Publications of François LALLEMAND
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See detailLe médicament anti-angiogénique Sunitinib contrarie le conditionnement ischémique rénal induit par l’irradiation
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Pasal, Rowart ULiege et al

Conference (2021, October 06)

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description ... [more ▼]

Introduction L’irradiation corporelle induit un conditionnement ischémique rénal(CIR) chez la souris. Les mécanismes cellulaires sont méconnus, hormis un possible rôle de la néo-angiogenèse. Description claire et complète de l'expérience Dans cette étude, nous étudions les voies impliquées dans l'irradiation rénale. Ensuite, nous analysons l'impact fonctionnel sur les reins avant ischémie rénale/reperfusion(I/R). Enfin, nous testons si l'inhibition de l'angiogenèse par le Sunitinib empêche le CIR associé à l'irradiation. Méthodes (une explication détaillée de votre analyse est attendue) Exp1. Une irradiation rénale(8Gy) est réalisée chez des C57bl/6 mâles(n=10). Un mois plus tard, l'ARN rénal total est extrait pour un RNAseq comparatif. Exp2. À 7- 14-28 jours post irradiation rénale, les reins droits sont néphrectomisés et les reins gauches subissent une ischémie(30min)/reperfusion(48h) (n=8/timing). Exp3. Suivant le même protocole d'I/R à J14, 3 groupes sont comparés(n=8/groupe) : 1/ irradiation ; 2 /irradiation et gavage au Sunitinib de J2 à J13 ; 3/ groupe témoin sans irradiation ni gavage. Résultats obtenus ou attendus Exp1. RNAseq montre une up-régulation des voies de l'angiogenèse. L’expression de VEGF et CD31 est significativement augmentée au niveau ARNm et protéique dans les reins irradiés. Exp2. Après I/R à J14 post irradiation, les taux sériques d’urée(BUN) et de créatinine(SCr) sont plus faibles chez les souris irradiées par rapport aux témoins(BUN : 86,2±6,8 vs 454,5±27,2 mg/dl ; SCr: 0,1±0,01 vs 1,7±0,2 mg/dl, p<0,01). L'infiltration rénale par les macrophages CD11b(187±32 vs 477±20/mm²) et F4-80(110±22 vs 212±25/mm²) est significativement moindre dans le groupe irradié. L'expression de VEGF et CD31 est majorée dans les reins irradiés à partir de J14. Exp3. Après I/R, les taux sériques de BUN et de SCr dans le groupe irradié-exposé au Sunitinib sont similaires au groupe contrôle(BUN 352,2±54,3 vs. 408,4 ± 54,9 mg/dl ; SCr : 1,5±0,3 vs. 1±0,2 mg/dl). Conclusion L'irradiation rénale induit l'activation de l'angiogenèse chez la souris et est associée à un CIR, avec fonction rénale préservée et inflammation atténuée post I/R. L'exposition au Sunitinib post-irradiation empêche ce CIR. [less ▲]

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See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, August 30)

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the ... [more ▼]

Background: Whole-body irradiation induces renal ischemic preconditioning (RIP) in mice, possibly via neoangiogenesis. Here, we test whether Sunitinib-mediated inhibition of angiogenesis prevents the irradiation-associated RIP. ● Methods: After kidney-centred irradiation (8.56 Gy), the right kidneys were removed and harvested, and the left kidneys underwent ischemia (30min) / reperfusion (48h) (I/R) at Day 14. Three groups were compared (n=8/group): 1/irradiation; 2/irradiation and gavage with Sunitinib (40 mg/kg) from D2 to D13; 3/control group without irradiation or gavage. Renal sections from the 3 groups post-I/R were stained by Periodic Acid Schiff (PAS). I/R-associated acute tubular necrosis was blindly evaluated by a renal pathologist using the histological Jablonski score. The expression of inflammatory markers CD11b and F4/80 was comparatively quantified by immunostaining. The expression of vascular markers CD31 and VEGF in nonischemic kidneys were quantified by real-time qPCR. ● Results: One-way analysis of variance followed by Tukey’s test showed that, following I/R, serum levels of urea (BUN) and creatinine (SCr) were significantly lower in pre-irradiated mice compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), as well as in pre-irradiated mice compared to the irradiated mice fed with Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl). No difference was observed between the Sunitinib group and the control group. Jablonski’s severity score was lower in pre-irradiated mice compared to control group and Sunitinib group (p<0.01). The renal infiltration by CD11b- (560±32 vs. 308±21/mm²) and F4-80 positive cells (430±35 vs. 312±19/mm²) was significantly reduced in the irradiated group compared to controls. At mRNA levels, the renal expression of VEGF and CD31 was increased in the irradiated group but not in the Sunitinib group (p<0.01). ● Conclusions: Renal irradiation before I/R is associated with preserved renal function and attenuated inflammation post I/R. Sunitinib administration prevents the irradiation-induced RIP. [less ▲]

