144 results on '"M. Marien"'
Search Results
2. Supplementary Fig 1 from Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer
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Zineb Mounir, Mark R. Lackner, Shih-Min A. Huang, Yannick Waumans, Mark Kockx, Koen M. Marien, Sarah Lynagh, Paul R. McAdam, Max Bylesjo, Adrian R. Carr, Daniel L. Halligan, Sanjeev Mariathasan, Edward E. Kadel, Kobe C. Yuen, Thomas Holcomb, Shrividhya Srinivasan, Joseph Castillo, and Marie-Claire Wagle
- Abstract
TMB, TFB and CRPC scores across individual samples and disease stages and crosscorrelation analyses
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- 2023
3. Data from Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer
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Zineb Mounir, Mark R. Lackner, Shih-Min A. Huang, Yannick Waumans, Mark Kockx, Koen M. Marien, Sarah Lynagh, Paul R. McAdam, Max Bylesjo, Adrian R. Carr, Daniel L. Halligan, Sanjeev Mariathasan, Edward E. Kadel, Kobe C. Yuen, Thomas Holcomb, Shrividhya Srinivasan, Joseph Castillo, and Marie-Claire Wagle
- Abstract
Prostate cancer is the second leading cause of cancer-related death in men. Despite having a relatively lower tumor mutational burden than most tumor types, multiple gene fusions such as TMPRSS2:ERG have been characterized and linked to more aggressive disease. Individual tumor samples have been found to contain multiple fusions, and it remains unknown whether these fusions increase tumor immunogenicity. Here, we investigated the role of fusion burden on the prevalence and expression of key molecular and immune effectors in prostate cancer tissue specimens that represented the different stages of disease progression and androgen sensitivity, including hormone-sensitive and castration-resistant prostate cancer. We found that tumor fusion burden was inversely correlated with tumor mutational burden and not associated with disease stage. High fusion burden correlated with high immune infiltration, PD-L1 expression on immune cells, and immune signatures, representing activation of T cells and M1 macrophages. High fusion burden inversely correlated with immune-suppressive signatures. Our findings suggest that high tumor fusion burden may be a more appropriate biomarker than tumor mutational burden in prostate cancer, as it more closely associates with immunogenicity, and suggests that tumors with high fusion burden could be potential candidates for immunotherapeutic agents.
- Published
- 2023
4. AutoTag and AutoSnap: Standardized, semi-automatic capture of regions of interest from whole slide images
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Koen M. Marien, Luc Andries, Stefanie De Schepper, Mark M. Kockx, and Guido R.Y. De Meyer
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AutoTag and AutoSnap ,Science - Abstract
Tumor angiogenesis is measured by counting microvessels in tissue sections at high power magnification as a potential prognostic or predictive biomarker. Until now, regions of interest1 1 ROI: region of interest. (ROIs) were selected by manual operations within a tumor by using a systematic uniform random sampling 2 SURS: systematic, uniform random sampling. (SURS) approach. Although SURS is the most reliable sampling method, it implies a high workload. However, SURS can be semi-automated and in this way contribute to the development of a validated quantification method for microvessel counting in the clinical setting. Here, we report a method to use semi-automated SURS for microvessel counting: • Whole slide imaging with Pannoramic SCAN (3DHISTECH) • Computer-assisted sampling in Pannoramic Viewer (3DHISTECH) extended by two self-written AutoHotkey applications (AutoTag and AutoSnap) • The use of digital grids in Photoshop® and Bridge® (Adobe Systems) This rapid procedure allows traceability essential for high throughput protein analysis of immunohistochemically stained tissue.
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- 2015
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5. Development and Validation of a Histological Method to Measure Microvessel Density in Whole-Slide Images of Cancer Tissue.
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Koen M Marien, Valerie Croons, Yannick Waumans, Ellen Sluydts, Stefanie De Schepper, Luc Andries, Wim Waelput, Erik Fransen, Peter B Vermeulen, Mark M Kockx, and Guido R Y De Meyer
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Medicine ,Science - Abstract
Despite all efforts made to develop predictive biomarkers for antiangiogenic therapies, no unambiguous markers have been identified so far. This is due to among others the lack of standardized tests. This study presents an improved microvessel density quantification method in tumor tissue based on stereological principles and using whole-slide images. Vessels in tissue sections of different cancer types were stained for CD31 by an automated and validated immunohistochemical staining method. The stained slides were digitized with a digital slide scanner. Systematic, uniform, random sampling of the regions of interest on the whole-slide images was performed semi-automatically with the previously published applications AutoTag and AutoSnap. Subsequently, an unbiased counting grid was combined with the images generated with these scripts. Up to six independent observers counted microvessels in up to four cancer types: colorectal carcinoma, glioblastoma multiforme, ovarian carcinoma and renal cell carcinoma. At first, inter-observer variability was found to be unacceptable. However, after a series of consensus training sessions and interim statistical analysis, counting rules were modified and inter-observer concordance improved considerably. Every CD31-positive object was counted, with exclusion of suspected CD31-positive monocytes, macrophages and tumor cells. Furthermore, if interconnected, stained objects were considered a single vessel. Ten regions of interest were sufficient for accurate microvessel density measurements. Intra-observer and inter-observer variability were low (intraclass correlation coefficient > 0.7) if the observers were adequately trained.
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- 2016
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6. Synergistic effect of a combination of nicarbazin and monensin against coccidiosis in the chicken caused by Eimeria spp
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M Marien, K De Gussem, Monita Vereecken, A C Berge, B. Dehaeck, and M Geerinckx
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Veterinary medicine ,General Immunology and Microbiology ,biology ,040301 veterinary sciences ,Monensin ,0402 animal and dairy science ,04 agricultural and veterinary sciences ,biology.organism_classification ,medicine.disease ,040201 dairy & animal science ,Eimeria ,0403 veterinary science ,Clinical study ,Eimeria acervulina ,chemistry.chemical_compound ,Coccidiosis ,Food Animals ,chemistry ,Nicarbazin ,medicine ,Animal Science and Zoology - Abstract
A clinical study was made into the abilities of nicarbazin and monensin and a nicarbazin + monensin combination to control Eimeria acervulina, E. maxima, and E. tenella in chickens. When included i...
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- 2020
7. The Relationship Between Tumor-Infiltrating Lymphocytes, PD-L1 Expression, Driver Mutations and Clinical Outcome Parameters in Non-Small Cell Lung Cancer Adenocarcinoma in Patients with a Limited to no Smoking History
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Lore Decoster, Erik Teugels, Sacha Mignon, Johan Vansteenkiste, Karen Willard-Gallo, Gert Van den Eynden, Roberto Salgado, Koen M. Marien, Jacques De Greve, Internal Medicine, Faculty of Medicine and Pharmacy, Medical Oncology, Laboratory for Medical and Molecular Oncology, Clinical sciences, and Medical Genetics
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Stromal cell ,H&E stain ,Adenocarcinoma of Lung ,medicine.disease_cause ,B7-H1 Antigen ,Disease-Free Survival ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Aged ,Lung ,Tumor-infiltrating lymphocytes ,business.industry ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Adenocarcinoma ,Immunohistochemistry ,Female ,Human medicine ,KRAS ,business - Abstract
Tumor infiltrating lymphocytes (TIL), programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression are important prognostic markers. This study aimed to investigate these markers in lung adenocarcinoma (ADC) biopsies from patients with stage IIIB or IV ADC with little or no smoking history, to investigate their prognostic value and to correlate these results with the presence of driver mutations in the tumors. TIL were retrospectively evaluated on hematoxylin and eosin stained slides from 152 tumor samples. PD-1/PD-L1 expression was retrospectively evaluated with PD-1/PD-L1 immunohistochemistry (IHC) double staining on 74 tumor samples with sufficient residual tissue. PD-L1 expression was analysed on stromal cells of the tumor compartment, the tumor cells and TIL and PD-1 on TIL. Median overall survival (OS) was longer in patients with high stromal TIL infiltration compared to patients with low stromal TIL infiltration (68 weeks vs. 35 weeks respectively; p = 0.003). This was observed most prominently in KRAS mutant tumors (95 weeks vs. 12 weeks; p = 0.003). Only PD-L1 expression on tumor stromal cells influenced OS and indicated a worse prognosis (77 weeks vs 25 weeks; p = 0.013). Stromal TIL counts nor PD-1/PD-L1 expression levels were associated with the presence of driver mutations. The results of the current study reinforce the prognostic role of TIL in lung ADC, which is most prominent in KRAS mutant cancers. The results of the PD-1/PD-L1 analysis suggest that stromal cells can effectively suppress the anti-tumor immune response via the PD-L1 pathway.
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- 2019
8. Stromal marker fibroblast activation protein drives outcome in T1 non-muscle invasive bladder cancer
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Koen M. Marien, Yannick Waumans, Thomas Gevaert, Tim Muilwijk, Thomas Van den Broeck, Frank Van der Aa, Mark M. Kockx, Murat Akand, Steven Joniau, Loïc Baekelandt, and Sofie Daelemans
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Male ,Oncology ,Kaplan-Meier Estimate ,Disease ,Biochemistry ,Basal (phylogenetics) ,Fibroblast activation protein, alpha ,Animal Cells ,Medicine and Health Sciences ,Genitourinary Cancers ,Medicine ,Connective Tissue Cells ,Multidisciplinary ,GATA3 ,Middle Aged ,Prognosis ,Bladder Cancer ,Progression-Free Survival ,Ovarian Cancer ,Chemistry ,Treatment Outcome ,Connective Tissue ,Disease Progression ,Female ,Cellular Types ,Anatomy ,Research Article ,Risk ,medicine.medical_specialty ,Stromal cell ,Urology ,Science ,Malignant Tumors ,Internal medicine ,Gastrointestinal Tumors ,Biomarkers, Tumor ,Humans ,Biology ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Colorectal Cancer ,Carcinoma, Transitional Cell ,Bladder cancer ,business.industry ,Surrogate endpoint ,Cancers and Neoplasms ,Biology and Life Sciences ,Cell Biology ,Fibroblasts ,medicine.disease ,Genitourinary Tract Tumors ,Gastric Cancer ,Biological Tissue ,Urinary Bladder Neoplasms ,Human medicine ,Neoplasm Recurrence, Local ,business ,Ovarian cancer ,Gynecological Tumors ,Software ,Biomarkers - Abstract
Fibroblast activation protein-α (FAP) is a transmembrane peptidase and a surrogate marker for cancer-associated fibroblasts (CAFs). FAP has been linked to worse prognosis and therapy resistance in several cancers. We hypothesised that FAP might have a prognostic 3biomarker potential to stratify patients with high-grade (HG) T1 non-muscle-invasive bladder cancer (NMIBC). We selected 30 patients with HG T1 NMIBC that progressed to ≥T2 disease which were pair-matched based on CUETO progression score variables with 90 patients that did not progress. After revision a final cohort of 86 patients was retained. Slides were stained for FAP, the luminal marker GATA3 and the basal marker CK5. All HG T1 tumour regions of interest (ROIs) within each patient were annotated, analysed and scored using image analysis software. FAP expression in HG T1 ROIs was significantly higher in progressors vs. non-progressors and was prognostic for recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival. FAP expression in HG T1 ROIs remained strongly prognostic for these outcomes in a bivariable model corrected for adequate BCG per FDA definition. Expression of GATA3 and CK5 did not differ between progressors vs. non-progressors, and were not prognostic for these outcomes. FAP might serve as an easily applicable prognostic biomarker to risk-stratify patients with HG T1 NMIBC if these results are prospectively validated in a larger series. ispartof: PLOS ONE vol:16 issue:9 ispartof: location:United States status: published
- Published
- 2021
9. Abstract P4-06-08: The spatial localization of immune cells predicts prognosis and response to therapy in inflammatory breast cancer
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Mark M. Kockx, S. Van Laere, Yannick Waumans, C. Rypens, Koen M. Marien, C. Van Berckelaer, C Colpaert, P. van Dam, L.Y. Dirix, and Peter B. Vermeulen
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Cancer Research ,Immune system ,Oncology ,Response to therapy ,business.industry ,Cancer research ,Medicine ,Spatial localization ,business ,medicine.disease ,Inflammatory breast cancer - Abstract
Introduction The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are still under investigation. Our lab reported a 79-gene signature that is shaped by specific immune response programs and discriminates between IBC and non-IBC (nIBC). Furthermore, the presence of cytotoxic CD8+ immune cells is associated with a better prognosis in proliferative subtypes of breast cancer. However, not only the presence of CD8+ cells, but also the interaction with other immune cells plays a role in the functional immune response. In this study we assessed the spatial associations between immune cells in IBC. Methodology Affymetrix gene expression data of 105 IBC patients were analyzed using CIBERSORT and xCell modules to narrow down the number of stainings for the immunophenotyping. To analyze the composition of the immune infiltrate, we used five validated antibodies: CD79α (B-cell lineage), CD8 (cytotoxic T-cells), FOXP3 (Tregs), CD163 (Tumor associated macrophages, TAMs) and the SP142 PDL1 antibody. A standard H&E stained section was used to mark the tumor area on pretreatment biopsy sections. Subsequently, 5 slides were stained according to a validated protocol, scanned and evaluated using VISIOPHARM® software that makes virtual multiplexing possible after the alignment of the scanned images. Using both point pattern analysis and the Morisita–Horn index (MHI), developed for ecological studies, we assessed the co-localization of the different types of immune cells. Currently, we report the result of our validation cohort (30 patient samples). Results Most of our IBC patients presented with a hormone receptor positive carcinoma (64.7%). Almost a quarter of the patients (23.3%) with initially localized disease achieved complete pathological response (pCR) after neo-adjuvant chemotherapy (NACT). For every staining we report the median relative marker area (RMA), MHI for colocalization with CD8 applying a square tessellation of 100 μm and the number of cells in a radius of 30 μm around CD8+ cells (direct cell-cell contact) in table 1. RMAMHI # X+ cells (30 μm)CD80.33 % CD1630.12 %0.7213.13CD79α0.04 %0.6522.52FOXP30.01 %0.7011.37PDL1 0.7460.70Table 1: Median spatial properties. The RMA of CD8 predicted pCR after NACT (RMA= 1.07% pCR vs 0.35% no pCR, P=0.04), but was not prognostic for OS (P= 0.445). PDL1 positivity predicted neither pCR nor OS in this cohort. However, OS of patients with more PDL1+ cells ( > 0.703) in close contact with the CD8+ cells was significantly shorter (5y OS: 50% vs 68%, P= 0.03). Interestingly, the colocalization of CD8+ cells with TAMs (MHI= 0.69 no pCR vs. 0.75 pCR, P= 0.04) and CD79α+ B-cells (MHI= 0.63 no pCR vs. 0.69 pCR, P= 0.04) was also associated with pCR after NACT, while the number of CD163+ or CD79α+ cells was not. Conclusion In this study we described the dynamic interplay between cancer and immune cells. In a validation cohort of 30 patient samples we showed that the colocalization of TAMs or B-cells with cytotoxic T cells was associated with pCR after NACT. Furthermore, patients with more PDL1+ cells around CD8+ cells (r= 30 μm) had a worse prognosis while solely the number of PDL1+ or CD8+ cells was not prognostic. By December we will present data on 179 IBC patients. Citation Format: Van Berckelaer C, Colpaert C, Rypens C, Marien KM, Waumans Y, Kockx M, Vermeulen P, Dirix L, Van Laere S, Van Dam P. The spatial localization of immune cells predicts prognosis and response to therapy in inflammatory breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-08.
