Publications of François LALLEMAND
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See detailLa radiothérapie centrée sur le rein atténue les lésions d'ischémie-reperfusion rénale chez la souris
Khbouz, Badr ULiege; Pascal, Rowart; LALLEMAND, François ULiege et al

Conference (2019, December 04)

Introduction: L'irradiation corporelle engendre un conditionnement ischémique rénal. L’impact fonctionnel et pathophysiologique d’une radiothérapie centrée sur les reins est cependant inconnu. Méthodes ... [more ▼]

Introduction: L'irradiation corporelle engendre un conditionnement ischémique rénal. L’impact fonctionnel et pathophysiologique d’une radiothérapie centrée sur les reins est cependant inconnu. Méthodes: Expérience 1: Sous anesthésie, 2 faisceaux de rayons X (225Kv, 13mA) ciblent spécifiquement les reins pour une dose totale de 8,56Gy. Trente jours plus tard, une néphrectomie droite est réalisée et une ischémie du rein gauche est induite pendant 30min. Après 48h de reperfusion, le rein gauche et le sang sont prélevés (n=6 souris). Un groupe témoin (n=6) subit une I/R rénale similaire sans irradiation préalable. Expérience 2: Une irradiation unilatérale des reins gauches (8,56Gy) est réalisée (n=11). Trente jours plus tard, le rein gauche est prélevé. Le rein gauche de souris non irradiées (n=5) est utilisé comme contrôle. L’ARN des reins irradiés et contrôles est extrait pour une transcriptomique comparative (BaseSpace Illumina; DAVID program). Résultats: À la suite d’une I/R rénale, le taux d’urée était significativement plus bas chez les animaux pré-irradiées (148±93mg/dl), comparativement aux contrôles (496±33, p<0,01). Le nombre de cellules en prolifération (PCNA-positives) était significativement inférieur chez les pré-irradiées par rapport aux témoins (131±53 vs. 545±257/mm², p<0,001). L'infiltration rénale par les cellules CD11b-positives (90±32 vs. 414±149/mm²) et les macrophages F4-80 (81±23 vs 179±68/mm²) était significativement réduite dans le groupe irradié. L’analyse transcriptomique montre une up-régulation des voies de signalisation de l'angiogenèse (Hmox1) et de la réponse au stress (Hspa1a, Hspa1b), et une down-régulation de l'oxydoréduction (Nox4). Conclusion: L'irradiation rénale induit un pré-conditionnement ischémique chez la souris, avec une fonction rénale préservée et une inflammation atténuée après I/R rénale. Les voies de signalisation susmentionnées, modulées lors de l’irradiation, participent probablement à la résistance du rein à l'I/R. [less ▲]

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See detailKidney targeted radiotherapy attenuates the renal ischemia-reperfusion injury in mice
Khbouz, Badr ULiege; Rowart, Pascal; LALLEMAND, François ULiege et al

Poster (2019, November 07)

BACKGROUND Whole-body irradiation has been associated with renal ischemic preconditioning in mice. Here, we investigate the functional and fundamental impact of radiotherapy centered on the kidneys before ... [more ▼]

BACKGROUND Whole-body irradiation has been associated with renal ischemic preconditioning in mice. Here, we investigate the functional and fundamental impact of radiotherapy centered on the kidneys before renal ischemia/reperfusion (I/R) in mice. METHODS Experience1: Animals (n=6) were anesthetized and placed in the irradiator. Two beams of X-rays (225Kv, 13 mA) specifically targeted both kidneys to deliver a dose a 8,56Gy. One month later, a right nephrectomy was performed, and a left renal ischemia was induced for 30min. After 48 hours of reperfusion, the left kidney was collected, as well as blood. Control group (n=6) underwent a similar renal I/R procedure, with no prior irradiation. Experience 2: Unilateral irradiation of the left kidney (8.56 Gy) was performed in mice (n=10). One month later, the left (irradiated) kidney was collected. Additionally, the left kidneys were collected from non-irradiated mice (n=5). Total RNAs were extracted from irradiated and control kidneys to perform comparative high-throughput RNA-Seq. BaseSpace Sequence Hub Illumina was used. Functional enrichment analysis was performed using DAVID program. Both experimental protocols have been approved by the IACUC of ULiège, Liège, Belgium. RESULTS Following kidney I/R, blood urea nitrogen (BUN) levels were significantly lower in pre-irradiated mice (148.4±93.1) compared to controls (495.7±33.3, p<0.01). The number of PCNA-positive proliferating cells was significantly lower in pre-irradiated mice (130.8±52.7) compared to controls (545.4±257.3, p<0.001). The renal infiltration by inflammatory CD11b-positive cells (90.2±32.2 vs. 414.5±148.6) and F4-80-positive macrophages (80.6±22.9 vs. 178.5±68) was significantly reduced in pre-irradiated animals vs. controls. Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B), and a down-regulation of oxidoreduction (NOX4). CONCLUSION Kidney irradiation induces ischemic preconditioning in mice, with improved renal function and decreased inflammation following renal I/R. The aforementioned signaling pathways may play a role in irradiation-associated kidney resistance to I/R. [less ▲]

