timone, Aix Marseille University, Marseille, France.

Background: Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane-prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion.

Methods: The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: Technetium-diethylenetriaminepentacetate (Tc-DTPA), which indicated blood-brain barrier permeability on day 3, Technetium-annexin V-128 (Tc-Anx-V128), which indicated apoptosis on day 4, and Technetium-hexamethylpropyleneamineoxime (Tc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified.

Results: Tc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. Tc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. Tc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α.

Conclusions: Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.
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http://dx.doi.org/10.1186/s13054-019-2338-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371436PMC
February 2019

Molecular profile and proangiogenic activity of the adipose-derived stromal vascular fraction used as an autologous innovative medicinal product in patients with systemic sclerosis.

Ann Rheum Dis 2019 03 5;78(3):391-398. Epub 2019 Jan 5.

Cell Therapy Department, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France

Objective: The autologous stromal vascular fraction (SVF) from adipose tissue is an alternative to cultured adipose-derived stem cells for use in regenerative medicine and represents a promising therapy for vasculopathy and hand disability in systemic sclerosis (SSc). However, the bioactivity of autologous SVF is not documented in this disease context. This study aimed to compare the molecular and functional profiles of the SVF-based medicinal product obtained from SSc and healthy subjects.

Methods: Good manufacturing practice (GMP)-grade SVF from 24 patients with SSc and 12 healthy donors (HD) was analysed by flow cytometry to compare the distribution of the CD45- and CD45+ haematopoietic cell subsets. The ability of SVF to form a vascular network was assessed using Matrigel in vivo assay. The transcriptomic and secretory profiles of the SSc-SVF were assessed by RNA sequencing and multiplex analysis, respectively, and were compared with the HD-SVF.

Results: The distribution of the leucocyte, endothelial, stromal, pericyte and transitional cell subsets was similar for SSc-SVF and HD-SVF. SSc-SVF retained its vasculogenic capacity, but the density of neovessels formed in SVF-loaded Matrigel implanted in nude mice was slightly decreased compared with HD-SVF. SSc-SVF displayed a differential molecular signature reflecting deregulation of angiogenesis, endothelial activation and fibrosis.

Conclusions: Our study provides the first evidence that SSc does not compromise the vascular repair capacity of SVF, supporting its use as an innovative autologous biotherapy. The characterisation of the specific SSc-SVF molecular profile provides new perspectives for delineating markers of the potency of SVF and its targets for the treatment of SSc.
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http://dx.doi.org/10.1136/annrheumdis-2018-214218DOI Listing
March 2019

Nonlinear ultrasound parameter to monitor cell death in cancer cell samples.

J Acoust Soc Am 2018 11;144(5):EL374

Aix-Marseille University, CNRS, Centrale Marseille, LMA, Marseille, France.

A scaling subtraction method was proposed to analyze the radio frequency data from cancer cell samples exposed to an anti-cancer drug and to estimate a nonlinear parameter. The nonlinear parameter was found to be well correlated (R= 0.62) to the percentage of dead cells in apoptosis and necrosis. The origin of the nonlinearity may be related to a change in contacts between cells, since the nonlinear parameter was well correlated to the average total coordination number of binary packings (R≥ 0.77). These results suggest that the scaling subtraction method may be used to early quantify chemotherapeutic treatment efficiency.
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http://dx.doi.org/10.1121/1.5066348DOI Listing
November 2018

Early prediction of revascularisation by angiomotin-targeting positron emission tomography.

Theranostics 2018 5;8(18):4985-4994. Epub 2018 Oct 5.

Aix Marseille Univ, INSERM 1263, INRA 1260, C2VN, Marseille, France.