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- 2019
10. Newer agents for blood glucose control in type 2 diabetes: systematic review and economic evaluation
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N Waugh, E Cummins, P Royle, C Clar, M Marien, B Richter, and S Philip
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blood glucose ,control ,type 2 diabetes ,newer agents ,systematic review ,economic evaluation ,sitagliptin ,vildagliptin ,Medical technology ,R855-855.5 - Abstract
Background: In May 2008, the National Institute for Health and Clinical Excellence (NICE) issued an updated guideline [clinical guideline (CG) 66] for the management of all aspects of type 2 diabetes. This report aims to provide information on new drug developments to support a ‘new drugs update’ to the 2008 guideline. Objective: To review the newer agents available for blood glucose control in type 2 diabetes from four classes: the glucagon-like peptide-1 (GLP-1) analogue exenatide; dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin; the long-acting insulin analogues, glargine and detemir; and to review concerns about the safety of the thiazolidinediones. Data sources: The following databases were searched: MEDLINE (1990–April 2008), EMBASE (1990–April 2008), the Cochrane Library (all sections) Issue 2, 2008, and the Science Citation Index and ISI Proceedings (2000–April 2008). The websites of the American Diabetes Association, the European Association for the Study of Diabetes, the US Food and Drug Administration, the European Medicines Evaluation Agency and the Medicines and Healthcare Products Regulatory Agency were searched, as were manufacturers’ websites. Review methods: Data extraction was carried out by one person, and checked by a second. Studies were assessed for quality using standard methods for reviews of trials. Meta-analyses were carried out using the Cochrane Review Manager (revman) software. Inclusion and exclusion criteria were based on current standard clinical practice in the UK, as outlined in NICE CG 66. The outcomes for the GLP-1 analogues, DPP-4 inhibitors and the long-acting insulin analogues were: glycaemic control, reflected by glycated haemoglobin (HbA1c) level, hypoglycaemic episodes, changes in weight, adverse events, quality of life and costs. Modelling of the cost-effectiveness of the various regimes used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model. Results: Exenatide improved glycaemic control by around 1%, and had the added benefit of weight loss. The gliptins were effective in improving glycaemic control, reducing HbA1c level by about 0.8%. Glargine and detemir were equivalent to Neutral Protamine Hagedorn (NPH) (and to each other) in terms of glycaemic control but had modest advantages in terms of hypoglycaemia, especially nocturnal. Detemir, used only once daily, appeared to cause slightly less weight gain than glargine. The glitazones appeared to have similar effectiveness in controlling hyperglycaemia. Both can cause heart failure and fractures, but rosiglitazone appears to slightly increase the risk of cardiovascular events whereas pioglitazone reduces it. Eight trials examined the benefits of adding pioglitazone to an insulin regimen; in our meta-analysis, the mean reduction in HbA1c level was 0.54% [95% confidence interval (CI) –0.70 to –0.38] and hypoglycaemia was marginally more frequent in the pioglitazone arms [relative risk (RR) 1.27, 95% CI 0.99 to 1.63]. In most studies, those on pioglitazone gained more weight than those who were not. In terms of annual drug acquisition costs among the non-insulin regimes for a representative patient with a body mass index of around 30 kg/m2, the gliptins were the cheapest of the new drugs, with costs of between £386 and £460. The glitazone costs were similar, with total annual costs for pioglitazone and for rosiglitazone of around £437 and £482, respectively. Exenatide was more expensive, with an annual cost of around £830. Regimens containing insulin fell between the gliptins and exenatide in terms of their direct costs, with a NPH-based regimen having an annual cost of around £468 for the representative patient, whereas the glargine and detemir regimens were more expensive, at around £634 and £716, respectively. Comparisons of sitagliptin and rosiglitazone, and of vidagliptin and pioglitazone slowed clinical equivalence in terms of quality-adjusted life-years (QALYs), but the gliptins were marginally less costly. Exenatide, when compared with glargine, appeared to be cost-effective. Comparing glargine with NPH showed an additional anticipated cost of around £1800. Within the comparison of detemir and NPH, the overall treatment costs for detemir were slightly higher, at between £2700 and £2600. Limitations: The UKPDS Outcomes Model does not directly address aspects of the treatments under consideration, for example the direct utility effects from weight loss or weight gain, severe hypoglycaemic events and the fear of severe hypoglycaemic events. Also, small differences in QALYs among the drugs lead to fluctuations in incremental cost-effectiveness ratios. Conclusions: Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful.
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- 2010
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11. Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer
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Mark M. Kockx, Edward E. Kadel, Max Bylesjö, Shrividhya Srinivasan, Shih-Min A. Huang, Daniel L. Halligan, Koen M. Marien, Kobe C. Yuen, Sanjeev Mariathasan, Zineb Mounir, Joseph Castillo, Yannick Waumans, Paul R. McAdam, Sarah Lynagh, Adrian R. Carr, Thomas Holcomb, Mark R. Lackner, and Marie-Claire Wagle
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Immunology ,Disease ,TMPRSS2 ,B7-H1 Antigen ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Immune system ,Lymphocytes, Tumor-Infiltrating ,Biomarkers, Tumor ,Medicine ,Humans ,Oncogene Fusion ,RNA-Seq ,Neoplasm Staging ,Regulation of gene expression ,business.industry ,Immunogenicity ,Macrophages ,Prostatic Neoplasms ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Biomarker (medicine) ,Neoplasm Grading ,business - Abstract
Prostate cancer is the second leading cause of cancer-related death in men. Despite having a relatively lower tumor mutational burden than most tumor types, multiple gene fusions such as TMPRSS2:ERG have been characterized and linked to more aggressive disease. Individual tumor samples have been found to contain multiple fusions, and it remains unknown whether these fusions increase tumor immunogenicity. Here, we investigated the role of fusion burden on the prevalence and expression of key molecular and immune effectors in prostate cancer tissue specimens that represented the different stages of disease progression and androgen sensitivity, including hormone-sensitive and castration-resistant prostate cancer. We found that tumor fusion burden was inversely correlated with tumor mutational burden and not associated with disease stage. High fusion burden correlated with high immune infiltration, PD-L1 expression on immune cells, and immune signatures, representing activation of T cells and M1 macrophages. High fusion burden inversely correlated with immune-suppressive signatures. Our findings suggest that high tumor fusion burden may be a more appropriate biomarker than tumor mutational burden in prostate cancer, as it more closely associates with immunogenicity, and suggests that tumors with high fusion burden could be potential candidates for immunotherapeutic agents.
- Published
- 2019
12. The spatial localization of CD163+ tumor-associated macrophages predicts prognosis and response to therapy in inflammatory breast cancer
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Steven Van Laere, Mark M. Kockx, Peter B. Vermeulen, Peter van Dam, Cecile Colpaert, Peter A. van Dam, Koen M. Marien, Christophe Van Berckelaer, C. Rypens, and Luc Dirix
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Cancer Research ,Oncology ,Response to therapy ,business.industry ,Cancer research ,Medicine ,Spatial localization ,skin and connective tissue diseases ,business ,medicine.disease ,Acquired immune system ,Inflammatory breast cancer ,CD163 - Abstract
3086 Background: The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are under investigation. A specific immune response seems to be an important driver, but the functional role of infiltrating immune cells in IBC remains unclear. Tumor-associated macrophages (TAMs) are associated with worse outcome, while CD8+ cytotoxic T cells demonstrate anti-tumor properties in breast cancer. In this study, we assessed spatial associations between CD163+ TAMs, CD8+ cells and cancer cells in IBC, using deep-learning and ecological statistics. Methods: We collected clinicopathological variables, evaluated PDL1-positivity (SP142, Ventana) and scored TILs according to the TIL working group guidelines on H&E slides for 144 IBC patients. Immunostainings for CD8 and CD163 (Hematoxylin-DAB) were done according to validated protocols. All slides were digitized, underwent virtual multiplexing and were evaluated in Visiopharm to quantify the number of DAB+ immune cells. Each immune cell was located using XY coordinates and spatial interactions were examined using a Morisita Horn Index (MHI). Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8-stained slide. This algorithm was trained in 18 images with more than 150.000 iterations (Deeplabv3+). Results: Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 30.6% (n= 30/98) of the patients with initially localized disease. Besides PDL1-postivity ( P= .03), infiltration with CD8+ T cells ( P= .02) and TAMs ( P= .01) also predicted pCR. However, a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, the colocalization of CD163+ and CD8+ cells (MHI >0.83) was associated with pCR (P= .01) and remained significant in a multivariate model (OR: 3.18; 95% CI: 1.04 – 10.6; P= .05) including TIL score, PDL1-positivity and hormone receptor (HR) status. Furthermore, a shorter disease-free survival (DFS) was associated with HR- status, no pCR and the colocalization of TAMs near tumor cells (HR: 3.3; 95% CI: 1.6 – 7.1; P= .002) in a multivariate model. The density of TAMs was not associated with outcome. Conclusions: The impact of TAMs on clinical outcome appears to depend on the spatial arrangement. The number of TAMs solely was not associated with outcome, but patients with more TAMs in proximity of the tumor cells had a worse DFS. Surprisingly, the clustering of TAMs near CD8+ cells was associated with pCR independent of the number of TAMs or TILs.
