Aude Bressenot

Publications of Aude Bressenot

• Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α and HNF-4α in rat liver.

  Authors: Shabnam Pooya, Sébastien Blaise, Maira Moreno Garcia, Jean Giudicelli, Jean-Marc Alberto, Rosa-Maria Guéant-Rodriguez, Elise Jeannesson, Naig Gueguen, Aude Bressenot, Bénédicte Nicolas, Yves Malthiery, Jean-Luc Daval, Laurent Peyrin-Biroulet, Jean-Pierre Bronowicki, Jean-Louis Guéant

  Journal of hepatology. 04/2012;

  BACKGROUND: Folate and cobalamin are methyl donors needed for synthesizing methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic and epigenomicBACKGROUND: Folate and cobalamin are methyl donors needed for synthesizing methionine, which is the precursor of S-adenosylmethionine, the substrate of methylation in epigenetic and epigenomic pathways. Methyl donor deficiency produces liver steatosis and predisposes to metabolic syndrome. Whether impaired fatty acid oxidation contributes to this steatosis remains unknown. METHODS: We evaluated the consequences of methyl donor deficient diet in liver of pups from dams subjected to deficiency during gestation and lactation. RESULTS: The deprived rats had microvesicular steatosis, with increased triglycerides, decreased methionine synthase activity, S-adenosylmethionine and S-adenosylmethionine/S-adenosylhomocysteine ratio. We observed no change in apoptosis markers, oxidant and reticulum stresses, and carnityl-palmitoyl transferase1 activity and a decreased expression of SREBP-1c. Impaired beta-oxidation of fatty acids and carnitine deficit were the predominant changes, with decreased free and total carnitines, increased C14:1/C16 acylcarnitine ratio, decrease of oxidation rate of palmitoyl-CoA and palmitoyl-L-carnitine and decrease of expression of novel organic cation transporter 1, acylCoA-dehydrogenase and trifunctional enzyme subunit alpha and decreased activity of complexes I and II. These changes were related to lower protein expression of ER-α, ERR-α and HNF-4α and hypomethylation of PGC-1α co-activator that reduced its binding with PPAR-α, ERR-α and HNF-4α. CONCLUSION: The liver steatosis resulted predominantly from hypomethylation of PGC1-α, decreased binding with its partners and subsequent impaired mitochondrial fatty acid oxidation. This link between methyl donor deficiency and epigenomic deregulations of energy metabolism opens new insights on pathogenesis of fatty liver disease, in particular in relation with the foetal programming hypothesis. (250 words).

• Expression of minichromosome maintenance MCM6 protein in meningiomas is strongly correlated with histologic grade and clinical outcome.

  Authors: Guillaume Gauchotte, Charlène Vigouroux, Fabien Rech, Shyue-Fang Battaglia-Hsu, Marc Soudant, Catherine Pinelli, Thierry Civit, Luc Taillandier, Jean-Michel Vignaud, Aude Bressenot

  The American journal of surgical pathology. 02/2012; 36(2):283-91.

  The 2007 World Health Organization histologic grading of meningiomas is associated with recurrence and clinical outcome. However, distinction of grade I from grade II (atypical) meningiomas can beThe 2007 World Health Organization histologic grading of meningiomas is associated with recurrence and clinical outcome. However, distinction of grade I from grade II (atypical) meningiomas can be challenging. In the World Health Organization classification, there are 4 parameters on the basis of which grade II status can be determined: mitotic rate, cytoarchitectural features, brain invasion, and/or histologic subtype. Furthermore, this classification fails to detect grade I recurrent meningiomas, for which other prognostic criteria would be needed. The aim of this study was to evaluate the respective value of several markers involved in cell cycle as effective tools to predict recurrence. This retrospective study was based on a series of 59 meningiomas (grade I: 32 of 59, grade II: 27 of 59, all harboring ≥4 mitoses/1.6 mm), analyzed with the following immunohistochemical markers: MCM6, Ki-67, PHH3, cyclin D1, and p53. We found a significant correlation between histologic grade and mean labeling index for MCM6 (grade I: 21.8% vs. grade II: 65.8%; P<0.001), Ki-67 (3.2% vs. 16.9%; P<0.001), PHH3 (0.7‰ vs. 2.8‰; P<0.001), cyclin D1 (50.4% vs. 70.0%; P=0.005), and p53 (17.3% vs. 32.4%; P=0.017). Histologic grading and mitotic index were correlated with progression-free survival (P=0.010 and P=0.020, respectively). A nearly linear correlation was found between progression-free survival and staining for MCM6 (P<0.001), Ki-67 (P=0.003), and PHH3 (P=0.037) but not for cyclin D1 (P=0.400) and p53 (P=0.758). The interobserver agreement coefficients for MCM6, Ki-67, PHH3, cyclin D1, and p53 were, respectively, 0.97 (95% confidence interval, 0.95-0.98), 0.93 (0.89-0.96), 0.81 (0.70-0.88), 0.90 (0.83-0.94), and 0.84 (0.73-0.90). In conclusion, because of its strong level of expression and sharp difference in labeling index between indolent and recurrent tumors, MCM6 is the most efficient marker to identify tumors with a high risk of recurrence.