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See detailKidney-centered radiotherapy attenuates renal ischemia-reperfusion injury in mice
Khbouz, Badr ULiege; Rowart, Pascal ULiege; LALLEMAND, François ULiege et al

Conference (2019, October 11)

Introduction Whole-body irradiation has been associated with renal ischemic preconditioning in mice. Here, we investigate the functional and fundamental impact of radiotherapy centered on the kidneys ... [more ▼]

Introduction Whole-body irradiation has been associated with renal ischemic preconditioning in mice. Here, we investigate the functional and fundamental impact of radiotherapy centered on the kidneys before renal ischemia/reperfusion (I/R) in mice. Materials and Methods Experience1: Animals (n=5) were anesthetized and placed in the irradiator. Two beams of X-rays (225Kv, 13 mA) specifically targeted both kidneys to delivered a dose of 8,56Gy. One month later, a right nephrectomy was performed, and a left renal ischemia was induced for 30min. After 48 hours of reperfusion, the left kidney was collected, as well as blood. Control group (n=6) underwent a similar renal I/R procedure, with no prior irradiation. Experience 2: Unilateral irradiation of left kidneys (8.56 Gy) was performed on mice (N=11). One month later, the left (irradiated) kidney was collected. Additionally, kidneys were collected from non-irradiated mice (N=5). Total RNAs were extracted from irradiated and control kidneys to perform comparative high-throughput RNA-Seq. BaseSpace Sequence Hub Illumina was used. Functional enrichment analysis was performed using DAVID program. Results Following kidney I/R, blood urea nitrogen (BUN) levels were significantly lower in pre-irradiated mice (148.4±93.1) compared to controls (495.7±33.3, p<0.01). The number of PCNA-positive proliferating cells was significantly lower in pre-irradiated mice (130.8±52.7) compared to controls (545.4±257.3, p<0.001). The renal infiltration by inflammatory CD11b-positive cells (90.2±32.2) vs. (414.5±148.6) and F4-80-positive macrophages (80.6±22.9) vs. (178.5±68) was significantly reduced in pre-irradiated animals. Comparative transcriptomics showed a significant up-regulation of signaling pathways involved in angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B), and a down-regulation of oxidoreduction (NOX4). Conclusion Kidney irradiation induces ischemic preconditioning in mice, with improved renal function and decreased inflammation following renal I/R. The aforementioned signaling pathways may play a role in irradiation-associated kidney resistance to I/R. [less ▲]

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See detailTumor modifications recorded with IVIM and DCE-MRI after Neoadjuvant radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2019, April), 133(Supplement 1), 284-285

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor ... [more ▼]

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. We hypothesized anti-cancer treatments (i.e. radiotherapy) modify tumor microenvironment and could potentially impact distant metastases occurrence. Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Leroi et al. Oncotarget 2015). Here, we aim to identify by fMRI noninvasive markers reflecting NeoRT related tumor microenvironment modifications that could predict the best timing for performing surgery and avoiding tumor spreading. Material and Methods To briefly delineate the NeoRT model, MDA-MB 231 tumor cells implanted in the flank of SCID mice were locally irradiated with 2x5Gy when tumor reached 100mm3 and then surgically removed at different time points. We performed fMRI, Diffusion Weighted (DW) and Dynamic Contract enhancement (DCE) – MRI, before RT and every 2 days between RT and surgery. We acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different Bvalue (from 40 to 1000) and B0. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed a T1 mapping with multiple TR and DCE acquisition with 200 repetitions of 3 sec each and gadolinium IV injection after 10 repetitions. We performed semi-quantitative analysis. We validated tumor perfusion by immunochemistry with injection of FITC-dextran IV 3 min before surgery and CD31 labelling. Human Ki67 was used for lung metastases labelling and quantification. Results After the tumor irradiation, we observed a significant and transient increase at day 6 (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modifications. The sham irradiated tumors used as control showed no modifications of all fMRI parameters. At the same timing, 6 days post-radiotherapy, DCE-MRI significantly demonstrated a WhashinSlope (n=13, p<0,05) increase. Immunochemistry confirmed the increase of tumor perfusion when surgery is performed at day 6. The sham irradiated tumors never demonstrated such changes. Finally, when surgery is performed on tumor increased perfusion measured by fMRI, it demonstrated a burst of lung metastasis compared to the other timings. Conclusion We showed a significant difference in perfusion-related parameters with fMRI and immunochemistry at a specific time point after NeoRT. These modifications are correlated with an increase of metastasis spreading related to surgery procedure. These results open new perspectives in the personalized medicine and MRI guided surgery timing after NeoRT. [less ▲]