- Published
- 2020
13. Abstract P5-04-04: The spatial interactions between FOXP3+ Tregs, CD8+ cytotoxic T cells and tumor cells predict response to therapy and prognosis in inflammatory breast cancer
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Steven Van Laere, Cecile Colpaert, Peter van Dam, Luc Dirix, Peter B. Vermeulen, Peter A. van Dam, Mark M. Kockx, Christophe Van Berckelaer, Koen M. Marien, and C. Rypens
- Subjects
Cancer Research ,business.industry ,FOXP3 ,Cancer ,chemical and pharmacologic phenomena ,medicine.disease ,Acquired immune system ,Inflammatory breast cancer ,Immune system ,Breast cancer ,Oncology ,medicine ,Cancer research ,Cytotoxic T cell ,skin and connective tissue diseases ,business ,CD8 - Abstract
Background: Inflammatory breast cancer (IBC) is a rare and aggressive type of locally advanced breast cancer. A 79-gene signature, reported by our lab, is shaped by specific immune response programs and discriminates between IBC and non-IBC (nIBC). However, it remains an enigma how infiltrating immune cells are able to determine the IBC phenotype. Furthermore, the presence of immune cells like FOXP3+ Tregs and CD8+ cytotoxic T cells is associated with outcome in proliferative subtypes of breast cancer and the interaction between these cells plays a role in the functional immune response. Therefore, we aimed to assess the spatial associations between immune cells in IBC. Additionally, we used deep-learning to examine interactions between cancer and immune cells. Methodology: Immunostainings (Hematoxylin-DAB, H-DAB) were done according to well-validated protocols for CD8 (cytotoxic T-cells), FOXP3 (Tregs) and CD163 (tumor-associated macrophages, TAMs) in a large population of 134 IBC patients. All slides were digitalized and evaluated using VISIOPHARM® software, allowing virtual multiplexing. We quantified the number of DAB+ immune cells and each positive immune cell was located using XY coordinates. Spatial co-localization was examined using statistics developed for ecological studies based on point pattern and quadrant analysis. TILs were scored according to the TIL working group guidelines on H&E slides. Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8 stained slide. To perform deep-learning, we aligned two consecutive slides: one PanCK stained slide and one slide stained for CD8 (H-DAB). Using virtual multiplexing and the PanCK staining, we determined the tumor regions on the H-DAB stained slide. Subsequently, 18 images were incorporated to train the algorithm with more than 150.000 iterations (Deeplabv3+), after which the algorithm was evaluated in a test set of 12 images, approved and applied to all images to locate the tumor cells. Results: Most of the patients presented with a hormone receptor (HR) positive carcinoma (60.6%, n= 82/132). The presence of distant disease, HR status and TIL score were associated with overall survival (OS), but the density of the different immune cells or the CD8/FOXP3 ratio was not. However, using an effector index we demonstrated that patients with more FOXP3+ cells in a radius of 30 μm surrounding a CD8+ cell had a significant worse outcome (Median OS: 2.7 vs. 6.3 years, P= .01) and this remained significant in a multivariate model (HR: 2.85, P< .001). Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 28.7% (n= 27/94) of the patients with initially localized disease. Infiltration with CD8+ T cells (P= .005), TAMs (P= .008) and TILs (P= .002) predicted pCR, but a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, pCR was less often achieved in patients that had colocalization of FOXP3+ cells near the tumor cells (P= .003). This colocalization was determined using a Morista-Horn index and independent of the number of Tregs, CD8+ cells or TILs. The deep-learning algorithm had a mean dice coefficient in the test set of 0.83, indicating a good overlap between the tumor area determined by the AI on the CD8 slides and the area on the PanCK stained slides. Conclusions: We have created a deep learning algorithm that adequately detects IBC tumor cells on H-DAB stained images and show, in a large cohort of 132 patients, that the negative impact of Tregs appears to depend on the spatial arrangement. While solely the number of Tregs is not associated with pCR or OS, patients with FOXP3+ Tregs that cluster together near CD8+ cytotoxic T cells had a worse outcome and pCR was achieved more often in patients with less Tregs near the tumor cells. Citation Format: Christophe Van Berckelaer, Charlotte Rypens, Steven Van Laere, Koen Marien, Pieter-Jan van Dam, Peter Vermeulen, Luc Dirix, Mark Kockx, Cecile Colpaert, Peter van Dam. The spatial interactions between FOXP3+ Tregs, CD8+ cytotoxic T cells and tumor cells predict response to therapy and prognosis in inflammatory breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-04.
- Published
- 2020
14. AutoTag and AutoSnap: Standardized, semi-automatic capture of regions of interest from whole slide images
- Author
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Mark M. Kockx, Luc Andries, Guido R.Y. De Meyer, Stefanie De Schepper, and Koen M. Marien
- Subjects
Tumor angiogenesis ,Computer science ,Stereology ,Clinical Biochemistry ,Magnification ,Whole slide image ,computer.software_genre ,Uniform random sampling ,Automation ,Agricultural and Biological Science ,Computer vision ,lcsh:Science ,Predictive biomarker ,Selection bias ,business.industry ,Pharmacology. Therapy ,Sampling (statistics) ,Computer-assisted image processing ,Medical Laboratory Technology ,Tissue sections ,Microvessels ,lcsh:Q ,Data mining ,Artificial intelligence ,Semi automatic ,Human medicine ,business ,computer ,Engineering sciences. Technology ,AutoTag and AutoSnap - Abstract
Tumor angiogenesis is measured by counting microvessels in tissue sections at high power magnification as a potential prognostic or predictive biomarker. Until now, regions of interest1 1 ROI: region of interest. (ROIs) were selected by manual operations within a tumor by using a systematic uniform random sampling 2 SURS: systematic, uniform random sampling. (SURS) approach. Although SURS is the most reliable sampling method, it implies a high workload. However, SURS can be semi-automated and in this way contribute to the development of a validated quantification method for microvessel counting in the clinical setting. Here, we report a method to use semi-automated SURS for microvessel counting: • Whole slide imaging with Pannoramic SCAN (3DHISTECH) • Computer-assisted sampling in Pannoramic Viewer (3DHISTECH) extended by two self-written AutoHotkey applications (AutoTag and AutoSnap) • The use of digital grids in Photoshop® and Bridge® (Adobe Systems) This rapid procedure allows traceability essential for high throughput protein analysis of immunohistochemically stained tissue.
- Published
- 2015
15. Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses
- Author
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Robert A. Burger, Wei Wei, Amreen Husain, Carlos Bais, Barbara Mueller, Nrg Oncology, Michael J. Birrer, Mark M. Kockx, Robert S. Mannel, Koen M. Marien, Mark F. Brady, and NRG Oncology Gynecologic Oncology
- Subjects
Vascular Endothelial Growth Factor A ,0301 basic medicine ,Oncology ,Cancer Research ,Pathology ,genetic structures ,Angiogenesis Inhibitors ,Carboplatin ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Aged, 80 and over ,Ovarian Neoplasms ,education.field_of_study ,Predictive marker ,Hazard ratio ,Middle Aged ,Proto-Oncogene Proteins c-met ,Intention to Treat Analysis ,Bevacizumab ,Platelet Endothelial Cell Adhesion Molecule-1 ,Vascular endothelial growth factor ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Paclitaxel ,Population ,Article ,Disease-Free Survival ,Drug Administration Schedule ,03 medical and health sciences ,Double-Blind Method ,Internal medicine ,Biomarkers, Tumor ,Confidence Intervals ,medicine ,Humans ,Progression-free survival ,education ,Aged ,Retrospective Studies ,business.industry ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Neuropilin-1 ,030104 developmental biology ,chemistry ,Microvessels ,Human medicine ,business ,Ovarian cancer - Abstract
Background: Combining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective. Methods: Patients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided. Results: The biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor–2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, Pinteraction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, Pinteraction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression. Conclusions: These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.
- Published
- 2017
16. The spatial relations among immune cells are prognostic in inflammatory breast cancer
- Author
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Yannick Waumans, Mark M. Kockx, C. Van Berckelaer, L.Y. Dirix, Peter B. Vermeulen, C. Rypens, P. van Dam, Koen M. Marien, Cecile Colpaert, and S. Van Laere
- Subjects
Immune system ,Oncology ,business.industry ,Cancer research ,Medicine ,Hematology ,business ,medicine.disease ,Inflammatory breast cancer - Published
- 2019
17. Development and Validation of a Histological Method to Measure Microvessel Density in Whole-Slide Images of Cancer Tissue
- Author
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Valerie Croons, Luc Andries, Guido R.Y. De Meyer, Erik Fransen, Mark M. Kockx, Wim Waelput, Stefanie De Schepper, Ellen Sluydts, Peter B. Vermeulen, Yannick Waumans, Koen M. Marien, and Pathology/molecular and cellular medicine
- Subjects
0301 basic medicine ,Pathology ,Colorectal cancer ,Intraclass correlation ,lcsh:Medicine ,Epithelium ,0302 clinical medicine ,Renal cell carcinoma ,Animal Cells ,Ovarian carcinoma ,Neoplasms ,Medicine and Health Sciences ,Blastomas ,lcsh:Science ,Neurological Tumors ,Staining ,Observer Variation ,Multidisciplinary ,Neovascularization, Pathologic ,Pharmacology. Therapy ,Cell Staining ,Ovarian Cancer ,Platelet Endothelial Cell Adhesion Molecule-1 ,Oncology ,Neurology ,030220 oncology & carcinogenesis ,Anatomy ,Cellular Types ,Engineering sciences. Technology ,Research Article ,medicine.medical_specialty ,Concordance ,Research and Analysis Methods ,Carcinomas ,03 medical and health sciences ,Breast cancer ,medicine ,Humans ,Colorectal Cancer ,business.industry ,lcsh:R ,Renal Cell Carcinoma ,Cancer ,Cancers and Neoplasms ,Biology and Life Sciences ,Endothelial Cells ,Reproducibility of Results ,Epithelial Cells ,Cell Biology ,medicine.disease ,Genitourinary Tract Tumors ,030104 developmental biology ,Biological Tissue ,Specimen Preparation and Treatment ,Cardiovascular Anatomy ,Blood Vessels ,lcsh:Q ,Ovarian cancer ,business ,Nuclear medicine ,Gynecological Tumors ,Glioblastoma Multiforme - Abstract
Despite all efforts made to develop predictive biomarkers for antiangiogenic therapies, no unambiguous markers have been identified so far. This is due to among others the lack of standardized tests. This study presents an improved microvessel density quantification method in tumor tissue based on stereological principles and using whole-slide images. Vessels in tissue sections of different cancer types were stained for CD31 by an automated and validated immunohistochemical staining method. The stained slides were digitized with a digital slide scanner. Systematic, uniform, random sampling of the regions of interest on the whole-slide images was performed semi-automatically with the previously published applications AutoTag and AutoSnap. Subsequently, an unbiased counting grid was combined with the images generated with these scripts. Up to six independent observers counted microvessels in up to four cancer types: colorectal carcinoma, glioblastoma multiforme, ovarian carcinoma and renal cell carcinoma. At first, inter-observer variability was found to be unacceptable. However, after a series of consensus training sessions and interim statistical analysis, counting rules were modified and inter-observer concordance improved considerably. Every CD31-positive object was counted, with exclusion of suspected CD31-positive monocytes, macrophages and tumor cells. Furthermore, if interconnected, stained objects were considered a single vessel. Ten regions of interest were sufficient for accurate microvessel density measurements. Intra-observer and inter-observer variability were low (intraclass correlation coefficient > 0.7) if the observers were adequately trained.