• A splicing variant leads to complete loss of function of betaine-homocysteine methyltransferase (BHMT) gene in hepatocellular carcinoma.

  Authors: Hélène Pellanda, Farès Namour, Ma'atem Fofou-Caillierez, Aude Bressenot, Jean-Marc Alberto, Céline Chéry, Ahmet Ayav, Jean-Pierre Bronowicki, Jean-Louis Guéant, Thierry Forges

  The international journal of biochemistry & cell biology. 11/2011; 44(2):385-92.

  The remethylation of homocyteine into methionine is catalyzed either by methionine synthase (MTR) or by betaine-homocysteine methyltransferase (BHMT), in the liver. Choline/betaine deficiency andThe remethylation of homocyteine into methionine is catalyzed either by methionine synthase (MTR) or by betaine-homocysteine methyltransferase (BHMT), in the liver. Choline/betaine deficiency and impaired BHMT pathway have been associated with hepatocellular carcinogenesis, in animal models. The molecular mechanisms that impair the BHMT pathway are unknown. We aimed to investigate BHMT, BHMT2, and MTR expression in HepG2 cells and human hepatocarcinoma tissues. Transcripts were quantified by RT-qPCR and splicing was assessed by analysis of exon junctions and sequencing of variants. Protein expression was studied by Western Blot, immunohistochemistry and enzyme activity. Tumor tissue was compared with surrounding healthy tissue. RT-qPCR of HepG2 cells and of tumor samples showed a strong decrease of transcripts of BHMT and BHMT2, compared to normal. MTR transcript levels were not different. The decreased BHMT expression resulted from the transcription of a splicing variant that produced a frameshift in exon 4, with a premature termination codon in exon 5 and a loss of function of the gene. This splicing variant did not fit with any mechanism resulting from known splicing consensus sequences and was not detected in normal adult and fetal liver. Consistently, BHMT activity was abolished in HepG2 and protein expression was not detectable in HepG2 and in 5 of the 6 tumor samples, compared to normal tissues. In conclusion, a transcription variant of exon 4 produces a loss of function of BHMT in human hepatocarcinoma. Whether this abnormal transcription of BHMT is part or consequence of liver carcinogenesis should deserve further investigations.

• BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis.

  Authors: Guillaume Gauchotte, Christophe Philippe, Stéphanie Lacomme, Brigitte Léotard, Marie-Pierre Wissler, Lila Allou, Bruno Toussaint, Marc Klein, Jean-Michel Vignaud, Aude Bressenot

  Pathology. 06/2011; 43(5):447-52.

