Mise à jour le : 07-02-2012
Les derniers abstracts de la revue Gut current issue : |
The term ‘(sessile) serrated adenoma’ should be abbreviated as SSA, instead of SA (serrated adenoma). SSA, characterised by abnormal proliferation, is included in the non-dysplastic group contrary to SA, which belongs to the dysplastic serrated polyp category because of the associated epithelial dysplasia.
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Only 5/77 (6.5%) cases of ‘interval CRC’ developed in HPS patients during follow-up: two...
Date de mise en ligne : Vendredi 03 février 2012 The global pandemic of novel influenza A (H1N1) affected 70 countries in 2009. There was particular concern for infection in immunocompromised patients, including those with IBD. The 2009 H1N1 influenza vaccine produced seroprotection rates of >85% in the general population but there are no data on the immunogenicity of the vaccine in patients with IBD. In this issue of Gut, Cullen et al report their observational prospective open-label study which examined the immunogenicity of the 2009 H1N1 influenza vaccine in IBD patients. Patients with IBD vaccinated with the 2009 H1N1 influenza vaccine had a low rate of seroprotection, particularly those who were immunosuppressed or received combination immunosuppression (see
El-Omar, E., Grady, W., Gerbes, A.
Highlights from this issue
Date de mise en ligne : Vendredi 03 février 2012 Epithelial to mesenchymal transition (EMT) correlates with high-grade malignancy including the competence to form metastases. In addition, EMT has recently been linked to cellular self-renewal programmes of cancer stem cells and apoptosis/anoikis resistance, which are all features of therapeutic resistance. The EMT programme is driven by several transcription factors (TFs), such as the transcriptional regulators SNAIL, SLUG, ZEB1 and ZEB2 and the basic helix–loop–helix factors E47 and TWIST. These proteins target and repress the CDH1 gene, which encodes for E-cadherin, an important caretaker of the epithelial state. Expression studies in human pancreatic cancer showed expression of SNAIL in 78% and of SLUG in 50% of cases.
Schneider, G., Kramer, O. H., Saur, D.
A ZEB1-HDAC pathway enters the epithelial to mesenchymal transition world in pancreatic cancer
Date de mise en ligne : Vendredi 03 février 2012 The mammalian gastrointestinal tract harbours a vast number of bacterial residents, recently referred to as the microbiota, which are instrumental in supporting energy metabolism and immune function of the host. A large number of studies have highlighted the fact that certain (pathogenic) micro-organisms can be harmful to the health of their host, while more recently an increasing number of papers have attributed direct beneficial health effects to the gut microbial community. As these bacteria encode 100 times more genes than present in the human genome, the partnership of the host with its microbiota constitute a ‘superorganism’.
Grangette, C.
Bifidobacteria and subsets of dendritic cells: friendly players in immune regulation!
Date de mise en ligne : Vendredi 03 février 2012 Chronic hepatitis B virus (HBV) infection is a serious public health problem, leading to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. In highly endemic areas and among immigrants from these areas, most cases of chronic hepatitis B are due to HBV infection at birth or during the first year of life. Cirrhosis and HCC may occur at any age, but infections early in life are typically asymptomatic for the first few decades. Sharp rises in the incidence of fibrosis, cirrhosis and HCC generally do not appear until after the age of 30, the incidence of HCC showing a sharp rise after the age of 40. Approximately 50% of deaths in HBV carriers may be due to either chronic liver disease or HCC. Cirrhosis is a consequence of hepatocyte death and chronic inflammation in the liver, while HCC, like many cancers, probably results from a combination of initiation (hepatocyte...
Zoulim, F., Mason, W. S.
Reasons to consider earlier treatment of chronic HBV infections
Date de mise en ligne : Vendredi 03 février 2012 The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology. (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied. (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p<0.001) and supine (R=0.40, p<0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p<0.001; expiration: R=0.78, p<0.001) and inspiratory GOPG (R=0.50, p<0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=–0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP. The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.
Derakhshan, M. H., Robertson, E. V., Fletcher, J., Jones, G.-R., Lee, Y. Y., Wirz, A. A., McColl, K. E. L.
Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy
Date de mise en ligne : Vendredi 03 février 2012 Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGC, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGC. Genetic alterations of TP53 are also frequently found in DGC. To examine the synergistic effect of the loss of E-cadherin and p53 on gastric carcinogenesis, a mouse line was established in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. Atp4b-Cre mice were crossed with Cdh1loxP/loxP and Trp53loxP/loxP mice, and the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP double conditional knockout (DCKO) mice was examined. Non-polarised E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in DCKO mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, histologically very similar to those in humans, were found from 6 to 9 months, respectively. Fatal DGC developed at 100% penetrance within a year, frequently metastasised to lymph nodes, and had tumourigenic activity in immunodeficient mice. Gene expression profiles of DGC in DCKO mice also resembled those of human DGC, and mesenchymal markers and epithelial-mesenchymal transition-related genes were highly expressed in mouse DGC as in human DGC. This mouse line is the first genetically engineered mouse model of DGC and is very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC.
Shimada, S., Mimata, A., Sekine, M., Mogushi, K., Akiyama, Y., Fukamachi, H., Jonkers, J., Tanaka, H., Eishi, Y., Yuasa, Y.
Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer
Date de mise en ligne : Vendredi 03 février 2012 Intestinal homoeostasis is dependent on immunological tolerance to the microbiota. To (1) determine if a probiotic could induce Foxp3 T cells in humans; (2) to elucidate the molecular mechanisms, which are involved in the induction of Foxp3 T cells by human dendritic cells. Cytokine secretion and Foxp3 expression were assessed in human volunteers following Bifidobacterium infantis feeding. Monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were incubated in vitro with B infantis and autologous lymphocytes. Transcription factor expression, costimulatory molecule expression, cytokine secretion, retinoic acid and tryptophan metabolism were analysed. Volunteers fed B infantis displayed a selective increase in secretion of interleukin (IL)-10 and enhanced Foxp3 expression in peripheral blood. In vitro, MDDCs, mDCs and pDCs expressed indoleamine 2,3-dioxygenase and secreted IL-10, but not IL-12p70, in response to B infantis. MDDC and mDC IL-10 secretion was Toll-like receptor (TLR)-2/6 dependent, while pDC IL-10 secretion was TLR-9 dependent. In addition, MDDCs and mDCs expressed RALDH2, which was TLR-2 and DC-SIGN dependent. B infantis-stimulated MDDCs, mDCs and pDCs induced T cell Foxp3 expression. TLR-2, DC-SIGN and retinoic acid were required for MDDC and mDC induction of Foxp3 T cells, while pDCs required indoleamine 2,3-dioxygenase. B infantis administration to humans selectively promotes immunoregulatory responses, suggesting that this microbe may have therapeutic utility in patients with inflammatory disease. Cross-talk between multiple pattern-recognition receptors and metabolic pathways determines the innate and subsequent T regulatory cell response to B infantis. These findings link nutrition, microbiota and the induction of tolerance within the gastrointestinal mucosa.
Konieczna, P., Groeger, D., Ziegler, M., Frei, R., Ferstl, R., Shanahan, F., Quigley, E. M. M., Kiely, B., Akdis, C. A., O'Mahony, L.
Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells
Date de mise en ligne : Vendredi 03 février 2012 In women presenting to gynaecological clinics with lower abdominal pain, the cause is frequently attributed to endometriosis irrespective of whether it is found to be minimal or extensive at laparoscopy. Irritable bowel syndrome (IBS) is also common in this setting, and it was speculated that the visceral hypersensitivity associated with this condition might be amplifying the symptoms of endometriosis. Visceral sensitivity to balloon distension, symptoms and psychological status were assessed following laparoscopy in 20 women with minimal to mild endometriosis, 20 with moderate to severe endometriosis, 20 with laparoscopy negative abdominal pain and 20 asymptomatic women undergoing laparoscopic sterilisation who acted as controls, and compared with 20 women with IBS. Compared with controls, patients with minimal to mild and moderate to severe endometriosis had a higher prevalence of symptoms consistent with IBS (0% vs 65% and 50%, respectively, p<0.001) with significantly lower mean pain thresholds (39.5 mm Hg (95% CI 36.0 to 43.0) vs 28.1 mm Hg (95% CI 24.5 to 31.6), p=0.001 and 28.8 mm Hg (95% CI 24.9 to 32.6), p=0.002) not explained by differences in rectal compliance. Patients with laparoscopy negative pain had symptoms and visceral sensitivity similar to patients with IBS. Controls undergoing laparoscopy had normal sensitivity, indicating that the laparoscopic procedure was not inducing hypersensitivity. Visceral hypersensitivity is extremely common in endometriosis and could be intensifying the pain. This finding might explain why mildly affected individuals often complain of severe symptoms out of proportion to the extent of their disease. This study has introduced a completely new concept into the understanding of pain in endometriosis and could open up new opportunities for treatment.
