Driffa Moussata

XIAP as a radioresistance factor and prognostic marker for radiotherapy in human rectal adenocarcinoma.

A differential responsiveness of patients to ionizing radiation is observed after preoperative radiotherapy for rectal adenocarcinoma that might be related, in part, to an apoptosis defect. To establish if proteins of the apoptotic cascades [pro-apoptotic: active caspase 3, 8, and 9 and DIABLO (direct inhibitor of apoptosis-binding protein with low pI); anti-apoptotic: XIAP (X-linked inhibitor of apoptosis)] are involved, we analyzed their profile in radioresistant (SW480) and radiosensitive (SW48) human colorectal cell lines. We demonstrated that, after irradiation, the SW48 cells increased the expression of the pro-apoptotic proteins, whereas the SW480 cells increased the expression of the anti-apoptotic protein XIAP. Moreover, XIAP knockdown in SW480 cells enhanced the basal and radiation-induced apoptotic index; the propensity of the SW480 cells to undergo apoptosis after radiation was higher compared with SW48 cells. In a translational study of 38 patients with rectal carcinoma, we analyzed the apoptotic profile for tumor and noncancerous tissue for each biopsy specimen using IHC. According to their response to preoperative radiotherapy, patients were classified into two groups: responsive and nonresponsive. Although no difference in expression of caspase 3, 8, or 9 was observed in the tumor/normal tissue ratio between responsive and nonresponsive patients, the ratio decreased for DIABLO and increased for XIAP. In conclusion, inhibition of XIAP rescues cellular radiosensitivity and both DIABLO and XIAP might be potential predictive markers of radiation responsiveness in rectal adenocarcinoma.

Urinary neopterin is a valuable tool in monitoring Crohn's disease activity

Background: The aim was to investigate the relation between urinary neopterin and the Crohns Disease Activity Index (CDAI) and to compare its ability to discriminate active versus inactive CD with serum C‐reactive protein (CRP). Methods: In all, 217 urinary samples for neopterin measurement were obtained in a cohort of 93 consecutive patients with CD and 66 samples in 33 healthy volunteers. Clinical parameters were recorded and blood samples for CRP were collected as well. Results: Whereas patients with inactive CD showed similar levels of urinary neopterin excretion than healthy volunteers (163 ± 8 versus 142 ± 7 nmol/mol of creatinine, respectively; P = 0.1), urinary neopterin excretion from mild to severe active CD was significantly higher (302 ± 15 nmol/mol of creatinine; P < 0.001). Serum CRP levels were higher in active CD (14.8 ± 2.1 mg/L) compared with inactive CD (5.6 ± 0.8 mg/L; P < 0.001). Urinary neopterin excretion, and to a lesser degree CRP, were positively and significantly correlated with CDAI (r = 0.64 and 0.43, respectively, P < 0.001). Based on the cutoff of 183 nmol/mol of creatinine for urinary neopterin, the sensitivity and specificity of urinary neopterin to discriminate between active and inactive CD were 73% and 82%, respectively, and the positive and negative predictive values were 80% and 78%, respectively. Conclusions: Urinary neopterin excretion is an objective, valuable, simple, and noninvasive biomarker to detect and follow fluctuations of CD activity. Further work is warranted to study its clinical value and relation to mucosal healing.

Tumor necrosis factor α reduces butyrate oxidation in vitro in human colonic mucosa: A link from inflammatory process to mucosal damage?

Background: Butyrate produced by colonic bacterial fermentation is the main fuel for colonocytes, glucose being an alternative fuel. During inflammatory bowel disease, butyrate oxidation by colonocytes is impaired, and increased production of proinflammatory cytokines is detected in the colonic mucosa. We hypothesized that proinflammatory cytokines might reduce butyrate oxidation, and we assessed the in vitro effects of 3 proinflammatory cytokines on butyrate and glucose oxidation in colonic mucosa. Methods: Colonic biopsies were obtained from normal mucosa in 42 patients who underwent a colonoscopy. Biopsies were incubated in RPMI 1640 with [1‐14C]‐butyrate or [U‐14C]‐glucose with or without 1 of the 3 following proinflammatory cytokines: tumor necrosis factor &agr; (TNF&agr;), interleukin (IL)‐1&bgr;, and IL‐6. For each cytokine, 4 different concentrations were tested in 8 subjects. Concentrations overlapped those commonly found in inflamed mucosa and had no cytotoxicity as assessed in preliminary experiments using both the trypan blue exclusion test and lactate dehydrogenase release. Production of 14CO2 (picomoles per microgram dry weight per hour) was measured after a 2‐hour incubation and expressed as a percentage of the control [14C]‐substrate oxidation without cytokines. Results: Whereas glucose oxidation was not affected, butyrate oxidation was reduced significantly (P < 0.05) by TNF&agr; at concentrations of 100 (−26 ± 6%), 1000 (−32 ± 7%), and 5000 pg/mL (−34 ± 5%). IL‐1&bgr; (0, 500, 5000, and 25,000 pg/mL) and IL‐6 (0, 100, 1000, and 5000 pg/mL) did not affect either substrate oxidation. Conclusions: TNF&agr; at concentrations found in inflamed mucosa reduces butyrate oxidation in vitro in mucosa from healthy controls. This result is not caused by a cytotoxic effect of TNF&agr; and is not balanced by an increased oxidation of glucose. Reduced butyrate oxidation results in a decreased energy supply to colonocytes and may explain, in part, mucosal damage occurring during attacks of inflammatory bowel disease.