  The aim of this study was to genotype a series of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) for BRAF mutation, and to evaluate p53 and SOX2 expression as factorsThe aim of this study was to genotype a series of papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) for BRAF mutation, and to evaluate p53 and SOX2 expression as factors implicated in tumour progression. The study included 17 PTCs and 14 ATCs. Analysis of the exon 15 of BRAF was based on direct sequencing. Immunohistochemistry was used to evaluate p53 and SOX2 expression. V600E (c.1799T>A) mutation was observed in 53% (9/17) of PTCs. Two cases of ATCs (2/14; 14%), both with PTC component, harboured BRAF mutation: the classical V600E mutation and an undocumented duplication of codon 599 (c.1795_1797dup; p.Thr599dup). These mutations were present in ATC as well as PTC tumour cells. Overexpression of p53 and SOX2 was depicted respectively in 64% (9/14) and 29% (4/14) of ATCs, and absent in PTCs. We confirm that V600E mutation is a frequent and specific event in PTC. BRAF-mutated ATCs are associated with a PTC component displaying the same mutation. We describe a new mutation of BRAF, T599dup, in a case of ATC with tall cell PTC component. Moreover, progression from PTC to ATC could be favoured by further TP53 mutation and SOX2 expression.

• Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury.

  Authors: Sylvain Normand, Anne Delanoye-Crespin, Aude Bressenot, Ludovic Huot, Teddy Grandjean, Laurent Peyrin-Biroulet, Yves Lemoine, David Hot, Mathias Chamaillard

  Proceedings of the National Academy of Sciences of the United States of America. 06/2011; 108(23):9601-6.

  The colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate thatThe colonic epithelium self-renews every 3 to 5 d, but our understanding of the underlying processes preserving wound healing from carcinogenesis remains incomplete. Here, we demonstrate that Nod-like receptor pyrin domain-containing protein 6 (NLRP6) suppresses inflammation and carcinogenesis by regulating tissue repair. NLRP6 was primarily produced by myofibroblasts within the stem-cell niche in the colon. Although NLRP6 expression was lowered in diseased colon, NLRP6-deficient mice were highly susceptible to experimental colitis. Upon injury, NLRP6 deficiency deregulated regeneration of the colonic mucosa and processes of epithelial proliferation and migration. Consistently, absence of NLRP6 accelerated colitis-associated tumor growth in mice. A gene-ontology analysis on a whole-genome expression profiling revealed a link between NLRP6 and self-renewal of the epithelium. Collectively, the integrity of the epithelial barrier is preserved by NLRP6 that may be manipulated to develop drugs capable of preventing adenoma formation in inflammatory bowel diseases.

• [Diagnostic accuracy of endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymph nodes].

  Authors: Guillaume Gauchotte, Marie-Pierre Wissler, Aude Bressenot, Christelle Clément-Duchêne, Béatrice Marie, Olivier Ménard, Jean-Michel Vignaud

  Annales de pathologie. 06/2011; 31(3):142-51.

  Endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymph nodes is a safe method that can be performed for mediastinal and hilar lymph nodes sampling. Because it allowsEndobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymph nodes is a safe method that can be performed for mediastinal and hilar lymph nodes sampling. Because it allows collecting only a small amount of materiel, an optimal processing of the samples is needed. Based on 150 consecutive procedures, we evaluate the overall diagnostic performances and of each technical methods used for the exploitation of the samples. The global diagnostic yield is 64.0% for the 50 first exams (learning phase), 88.0% for the next 100 exams. The maximal sensitivity and negative predictive value (NPV) are 79.3%, 96.3% and 92.7%, respectively. The yield, sensitivity and NPV of smears are 68.0%, 75.0% and 66.0%, of monolayer preparation 77.8%, 62.1% and 50.0%, of sections from tissue cores of 65.8%, 94.4% and 86.7%. The combination of the different methods increases the yield comparing to tissue cores and smears when taken alone (P < 0.05), and the sensibility and the NPV comparing to smears (P < 0.0005 and P < 0.01, respectively) and monolayer preparation (P < 0.0001 and P < 0.0005, respectively). The sensitivity of tissue cores is greater than smears (P < 0.005) and monolayer preparations (P < 0.0001). This increase in sensitivity is significant for granuloma (sarcoidosis), but not for carcinoma. Endobronchial ultrasound-guided transbronchial needle aspiration is an accurate and sensitive technique. Liquid based conditioning of samples and paraffin embedded tissue cores increases the diagnostic performances comparing to smears, notably for the diagnosis of sarcoidosis.

• [Metaplastic carcinomas of the breast: a morphological and immunohistochemical study].