This study aimed to develop a PET imaging agent of angiomotin (AMOT) expression, a potential biomarker of functional tissue regeneration in post-ischaemic conditions. Hindlimb ischaemia was induced by ligature and resection of the right femoral artery in mice, and clinical score and limb perfusion were evaluated up to 30 days after surgery. AMOT expression was evaluated by histology and Western blot analysis. NODAGA-conjugates of AMOT ligand, sCD146, were designed, synthesised and radiolabelled with gallium-68. Ga-sCD146 microPET/CT imaging was performed from day 1 to day 30 after ischaemia. Ga-sCD146 specificity for AMOT was evaluated by autoradiography. Immunohistochemistry showed a significant endothelial overexpression of AMOT from day 5 up to day 10 in the ischaemic hindlimb. Ga-sCD146 PET signal intensity correlated significantly with AMOT immunohistochemistry evaluation. Ga-sCD146 PET imaging showed a significant uptake in the ischaemic hindlimb from day 2 to day 15, peaking on day 5 (ipsi/contralateral ratio = 2.4 ± 1.3, P = 0.0005) and significantly decreased after pharmacological blocking (62.57 ± 11% decrease in PET signal P = 0.032). Finally, we observed a significant correlation between day 5 Ga-sCD146 PET signal intensity and clinical recovery (day 28) or hindlimb perfusion recovery (day 30). This work reports for the first time an early and sustained increase in AMOT expression after hindlimb ischaemia in mice. We therefore developed an AMOT-targeting imaging agent, Ga-sCD146, and showed its specific uptake up to 21 days after ischaemic hindlimb using microPET imaging. Correlation of early post-ischaemic PET signal with both delayed perfusion recovery and clinical outcome allows us to postulate that Ga-sCD146 represents a promising radiotracer for tissue angiogenesis assessment.
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http://dx.doi.org/10.7150/thno.27728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217063PMC
September 2019

Self-assembling supramolecular dendrimer nanosystem for PET imaging of tumors.

Proc Natl Acad Sci U S A 2018 11 22;115(45):11454-11459. Epub 2018 Oct 22.

Aix-Marseille University, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Equipe Labellisée Ligue Contre le Cancer, 13288 Marseille, France;

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the "enhanced permeation and retention" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nanosystem for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([F]FDG). Most importantly, this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently, this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling dendrimers provides a fresh perspective for biomedical imaging and cancer diagnosis.
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http://dx.doi.org/10.1073/pnas.1812938115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233080PMC
November 2018

Stem cell properties of peripheral blood endothelial progenitors are stimulated by soluble CD146 via miR-21: potential use in autologous cell therapy.

Sci Rep 2018 06 20;8(1):9387. Epub 2018 Jun 20.

Aix Marseille Univ, INSERM 1263, INRA 1260, C2VN, Marseille, France.

Cell-based therapies constitute a real hope for the treatment of ischaemic diseases. One of the sources of endothelial progenitors for autologous cell therapy is Endothelial Colony Forming Cells (ECFC) that can be isolated from peripheral blood. However, their use is limited by their low number in the bloodstream and the loss of their stem cell phenotype associated with the acquisition of a senescent phenotype in culture. We hypothesized that adding soluble CD146, a novel endothelial growth factor with angiogenic properties, during the isolation and growth procedures could improve their number and therapeutic potential. Soluble CD146 increased the number of isolated peripheral blood ECFC colonies and lowered their onset time. It prevented cellular senescence, induced a partial mesenchymal phenotype and maintained a stem cell phenotype by stimulating the expression of embryonic transcription factors. These different effects were mediated through the induction of mature miR-21. When injected in an animal model of hindlimb ischaemia, sCD146-primed ECFC isolated from 40 ml of blood from patients with peripheral arterial disease were able to generate new blood vessels and restore blood flow. Treatment with sCD146 could thus constitute a promising strategy to improve the use of autologous cells for the treatment of ischaemic diseases.
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http://dx.doi.org/10.1038/s41598-018-27715-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010456PMC
June 2018

Prospective evaluation of Ga-DOTATATE PET/CT in limited disease neuroendocrine tumours and/or elevated serum neuroendocrine biomarkers.

Clin Endocrinol (Oxf) 2018 Aug 13;89(2):155-163. Epub 2018 Jun 13.

Department of Nuclear Medicine, La Timone & North University Hospital, Aix-Marseille University, Marseille, France.

Context: The Ga-labelled somatostatin analogues ( Ga-DOTA-SSAs) is becoming popular as an important diagnostic tool in neuroendocrine tumours as evidenced by a growing number of reports detailing institutional experience with various DOTA peptides. However, only few prospective studies have compared Ga-DOTA-SSAs and somatostatin receptor scintigraphy (SRS) in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and pulmonary neuroendocrine tumours.