- Published
- 2016
18. Simultaneous zoonotic transmission of Chlamydophila psittaci genotypes D, F and E/B to a veterinary scientist
- Author
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Daisy Vanrompay, Hans Nauwynck, M. Marien, Caroline Van Droogenbroeck, Kristel Verminnen, Delphine Sylvie Anne Beeckman, and Leopold de Thibault de Boesinghe
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Turkeys ,Veterinary medicine ,Microbiology ,Veterinarians ,Serology ,Zoonoses ,medicine ,Animals ,Humans ,Chlamydiaceae ,Metapneumovirus ,Chlamydophila Infections ,Poultry Diseases ,Ornithobacterium rhinotracheale ,Chlamydia psittaci ,Chlamydophila ,General Veterinary ,biology ,Zoonosis ,General Medicine ,bacterial infections and mycoses ,biology.organism_classification ,medicine.disease ,Virology ,Chlamydophila psittaci ,Nested polymerase chain reaction - Abstract
Two groups of five 1-day-old conventional turkeys were housed in negative pressure stables to become experimentally infected with Avian Metapneumovirus (aMPV) and Ornithobacterium rhinotracheale (ORT) at the age of 3 weeks. However, during the first 2 weeks, turkeys started to show respiratory disease characterized by rhinitis and dyspnoea. Routine bacterial and viral diagnoses remained negative. Therefore, pharyngeal swabs from the turkeys and from the veterinary scientist handling the animals were examined for the presence of Chlamydophila (C.) psittaci by using a combination of cell culture, nested PCR and ompA genotype-specific quantitative real-time PCR, as well as by serology. Results revealed simultaneous transmission of C. psittaci outer membrane protein A (ompA) genotypes D, F and E/B from infected turkeys to the veterinary scientist.
- Published
- 2009
19. Protéinogramme
- Author
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M. Marien
- Published
- 2009
20. Notes on the Education Complex as an Emerging Macro-System
- Author
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M. Marien
- Subjects
International education ,Knowledge management ,Systems theory ,business.industry ,Management science ,Political science ,Beneficiary ,Public policy ,Social complexity ,Informal education ,Lagging ,business ,Boundary (real estate) - Abstract
In a dynamic, knowledge-based era, new conceptual approaches are required to supplement the traditional focus on single organizations confined in spatial boundaries. Growing social complexity also necessitates transdisciplinary program overviews to aid public policy formulation. ‘The Education Complex’ focuses on the interaction of four components (core educating systems, peripheral programs, selected suppliers, and organized beneficiaries), and places special emphasis on system relationships to informal education and international education. The initial task of entitation entails a consideration of functional, spatial, input and beneficiary boundaries. The resultant entity of the education complex is justified by exploring a fifth boundary — time — in which evidence is provided to support the view of an emerging macro-system. The suggested realities of emerging and overlapping macro-systems require certain adaptations for general systems theory : accepting a world of blurring boundaries and lagging concepts, and moving from a focus on isomorphic traits to one involving a systems spectrum. These adaptations will hopefully result in greater attention to understanding the systems most important to shaping the future human condition.
- Published
- 2015
21. Comparison of the efficacy of four antimicrobial treatment schemes against experimentalOrnithobacterium rhinotrachealeinfection in turkey poults pre-infected with avian pneumovirus
- Author
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Annemie Decostere, Robrecht Froyman, Luc Duchateau, Luc Devriese, Koen Chiers, Hans Nauwynck, An Martel, M. Marien, Bacteriology, Faculty of Veterinary Medicine, Laboratory of Virology, Universiteit Gent = Ghent University [Belgium] (UGENT), Department of Physiology and Biometrics, Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine - Faculteit Diergeneeskunde [UGhent, Belgium], Universiteit Gent = Ghent University [Belgium] (UGENT)-Universiteit Gent = Ghent University [Belgium] (UGENT), Animal Health Division, and Bayer HealthCare AG
- Subjects
Florfenicol ,Turkeys ,Pathology ,medicine.medical_specialty ,Veterinary medicine ,040301 veterinary sciences ,0403 veterinary science ,03 medical and health sciences ,chemistry.chemical_compound ,Food Animals ,Flavobacteriaceae Infections ,Enrofloxacin ,Animals ,Medicine ,Poultry Diseases ,Ornithobacterium rhinotracheale ,030304 developmental biology ,Thiamphenicol ,0303 health sciences ,Air sacs ,Paramyxoviridae Infections ,General Immunology and Microbiology ,business.industry ,Inoculation ,Amoxicillin ,Life Sciences ,04 agricultural and veterinary sciences ,Antimicrobial ,medicine.disease ,Ornithobacterium ,Anti-Bacterial Agents ,Specific Pathogen-Free Organisms ,3. Good health ,Avian pneumovirus ,chemistry ,Animal Science and Zoology ,Metapneumovirus ,business ,Fluoroquinolones ,medicine.drug - Abstract
The clinical efficacy of drinking-water administration of enrofloxacin for 3 and 5 days, amoxicillin for 5 days and florfenicol for 5 days for the treatment of respiratory disease induced by an experimental Ornithobacterium rhinotracheale infection in turkeys pre-infected with avian pneumovirus (APV) was assessed based on clinical, bacteriological and histopathological examinations. Experimental groups of 15 susceptible 3-week-old turkeys were each inoculated oculonasally with APV subtype A and 3 days later with susceptible O. rhinotracheale bacteria. Antimicrobial treatment started 1 day after O. rhinotracheale inoculation. After infection, the birds were examined and scored for clinical signs, swabbed daily and weighed at different times. Five birds were euthanized and examined for macroscopic lesions at necropsy at 5 days post bacterial inoculation, and the remainder at 15 days post bacterial inoculation. Samples of the turbinates, trachea, lungs, air sacs, heart and pericardium were collected for bacteriological and/or histological examination. Recovery from respiratory disease caused by an APV/O. rhinotracheale dual infection was most successful after enrofloxacin treatment, irrespective of treatment duration, followed by florfenicol. Amoxicillin treatment was not efficacious. Clinical signs and the number of O. rhinotracheale organisms re-isolated from the trachea and the different respiratory organs were significantly reduced by enrofloxacin treatment for 3 and 5 days. O. rhinotracheale bacteria were not re-isolated from the tracheas of the birds treated with enrofloxacin except for one bird in the 5-day group, as early as 1 day after medication onset. In the group treated with enrofloxacin for 5 days, O. rhinotracheale organisms with a higher minimal inhibitory concentration value (x8) were isolated starting 2 days following treatment onset, initially from a single turkey and subsequently from the other animals.
- Published
- 2006
22. Synergy between avian pneumovirus andOrnithobacterium rhinotrachealein turkeys
- Author
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An Martel, Hans Nauwynck, Annemie Decostere, Robrecht Froyman, Koen Chiers, and M. Marien
- Subjects
Turkeys ,Pathology ,medicine.medical_specialty ,Time Factors ,Food Animals ,Flavobacteriaceae Infections ,medicine ,Animals ,Poultry Diseases ,Ornithobacterium rhinotracheale ,Histological examination ,Specific-pathogen-free ,Air sacs ,Paramyxoviridae Infections ,General Immunology and Microbiology ,Inoculation ,business.industry ,Respiratory disease ,medicine.disease ,Ornithobacterium ,Virology ,Specific Pathogen-Free Organisms ,Avian pneumovirus ,medicine.anatomical_structure ,Animal Science and Zoology ,Metapneumovirus ,business ,Respiratory tract - Abstract
The purpose of this study was to assess the possible synergism between Ornithobacterium rhinotracheale (ORT) and avian pneumovirus (APV), inoculated into turkeys via the natural route, for the reproduction of respiratory disease. Three-week-old specific pathogen free turkeys were inoculated oculonasally with either APV subtype A, ORT or both agents using two different time intervals (3 and 5 days) between APV and ORT. The birds were observed clinically on a daily basis and swabbed intratracheally at short, regular intervals. They were killed at 1, 3, 5, 8 and 15 days post single or dual inoculation and examined for gross lesions at necropsy. Samples of the turbinates, trachea, lungs, air sacs, heart, pericardium and liver were taken for bacteriological and/or histological examination. Combined APV/ORT infections resulted in overt clinical signs and a longer persistence of ORT in the respiratory tract and aggravated the macroscopic and histological lesions in comparison with the groups given single infections. In all ORT-challenged turkeys, ORT was isolated from the turbinates, trachea and lungs, but in turkeys infected with both agents ORT was frequently found in the air sacs and on a single occasion in the heart and pericardium. The time interval between APV and ORT inoculation did not have a significant effect on the outcome of the dual infection. A conspicuous important feature was the attachment of ORT to the cilia of the epithelium of the turbinates and trachea of both ORT-infected and APV/ORT-infected birds. In conclusion, the results show that ORT is able to adhere to and colonize the respiratory tract but, under the circumstances used in this study, is not capable of inducing respiratory disease without viral priming.
- Published
- 2005
23. Effect of intrastriatal 6-OHDA lesion on dopaminergic innervation of the rat cortex and globus pallidus
- Author
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Stéphanie Laurens, Rita Raisman-Vozari, Francis Colpaert, Chantal François, Thomas Debeir, Laure Ginestet, M. Marien, Jean-Claude Martel, and Philippe Chopin
- Subjects
Male ,Tyrosine 3-Monooxygenase ,Dopamine ,Nigrostriatal pathway ,Cell Count ,Substantia nigra ,Striatum ,Biology ,Globus Pallidus ,Functional Laterality ,Rats, Sprague-Dawley ,Adrenergic Agents ,Nerve Fibers ,Developmental Neuroscience ,Cortex (anatomy) ,Neural Pathways ,Basal ganglia ,medicine ,Animals ,Oxidopamine ,Cerebral Cortex ,Anatomy ,Immunohistochemistry ,Rats ,Substantia Nigra ,Ventral tegmental area ,Globus pallidus ,medicine.anatomical_structure ,nervous system ,Neurology ,medicine.drug - Abstract
The present study examined in the rat the effect of a partial lesion of the nigrostriatal dopaminergic pathway induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA), on the dopaminergic innervation of the cortex and the globus pallidus as revealed using tyrosine hydroxylase (TH) immunoreactivity. Twenty-eight days after unilateral injection of 6-OHDA into the dorsal part of the striatum, TH-positive fiber density was reduced by 41% in the dorsal and central part of the structure, and was accompanied by a retrograde loss of 33% of TH-positive neurons in the substantia nigra (SN), while the ventral tegmental area was completely spared. In the SN, TH-positive cell loss was most severe in the ventral part of the structure (-55%). In the same animals, a substantial loss of TH-positive fibers was evident in the dorsal part of the globus pallidus, and involved both thick fibers of passage and thin varicose terminal axonal branches. In the cortex, a loss of TH-positive fibers was prominent in the cingulate area, moderate in the motor area and less affected in the insular area, while the noradrenergic innervation revealed using dopamine-beta-hydroxylase immunoreactivity was preserved in all of these cortical subregions. These results demonstrate that the intrastriatal 6-OHDA lesion model in rats produces a significant loss of dopaminergic axons in extrastriatal structures including the pallidum and cortex, which may contribute to functional sequelae in this animal model of Parkinson's disease.
- Published
- 2005
24. In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration
- Author
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Juan E. Ferrario, M. Marien, Francis Colpaert, Annick Prigent, Thomas Debeir, Rita Raisman-Vozari, and Pamela Rizk
- Subjects
medicine.medical_specialty ,Central nervous system ,Enzyme-Linked Immunosorbent Assay ,Nucleus basalis ,Brain Ischemia ,Developmental Neuroscience ,Internal medicine ,Nerve Growth Factor ,medicine ,Animals ,Benzopyrans ,Cholinergic neuron ,Neurons ,biology ,Neurodegeneration ,Imidazoles ,Somatosensory Cortex ,Adrenergic alpha-2 Receptor Antagonists ,medicine.disease ,Immunohistochemistry ,Choline acetyltransferase ,Acetylcholine ,Rats ,Up-Regulation ,Neuroprotective Agents ,medicine.anatomical_structure ,Endocrinology ,Nerve growth factor ,nervous system ,Neurology ,Nerve Degeneration ,biology.protein ,Cholinergic ,Neurotrophin - Abstract
We have previously reported that the alpha2-adrenoceptor antagonist dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since nerve growth factor (NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of dexefaroxan in the devascularization model was associated with regional induction of NGF biosynthesis. Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or sham operation procedures. In vehicle-treated devascularized rats, NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation; NGF levels in NbM remained unchanged during this time. In dexefaroxan-treated devascularized rats, increases in NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of NGF's actions, including increases in choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM cholinergic cell numbers. Dexefaroxan also increased NGF protein levels in sham-operated rats, but without any significant consequence to the otherwise normal NbM cholinergic phenotype in these animals. Results indicate that activation of endogenous NGF systems could contribute to the cholinergic protective effect of dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of dexefaroxan in neurodegenerative diseases where central cholinergic function is progressively compromised.