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See detailTumor microenvironment modifications recorded with IVIM perfusion analysis after radiotherapy.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 1285-1286

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the ... [more ▼]

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some clinical studies demonstrated that the timing of surgery and the RT schedule influence tumor dissemination and subsequently patient overall survival (Acta Oncol 2006). Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Oncotarget 2015). Here, we used functional MRI (fMRI) to record tumor microenvironment modifications after NeoRT. We aim to get non-invasive markers to establish the best timing to perform surgery and avoiding tumor spreading. Material and Methods Based on our NeoRT model, MDA-MB 231 and 4T1 cells were implanted in the flank of SCID and BalbC mice, respectively. We locally irradiated (PXI, X-Rad SmART) tumors with 2x5Gy and then surgically removed at different time points after RT. We acquired fMRI (9,4T Agilent) before and after RT. Diffusion Weighted (DW) - MRI was performed every 2 days between RT and surgery. For each tumor, we acquired 8 slices of 1 mm thickness and 0.5 mm gap with an "in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different B-value (from 40 to 1000) and B0, in the 3 main directions. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results With the MDA-MB 231, we observed a significant and transient increase (60% of the basal value (n=6, p<0,05)) of F and D* parameters related to perfusion. The other parameters of the DW-MRI, ADC and D presented no modification. We observed similar results with 4T1 cells, where F increased at day 3 (55% of the basal value, n=10, p<0,05) then returned to initial level. The difference in timing for the peak of F (day 6 vs day 3) could be related to the difference in tumor growth according to the cell line (four weeks for MDA-MB 231 cells vs one week for 4T1 cells). We also observed a decrease of hypoxia (pimonidazole staining) when surgery was performed on the peak but vascular architecture was not affected. Moreover, performing surgery during F and D* peak, in the MDA-MB 231model, is associated with an increase of lung metastases: 115% and 187% compared to a surgery performed before or after the peak. Conclusion We demonstrated the feasibility of repetitive fMRI imaging in preclinical models after NeoRT. We showed a significant difference in perfusion-related parameters (D* and F) at a specific time point depending of tumor cells correlated with tumor metastases. We demonstrated the feasibility of Image Guided Surgery for decreasing tumor metastases after NeoRT. [less ▲]

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See detailBrain modifications after stereotactic radiotherapy recorded by Functional MRI.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2018, April), 127(Supplement 1), 582

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson ... [more ▼]