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See detailPhotoperiodic control of singing behavior and reproductive physiology in male fife fancy canaries
Chiver, Ioana ULiege; LALLEMAND, François ULiege; Cornil, Charlotte ULiege et al

Poster (2021, June 29)

Temperate-zone birds often display marked seasonal changes in reproductive behaviors and in the underlying hormonal and neural mechanisms. These changes have been extensively studied in canaries (Serinus ... [more ▼]

Temperate-zone birds often display marked seasonal changes in reproductive behaviors and in the underlying hormonal and neural mechanisms. These changes have been extensively studied in canaries (Serinus canaria) and there is emerging evidence of variation among strains in physiological responses to seasonal cues. Fife fancy male canaries were previously shown to change their reproductive physiology in response to variations in day length but it remained unclear whether they display absolute refractoriness, as Border canaries do, or only display relative refractoriness or simply track day length to control gonadal activity, singing behavior and the associated neural plasticity. Male birds maintained on 8L:16D (SD) for 6 months that had become reproductively competent (high song output and large testes) were divided into two groups: control birds remained on SD and experimental birds were switched to long days (16L:8D). During the following 11 weeks, singing behavior (recorded and quantitatively analyzed for 3X2 hours everyweek) and gonadal size (repeatedly measured by CT X-ray scans) remained similar for birds in both groups except for trill numbers that increased in the experimental group. Prolonged exposure to SD had thus induced a nearly full activation of reproductive physiology and behavior. Day length was then decreased back to 8L:16D for experimental birds which immediately induced a cessation of song, a decrease in testes size and a decrease in the volume of song control nuclei (Area X, HVC, RA). These data demonstrate that Fife fancy canaries sharply respond to changes in photoperiod but only display relative photorefractoriness. [less ▲]

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See detailEffect of renal irradiation in neo-angiogenesis and ischemic preconditioning
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Conference (2021, June 05)

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the ... [more ▼]

Background and Aims: Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method: Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNAs were extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. Fourteen days later, the right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8). Experiment 3: Following the same protocol of renal I/R, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 animals per group): 1/ irradiation 2/ irradiation and gavage with Sunitinib for 14days 3/ control group without irradiation or gavage. All groups undergo an I/R after treatments. Results: Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) shows an increase at both mRNA (real-time qPCR) and protein (immune-staining) levels in irradiated kidneys compared to controls (p<0.01). Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b-positive cells (187±32 vs. 477±20/mm²) and F4-80 macrophages (110±22 vs. 212±25/mm²) was significantly reduced in the irradiated group. The real-time qPCR mRNA levels of the angiogenic markers, TGFb1 and CD31, were significantly increased in the irradiated group compared to controls (p<0,01). The CD31-immunostaining was increased in irradiated group compared to controls (p<0.01). Experiment 3: Following I/R, the serum levels of BUN and SCr were lower in pre-irradiated animals compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). No difference observed between the irradiated-exposed mice to Sunitnib and the controls. Conclusion: Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal irradiation causes ischemic preconditioning, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced nephroprotection against I/R. [less ▲]

Detailed reference viewed: 43 (10 ULiège)
See detailThe irradiation-induced renal ischemic preconditioning is blunted by the oral administration of the anti-angiogenic agent, Sunitinib
Khbouz, Badr ULiege; LALLEMAND, François ULiege; Rowart, Pascal ULiege et al

Poster (2021, May 27)

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys ... [more ▼]

● Objective: Irradiation has been suggested to induce renal ischemic preconditioning (RIP) in mice, possibly via angiogenesis. First, we comprehensively investigate the pathways involved in kidneys-centered irradiation. Next, we assess the functional impact of renal irradiation applied before renal ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the angiogenesis prevents irradiation-associated RIP. ● Methods: Exp1: Renal irradiation (8.56 Gy) was performed in male C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative RNA-Seq. Exp2: After renal irradiation, the right kidneys were removed, and the left kidneys undergo ischemia(30min)/reperfusion(48h) at Days 7-14-28 post irradiation (n=8). Exp3: Following the same protocol of I/R at Day14, 3 groups were compared (n=8): 1/irradiation; 2/irradiation and gavage with Sunitinib from Day2 to 13; 3/control group without irradiation or gavage. ● Results: Exp1: RNA-Seq showed up-regulation of angiogenesis signaling pathways. Expressions of angiogenesis markers (CD31, VEGF) showed an increase at both mRNA and protein levels in irradiated kidneys (p<0.01). Exp2: Following I/R, BUN and SCr levels were lower in the irradiated mice compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p<0.01). The renal infiltration by CD11b (187±32 vs. 477±20/mm²) and F4-80 positive cells (110±22 vs.212±25/mm²) was reduced in the irradiated group. VEGF and CD31, were increased in irradiated kidneys at both mRNA and protein levels (p<0,01). Exp3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, BUN and SCr levels were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p<0.01). ● Conclusions: Kidneys-centered irradiation induces the activation of angiogenesis pathways in mice. Renal irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP. [less ▲]