- Published
- 2004
25. Effects of the α2-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death
- Author
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François Jourdan, S Bauer, Jean-Claude Martel, Francis Colpaert, M. Marien, and Emmanuel Moyse
- Subjects
Male ,Olfactory system ,medicine.medical_specialty ,Rostral migratory stream ,Subventricular zone ,Biology ,Neuroprotection ,Rats, Sprague-Dawley ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Subependymal zone ,medicine ,Animals ,Benzopyrans ,Adrenergic alpha-Antagonists ,Neurons ,Cell Death ,General Neuroscience ,Neurogenesis ,Imidazoles ,Adrenergic alpha-2 Receptor Antagonists ,Olfactory Bulb ,Neural stem cell ,Rats ,Olfactory bulb ,Neuroprotective Agents ,Endocrinology ,medicine.anatomical_structure ,Neuroscience - Abstract
A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has been hypothesised to be the critical factor underlying the evolution of central neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating central noradrenergic transmission, afford neuroprotection in vivo in models of cerebral ischaemia, excitotoxicity and devascularization-induced neurodegeneration. The present study utilised the rat olfactory bulb as a model system for examining the effects of the selective alpha(2)-adrenoceptor antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'-deoxyuridine labelling) and cell death associated with DNA fragmentation (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling assay) were quantified following a 7-day treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times daily), followed by a 3-day washout period. The number of terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated rats, this difference being greatest and significant in the subependymal layer (-52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences were detected in the proliferating region of the subventricular zone. Terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling combination with glial fibrillary acidic protein or neuronal-specific antigen immunohistochemistry revealed that terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei were associated primarily with a neuronal cell phenotype. These findings suggest that dexefaroxan increases neuron survival in the olfactory bulb of the adult rat in vivo, putatively as a result of reducing the apoptotic fate of telencephalic stem cell progenies.
- Published
- 2003
26. Protective effects of the α2-adrenoceptor antagonist, dexefaroxan, against degeneration of the basalocortical cholinergic system induced by cortical devascularization in the adult rat
- Author
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Jean-Claude Martel, Thomas Debeir, Francis Colpaert, Rita Raisman-Vozari, Philippe Chopin, and M. Marien
- Subjects
Male ,medicine.medical_specialty ,Rats, Sprague-Dawley ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Vesicular acetylcholine transporter ,medicine ,Animals ,Benzopyrans ,Cholinergic neuron ,Adrenergic alpha-Antagonists ,business.industry ,General Neuroscience ,Imidazoles ,Antagonist ,Somatosensory Cortex ,Adrenergic alpha-2 Receptor Antagonists ,Choline acetyltransferase ,Rats ,Neuroprotective Agents ,Endocrinology ,Nerve growth factor ,Cholinergic Fibers ,Basal Nucleus of Meynert ,Nerve Degeneration ,Cholinergic ,Locus coeruleus ,business ,Neuroscience ,Acetylcholine ,medicine.drug - Abstract
It has been hypothesized [Colpaert, F.C., 1994. In: Briley, M., Marien, M. (Eds.), Noradrenergic Mechanisms in Parkinson’s Disease. CRC Press, Boca Raton, FL, pp. 225–254] that a deficiency in the noradrenergic system originating from the locus coeruleus is a decisive factor in the progression of central neurodegenerative disorders including Alzheimer’s disease, and that treatments which boost noradrenergic transmission (e.g. via blockade of α 2 -adrenoceptors) could provide both symptomatic and trophic benefits against the disease. Studies in the rat in vivo demonstrating that the selective α 2 -adrenoceptor antagonist dexefaroxan increases acetylcholine release in the cortex, improves measures of cognitive performance and protects against excitotoxin lesions, support this concept. As a further test of the hypothesis, we investigated the effect of dexefaroxan in a rat model of unilateral cortical devascularization that induces a loss of the cortical cholinergic terminal network and a retrograde degeneration of the cholinergic projections that originate in the nucleus basalis magnocellularis. Lesioned and sham-operated rats received a 28-day subcutaneous infusion of dexefaroxan (0.63 mg/rat/day) or vehicle, delivered by osmotic minipumps implanted on the day of the cortical devascularization procedure. In lesioned rats, the dexefaroxan treatment was associated with a significantly higher number and size of vesicular acetylcholine transporter-immunoreactive boutons in comparison to the vehicle treatment; this effect was most marked within cortical layer V. Dexefaroxan also significantly reduced the atrophy of cholinergic neurons within the nucleus basalis magnocellularis. Dexefaroxan had no observable effect on any of these parameters in sham-operated cohorts. These results show that systemically administered dexefaroxan mitigates cholinergic neuronal degeneration in vivo , and provide further evidence for a therapeutic potential of the drug in neurodegenerative diseases such as Alzheimer’s disease, where central cholinergic function is progressively compromised.
- Published
- 2002
27. P3.02c-087 The Relationship of TILs and PD-L1 Expression in NSCLC Adenocarcinoma in Little to Non-Smokers with Driver Mutations and Outcome Parameters
- Author
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Wim Waelput, Koen M. Marien, Sacha Mignon, Lore Decoster, Roberto Salgado, Johan Vansteenkiste, Gert Van den Eynden, Erik Teugels, Jacques De Greve, Karen Willard-Gallo, Faculty of Medicine and Pharmacy, Pathology/molecular and cellular medicine, Pathology, Clinical sciences, Medical Oncology, and Laboratory of Molecular and Medical Oncology
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Tumor-infiltrating lymphocytes ,medicine.disease ,Outcome parameter ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adenocarcinoma ,Pd l1 expression ,business - Published
- 2017
28. Effects of kainic acid lesioning on poly(ADP-ribose) polymerase (PARP) activity in the rat striatum in vivo
- Author
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Cristina Cosi, A. Carcereri De Prati, M. Marien, Hisanori Suzuki, and Elisabetta Cavalieri
- Subjects
Male ,Kainic acid ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Excitotoxicity ,Endogeny ,Biology ,medicine.disease_cause ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Enzyme activator ,In vivo ,medicine ,Animals ,Kainic Acid ,Organic Chemistry ,Neurodegeneration ,medicine.disease ,Molecular biology ,Corpus Striatum ,Rats ,Enzyme Activation ,chemistry ,Toxicity ,Poly(ADP-ribose) Polymerases - Abstract
Poly(ADP-ribose) polymerase (PARP) is activated in glutamate-induced toxicity of neurons in culture (Cosi et al., 1994). Since injection of the excitatory amino acid, kainic acid (KA) into the rat striatum induces a delayed neuronal death, the effects of this in vivo excitotoxin lesioning procedure on striatal PARP activity was investigated. PARP activity was measured in striatal extracts both in the absence ("endogenous" activity) and presence ("total" activity) of exogenously-added fragmented DNA. KA (5 nmols/1 μl) produced significant and time-dependent changes in striatal PARP activity, compared to saline-injected control animals: no changes at 6 h after intrastriatal KA, a 68% and 48% decrease in endogenous and total PARP activity respectively at 12 h, a doubling in endogenous PARP activity at 24 h, and a 382% and 60% increase in endogenous and total activities at 1 week after KA. PARP cleavage was not detected at any time point. These results suggest a participation of PARP in KA-induced toxicity in the brain in vivo.
- Published
- 2000
29. Central Noradrenergic Neurotoxicity of DSP4 in Mice: Studies on the Neuroprotective Potential of the Poly(ADP-Ribose) Polymerase Inhibitor, Benzamide
- Author
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M. Marien and Cristina Cosi
- Subjects
Benzylamines ,General Neuroscience ,Neurotoxins ,Neurotoxicity ,Poly(ADP-ribose) Polymerase Inhibitors ,NAD ,medicine.disease ,Neuroprotection ,Poly (ADP-Ribose) Polymerase Inhibitor ,General Biochemistry, Genetics and Molecular Biology ,Frontal Lobe ,Adenosine Diphosphate ,Mice, Inbred C57BL ,Mice ,Norepinephrine ,chemistry.chemical_compound ,Adenosine Triphosphate ,History and Philosophy of Science ,chemistry ,Biochemistry ,Benzamides ,medicine ,Animals ,Benzamide - Published
- 1999
30. Implication of Poly(ADP-Ribose) Polymerase (PARP) in Neurodegeneration and Brain Energy Metabolism: Decreases in Mouse Brain NAD+ and ATP Caused by MPTP Are Prevented by the PARP Inhibitor Benzamide
- Author
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M. Marien and Cristina Cosi
- Subjects
Male ,Dopamine ,Poly ADP ribose polymerase ,Dopamine Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,Biology ,Nicotinamide adenine dinucleotide ,Pharmacology ,Poly (ADP-Ribose) Polymerase Inhibitor ,Neuroprotection ,General Biochemistry, Genetics and Molecular Biology ,Mice ,chemistry.chemical_compound ,Adenosine Triphosphate ,History and Philosophy of Science ,Mesencephalon ,Animals ,General Neuroscience ,MPTP ,Brain ,NAD ,Molecular biology ,Corpus Striatum ,Frontal Lobe ,Mice, Inbred C57BL ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Benzamides ,PARP inhibitor ,NAD+ kinase ,Poly(ADP-ribose) Polymerases ,Adenosine triphosphate - Abstract
Poly(ADP-ribose) polymerase (PARP) is a DNA binding protein that uses nicotinamide adenine dinucleotide (NAD+) as a substrate. Evidence from in vitro studies on nonneuronal cells in culture have shown that when fully activated by free radical-induced DNA damage, PARP depletes cellular NAD+ and consequently adenosine triphosphate (ATP) levels within a matter of minutes, and that this depletion is associated with a cell death that can be prevented by PARP inhibitors. The present in vivo study utilized the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, a model of central nigrostriatal dopamine neurotoxicity that recapitulates certain features of Parkinson's disease (PD), and one in which we have previously shown PARP inhibitors to be protective, to examine whether MPTP acutely caused region- and time-dependent changes in levels of NAD+ and ATP in the brain in vivo and whether such effects were modified by treatments with neuroprotective doses of the PARP inhibitor benzamide. The results confirm that MPTP reduces striatal ATP levels, as previously reported by Chan et al., show that MPTP causes a regionally-selective (striatal and midbrain) loss of NAD+, and indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release. These findings suggest an involvement of PARP in the control of brain energy metabolism during neurotoxic insult, provide further evidence in support of the participation of PARP in MPTP-induced neurotoxicity in vivo and suggest that PARP inhibitors might be beneficial in the treatment of PD.