Purpose or Objective Brain irradiation is commonly used in malignant diseases (i.e. metastases or Glioblastoma) and in benign diseases (i.e. meningioma, epilepsy, vestibular schwannoma or Parkinson disease). The use of stereotactic radiosurgery (SRS) allows the administration of very high doses in a single fraction (e.g. 120Gy), in a small brain volume. After irradiation, morphological and functional cerebral changes occur depending on the total dose, dose per fraction and the irradiated brain volume. The aim of this work is to use f-MRI to record adult normal brain tissue modification after irradiation with different radiotherapy doses and schedules and to identify new parameters of brain radio-damages. Material and Methods With a dedicated small animal radiotherapy device allowing IGRT (PXI, X-Rad SmART), we specifically irradiated with a 2mm-collimator, mimicking SRS, a small part of adult brain mice (n=72), known to have no impact on vital function, with dose schedules: 1X20Gy, 3X10Gy, 4X5Gy and no RT as control. We imaged brain mice longitudinally with a dedicated 9.4-T MRI (Agilent). Imaging was realized once before as reference level and after irradiation every month for the first 6 months and every 3 months during one year. For each mouse we acquired 14 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. We performed T1-weighted, T2-weighted, T1-mapping, T2-mapping and DW-MRI. For DW-MRI, we performed Fast Spin Echo MultiSlice sequences, with 9 different B-value and B0 (from 20 to 1000). We performed IntraVoxel Incoherent Motion (IVIM) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor). Results Only mice irradiated with 120Gy showed brain modifications in T1 and T2 anatomic images and in T1 mapping, ADC, D and F but no changes were recorded in D* or T2 mapping. All these changes started 5 weeks after SRS and then stabilized after 7 weeks. The mean values for the control group were stable during the 5 months (ADC 0,73μm²/ms; D 0,66μm²/ms; F 4,67%, T1 1,25 sec). For the 120Gy group, values were significantly higher after 5 weeks (Δ = compared to the control group) with ADC 1,66μm²/ms (Δ=151%); D 1,37μm²/ms (Δ=107%); F 18,84% (Δ=303%); T1 1,99 sec (Δ=59%). No specific behaviour changes were observed during all the experiment. Conclusion In this work, we studied normal brain modifications after SRS therapy with anatomical and functional MRI. SRS doses and schedules in this work reflected those used in clinic for tumor treatment or functional SRS. We showed an increase of ADC value 5 weeks after one single dose of 120Gy, compared to normal brain tissue. These results are consistent with radio-necrosis. In addition, we highlighted an increase of IVIM parameters D and F and an increase of T1 mapping in radio-necrosis area. These results increase the numbers of MRI parameters that could be used for following brain damage after radiation. [less ▲]

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See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of Epidermal Growth Factor Receptor Over-Expressing Tumors
Goux, Marine; Becker, Guillaume ULiege; Gorre, Harmony et al

Scientific conference (2018, January 19)

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a ... [more ▼]

In this study, we provide the first report of the use of the Nanofitin scaffold for generating targeted PET radiotracers, using the anti-EGFR B10 Nanofitin as proof-of-concept. 18F-FBEM-Cys-B10 shows a favorable in vivo profile. The posibility to drive Nanofitin molecular recognition capability, over a fast and tunable in vitro selection system could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

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See detailCorrection to: A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes (Nature Immunology, (2017), 18, 12, (1310-1320), 10.1038/ni.3857)
Machiels, Bénédicte ULiege; Dourcy, Mickael ULiege; Xiao, X. et al

in Nature Immunology (2018), 19(9), 1035

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ ... [more ▼]

In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the ‘Data availability’ subsection of the Methods section. The accession code is SRP125477. © 2017, The Author(s). [less ▲]

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See detailNanofitin as a New Molecular-Imaging Agent for the Diagnosis of 2 Epidermal Growth Factor Receptor Over-Expressing Tumors.
Goux, Marine; Becker, Guillaume ULiege; Gorré, Harmony et al

in Bioconjugate Chemistry (2017), 28(9), 2361-2371

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for ... [more ▼]

Epidermal growth-factor receptor (EGFR) is involved in cell growth and proliferation and is over-expressed in malignant tissues. Although anti-EGFR-based immunotherapy became a standard of care for patients with EGFR-positive tumors, this strategy of addressing cancer tumors by targeting EGFR with monoclonal antibodies is less-developed for patient diagnostic and monitoring. Indeed, antibodies exhibit a slow blood clearance, which is detrimental for positron emission tomography (PET) imaging. New molecular probes are proposed to overcome such limitations for patient monitoring, making use of low-molecular-weight protein scaffolds as alternatives to antibodies, such as Nanofitins with better pharmacokinetic profiles. Anti-EGFR Nanofitin B10 was reformatted by genetic engineering to exhibit a unique cysteine moiety at its C-terminus, which allows the development of a fast and site-specific radiolabeling procedure with 18F−4-fluorobenzamido-N-ethylamino-maleimide (18F−FBEM). The in vivo tumor targeting and imaging profile of the anti-EGFR Cys−B10 Nanofitin was investigated in a double-tumor xenograft model by static small-animal PET at 2 h after tail-vein injection of the radiolabeled Nanofitin 18F−FBEM−Cys−B10. The image showed that the EGFR- positive tumor (A431) is clearly delineated in comparison to the EGFR-negative tumor (H520) with a significant tumor-to-background contrast. 18F−FBEM−Cys−B10 demonstrated a significantly higher retention in A431 tumors than in H520 tumors at 2.5 h post-injection with a A431-to-H520 uptake ratio of 2.53 ± 0.18 and a tumor-to-blood ratio of 4.55 ± 0.63. This study provides the first report of Nanofitin scaffold used as a targeted PET radiotracer for in vivo imaging of EGFR-positive tumor, with the anti-EGFR B10 Nanofitin used as proof-of-concept. The fast generation of specific Nanofitins via a fully in vitro selection process, together with the excellent imaging features of the Nanofitin scaffold, could facilitate the development of valuable PET-based companion diagnostics. [less ▲]