Rectocolite ulcéro-hémorragique chronique active: Efficacité de la ciclosporine intra-veineuse puis orale, associée à l’azathioprine

OBJECTIVEnTo know whether the therapeutic protocol applied in the case of severe acute ulcerative colitis (UC) associating ciclosporine and azathioprine was also effective in the case of moderate chronic active ulcerative colitis (UC).nnnSUBJECTS AND METHODSnin this retrospective study 10 patients (31-65 years, 6 distal colitis, 1 left colitis, 3 pancolitis) moderately active and corticosteroid-resistant or dependent were included. Patients received ciclosporine intraveinously (4 mg/kg/d) and were evaluated 10 days later. If efficient, ciclosporine was given orally for 3 Months, azathioprine was introduced and steroids were progressively tapered.nnnRESULTSnon inclusion the clinical score, based on the Mayo Clinic score, was of 5.7 +/- 0.5. On Day 10, the score decreased significantly (2.1 +/- 0.7, p<0.001) and the therapeutic effect was sustained at the third Month (1.8 +/- 0.7). With azathioprine, 4 patients were still in remission with a mean follow up of 23.3 +/- 15.5 Months.nnnCONCLUSIONntherapeutic scheme proposed in severe acute UC failing to respond to steroids may be helpful in some patients with a chronic active UC. Clinical improvement is rapid and long-term response is maintained in about 1 patient out of 2.Resume Objectif Savoir si le protocole therapeutique applique en cas de rectocolite ulcero-hemorragique (RCH) severe associant la ciclosporine a l’azathioprine etait egalement efficace en cas de RCH moderee chronique active. Methode Dans cette etude prospective, 10 patients (31-65 ans, 6 colites distales, 1 colite gauche, 3 pancolites) en poussee moderee et cortico-resistants ou cortico-dependants depuis au moins 3 mois ont ete inclus. Ils ont ete traites par ciclosporine intra-veineuse (4 mg/kg/jour) et reevalues 10 jours plus tard. En cas d’efficacite, la ciclosporine etait prescrite per os , l’azathioprine introduite et la decroissance des corticoides debutee. La ciclosporine etait maintenue 3 mois avec relais par l’azathioprine. Resultats A l’inclusion le score clinique, evalue a partir des criteres de la Mayo Clinic , etait de 5,7 ± 0,5. Au 10 e jour, le score baissait significativement (2,1 ± 0,7 p e mois (score 1,8 ± 0,7). Sous azathioprine, 4 patients etaient toujours en remission avec un suivi moyen de 23,3 ± 15,5 mois. Conclusion Le protocole therapeutique applique en cas de colite grave de RCH peut etre une aide therapeutique chez certains malades ayant une forme chronique active de la maladie. L’amelioration clinique est rapide et se maintient a long terme chez environ 1 patient sur 2.

Dysplasie colique au cours des MICI: prise en charge en 2010

Compte tenu de la difficulte et des consequences du diagnostic de dysplasie, toute dysplasie, quelle soit de bas grade, de haut grade ou incertaine, doit etre confirmee par un second anatomopathologiste. La decouverte dune dysplasie de haut grade sur une muqueuse colique plane ou apparemment plane en coloscopie conventionnelle doit conduire a pratiquer une proctocolectomie. La conduite a tenir en cas de decouverte dune dysplasie de bas grade sur une muqueuse colique plane ou apparemment plane reste controversee, certains preconisant une proctocolectomie, dautres une surveillance endoscopique rapprochee. Apres polypectomie ou, a defaut, biopsies, en cas de constatation dune dysplasie sur une lesion polypoide siegeant dans une zone non atteinte actuellement ou anterieurement par la colite, la lesion doit etre consideree comme un adenome sporadique ne necessitant que la surveillance habituelle a ce type de lesion. Lorsque la lesion polypoide siege dans une zone atteinte ou prealablement atteinte par la colite, une polypectomie est suffisante, a condition que la lesion soit un simple adenome et ait ete enlevee totalement ou puisse letre ulterieurement, quil ny ait pas de dysplasie a la base ou sur les marges du polype, ni dautres zones dysplasiques dans le colon, que ce dernier puisse etre surveille facilement et, pour certains, que le patient soit âge de plus de 40 ans. Enfin, si la lesion dysplasique ne ressemble pas un polype adenomateux banal, si son exerese parait difficile et si de la dysplasie est trouvee egalement au pourtour de la lesion ou a distance sur le colon, la lesion doit etre consideree comme une dysplasia-associated lesion or mass (DALM) et necessite la realisation dune proctocolectomie.