  Authors: Guillaume Gauchotte, Emilie Gauchotte, Aude Bressenot, Jean-Luc Verhaeghe, François Guillemin, Agnès Leroux, Pascal Genin

  Annales de pathologie. 02/2011; 31(1):18-27.

  Metaplastic carcinomas of the breast are rare and form a heterogenic group of tumors, characterized by the presence of squamous or sarcomatoid differentiation. In 23 cases, we study the mainMetaplastic carcinomas of the breast are rare and form a heterogenic group of tumors, characterized by the presence of squamous or sarcomatoid differentiation. In 23 cases, we study the main histoprognostic features, hormonal status, and the expression of HER2, CK5/6, CK14, p63, EGFR, beta-catenin, MUC1 and E-cadherin, the expression of this seven last antigens being also studied in nodal metastases. The different metaplastic types are spindle cell carcinoma (35%), squamous cell carcinoma (26%), osteo- or chondrosarcomatoid (11%) or mixed type (26%). Vascular emboli are seen in 30% of the tumors and perinervous infiltration in 4%. 33% of the patients have nodal metastases. The immunohistochemical features are: RO+: 4%; RP+: 8%; HER2+: 0%; p63+: 74%; CK14+: 83%; CK5/6+: 74%; EGFR+: 100%; E-cadherin+: 70%; beta-catenin: aberrant staining (cytoplasm or weak membrane staining greater than 5%): 74%, negative: 13%; MUC1: aberrant staining (cytoplasm or complete membrane staining greater than 5%): 35%, pure partial membrane staining: 22%, negative: 43%. In 43% of tumors, more aberrant staining for MUCI is present in nodal metastases compared with primitive tumor. Metaplastic carcinomas are aggressive tumors, generally with a "triple-negative" and basal phenotype. The expressions of MUC1 and beta-catenin are often absent or aberrant, which could favor metastatic dissemination.

• Salivary gland anlage tumor: a clinicopathological study of two cases.

  Authors: Guillaume Gauchotte, Laurent Coffinet, Emmanuelle Schmitt, Aude Bressenot, Virginie Hennequin, Jacqueline Champigneulle, Jean-Michel Vignaud

  Fetal and pediatric pathology. 01/2011; 30(2):116-23.

  We report two cases of salivary gland anlage tumor (SGAT), a nasopharyngeal lesion that affects newborns. The first case concerned a male newborn, presenting respiratory distress secondary to aWe report two cases of salivary gland anlage tumor (SGAT), a nasopharyngeal lesion that affects newborns. The first case concerned a male newborn, presenting respiratory distress secondary to a nasopharyngeal mass. The second case was diagnosed in a 6-week-old girl, suffering from respiratory difficulties due to a nasal cavity mass. A magnetic resonance imaging (MRI) in the second case revealed the presence of several small round and linear fluid-like areas. Histologically, both lesions were suggestive of SGAT, characterized by epithelial structures that blended with spindle-cells, drawing highly cellular nodules. Connective tissue between nodules contained squamous cystic nests and ducts.

• Methyl deficient diet aggravates experimental colitis in rats.

  Authors: Min Chen, Laurent Peyrin-Biroulet, Amandine George, Florence Coste, Aude Bressenot, Carine Bossenmeyer-Pourie, Jean-Marc Alberto, Bing Xia, Bernard Namour, Jean-Louis Guéant

  Journal of cellular and molecular medicine. 12/2010; 15(11):2486-97.