Issa, B., Onon, T. S., Agrawal, A., Shekhar, C., Morris, J., Hamdy, S., Whorwell, P. J.
Visceral hypersensitivity in endometriosis: a new target for treatment?
Date de mise en ligne : Vendredi 03 février 2012 The extent to which numerous strains of genetically engineered mice, including mice lacking Toll-like receptor 5 (T5KO), display colitis is environment dependent. Gut microbiota underlie much of the variation in phenotype. Accordingly, embryonic rederivation of T5KO mice ameliorated their spontaneous colitis despite only partially correcting elevated proinflammatory gene expression. It was postulated that endogenous anti-inflammatory pathways mediated the absence of overt inflammation in these mice when their gut microbiota were reset. Consequently, it was hypothesised that neutralisation of the anti-inflammatory cytokine interleukin 10 (IL-10) might induce uniform colitis in T5KO mice, and thus provide a practical means to study mechanisms underlying their inflammation. Two distinct strains of non-colitic T5KO mice, as well as mice lacking MyD88, Toll-like receptor 4 (TLR4), IL-1 receptor (IL-1R) and various double knockouts (DKOs) were treated weekly for 4 weeks with 1 mg/mouse of IL-10 receptor neutralising antibody (IL-10R mAb) and colitis assayed 1 week later. The composition of the caecal microbiota was determined by 454 pyrosequencing of 16S rRNA genes. Anti-IL-10R mAb treatment led to severe uniform intestinal inflammation in both strains of T5KO mice. Such neutralisation of IL-10 signalling did not cause colitis in wild-type littermates nor mice lacking TLR4, MyD88 or IL-1R. The susceptibility of T5KO mice to this colitis model was not rescued by absence of TLR4 in that T4/T5 DKO mice displayed severe colitis in response to anti-IL-10R mAb treatment. IL-1β signalling was crucial for this colitis model in that IL-1R/T5 DKOs were completely protected from colitis in response to IL-10R mAb treatment. Lastly, it was observed that blockade of IL-10R function was associated with changes in the composition of gut microbiota, which were observed in mice that were susceptible and resistant to IL-10R mAb-induced colitis. Regardless of whether they harbour a colitogenic microbiota, loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1β-dependent pathway.
Carvalho, F. A., Nalbantoglu, I., Ortega-Fernandez, S., Aitken, J. D., Su, Y., Koren, O., Walters, W. A., Knight, R., Ley, R. E., Vijay-Kumar, M., Gewirtz, A. T.
Interleukin-1{beta} (IL-1{beta}) promotes susceptibility of Toll-like receptor 5 (TLR5) deficient mice to colitis
Date de mise en ligne : Vendredi 03 février 2012 Influenza vaccination is recommended for patients with inflammatory bowel disease (IBD). The 2009 H1N1 influenza vaccine produced seroprotection rates of >85% in the general population but there are no data on the immunogenicity of the vaccine in patients with IBD. An observational prospective open-label study was conducted to examine the immunogenicity of the 2009 H1N1 influenza vaccine in 108 patients with IBD. Patient details, medications and disease activity were recorded. Pre- and post-vaccination haemagglutinin inhibition titres and geometric mean titres were measured. A functional assay of T lymphocyte activity was measured at vaccination in a subset of patients as an alternative measure of immunosuppression. Subjects were followed for 6 months post-vaccination. Of 108 patients enrolled, 105 completed the study. The post-vaccination seroprotection rate was 50%. Immunosuppressed subjects had a lower rate of seroprotection than non-immunosuppressed subjects (44% vs 64%, p=0.06). The proportion with seroprotection was significantly lower in subjects on combination immunosuppression than in those receiving no immunosuppression (36% vs 64%, p=0.02). Patients receiving combined immunosuppression had a significantly lower fold increase in geometric mean titres than those on monotherapy immunosuppression (3.5 vs 11.5, p=0.03). An assay of T lymphocyte activity was performed in a subgroup of 48 subjects. Those with intermediate activity had lower seroprotection than those with high activity (28% vs 61%, p=0.02). The vaccine was well tolerated. Patients with IBD vaccinated with the 2009 H1N1 influenza vaccine had a low rate of seroprotection, particularly among those who were immunosuppressed. Although there is a need for studies of the clinical benefit of vaccines in this population, patients with IBD need to be aware of this reduced immunogenicity.