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See detailFollowing tumour microenvironment after Neoadjuvant radiotherapy with IVIM perfusion analysis.
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

in Radiotherapy and Oncology (2017, May), 123(Supplement 1), 545

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the ... [more ▼]

Purpose or Objective Neoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. The timing between the end of the NeoRT and surgery is driven by the occurrence of side effects or the tumor downsizing. Some clinical studies demonstrated that the timing of surgery and the RT schedule influence tumor dissemination and subsequently patient overall survival. Previously, we developed a pre-clinical model demonstrating an impact of NeoRT schedule and the timing of surgery on metastatic spreading (Leroi et al. Oncotarget 2015). Here, we evaluate the impact of NeoRT on the tumor microenvironment by functional MRI (fMRI). We aim to identify non-invasive markers allowing to determine the best timing to perform surgery and avoiding tumor spreading. Material and Methods Based on our NeoRT model, MDA-MB 231 and 4T1 cells were implanted in the flank of SCID and BalbC mice, respectively. We locally irradiated tumors with 2x5Gy and then surgically removed at different time points after RT. Diffusion Weighted (DW) -MRI was performed every 2 days between RT and surgery. For each tumors we acquired 8 slices of 1 mm thickness and 0.5 mm gap with an 'in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different B-value (from 40 to 1000) and B0, in the 3 main directions. We performed IVIM (IntraVoxel Incoherent Motion) analysis to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results With the MDA-MB 231, we observed a significant peak of F at day 6 after irradiation, this increasing is about 60% of the basal value (n=6, p<0,05). Moreover, D* parameters (also related to perfusion) increase at the same time. The other parameters of the DW-MRI, ADC and D presented no modification. We observed similar results with 4T1 cells, where F increased at day 3 (about 55%, n=10, p<0,05) then returned to initial level. The difference in timing for the peak of F (day 6 vs day 3) could be related to the difference in tumor growth according to the cell line (four weeks for MDA-MB 231 cells vs one week for 4T1cells). We performed surgery at the time of the F parameter peak in the MDA-MB 231 and we observed a decrease of the metastasic burden compared to surgery performed at day 4 or day 11(absolute number of metastasis 23 VS 1 VS 8 with n=4). Conclusion For the first time, we demonstrate the feasibility of repetitive fMRI imaging in preclinical models after NeoRT. With these models, we show a significant difference in perfusion-related parameters (D* and F) at a specific time point depending of the tumor cells. These modifications are correlated to a decrease of metastasis spreading related to the surgery procedure. These results open new perspectives in the personalized medicine and MRI guided surgery timing after NeoRT. [less ▲]

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See detailAutomated multimodal volume registration based on supervised 3D anatomical landmark detection
Vandaele, Rémy ULiege; LALLEMAND, François ULiege; MARTINIVE, Philippe ULiege et al

in SCITEPRESS Digital Library (2017)

We propose a new method for automatic 3D multimodal registration based on anatomical landmark detection. Landmark detectors are learned independantly in the two imaging modalities using Extremely ... [more ▼]

We propose a new method for automatic 3D multimodal registration based on anatomical landmark detection. Landmark detectors are learned independantly in the two imaging modalities using Extremely Randomized Trees and multi-resolution voxel windows. A least-squares fitting algorithm is then used for rigid registration based on the landmark positions as predicted by these detectors in the two imaging modalities. Experiments are carried out with this method on a dataset of pelvis CT and CBCT scans related to 45 patients. On this dataset, our fully automatic approach yields results very competitive with respect to a manually assisted state-of-the-art rigid registration algorithm. [less ▲]

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See detailCXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone.
Goffart, Nicolas ULiege; Lombard, Arnaud; Lallemand, François ULiege et al

in Neuro-Oncology (2017), 19(1), 66-77

BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that ... [more ▼]

BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse. [less ▲]

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See detailA gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes.
Machiels, Bénédicte ULiege; Dourcy, Mickael ULiege; Xiao, Xue ULiege et al

in Nature Immunology (2017)

The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we ... [more ▼]

The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection. [less ▲]

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See detailNew role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity
Henry, Aurélie ULiege; Nokin, Marie-Julie ULiege; Leroi, Natacha ULiege et al

in Oncotarget (2016)

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness ... [more ▼]

Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was signi cantly decreased in OPN-de cient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a signi cant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further con rming its major role in GBM aggressive disease. [less ▲]

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See detailCXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone
Goffart, Nicolas; LOMBARD, Arnaud ULiege; Dedobbeleer, Matthias ULiege et al

in Neuro-Oncology (2016)

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months despite multimodal therapy, due to systematic relapses. We previously demonstrated that GBM-initiating cells (GIC ... [more ▼]

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months despite multimodal therapy, due to systematic relapses. We previously demonstrated that GBM-initiating cells (GIC) are able to escape the tumor mass and specifically colonize the sub-ventricular zone (SVZ) after experimental striatal xenotransplantation. Using the same approach, we demonstrated in vivo a higher survival rate of SVZ-nested GIC after irradiation and investigated the pathway implied. [less ▲]

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See detailImpacts of Ionizing Radiation on the Different Compartments of the Tumor Microenvironment
Leroi, Natacha ULiege; LALLEMAND, François ULiege; COUCKE, Philippe ULiege et al

in Frontiers in Pharmacology (2016), 7

During the last decade, the initial cancer cell-centered view of tumors has greatly evolved to an integrated vision of tumor biology taking into account the key contribution of the TME. Obviously, the ... [more ▼]

During the last decade, the initial cancer cell-centered view of tumors has greatly evolved to an integrated vision of tumor biology taking into account the key contribution of the TME. Obviously, the different compartments of TME are closely related and contribute not only to tumor progression, but also to its response to treatments. Importantly, the TME evolves over time during the different steps of cancer development and is also affected by different therapeutic modalities. Although, improvements have been achieved regarding RT delivery to the primary tumor, ionizing radiation also target nontumor cells that influence tumor growth and metastatic dissemination. Different approaches have been proposed to overcome the radioresistance of cancer cells. The TME-mediated radioresistance is now the object of researches, which has been elegantly reviewed recently by Barker et al. (2015) and severalarticles pointed out the importance of treatments that modify the TME and likely radiosensitize tumor (Ansiaux et al., 2005; Crokart et al., 2005b; Frérart et al., 2008). However, the impact of anti-cancer treatments on the TME and consequently on the tumor phenotype, response to treatment and metastases, is often neglected. Here we pointed out the impact of RT on the TME. Recent findings emphasize the interest to optimize RT (i.e., dose per fraction) and timing of surgery (Leroi et al., 2015; Surace et al., 2015) in order to prevent metastatic spreading. The future challenge in RT will be to define the most appropriate combinations between RT, and other therapeutic modalities with the optimal sequence and timing of treatments. In this context, investigation of the TME-related acquired resistance will be essential and will provide important innovative data. [less ▲]

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See detailFeasibility study of repetitive diffusion MRI after Neoadjuvant radiotherapy for following tumor microenvironment.
LALLEMAND, François ULiege; Leroi, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

Conference (2016, March 22)

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence ... [more ▼]