- Published
- 1999
31. α2-Adrenoceptor modulation of cortical acetylcholine release in vivo
- Author
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M Marien, Francis Colpaert, and S Tellez
- Subjects
Benzylamines ,medicine.medical_specialty ,Microdialysis ,Epinephrine ,Prefrontal Cortex ,DSP-4 ,In Vitro Techniques ,Globus Pallidus ,chemistry.chemical_compound ,Substantia Innominata ,Receptors, Adrenergic, alpha-2 ,Cerebellum ,Parietal Lobe ,Quinoxalines ,Internal medicine ,medicine ,Animals ,Neurotoxin ,Sympathomimetics ,Neurotransmitter ,Prefrontal cortex ,Adrenergic alpha-Antagonists ,Antihypertensive Agents ,Benzofurans ,Cerebral Cortex ,General Neuroscience ,Imidazoles ,Acetylcholine ,Rats ,Kinetics ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Cerebral cortex ,Brimonidine Tartrate ,Anesthesia ,Locus coeruleus ,Adrenergic alpha-Agonists ,medicine.drug - Abstract
Acetylcholine release in the rat cortex in vivo has been shown to be modulated by alpha2-adrenoceptor ligands. We have previously reported that the systemic administration of selective alpha2-antagonists including (+)-efaroxan increase, while alpha2-adrenoceptor agonists such as UK-14304 reduce the release of acetylcholine in the medial prefrontal cortex of conscious rats as measured by microdialysis. To evaluate the extent to which noradrenergic afferent inputs are required for the expression of these different effects, the present study examined the drug-induced changes in cortical acetylcholine release in rats which had undergone prior noradrenergic deafferentation. Rats were pretreated with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (40 mg/kg, i.p.), which after three days had reduced noradrenaline levels in the medial prefrontal cortex by 84%. At that time, slices of cortex were incubated with [3H]choline, superfused and stimulated by consecutive exposures to increasing concentrations of K+. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated tissue, the [3H] outflows evoked by 20, 35 and 45 mM K+ were lower by 12%, 22% and 43%, respectively, in comparison to slices prepared from vehicle-pretreated control animals. For in vivo microdialysis experiments, rats were pretreated as above with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, or prepared seven to eight days in advance with bilateral 6-hydroxydopamine lesions of the locus coeruleus. Neither of these lesioning procedures significantly affected the basal outflow of endogenous acetylcholine in the cortex. In control rats, cortical acetylcholine outflow was increased by up to 300% of baseline values by (+)-efaroxan (0.63 mg/kg, i.p.), and was reduced to 21% of baseline by UK-14304 (2.5 mg/kg, i.p.), confirming our previous findings. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated rats, the inhibitory effect of UK-14304 on acetylcholine outflow persisted, while the ability of (+)-efaroxan to increase outflow was essentially eliminated. In locus coeruleus-lesioned rats, where cortical noradrenaline levels were reduced by 64%, (+)-efaroxan still increased acetylcholine outflow, but this effect was significantly attenuated and less sustained in comparison to sham-operated control rats. Viewed together with complimentary biochemical, electrophysiological and neuroanatomical evidence in the literature, a model is presented to account for these findings, and indicates that alpha2-adrenoceptors both on noradrenergic neurons (autoreceptors) and on non-noradrenergic cells (heteroreceptors) can participate in mediating drug-induced changes in medial prefrontal cortical acetylcholine release in vivo. The acetylcholine release-enhancing effect of (+)-efaroxan appears to be dependent on at least a partially intact cortical noradrenergic innervation.
- Published
- 1999
32. Arylpiperazide derivatives of phenylpiperazines as a new class of potent and selective 5-HT1B receptor antagonists
- Author
-
Serge Halazy, Christiane Palmier, M. Marien, Petrus J. Pauwels, Catherine Jorand-Lebrun, Philippe Chopin, and C. Moret
- Subjects
medicine.drug_class ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Antagonist ,Pharmaceutical Science ,Carboxamide ,Pharmacology ,Biochemistry ,In vitro ,In vivo ,Oral administration ,Drug Discovery ,medicine ,Extracellular ,Systemic administration ,Molecular Medicine ,Receptor ,Molecular Biology - Abstract
A new series of arylpiperazide derivatives of phenylpiperazines of general formula 4 has been prepared and evaluated as 5-HT1B receptor antagonists. In vitro experiments at human cloned 5-HT1B receptors show that these derivatives are potent and selective 5-HT1B receptor antagonists. Among them, compound 4f was found to be orally active, to gain access to the CNS and more importantly to induce an increase in extracellular brain 5-HT upon systemic administration.
- Published
- 1997
33. Poly(ADP-ribose) polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57Bl/6 mice
- Author
-
M. Marien, Anne Degryse, Wouter Koek, Cristina Cosi, and Francis Colpaert
- Subjects
biology ,General Neuroscience ,Poly ADP ribose polymerase ,MPTP ,Pharmacology ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Enzyme inhibitor ,Dopamine ,biology.protein ,Catecholamine ,medicine ,Neurotoxin ,Neurology (clinical) ,Benzamide ,Neurotransmitter ,Molecular Biology ,Developmental Biology ,medicine.drug - Abstract
Treatment of C57B1/6 mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduced striatal dopamine and cortical noradrenaline levels by 77-83% and 43-46%, respectively, at 7 days post-treatment. Co-treatments with five different inhibitors of poly(ADP-ribose) polymerase (PARP), including benzamide, significantly prevented the MPTP-induced catecholamine depletions. Benzamide was present in the striatum, 30 min after single i.p. injection, at low millimolar concentrations known to selectively inhibit PARP in vitro. The protective activities of benzamide and its derivatives paralleled their in vitro efficacies and potencies both as neuroprotective agents and as inhibitors of PARP, while the activity of 1,5-dihydroxyisoquinoline, a structurally-unrelated compound, did not. In naive animals, the PARP inhibitors by themselves did not alter striatal dopamine levels at 7 days post-treatment. However, in acute studies, 1,5-dihydroxyisoquinoline and nicotinamide caused marked alterations in striatal dopamine metabolite levels; on the contrary, benzamide and its amino-derivatives showed little or no effect on dopamine metabolism. These results indicate that, although these compounds might act at other sites in addition to PARP, PARP inhibitors possess neuroprotective potential in vivo and suggest a role for PARP in MPTP neurotoxicity.
- Published
- 1996
34. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety
- Author
-
Laurent Bardin, J.A. O'Connor, M.B. Assié, Didier Cussac, Agnès Auclair, Adrian Newman-Tancredi, P. Heusler, Ronan Depoortère, M. Marien, and Jean-Claude Martel
- Subjects
Cyclopropanes ,Male ,medicine.medical_specialty ,Serotonin ,Dopamine ,Venlafaxine Hydrochloride ,5-HT ,Venlafaxine ,Thiophenes ,Duloxetine Hydrochloride ,Pharmacology ,Anxiety ,Motor Activity ,Reuptake ,chemistry.chemical_compound ,Cellular and Molecular Neuroscience ,Mice ,Norepinephrine ,Levomilnacipran ,Milnacipran ,Internal medicine ,Neurotransmitter Transport Proteins ,medicine ,Duloxetine ,Animals ,Humans ,Cerebral Cortex ,SNRI ,Adrenergic Uptake Inhibitors ,Behavior, Animal ,Depression ,Cyclohexanols ,Antidepressive Agents ,Rats ,Endocrinology ,chemistry ,Anti-Anxiety Agents ,Rat ,Reuptake inhibitor ,medicine.drug ,Synaptosomes - Abstract
Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.
- Published
- 2012
35. ChemInform Abstract: Arylpiperazide Derivatives of Phenylpiperazines as a New Class of Potent and Selective 5-HT1B Receptor Antagonists
- Author
-
Petrus J. Pauwels, Serge Halazy, Philippe Chopin, Catherine Jorand-Lebrun, C. Moret, Christiane Palmier, and M. Marien
- Subjects
Orally active ,Chemistry ,Extracellular ,Systemic administration ,General Medicine ,Pharmacology ,Receptor ,In vitro - Abstract
A new series of arylpiperazide derivatives of phenylpiperazines of general formula 4 has been prepared and evaluated as 5-HT1B receptor antagonists. In vitro experiments at human cloned 5-HT1B receptors show that these derivatives are potent and selective 5-HT1B receptor antagonists. Among them, compound 4f was found to be orally active, to gain access to the CNS and more importantly to induce an increase in extracellular brain 5-HT upon systemic administration.
- Published
- 2010
36. ChemInform Abstract: Dimerization of Sumatriptan as an Efficient Way to Design a Potent, Centrally and Orally Active 5-HT1B Agonist
- Author
-
Michel Perez, Petrus J. Pauwels, M. Marien, Serge Halazy, C. Fourrier, Gareth W. John, Philippe Chopin, and Jean-Pierre Valentin
- Subjects
Agonist ,biology ,medicine.drug_class ,Chemistry ,Zolmitriptan ,General Medicine ,Pharmacology ,Ligand (biochemistry) ,biology.organism_classification ,In vitro ,Sumatriptan ,New Zealand white rabbit ,Oral administration ,medicine ,Receptor ,medicine.drug - Abstract
A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.
- Published
- 2010
37. The effect of commonly used anticoccidials and antibiotics in a subclinical necrotic enteritis model
- Author
-
M. de Gussem, D Vancraeynest, Freddy Haesebrouck, M Marien, Richard Ducatelle, Anouk Lanckriet, Leen Timbermont, F. Van Immerseel, Pathology, bacteriology and avian diseases, Universiteit Gent = Ghent University [Belgium] (UGENT), and Alpharma Animal Health
- Subjects
Clostridium perfringens ,040301 veterinary sciences ,animal diseases ,Narasin ,Microbial Sensitivity Tests ,Biology ,Tylosin ,Enteritis ,Microbiology ,0403 veterinary science ,Necrosis ,chemistry.chemical_compound ,Food Animals ,Drug Resistance, Bacterial ,medicine ,Animals ,Maduramicin ,Poultry Diseases ,Salinomycin ,Lasalocid ,General Immunology and Microbiology ,Coccidiosis ,0402 animal and dairy science ,Life Sciences ,04 agricultural and veterinary sciences ,medicine.disease ,Animal Feed ,040201 dairy & animal science ,Anti-Bacterial Agents ,Coccidia ,3. Good health ,Lincomycin ,Disease Models, Animal ,chemistry ,Nicarbazin ,Clostridium Infections ,Coccidiostats ,Food Additives ,Animal Science and Zoology ,Chickens ,medicine.drug - Abstract
International audience; Necrotic enteritis poses an important health risk to broilers. The ionophore anticoccidials lasalocid, salinomycin, maduramicin, narasin and a combination of narasin and nicarbazin were tested in feed for their prophylactic effect on the incidence of necrotic enteritis in a subclinical experimental infection model that uses coccidia as predisposing factor. In addition, drinking water medication with the antibiotics amoxicillin, tylosin and lincomycin was evaluated as curative treatment in the same experimental model. The Minimal Inhibitory Concentrations (MICs) of all antibiotics and anticoccidials were determined in vitro against 51 C. perfringens strains isolated from broilers. The strains examined appeared uniformly susceptible to lasalocid, maduramicin, narasin, salinomycin, amoxicillin and tylosin whereas an extended frequency distribution range of MICs of lincomycin was seen, indicating acquired resistance in thirty-six isolates in the higher range of MICs. Nicarbazin did not inhibit the in vitro growth of the C. perfringens strains even at a concentration of 128 µg/ml. Supplementation of the diet from day 1 onwards with lasalocid, salinomycin, narasin or maduramicin lead to a reduction in birds with necrotic enteritis lesions as compared to the non-medicated infected control group. A combination product of narasin and nicarbazin had no significant protective effect. Treatment with amoxicillin, lincomycin and tylosin completely stopped the development of necrotic lesions.
- Published
- 2010
38. Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: A possible role for the locus coeruleus in the progression of Parkinson's disease
- Author
-
M. Marien, A. J. Lategan, Francis Colpaert, A.-D. Degryse, and M. Mavridis
- Subjects
medicine.medical_specialty ,Parkinson's disease ,Dopamine ,Substantia nigra ,Motor Activity ,chemistry.chemical_compound ,Hypokinesia ,Reference Values ,Physical Stimulation ,Internal medicine ,Tremor ,medicine ,Animals ,Parkinson Disease, Secondary ,Saimiri ,Neurons ,Pars compacta ,business.industry ,General Neuroscience ,MPTP ,Putamen ,medicine.disease ,Corpus Striatum ,nervous system diseases ,Electrophysiology ,Substantia Nigra ,Endocrinology ,Acoustic Stimulation ,nervous system ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Anesthesia ,Locus coeruleus ,Female ,Locus Coeruleus ,medicine.symptom ,business ,Locomotion ,medicine.drug - Abstract
Six pairs of female squirrel monkeys were given a daily intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 9-14 days, beginning the same day on which they received either a bilateral 6-hydroxydopamine lesion or a sham lesion of the locus coeruleus. Sham animals developed typical parkinsonian signs (i.e. tremor, bradykinesia, hypokinesia and reduced blink rate) which largely recovered by six to nine weeks after the start of MPTP treatment. At nine weeks, post mortem levels of striatal dopamine in these same animals were partially reduced (by 45%), and this only in the putamen, compared to values obtained from three non-operated, normal control animals. Additionally, histological examination revealed a moderate loss of neuronal cell bodies in the substantia nigra, pars compacta. In marked contrast, the locus coeruleus-lesioned monkeys exhibited little or no recovery from the parkinsonian signs induced by MPTP. Post mortem examination of these animals revealed profound decreases in caudate (by 84%) and putamen (by 91%) dopamine content, and severe neuronal cell loss in the substantia nigra pars compacta of all animals. These neurological, biochemical and histological assessments indicate that lesioning of the locus coeruleus impairs the recovery which usually occurs from the parkinsonian manifestations induced by MPTP in squirrel monkeys. The results support the hypothesis that deficient locus coeruleus noradrenergic mechanisms underlie the progression of Parkinson's disease.