  Inflammatory bowel diseases (IBD) result from complex interactions between environmental and genetic factors. Low blood levels of vitamin B12 and folate and genetic variants of related target enzymesInflammatory bowel diseases (IBD) result from complex interactions between environmental and genetic factors. Low blood levels of vitamin B12 and folate and genetic variants of related target enzymes are associated with IBD risk, in population studies. To investigate the underlying mechanisms, we evaluated the effects of a methyl-deficient diet (MDD, folate, vitamin B12 and choline) in an experimental model of colitis induced by dextran sodium sulphate (DSS), in rat pups from dams subjected to the MDD during gestation and lactation. Four groups were considered (n = 12-16 per group): C DSS(-) (control/DSS(-)), D DSS(-) (deficient/DSS(-)), C DSS(+) (control/DSS(+)) and D DSS(+) (deficient/DSS(+)). Changes in apoptosis, oxidant stress and pro-inflammatory pathways were studied within colonic mucosa. In rat pups, the MDD produced a decreased plasma concentration of vitamin B12 and folate and an increased homocysteine (7.8 ± 0.9 versus 22.6 ± 1.2 μmol/l, P < 0.001). The DSS-induced colitis was dramatically more severe in the D DSS(+) group compared with each other group, with no change in superoxide dismutase and glutathione peroxidase activity, but decreased expression of caspase-3 and Bax, and increased Bcl-2 levels. The mRNA levels of tumour necrosis factor (TNF)-α and protein levels of p38, cytosolic phospolipase A2 and cyclooxygenase 2 were significantly increased in the D DSS(+) pups and were accompanied by a decrease in the protein level of tissue inhibitor of metalloproteinases (TIMP)3, a negative regulator of TNF-α. MDD may cause an overexpression of pro-inflammatory pathways, indicating an aggravating effect of folate and/or vitamin B12 deficiency in experimental IBD. These findings suggest paying attention to vitamin B12 and folate deficits, frequently reported in IBD patients.

• Compartmental targeting for mTHPC-based photodynamic treatment in vivo: Correlation of efficiency, pharmacokinetics, and regional distribution of apoptosis.

  Authors: Julie Garrier, Aude Bressenot, Susanna Gräfe, Sophie Marchal, Soumya Mitra, Thomas H Foster, François Guillemin, Lina Bezdetnaya

  International journal of radiation oncology, biology, physics. 10/2010; 78(2):563-71.

  The present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeuticThe present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeutic efficacy was, furthermore, related to a regional photoinduced distribution of apoptosis and an mTHPC biodistribution profile. Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm(2)) of red laser light (652 nm) at different intervals after a single- (0.3 mg/kg or 0.15 mg/kg) or double-intravenous (2 × 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumor regrowth. mTHPC pharmacokinetics were assessed by high-performance liquid chromatography analysis of excised organs. The regional distribution of apoptosis in tumor sections was investigated with a newly developed colabelling immunohistochemistry technique. A fractionated double-injection protocol of mTHPC with 24-h and 3-h drug-light intervals (DLI) yielded 100% tumor cure, with tumors presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumor cure and corresponded to a DLI of 3 h. At this DLI, tumors showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumor for the fractionated injection were not statistically different and were less than the total drug dose in each compartment. The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatiotemporal drug distribution.

• Diffusion-weighted magnetic resonance without bowel preparation for detecting colonic inflammation in inflammatory bowel disease.

  Authors: Abderrahim Oussalah, Valérie Laurent, Olivier Bruot, Aude Bressenot, Marc-André Bigard, Denis Régent, Laurent Peyrin-Biroulet

  Gut. 08/2010; 59(8):1056-65.