Cullen, G., Bader, C., Korzenik, J. R., Sands, B. E.
Serological response to the 2009 H1N1 influenza vaccination in patients with inflammatory bowel disease
Date de mise en ligne : Vendredi 03 février 2012 The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs. Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75). Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034). Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.
Okamoto, Y., Sawaki, A., Ito, S., Nishida, T., Takahashi, T., Toyota, M., Suzuki, H., Shinomura, Y., Takeuchi, I., Shinjo, K., An, B., Ito, H., Yamao, K., Fujii, M., Murakami, H., Osada, H., Kataoka, H., Joh, T., Sekido, Y., Kondo, Y.
Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
Date de mise en ligne : Vendredi 03 février 2012 A 61-year-old man presented with a 4-week history of rectal bleeding, constipation, bloating, abdominal distension and low back pain. His bowels had not opened for 4 days prior to admission. Physical examination revealed a distended, tympanic abdomen. Routine laboratory tests confirmed renal failure (urea 13 mmol/l, creatinine 200 μmol/l), hypercalcaemia (3.7 mmol/l), albumin 32 g/l and C-reactive protein (CRP) 25 mg/l. Parathormone was suppressed (7 pg/l (15–65)). Abdominal x-ray suggested an ileus. CT abdomen revealed mural thickening of the left hemi-colon along with collapse of the third lumbar vertebra. An isotope bone scan was unremarkable, while MRI of the spine confirmed the presence of multiple lytic lesions. Immunoglobulin G (IgG) was 27.39 g/l (6.0–16.0) and electrophoresis showed a band in the fast region. Light chains were elevated 6653.5 mg/l (5.7–26.3). He was managed with intravenous fluids and bisphosphonate with improvement in both renal function and corrected calcium. Over the course of admission he developed...
McCorry, R. B., Nair, B., Mooney, P., Shields, P. L.
A rare gastrointestinal presentation of a common malignancy
Date de mise en ligne : Vendredi 03 février 2012 Cap-assisted colonoscopy (CAC) uses a small plastic transparent cap attached to the tip of the colonoscope that can depress and flatten colonic folds and thus improve visualisation of their proximal aspects. The aim of this study was to compare CAC with standard colonoscopy (SC; high-definition white light) for adenoma detection rates. This is a prospective randomised controlled trial. The study was performed in a tertiary-care Veterans Affairs Medical Center in the USA. Subjects undergoing screening or surveillance colonoscopy were enrolled. Subjects were randomised to undergo either CAC or SC. The outcome measures were the proportion of subjects with at least one adenoma, the number of adenomas detected per subject, insertion time, caecal intubation rates and complications. 420 subjects were enrolled and included in the study (210 in each group). The proportion of subjects with at least one adenoma was higher with CAC compared to SC (69% vs 56%, p=0.009). CAC also detected a higher number of adenomas per subject (2.3 vs 1.4, p<0.001). The caecal intubation time was shorter with CAC (3.29 min vs 3.98 min, p<0.001). The caecal intubation rates were similar in the two groups (99% vs 98%, p=0.37). There were no complications associated with CAC or SC. CAC detected a 13% higher number of subjects with at least one adenoma and 59% higher adenomas per subject. CAC is a safe, effective and practical means to improve adenoma detection rates. NCT 01211132.
Rastogi, A., Bansal, A., Rao, D. S., Gupta, N., Wani, S. B., Shipe, T., Gaddam, S., Singh, V., Sharma, P.