- Published
- 1991
39. In vivo selection of reduced enrofloxacin susceptibility in Ornithobacterium rhinotracheale and its resistance-related mutations in gyrA
- Author
-
Robrecht Froyman, Annemie Decostere, Hans Nauwynck, Luc Devriese, M. Marien, and Freddy Haesebrouck
- Subjects
Microbiology (medical) ,Turkeys ,animal diseases ,Immunology ,Molecular Sequence Data ,Antimicrobial susceptibility ,Microbial Sensitivity Tests ,Biology ,Microbiology ,In vivo ,Flavobacteriaceae Infections ,Drug Resistance, Bacterial ,Enrofloxacin ,medicine ,Animals ,Point Mutation ,Amino Acid Sequence ,skin and connective tissue diseases ,Ornithobacterium rhinotracheale ,Poultry Diseases ,Pharmacology ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Ornithobacterium ,Anti-Bacterial Agents ,DNA Gyrase ,Mic values ,sense organs ,medicine.drug ,Fluoroquinolones - Abstract
This study determines the genetic background of the change in antimicrobial susceptibility to enrofloxacin of Ornithobacterium rhinotracheale (ORT) isolates with increased MIC values, isolated either from the field or from turkeys treated with enrofloxacin under experimental challenge conditions. In the field strains of ORT that were either less susceptible or, occasionally, resistant to enrofloxacin, point mutations had occurred in amino acids at positions 83 (serine) or 87 (aspartic acid) of the GyrA subunit. In the isolates showing reduced susceptibility following experimental enrofloxacin treatment (increase in MIC fromor =0.03 to 0.25 microg/ml), molecular analysis revealed a constantly recurring point mutation (G--T) at nucleic acid position 646 (E. coli numbering) of gyrA resulting in an amino acid change from aspartic acid to tyrosine at position 87 of the GyrA subunit, which is a known hot spot for fluoroquinolone resistance. This study indicates that a single course of enrofloxacin treatment may contribute to the selection of the first mutant with reduced fluoroquinolone susceptibility in ORT. Acquired fluoroquinolone resistance is commonly encountered in ORT isolates. This is the first time that the causal mechanism of fluoroquinolone resistance in ORT has been investigated.
- Published
- 2006
40. Efficacy of enrofloxacin, florfenicol and amoxicillin against Ornithobacterium rhinotracheale and Escherichia coli O2:K1 dual infection in turkeys following APV priming
- Author
-
Annemie Decostere, Robrecht Froyman, Hans Nauwynck, Luc Duchateau, M. Marien, and Koen Chiers
- Subjects
Florfenicol ,Turkeys ,medicine.drug_class ,Antibiotics ,Respiratory Tract Diseases ,Microbial Sensitivity Tests ,Biology ,Microbiology ,chemistry.chemical_compound ,Flavobacteriaceae Infections ,medicine ,Enrofloxacin ,Escherichia coli ,Animals ,Ornithobacterium rhinotracheale ,Escherichia coli Infections ,Poultry Diseases ,Antibacterial agent ,Thiamphenicol ,Paramyxoviridae Infections ,General Veterinary ,Respiratory disease ,Body Weight ,Amoxicillin ,General Medicine ,medicine.disease ,Ornithobacterium ,Anti-Bacterial Agents ,Specific Pathogen-Free Organisms ,Trachea ,medicine.anatomical_structure ,chemistry ,Area Under Curve ,Metapneumovirus ,medicine.drug ,Respiratory tract ,Fluoroquinolones - Abstract
Experimental groups of 15 susceptible 3-week-old turkeys were inoculated oculonasally with avian metapneumovirus (APV) subtype A and susceptible Escherichia coli O2:K1 and Ornithobacterium rhinotracheale (ORT) bacteria, with a 3 days interval between viral and bacterial inoculation and approximately 8h between the two bacterial inoculations. The aims of the present study were to assess the efficacy of drinking-water administration of enrofloxacin for 3 and 5 days, amoxicillin for 5 days and florfenicol for 5 days for the treatment of the resulting respiratory disease, based on clinical and bacteriological examinations. Antimicrobial treatment started 1 day after dual bacterial inoculation. After infection, the birds were examined and scored for clinical signs daily, weighed at different times, and their tracheae swabbed daily. Five birds were euthanised and examined for macroscopic lesions at necropsy at 5 days post-bacterial inoculation (dpbi) and the remainder at 15dpbi. Samples of the turbinates, trachea, lungs, sinuses, air sacs, heart, pericardium and liver were collected for bacteriological examination. Recovery from respiratory disease caused by an APV/E. coli/ORT triple infection in 3-week-old turkey poults was overall most successful after enrofloxacin treatment, irrespective of treatment duration, followed by florfenicol treatment. Compared with the untreated group, clinical signs as well as ORT and E. coli multiplication in the respiratory tract were significantly reduced by both enrofloxacin treatments and the florfenicol treatment, with the enrofloxacin treatments showing significantly better reductions than the florfenicol treatment. Five-day treatment with amoxicillin, compared with the untreated group, did not cause a significant reduction in any of the aforementioned parameters.
- Published
- 2006
41. Comparison and transferability of the **erm**(B) genes between human and farm animal streptococci
- Author
-
Annemie Decostere, E. M. De Graef, Marc Heyndrickx, Luc Devriese, Freddy Haesebrouck, Christine Lammens, M. Marien, H. Goossens, An Martel, and E. De Leener
- Subjects
DNA, Bacterial ,Microbiology (medical) ,Tetracycline ,Immunology ,Transferability ,Streptococcus suis ,Biology ,Microbiology ,Bacterial Proteins ,stomatognathic system ,Streptococcal Infections ,Drug Resistance, Bacterial ,medicine ,Animals ,Humans ,Gene ,Pharmacology ,Genetics ,Streptococcus ,food and beverages ,Methyltransferases ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,In vitro ,Erythromycin ,Animals, Domestic ,Carrier State ,Human medicine ,medicine.drug - Abstract
To obtain better insights into the possible exchange of resistance genes between human and animal streptococci, the sequences of the erm(B) genes of streptococcal isolates from humans, pigs, pork carcasses, chickens, and calves were compared. Identical erm(B) gene sequences were present in strains from humans, pigs, pork carcasses, and calves. During in vitro mating experiments, the erm(B) gene was exchanged between porcine Streptococcus suis and human S. pneumoniae, S. pyogenes, and S. oralis strains. The presence of different tetracycline resistance genes and the int Tn1545 gene was determined in animal streptococci carrying the erm(B) gene. Although tet(M) and int Tn1545 genes were detected in 24% of the porcine and pork carcass streptococcal strains, the tet(O) gene was the predominant tetracycline resistance gene in these strains (81%). The latter gene was co-transferred with the erm(B) gene from porcine S. suis strains to human streptococci in the mating experiments. These results show that, identical erm(B) gene sequences were present in animal and human streptococci and that transfer of the erm(B) gene from porcine S. suis to human streptococci and vice versa is possible, but probably occurs at a low frequency.
- Published
- 2005
42. Protective effect of the alpha2-adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat
- Author
-
M. Marien, Francis Colpaert, Thomas Debeir, Philippe Chopin, and Rita Raisman-Vozari
- Subjects
Male ,medicine.medical_specialty ,Central nervous system ,Morris water navigation task ,Spatial Behavior ,Nucleus basalis ,Neuroprotection ,Brain Ischemia ,Central nervous system disease ,Rats, Sprague-Dawley ,Degenerative disease ,Developmental Neuroscience ,Internal medicine ,medicine ,Animals ,Memory disorder ,Benzopyrans ,Adrenergic alpha-Antagonists ,Cerebral Cortex ,Memory Disorders ,Behavior, Animal ,business.industry ,Antagonist ,Imidazoles ,Adrenergic alpha-2 Receptor Antagonists ,medicine.disease ,Rats ,Endocrinology ,medicine.anatomical_structure ,Neurology ,business ,Neuroscience ,Vascular Surgical Procedures - Abstract
The α2-adrenoceptor antagonist, dexefaroxan, has been shown in the rat to have neuroprotective and plastic effects against degenerative structural changes in elements of the basalocortical cholinergic system that result from cortical devascularization [Neuroscience 115 (2002) 41]. The present study, using the same experimental protocol, examined the functional consequences of cortical devascularization and dexefaroxan treatment in the Morris water maze memory test. Rats were first trained to find the hidden platform in the test, and then subjected to the devascularization procedure. Thirty-one days later, lesioned rats exhibited a significant deficit in recalling the platform location, compared with sham control animals. A 28-day subcutaneous infusion with dexefaroxan (0.63, 2.5, and 10 mg rat−1 day−1), starting from the moment of the devascularization, protected against this spatial memory deficit.
- Published
- 2003
43. Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress
- Author
-
J D, Troadec, M, Marien, F, Darios, A, Hartmann, M, Ruberg, F, Colpaert, and P P, Michel
- Subjects
Neurons ,Cell Death ,Cell Survival ,Dopamine ,Iron ,Catechols ,Receptors, Adrenergic, alpha ,Catalase ,Embryo, Mammalian ,Glutathione ,Antioxidants ,Rats ,Norepinephrine ,Oxidative Stress ,Structure-Activity Relationship ,Mesencephalon ,Receptors, Adrenergic, beta ,Animals ,Rats, Wistar ,Oxidation-Reduction ,Cells, Cultured ,Chelating Agents - Abstract
To better understand the neurotrophic function of the neurotransmitter noradrenaline, we have developed a model of mesencephalic cultures in which we find low concentrations (0.3-10 microM) of noradrenaline to be remarkably effective in promoting long-term survival and function of dopaminergic neurons. This protective action reproduced the effect of caspase inhibition. It was atypical in that it occurred independently of adrenoceptor activation and was mimicked by some antioxidants, redox metal chelators and the hydroxyl radical detoxifying enzyme catalase. Interestingly, intracellular reactive oxygen species (ROS) were drastically reduced by treatment with noradrenaline, indicating that the neurotransmitter itself acted as an antioxidant. Prevention of oxidative stress was, however, independent of the glutathione antioxidant defense system. Chemical analogues of noradrenaline bearing two free hydroxyl groups in the ortho position of the aromatic ring (o-catechols), as well as o-catechol itself, mimicked the survival promoting effects of the neurotransmitter, suggesting that this diphenolic structure was critical for both neuroprotection and reduction of ROS production. Paradoxically, the autoxidation of noradrenaline and the ensuing production of quinone metabolites may be required for both effects, as the neurotransmitter was spontaneously and rapidly degraded over time in the culture medium. These results support the concept that central noradrenergic mechanisms have a neuroprotective role, perhaps in part by reducing oxidative stress.