Purpose/Objective. Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery is mostly driven by the occurrence of side effects or the tumor downsizing. We previously demonstrated in an in vivo model that the timing of surgery and the schedule of NeoRT influenced the tumor dissemination. Here, our aim is to evaluate with functional MRI (fMRI) the impact of the radiation treatment on the tumor microenvironment and subsequently to identify non-invasive markers helping to determine the best timing to perform surgery for avoiding tumor spreading. First, we needed to demonstrate the feasibility of repetitive MRI imaging after NeoRT in mice. Material/methods. We used two models of NeoRT we previously developed in mice: MDA-MB 231 and 4T1 cells implanted in the flank of mice. When tumors reached the planned volume, they are irradiated with 2x5 Gy and then surgically removed at different time points after RT. In the mean time between the end of RT and the surgical procedure, mice were imaged in a 9,4T Agilent® MRI. Diffusion Weighted (DW) -MRI was performed every 2 days between RT and surgery. For each tumors we acquired 8 slices of 1 mm thickness and 0.5 mm gap with an “in plane voxel resolution” of 0.5 mm. For DW-MRI, we performed FSEMS (Fast Spin Echo MultiSlice) sequences, with 9 different B-values (from 40 to 1000) and B0, in the 3 main directions. We also performed IVIM (IntraVoxel Incoherent Motion) analysis, in the aim to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. Results. As preliminary results, with the MBA-MB 231 we observed a significant increase of F at day 6 after irradiation than a decrease and stabilization until surgery. No other modifications of the MRI signal, ADC, D or D* were observed. We observed similar results with 4T1 cells, F increased at day 3 than returned to initial signal. The difference in the timing of the peak of F can be related to the difference in tumor growth between MBA-MB 231 and 4T1 (four weeks vs one week). Conclusion. For the first time, we demonstrate the feasibility of repetitive fMRI imaging in mice models after NeoRT. With these models, we show a significant peak of the perfusion factor (F) at day 6 or day 3. This change occurs between the two previous time points of surgery demonstrating a difference in the metastatic spreading. Indeed, after a NeoRT of 2X5Gy we observed more metastases in the lung when MDA-MB 231 tumor bearing mice are operated 4 days after RT compared to 11 days. These preliminary results are very promising for identifying noninvasive markers for determining the best timing for surgery. [less ▲]

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See detailOsteopontin predicts radiotherapy response of glioblastoma patients : new role in DNA damage repair
Henry, Aurélie ULiege; Nokin, Marie-Julie ULiege; Leroi, Natacha ULiege et al

Conference (2016, March 22)

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These ... [more ▼]

- Introduction: Glioblastoma (GBM) is the most aggressive and common solid human brain tumor. Because of GBM heterogeneity, location and aggressiveness, none of the available treatment is curative. These treatments include maximal surgical resection, radiotherapy and concomitant or adjuvant chemotherapy with Temozolomide. However, the prognosis of adult patients with GBM remains poor and the survival outcome after treatment does not exceed 15 months. GBM-composing cells have developed many strategies to counteract these current therapies. Among the wide hallmarks acquired to survive, high osteopontin (OPN) expression correlates with lower overall and disease-free/relapse-free survival in all tumors combined, as well in brain cancer. Our recent study (Lamour V and Henry A, IJC 2015) has demonstrated the role of OPN in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem characters. In the continuation of this work, our recent studies focused on the potential role of OPN in the resistance of GBM cells to radiotherapy and its potential implication in the initiation of Double Strand Breaks (DSBs) repair mechanisms. - Aims: In the context of this study, different GBM cell lines (U251-MG, U87-MG and U87 Viii) were used to assess the role of OPN in the initiation of the DSBs repair mechanism after an exposure to gamma-irradiation. - Methods and results: We performed the transient transfection of different GBM cell lines (U251-MG, U87-MG and U87-MG overexpressing EGFR VIII) with siRNAs specifically directed against OPN. After irradiation, all these OPN-depleted cells consistently showed a lower induction of γ–H2AX compared to control (irrelevant siRNA) as evidenced by western blot and immunofluorescence techniques. Thereafter, clonogenic assays allowed to prove that the survival of OPN-depleted cells was affected after an exposure to irradiation. To assess the importance of OPN expression in the response to radiotherapy, an heterotopic xenograft model was used. In brief, IPTG-inducible U87 shOPN clones were injected subcutaneously in NOD-SCID mice and were allowed to form a tumor. When average tumor volume reached a predetermined size range, mice were treated (or not) with IPTG by intraperitoneal injection during five days. At the end of the treatment, tumors were selectively exposed to gamma-irradiation by using a small animal irradiator X-RAD 225Cx (Precision X-Ray Inc., North Branford, CT). One week later, mice were sacrificed and tumors were measured. In this pilot study, we observed that mice in which the tumor was depleted in OPN displayed a slight regression in the tumor growth compared to mice that received radiotherapy alone (no IPTG), where the tumor volume remained constant. - Conclusions: Taken together, these preliminary data meet the fact that OPN is important in the response of GBM to radiotherapy. The in vitro results converge to the fact that OPN might be implicated in the initiation of the DSBs repair following irradiation. Currently, we would like to investigate this hypothesis in vivo but also to check the effect of OPN depletion combined to radiotherapy on the survival of mice in an orthotopic xenograft model. [less ▲]

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