  Magnetic resonance imaging (MRI) enables accurate assessment of inflammatory bowel diseases (IBD), but its main limitation is the need for bowel preparation. Diffusion-weighted imaging is feasible inMagnetic resonance imaging (MRI) enables accurate assessment of inflammatory bowel diseases (IBD), but its main limitation is the need for bowel preparation. Diffusion-weighted imaging is feasible in Crohn's disease. We evaluated the accuracy of MRI in combination with diffusion-weighted imaging (DWI-MRI) without oral or rectal preparation in assessing colonic inflammation in both ulcerative colitis and Crohn's disease. This was an observational study of a single-centre cohort. All patients who underwent DWI-MRI-colonography without bowel preparation between January 2008 and February 2010 in our centre were analysed. Among the 96 patients (ulcerative colitis=35; Crohn's disease=61) who had DWI-MRI-colonography, 68 had concomitant endoscopy. In ulcerative colitis a segmental magnetic resonance score (MR-score-S) >1 detected endoscopic inflammation with a sensitivity and specificity of 89.47% and 86.67%, respectively (AUROC=0.920, p=0.0001). In the Crohn's disease group, a MR-score-S >2 detected endoscopic inflammation in the colon with a sensitivity and specificity of 58.33% and 84.48%, respectively (AUROC=0.779, p=0.0001). The MR-score-S demonstrated better accuracy for the detection of endoscopic inflammation in the ulcerative colitis group than in the Crohn's disease group (p=0.003). In ulcerative colitis, the proposed total magnetic resonance score (MR-score-T) correlated with the total modified Baron score (r=0.813, p=0.0001) and the Walmsley index (r=0.678, p<0.0001). In Crohn's disease, the MR-score-T correlated with the simplified endoscopic activity score for Crohn's disease (r=0.539, p=0.001) and the Crohn's disease activity index (r=0.367, p=0.004). The DWI hyperintensity was a predictor of colonic endoscopic inflammation in ulcerative colitis (OR=13.26, 95% CI 3.6 to 48.93; AUROC=0.854, p=0.0001) and Crohn's disease (OR=2.67, 95% CI 1.25 to 5.72; AUROC=0.702, p=0.0001). The accuracy of the DWI hyperintensity for detecting colonic inflammation was greater in ulcerative colitis than in Crohn's disease (p=0.004). DWI-MRI-colonography without bowel preparation is a reliable tool for detecting colonic inflammation in ulcerative colitis.

• Colonic cryptosporidiosis in allograft patients: a rare differential diagnosis of acute graft-versus-host disease.

  Authors: Guillaume Gauchotte, Aude Bressenot

  Human pathology. 06/2010; 41(6):918-9; author reply 919-20.

• Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.

  Authors: Laurent Peyrin-Biroulet, Julia Beisner, Guoxing Wang, Sabine Nuding, Sajit Thottathil Oommen, Denise Kelly, Erika Parmentier-Decrucq, Rodrigue Dessein, Emilie Merour, Philipe Chavatte, Teddy Grandjean, Aude Bressenot, Pierre Desreumaux, Jean-Frédéric Colombel, Béatrice Desvergne, Eduard F Stange, Jan Wehkamp, Mathias Chamaillard

  Proceedings of the National Academy of Sciences of the United States of America. 05/2010; 107(19):8772-7.

  Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gammaCrohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.

• [Glyoxal: a possible polyvalent substitute for formaldehyde in pathology?]

  Authors: Nathalie Marcon, Aude Bressenot, Karine Montagne, Claire Bastien, Jacqueline Champigneulle, Nathalie Monhoven, Eliane Albuisson, François Plénat

  Annales de pathologie. 12/2009; 29(6):460-7.

  The quest for formaldehyde substitutes is motivated by two fundamental developments: the OSHA regulation standard declaring it hazardous and advocating its substitution with less dangerous chemicalsThe quest for formaldehyde substitutes is motivated by two fundamental developments: the OSHA regulation standard declaring it hazardous and advocating its substitution with less dangerous chemicals and the fact that formalin is a poor preserver of nucleic acids. Among the non-alcoholic formalin substitute, glyoxal has been hailed as the best alternative. In this work, we showed that glyoxal-containing fixatives are not plausible polyvalent substitution options.

• [Detection of apoptosis in vivo: comparison of different methods in histological sections of subcutaneous xenografts of HT29 human colon adenocarcinoma]

  Authors: Aude Bressenot, Olivia Zimmer, Sophie Marchal, Guillaume Gauchotte, Karine Montagne, François Plénat

  Annales de pathologie. 10/2009; 29(5):370-5.

  Apoptosis detection in histological section is very important, but usual methods (TUNEL and morphologic changes) are controversial. Immunohistochemical stains of activated proteins during apoptosisApoptosis detection in histological section is very important, but usual methods (TUNEL and morphologic changes) are controversial. Immunohistochemical stains of activated proteins during apoptosis improve detection of cell death in tissue sections. Activated caspase-3 and cleaved cytokeratin-18 are more and more used. OBJECTIVE: This study compared immunohistochemical markers (activated caspase-3, cleaved cytokeratin-18 and two antibodies not yet evaluated: activated caspase-7 and cleaved PARP-1), cellular morphology and TUNEL. MATERIAL AND METHODS: Tumour xenografts of the human colon cancer cell line HT29 were used, treated by photodynamic therapy, to obtain large numbers of cells undergoing apoptosis. Apoptotic cells were quantified and apoptotic indices were determined for each marker. RESULTS: Comparison of apoptosis index indicated statistically best sensibility with activated-caspase-3 and cleaved-cytokeratin-19. CONCLUSION: Immunohistochemistry for activated caspase-3 and cleaved cytkeratin-18 appear to be an easy, sensitive, and reliable method for detecting and quantifying apoptosis in this model. There are therefore recommended for the detection and quantification of apoptosis in tissue sections. Other markers as cleaved PARP-1 and activated caspase-7 can be an interessant solution: advantages and inconvenience for each methods are exposed.