Higher adenoma detection rates with cap-assisted colonoscopy: a randomised controlled trial
Date de mise en ligne : Vendredi 03 février 2012 Knowledge of the epidemiology of non-alcoholic fatty liver disease (NAFLD) is incomplete because liver biopsy cannot be performed on the general population to assess disease severity. New non-invasive tests allow accurate and safe assessment in healthy individuals. The aim of this study was to examine the prevalence of NAFLD and advanced fibrosis in the general Hong Kong Chinese population. Subjects were recruited from the community by random selection from the government census database. Liver fat and fibrosis were assessed by proton-magnetic resonance spectroscopy and transient elastography, respectively. Overall, 264 of 922 (28.6%) subjects had intrahepatic triglyceride content ≥5%. Excluding 12 subjects with significant alcohol consumption, the population prevalence of NAFLD was 27.3% (95% CI 24.5% to 30.2%). Each component of the metabolic syndrome increased the risk of fatty liver in a dose-dependent manner (prevalence of 4.5% in subjects without any component and 80.0% in those with all five components). 8 (3.7%) patients with fatty liver had liver stiffness ≥9.6 kPa, a level suggestive of advanced fibrosis. Body mass index and alanine aminotransferase level were independent factors associated with liver stiffness. Together with other clinical prediction scores, the estimated prevalence of advanced fibrosis in patients with fatty liver in the community was <10%. Compared with non-drinkers, modest drinkers (<10 g per day) did not have higher risk of fatty liver after adjustment for demographic and metabolic factors. The liver stiffness was 4.7±1.9 kPa in modest drinkers and 4.6±1.7 kPa in non-drinkers (p=0.54). NAFLD is found in over a quarter of the general adult Chinese population, but the proportion of patients with advanced fibrosis is low. Modest alcohol consumption does not increase the risk of fatty liver or liver fibrosis.
Wong, V. W.-S., Chu, W. C.-W., Wong, G. L.-H., Chan, R. S.-M., Chim, A. M.-L., Ong, A., Yeung, D. K.-W., Yiu, K. K.-L., Chu, S. H.-T., Woo, J., Chan, F. K.-L., Chan, H. L.-Y.
Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography
Date de mise en ligne : Vendredi 03 février 2012 Monocyte chemoattractant protein-1 (MCP-1, CCL2), the primary ligand for chemokine receptor C–C chemokine receptor 2 (CCR2), is increased in livers of patients with non-alcoholic steatohepatitis (NASH) and murine models of steatohepatitis and fibrosis. It was recently shown that monocyte/macrophage infiltration into the liver upon injury is critically regulated by the CCL2/CCR2 axis and is functionally important for perpetuating hepatic inflammation and fibrogenesis. The structured L-enantiomeric RNA oligonucleotide mNOX-E36 (a so-called Spiegelmer) potently binds and inhibits murine MCP-1. Pharmacological inhibition of MCP-1 with mNOX-E36 was investigated in two murine models of chronic liver diseases. Pharmacological inhibition of MCP-1 by thrice-weekly mNOX-E36 subcutaneously was tested in murine models of acute or chronic carbon tetrachloride (CCl4)- and methionine–choline-deficient (MCD) diet-induced chronic hepatic injury in vivo. Antagonising MCP-1 by mNOX-E36 efficiently inhibited murine monocyte chemotaxis in vitro as well as migration of Gr1+ (Ly6C+) blood monocytes into the liver upon acute toxic injury in vivo. In murine models of CCl4- and MCD diet-induced hepatic injury, the infiltration of macrophages into the liver was significantly decreased in anti-MCP-1-treated mice as found by fluorescence-activated cell sorting (FACS) analysis and immunohistochemistry. In line with lower levels of intrahepatic macrophages, proinflammatory cytokines (tumour necrosis factor α, interferon and interleukin 6) were significantly reduced in liver tissue. Overall fibrosis progression over 6 (CCl4) or 8 weeks (MCD diet) was not significantly altered by anti-MCP-1 treatment. However, upon MCD diet challenge a lower level of fatty liver degeneration (histology score, Oil red O staining, hepatic triglyceride content, lipogenesis genes) was detected in mNOX-E36-treated animals. mNOX-E36 also ameliorated hepatic steatosis upon therapeutic administration. These results demonstrate the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration by blocking MCP-1 during chronic liver damage in two in vivo models. The associated ameliorated steatosis development suggests that inhibition of MCP-1 is an interesting novel approach for pharmacological treatment in liver inflammation and steatohepatitis.