Objective: The aim of our prospective study was to perform head-to-head comparison between Ga-DOTATATE PET/CT and standard imaging work-up (SI) that included multiphasic CT, liver MRI and SRS using single photon emission computed tomography.

Design: In this prospective study, the patients were enrolled only if they met any of the following inclusion criteria: (i) initial staging of a NETs without distant metastases on SI or neuroendocrine tumour with unknown primary on SI; (ii) restaging of NETs that could be treated by focused therapeutic interventions; (iii) elevated serum neuroendocrine hormones or peptides. The exclusion criteria was grade 3 GEP-NETs.

Results: Thirty-two patients were enrolled in the study. Eleven patients (6 pancreas, 4 ileum, 1 duodenal) were included for initial evaluation and staging of NETs, 8 patients (5 pancreas, 1 ileal, 1 lung, 1 duodenal gastrinoma) for restaging, and 13 patients for elevated serum neuroendocrine biomarkers (5 ectopic Cushing's syndrome, 5 organic hypoglycaemia, 1 patient each with elevated vasoactive inhibitory peptide, chromogranin A and neuron-specific enolase). Ga-DOTATATE PET/CT detected more primary tumours than SRS (15/18 vs 10/18: P = .074). The missed tumours on Ga-DOTATATE PET/CT were located in the lung in two cases and duodenum in one case. For other anatomical regions (nodal and distant metastasis), no statistical difference was observed between imaging modalities using Ga-DOTATATE PET/CT and SRS. Overall, Ga-DOTATATE PET/CT+CT+MRI detected 31/33 of the involved regions (including primaries) (29 and 22 for Ga-DOTATATE and SRS, respectively).

Conclusion: Our study shows that Ga-DOTATATE PET/CT detected similar number of sites than combination of SRS, liver MRI and thoraco-abdominopelvic CT on region-based analysis. Ga-DOTATATE PET/CT missed half of primary lung carcinoids with ectopic Cushing's syndrome.
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http://dx.doi.org/10.1111/cen.13745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450718PMC
August 2018

A combination of lipidomics, MS imaging, and PET scan imaging reveals differences in cerebral activity in rat pups according to the lipid quality of infant formulas.

FASEB J 2018 09 22;32(9):4776-4790. Epub 2018 Mar 22.

Centre de Recherche Cardiovasculaire et Nutritionnelle (C2VN), INSERM, Institut National de la Recherche Agricole (INRA), BioMet, Aix-Marseille University, Marseille, France.

We evaluated the effect of adding docosahexaenoic:arachidonic acids (3:2) (DHA+ARA) to 2 representative commercial infant formulas on brain activity and brain and eye lipids in an artificially reared rat pup model. The formula lipid background was either a pure plant oil blend, or dairy fat with a plant oil blend (1:1). Results at weaning were compared to breast milk-fed pups. Brain functional activity was determined by positron emission tomography scan imaging, the brain and eye fatty acid and lipid composition by targeted and untargeted lipidomics, and DHA brain regional location by mass-spectrometry imaging. The brain functional activity was normalized to controls with DHA+ARA added to the formulas. DHA in both brain and eyes was influenced by formula intake, but more than two-thirds of tissue DHA-glycerolipids remained insensitive to the dietary challenge. However, the DHA lipidome correlated better with brain function than sole DHA content ( r = 0.70 vs. r = 0.48; P < 0.05). Brain DHA regional distribution was more affected by the formula lipid background than the provision of PUFAs. Adding DHA+ARA to formulas alters the DHA content and lipidome of nervous tissue in the neonate, making it closer to dam milk-fed controls, and normalizes brain functional activity.-Aidoud, N., Delplanque, B., Baudry, C., Garcia, C., Moyon, A., Balasse, L., Guillet, B., Antona, C., Darmaun, D., Fraser, K., Ndiaye, S., Leruyet, P., Martin, J.-C. A combination of lipidomics, MS imaging, and PET scan imaging reveals differences in cerebral activity in rat pups according to the lipid quality of infant formulas.
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http://dx.doi.org/10.1096/fj.201800034RDOI Listing
September 2018
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