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See detailLa radiothérapie palliative, c’est aussi notre rayon !
Lamande, Maréva ULiege; Lallemand, François ULiege; BEN MUSTAPHA, Selma ULiege et al

in Revue Médicale de Liège (2021), 76(5-6), 375-379

Radiotherapy (RT), both with a curative and a palliative intent, is one of the cornerstones of oncological treatments. A variety of symptoms linked to cancer can be relieved with RT (such as pain ... [more ▼]

Radiotherapy (RT), both with a curative and a palliative intent, is one of the cornerstones of oncological treatments. A variety of symptoms linked to cancer can be relieved with RT (such as pain, bleeding, compression exerted by a tumour lesion…). Very often, palliative RT is proposed when other medical treatments (painkillers, morphine…) are no longer efficient, or the patient does not tolerate them anymore. Palliative RT is an integral part of the global supportive oncological care. Indeed, patients’ wishes and prognosis are taken into account in each and every step of the treatment pathway. Every treatment deserves an individualized approach and benefits from the best available techniques. [less ▲]

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See detailRôle de l’irradiation dans le préconditionnement ischémique rénal chez la souris
Khbouz, Badr ULiege; Rowart, Pascal ULiege; KRZESINSKI, Jean-Marie ULiege et al

Conference (2020, October 08)

Introduction L’irradiation corporelle chez la souris, a été associée à un conditionnement ischémique rénal. Cependant les mécanismes par lesquels l’irradiation établit ce processus restent inconnus. Dans ... [more ▼]

Introduction L’irradiation corporelle chez la souris, a été associée à un conditionnement ischémique rénal. Cependant les mécanismes par lesquels l’irradiation établit ce processus restent inconnus. Dans cette étude, nous analysons l'impact fonctionnel et fondamental de la radiothérapie centrée sur les reins avant ischémie rénale/reperfusion (I/R) chez la souris. 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 detailRole of irradiation in renal ischemic preconditioning in mice
Khbouz, Badr ULiege; Rowart, Pascal ULiege; LALLEMAND, François ULiege et al

Poster (2020, March 11)

Introduction: Whole-body irradiation has been associated with renal ischemic preconditioning in mice. We investigate the fundamental impact of radiotherapy centered on the kidneys before renal ischemia ... [more ▼]

Introduction: Whole-body irradiation has been associated with renal ischemic preconditioning in mice. We investigate the fundamental impact of radiotherapy centered on the kidneys before renal ischemia-reperfusion(IR). Methods: Experience1: Two beams of X-rays targeted mice kidneys to deliver a 8,56Gy dose. One month later, a right nephrectomy was performed, and a left renal ischemia was induced for 30min. After 48hours of reperfusion, the blood and left kidneys were collected. Controls underwent a similar renal IR procedure, without irradiation. Experience2: Unilateral irradiation of left kidneys(8.56 Gy) was performed on mice. One month later, the left kidneys were collected. Additionally, kidneys were collected from non-irradiated mice. Irradiated and control kidneys were used for comparative RNA-Seq. Illumina and DAVID program were used. Results: Following renal IR, blood urea nitrogen levels were lower in irradiated mice(148.4±93.1) compared to controls(495.7±33.3,p<0.01). The number of PCNA-positives cells was lower in irradiated mice(130.8±52.7) compared to controls(545.4±257.3,p<0.001). The renal infiltration by CD11b-positives cells(90.2±32.2)vs.(414.5±148.6) and F4-80 macrophages(80.6±22.9)vs.(178.5±68) was reduced in irradiated animals. Comparative transcriptomics showed an upregulation of signaling pathways of angiogenesis(HMOX1) and stress response(HSPA1A, HSPA1B) and a downregulation of oxidoreduction(NOX4). Conclusion Kidney irradiation induces ischemic preconditioning in mice, with improved renal function and decreased inflammation following renal IR. The aforementioned signaling pathways may play a role in irradiation-associated kidney resistance to IR. [less ▲]

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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 ▲]

Detailed reference viewed: 66 (24 ULiège)
See detailKidney targeted radiotherapy attenuates the renal ischemia-reperfusion injury in mice
Khbouz, Badr ULiege; Rowart, Pascal ULiege; 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 ▲]

Detailed reference viewed: 69 (22 ULiège)
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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 detailEvaluation of tumor perfusion with IVIM analysis after radiotherapy
LALLEMAND, François ULiege; LEROI, Natacha ULiege; Bahri, Mohamed Ali ULiege et al

Conference (2018, March 14)

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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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