- Published
- 2001
44. Drug treatments to reduce excitotoxicity in vivo: a potential for alpha2-adrenoceptor antagonists?
- Author
-
M. Marien, Francis Colpaert, Jean-Claude Martel, and Philippe Chopin
- Subjects
Male ,Microdialysis ,Taurine ,Clinical Biochemistry ,Excitotoxicity ,Striatum ,Pharmacology ,Biology ,medicine.disease_cause ,Biochemistry ,Neuroprotection ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,In vivo ,Idazoxan ,medicine ,Animals ,Adrenergic alpha-Antagonists ,Benzofurans ,Behavior, Animal ,Organic Chemistry ,Imidazoles ,Adrenergic alpha-2 Receptor Antagonists ,Choline acetyltransferase ,Corpus Striatum ,Rats ,chemistry ,Quinolinic acid - Abstract
It is hypothesized that the locus coeruleus-noradrenergic system controls compensatory and repair mechanisms in the CNS, and that its dysfunction is a critical factor in the progression of central neurodegenerative diseases. Pharmacological activation of locus coeruleus neurons can be achieved with alpha2-adrenoceptor antagonists, and such compounds are protective in vivo in some models of brain injury where excitotoxicity is thought to be a causative factor. To further explore this neuroprotective potential, the effects of a 7-day treatment with the alpha2-antagonists, (+)-efaroxan and (+/-)-idazoxan, were evaluated in rats undergoing a unilateral lesioning of the striatum with the excitotoxin, quinolinic acid. The alpha2-antagonist treatments reduced both the ipsiversive circling response to apomorphine and the deficit of choline acetyltransferase in the lesioned animals. To elucidate the mechanisms underlying this neuroprotective effect, a modulation of the extracellular levels of amino acids within the striatum was investigated using in vivo microdialysis. Intrastriatal injection of quinolinic acid increased taurine and tyrosine levels by 2-2.5 fold, while most other amino acids were not significantly altered; the effect of (+)-efaroxan on these changes is being investigated. Further research is required to identify which of several possible mechanisms is involved in the neuroprotective action of alpha2-antagonists in vivo.
- Published
- 2000
45. F 11356, a novel 5-hydroxytryptamine (5-HT) derivative with potent, selective, and unique high intrinsic activity at 5-HT1B/1D receptors in models relevant to migraine
- Author
-
G W, John, P J, Pauwels, M, Perez, S, Halazy, B, Le Grand, Y, Verscheure, J P, Valentin, C, Palmier, T, Wurch, P, Chopin, M, Marien, M S, Kleven, W, Koek, M B, Assie, E, Carilla-Durand, J P, Tarayre, and F C, Colpaert
- Subjects
Male ,Swine ,Migraine Disorders ,Guinea Pigs ,Hypothermia ,In Vitro Techniques ,Muscle, Smooth, Vascular ,Piperazines ,Radioligand Assay ,Dogs ,Nitriles ,Cyclic AMP ,Animals ,Humans ,Saphenous Vein ,Neurons ,Dose-Response Relationship, Drug ,Colforsin ,Hemodynamics ,Heart ,Tryptamines ,Rats ,Disease Models, Animal ,Carotid Arteries ,Trigeminal Ganglion ,Guanosine 5'-O-(3-Thiotriphosphate) ,Receptor, Serotonin, 5-HT1D ,Receptors, Serotonin ,Receptor, Serotonin, 5-HT1B ,Rabbits - Abstract
F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.
- Published
- 1999
46. Effects of alpha-2 adrenoceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway
- Author
-
P, Chopin, F C, Colpaert, and M, Marien
- Subjects
Male ,Apomorphine ,Behavior, Animal ,Imidazoles ,Stereoisomerism ,Ligands ,Clonidine ,Rats ,Rats, Sprague-Dawley ,Substantia Nigra ,Idazoxan ,Receptors, Adrenergic, alpha-2 ,Brimonidine Tartrate ,Quinoxalines ,Dopamine Agonists ,Methylphenidate ,Animals ,Stereotyped Behavior ,Oxidopamine ,Adrenergic alpha-Agonists ,Adrenergic alpha-Antagonists ,Benzofurans - Abstract
The present study examined the influence of alpha-2 adrenoceptor ligands on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. The alpha-2 adrenoceptor agonists, clonidine and UK 14304, inhibited both the ipsilateral rotation induced by the indirect dopaminergic agonist, methylphenidate, and the contralateral circling induced by the direct dopaminergic agonist, apomorphine. In contrast, the alpha-2 adrenoceptor antagonists, idazoxan and (+/-)-efaroxan, enhanced the circling induced by either methylphenidate or apomorphine. The facilitating activity of efaroxan was stereoselective because the (+)-enantiomer mimicked the effect of (+/-)-efaroxan, whereas the (-)-enantiomer was essentially inactive, thus indicating a mediation by alpha-2 adrenoceptors. Upon administration alone, the above-mentioned compounds did not modify spontaneous circling behavior, except for UK 14304, which decreased, and (+)-efaroxan, which slightly increased, the ipsilateral rotation. We conclude that activation and antagonism of alpha-2 adrenoceptors inhibit and enhance, respectively, the circling behavior evoked by both direct and indirect dopaminergic agonists. Although a modulation of dopamine release may be involved in some of these drug effects, the effects on apomorphine-induced circling indicate an influence of alpha-2 adrenoceptor compounds on nigrostriatal neurotransmission at sites downstream from the dopaminergic neurons themselves. These findings support the notion of a potential benefit of alpha-2 adrenoceptor antagonists in the treatment of Parkinson's disease.
- Published
- 1999
47. Neuroprotective effects of the alpha2-adrenoceptor antagonists, (+)-efaroxan and (+/-)-idazoxan, against quinolinic acid-induced lesions of the rat striatum
- Author
-
Francis Colpaert, M. Marien, Philippe Chopin, and Jean-Claude Martel
- Subjects
Male ,medicine.medical_specialty ,Apomorphine ,Neurotoxins ,Excitotoxicity ,Striatum ,Biology ,medicine.disease_cause ,Neuroprotection ,Choline O-Acetyltransferase ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Glutamatergic ,Developmental Neuroscience ,Idazoxan ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,medicine ,Animals ,Adrenergic alpha-Antagonists ,Benzofurans ,Behavior, Animal ,Imidazoles ,Quinolinic Acid ,Efaroxan ,Corpus Striatum ,Rats ,Enzyme Activation ,Disease Models, Animal ,Endocrinology ,Huntington Disease ,Neuroprotective Agents ,Neurology ,chemistry ,Dopamine Agonists ,Nerve Degeneration ,Locus coeruleus ,Quinolinic acid ,medicine.drug - Abstract
A deficient control of neuronal repair mechanisms by noradrenergic projections originating from the locus coeruleus may be a critical factor in the progression of neurodegenerative diseases. Blockade of presynaptic inhibitory alpha2-adrenergic autoreceptors can disinhibit this system, facilitating noradrenaline release. In order to test the neuroprotective potential of this approach in a model involving excitotoxicity, the effects of treatments with the alpha2-adreneceptor antagonists, (+)-efaroxan (0.63 mg/kg i.p., thrice daily for 7 days) or (+/-)-idazoxan (2.5 mg/kg i.p., thrice daily for 7 days), were evaluated in rats which received a quinolinic acid-induced lesion of the left striatum. Both drug treatments resulted in a reduced ipsiversive circling response to apomorphine and a reduced choline acetyltransferase deficit in the lesioned striatum. The mechanisms underlying this effect are not known for certain, but may include noradrenergic receptor modulation of glial cell function, growth factor synthesis and release, activity of glutamatergic corticostriatal afferents, and/or events initiated by NMDA receptor activation. These results suggest a therapeutic potential of alpha2-adrenoceptor antagonists in neurodegenerative disorders where excitotoxicity has been implicated.
- Published
- 1999
48. Decreases in mouse brain NAD+ and ATP induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP): prevention by the poly(ADP-ribose) polymerase inhibitor, benzamide
- Author
-
Cristina Cosi and M. Marien
- Subjects
Male ,medicine.medical_specialty ,1-Methyl-4-phenylpyridinium ,Poly ADP ribose polymerase ,Dopamine ,Dopamine Agents ,Poly (ADP-Ribose) Polymerase-1 ,Pyridinium Compounds ,Nicotinamide adenine dinucleotide ,chemistry.chemical_compound ,Mice ,Adenosine Triphosphate ,Mesencephalon ,Internal medicine ,medicine ,Neurotoxin ,Animals ,Benzamide ,Molecular Biology ,Chromatography, High Pressure Liquid ,Brain Chemistry ,General Neuroscience ,MPTP ,NAD+ ADP-Ribosyltransferase ,Proteins ,NAD ,Adenosine Monophosphate ,Corpus Striatum ,Frontal Lobe ,Adenosine Diphosphate ,Mice, Inbred C57BL ,Endocrinology ,Neuroprotective Agents ,nervous system ,chemistry ,Biochemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,PARP inhibitor ,Benzamides ,Neurology (clinical) ,NAD+ kinase ,Poly(ADP-ribose) Polymerases ,Developmental Biology - Abstract
Inhibitors of poly(ADP-ribose) polymerase (PARP), including benzamide, protect against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced dopamine neurotoxicity in vivo [Cosi et al., Brain Res. 729 (1996) 264-269]. In vitro, the activation of PARP by free radical damaged DNA has been shown to be correlated with rapid decreases in the cellular levels of its substrate nicotinamide adenine dinucleotide (NAD+), and ATP. Here, we investigated in vivo whether MPTP acutely caused region- and time-dependent changes in brain levels of NAD+, ATP, ADP and AMP in C57BL/6N mice killed by head-focused microwave irradiation, and whether such effects were modified by treatments with neuroprotective doses of benzamide. At 1 h after MPTP injections (4x20 mg/kg i.p.), NAD+ was reduced by 11-13% in the striatum and ventral midbrain, but not in the frontal cortex. The ATP/ADP ratio was reduced by 10% and 32% in the striatum and cortex, respectively, but was unchanged in the midbrain. All of these regional changes were prevented by co-treatment with benzamide (2x160 mg/kg i.p.), which by itself did not alter regional levels of NAD+, ATP, ADP or AMP in control mice. In a time-course study, a single dose of MPTP (30 mg/kg i.p.) resulted in maximal and transient increases in striatal levels of MPP+ and 3-methoxytyramine (+540%) at 0.5-2 h, followed by maximal and coincidental decreases in NAD+ (-10%), ATP (-11%) and dopamine content (-39%) at 3 h. Benzamide (1x640 mg/kg i. p., 30 min before MPTP) partially reduced MPP+ levels by 30% with little or no effect on MPTP or MPDP+ levels, did not affect or even slightly potentiated the increase in 3-methoxytyramine, and completely prevented the losses in striatal NAD+, ATP and dopamine content, without by itself causing any changes in these latter parameters in control mice. These results (1) confirm that MPTP reduces striatal ATP levels [Chan et al., J. Neurochem. 57 (1991) 348-351.]; (2) show that MPTP causes a regionally-dependent (striatal and midbrain) loss of NAD+; (3) indicate that the PARP inhibitor benzamide can prevent these losses without interfering with MPTP-induced striatal dopamine release; and (4) provide further evidence to suggest an involvement of PARP in MPTP-induced neurotoxicity in vivo.
- Published
- 1998
49. Poly(ADP-ribose) polymerase (PARP) revisited. A new role for an old enzyme: PARP involvement in neurodegeneration and PARP inhibitors as possible neuroprotective agents
- Author
-
Marta Menegazzi, Francis Colpaert, Laura Facci, Cristina Cosi, Wouter Koek, G. Vantini, M. Marien, Hisanori Suzuki, Stephen D. Skaper, D. Milani, A. Degryse, and Yoshiyuki Kanai
- Subjects
Transcription, Genetic ,Cell Survival ,Poly ADP ribose polymerase ,Dopamine ,Neurotoxins ,Glutamic Acid ,Pharmacology ,Poly(ADP-ribose) Polymerase Inhibitors ,Neuroprotection ,Benzoates ,General Biochemistry, Genetics and Molecular Biology ,PARP ,chemistry.chemical_compound ,Mice ,Catecholamines ,Benzamide ,History and Philosophy of Science ,Cerebellum ,neurotoxicity ,medicine ,Animals ,RNA, Messenger ,Enzyme Inhibitors ,Cells, Cultured ,chemistry.chemical_classification ,Neurons ,Chemistry ,General Neuroscience ,Neurodegeneration ,Neurotoxicity ,Brain ,MPTP Poisoning ,Benzoic Acid ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Enzyme ,Neuroprotective Agents ,Benzamides ,Poly(ADP-ribose) Polymerases - Published
- 1997
50. Trismus: causes, differential diagnosis, and treatment
- Author
-
M, Marien
- Subjects
Diagnosis, Differential ,Temporomandibular Joint ,Humans ,Trismus ,Range of Motion, Articular - Abstract
Successful treatment of trismus depends upon prompt recognition of its cause and the initiation of appropriate management. Otherwise, trismus may lead to permanent functional impairment. Differential diagnosis and modes of treatment are reviewed.
- Published
- 1997
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