• Contrast-enhanced ultrasonography in patients with glycogen storage disease type Ia and adenomas.

  Authors: Anh T Nguyen, Aude Bressenot, Simona Manolé, Marie A Galloy, Jean P Bronowicki, Michel Vidailhet, François Feillet, Michel Claudon

  Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 05/2009; 28(4):497-505.

  OBJECTIVE: The purpose of this series was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the characterization of focal liver lesions (FLLs) in patients with glycogen storageOBJECTIVE: The purpose of this series was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the characterization of focal liver lesions (FLLs) in patients with glycogen storage diseases (GSDs). METHODS: Contrast-enhanced ultrasonographic data obtained for characterization of 8 FLLs (size, 0.9-10.2 cm) in 2 patients with GSD type Ia (GSD-Ia) and lesion growth or recurrent abdominal pain were reviewed and compared with computed tomographic (CT) and magnetic resonance imaging (MRI) data. After total and left hepatectomy, pathologic examination confirmed benign adenomas in 6 of the evaluated lesions. Follow-up confirmed benignity in the 2 remaining lesions. RESULTS: In all FLLs, CEUS showed marked hypervascularity in the early arterial phase. Centripetal filling was shown in only 1 lesion, and diffuse enhancement without any clear direction was shown in all other lesions. During the portal and late phases, 6 of the 8 lesions showed sustained enhancement, including 2 lesions that appeared heterogeneous during all phases of CT and MRI. In an aspect of 1 of these 6 large adenomas, late wash-out could be explained by sinusoid compression. The other 2 adenomas showed moderate wash-out but remained homogeneous. CONCLUSIONS: Focal liver lesions found in patients with GSD-Ia have similar patterns on CEUS compared with incidental adenomas. Global or partial hypoenhancement observed in the late phase did not indicate a transition to hepatocellular carcinoma but may have been related to ischemia.

• CK20/CK7 protein expression in colorectal cancer: a marker for progression of colorectal cancer.

  Authors: Aude Bressenot, Olivia Zimmer

  Human pathology. 12/2008; 39(11):1714; author reply 1715.

• Immunohistochemical markers to distinguish between hemangioblastoma and metastatic clear-cell renal cell carcinoma in the brain: utility of aquaporin1 combined with cytokeratin AE1/AE3 immunostaining.

  Authors: Nicolas Weinbreck, Béatrice Marie, Aude Bressenot, Karine Montagne, Antony Joud, Cédric Baumann, Olivier Klein, Jean-Michel Vignaud

  The American journal of surgical pathology. 08/2008; 32(7):1051-9.

  Distinguishing hemangioblastomas from metastatic clear-cell renal cell carcinomas (CCRCCs) in the brain is a diagnostic challenge owing to similar clinical and morphologic presentations.Distinguishing hemangioblastomas from metastatic clear-cell renal cell carcinomas (CCRCCs) in the brain is a diagnostic challenge owing to similar clinical and morphologic presentations. Inhibin-alpha and aquaporin1 were shown as positive markers of hemangioblastoma, but are not totally reliable distinguishing hemangioblastoma from metastatic CCRCC. This study shows that the diagnosis can be achieved using a combination of markers. To identify the panel of markers useful for this differential, 67 hemangioblastomas and 34 metastatic CCRCCs were analyzed using a panel of antibodies including aquaporin1, inhibin-alpha, D2-40, cytokeratin AE1/AE3, epithelial membrane antigen, and CD10. The study confirms the usefulness of aquaporin1 (97% sensitivity, 83% specificity) and inhibin-alpha (88% sensitivity, 79% specificity) as positive markers of hemangioblastoma and shows that aquaporin1 is a superior positive marker versus inhibin-alpha for the differential. Positivity of tumor cells with cytokeratin AE1/AE3 is the signature of a metastatic CCRCC (100% specificity, 88% sensitivity) and CD10 expression as well (100% specificity, 79% sensitivity). The combined use of aquaporin1 and AE1/AE3 yields a high degree of sensitivity and specificity to differentiate between hemangioblastoma and metastatic CCRCC. All tumors but one aquaporin1 positive and cytokeratin AE1/AE3 negative (65/66) correspond to hemangioblastomas (97% sensitivity, 97% specificity, 98.5% diagnostic positive predictive value). Tumors with the opposite profile, aquaporin1 negative, and cytokeratin AE1/AE3 positive, (25/25), correspond to metastatic CCRCC (74% sensitivity, 100% specificity, 100% diagnostic positive predictive value). In summary, aquaporin1 is the most sensitive positive marker of hemangioblastoma. Despite its moderate specificity, when used in combination with epithelial marker AE1/AE3, it allowed to reliably distinguish hemangioblastoma from metastatic CCRCC.

• Clear cell adenocarcinoma: a rare variant of primary colonic tumour.

  Authors: Aude Bressenot, Nathalie Marcon, Karine Montagne, François Plénat

  International journal of colorectal disease. 02/2008; 23(1):137-8.

• Role of alpha1beta1-integrin in arterial stiffness and angiotensin-induced arterial wall hypertrophy in mice.

  Authors: Huguette Louis, Augustine Kakou, Veronique Regnault, Carlos Labat, Aude Bressenot, Jacqueline Gao-Li, Humphrey Gardner, Simon N Thornton, Pascal Challande, Zhenlin Li, Patrick Lacolley

  American journal of physiology. Heart and circulatory physiology. 11/2007; 293(4):H2597-604.

  We examined the arterial phenotype of mice lacking alpha(1)-integrin (alpha(1)(-/-)) at baseline and after 4 wk of ANG II or norepinephrine (NE) administration. Arterial mechanical properties wereWe examined the arterial phenotype of mice lacking alpha(1)-integrin (alpha(1)(-/-)) at baseline and after 4 wk of ANG II or norepinephrine (NE) administration. Arterial mechanical properties were determined in the carotid artery (CA). Integrin expression, MAPK kinases, and focal adhesion kinase (FAK) were assessed in the aorta. No change in arterial pressure was observed in alpha(1)(-/-) mice. Elastic modulus-wall stress curves were similar in alpha(1)(-/-) and alpha(1)(+/+) animals, indicating no change in arterial stiffness. The rupture pressure was lower in alpha(1)(-/-) mice, demonstrating decreased mechanical strength. Lack of alpha(1)-integrin was accompanied by an increase in beta(1)-, alpha(v)-, and alpha(5)-integrins but no change in alpha(2)-integrin. ANG II increased medial cross-sectional area of the CA in alpha(1)(+/+), but not alpha(1)(-/-), mice, whereas equivalent pressor doses of NE did not produce a significant increase in either group. In alpha(1)(+/+) mice, ANG II induced alpha(1)-integrin expression and smooth muscle cell (SMC) hypertrophy in the CA in association with increased aortic expression of alpha-smooth muscle actin and smooth muscle myosin heavy chain and phosphorylation of ERK1/2, p38 MAPK, and FAK. ANG II did not induce SMC hypertrophy or phosphorylation of p38 MAPK and FAK in alpha(1)(-/-) mice. A functional anti-alpha(1)-integrin antibody inhibited in vitro the ANG II-induced phosphorylation of FAK and p38 MAPK. In conclusion, alpha(1)(-/-) mice exhibit a reduced mechanical strength at baseline and a lack of ANG II-induced SMC hypertrophy. These results emphasize the importance of alpha(1)beta(1)-integrin in p38 MAPK and FAK phosphorylation during vascular hypertrophy in response to ANG II.