Baeck, C., Wehr, A., Karlmark, K. R., Heymann, F., Vucur, M., Gassler, N., Huss, S., Klussmann, S., Eulberg, D., Luedde, T., Trautwein, C., Tacke, F.
Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury
Date de mise en ligne : Vendredi 03 février 2012 Hepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated. Using quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearest-template prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182. The identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8+ T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death. A 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease.
Chew, V., Chen, J., Lee, D., Loh, E., Lee, J., Lim, K. H., Weber, A., Slankamenac, K., Poon, R. T. P., Yang, H., Ooi, L. L. P. J., Toh, H. C., Heikenwalder, M., Ng, I. O. L., Nardin, A., Abastado, J.-P.
Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma
Date de mise en ligne : Vendredi 03 février 2012 Pancreatic cancer is characterised by invasive tumour spread and early metastasis formation. During epithelial–mesenchymal transition, loss of the cell adhesion molecule E-cadherin is frequent and can be caused by genetic or epigenetic modifications, recruitment of transcriptional activators/repressors or post-translational modifications. A study was undertaken to investigate how E-cadherin expression in human pancreatic adenocarcinoma and pancreatic cancer cell lines is regulated. In 25 human pancreatic cancer resection specimens, the coding region of the E-cadherin gene (CDH1) was sequenced for somatic mutations. The tumour samples and 11 established human pancreatic cancer cell lines were analysed by immunohistochemistry, western blot analysis, chromatin immunoprecipitation and methylation-specific PCR. The role of specific histone deacetylase inhibitors (HDACi) on pancreatic tumour cell migration and proliferation was studied in vitro. Neither somatic mutations nor CDH1 promoter hypermethylation were found to be responsible for downregulation of E-cadherin in pancreatic cancer. In the transcriptionally active CDH1 promoter, acetylation of histones H3 and H4 was detected whereas HDAC1 and HDAC2 were found attached only to a silent promoter. Expression of ZEB1, a transcription factor known to recruit HDACs, was seen in E-cadherin-deficient cell lines in which ZEB1/HDAC complexes were found attached to the CDH1 promoter. Moreover, knockdown of ZEB1 prevented HDAC from binding to the CDH1 promoter, resulting in histone acetylation and expression of E-cadherin. HDACi treatment attenuated tumour cell migration and proliferation. These findings imply an important role for histone deacetylation in the downregulation of E-cadherin in human pancreatic cancer. Recruitment of HDACs to the CDH1 promoter is regulated by the transcription factor ZEB1, and inhibition of HDACs may be a promising antitumour therapy for pancreatic cancer.
Aghdassi, A., Sendler, M., Guenther, A., Mayerle, J., Behn, C.-O., Heidecke, C.-D., Friess, H., Buchler, M., Evert, M., Lerch, M. M., Weiss, F. U.
Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer
Date de mise en ligne : Vendredi 03 février 2012 Pancreatic ductal adenocarcinoma (PDAC) has long been considered to arise from pancreatic ducts on the basis of its morphology, the occurrence of dysplasia in putative preneoplastic ductal lesions, and the absence of acinar dysplasia in the pancreas of patients with PDAC. However, evidence gathered through both in vitro studies and—more importantly—genetic mouse models of PDAC shows that ductal-type tumours can arise from acinar cells. These findings raise new important questions related to PDAC pathophysiology and call for in-depth studies of acinar cell differentiation in order to better understand PDAC biology. The authors review these issues and discuss how the novel findings should impact on future work aiming at early diagnosis and improved outcome of patients with PDAC.
Rooman, I., Real, F. X.
Pancreatic ductal adenocarcinoma and acinar cells: a matter of differentiation and development?
Date de mise en ligne : Vendredi 03 février 2012 The treatment of inflammatory bowel disease is becoming more complicated with new medications and new treatment paradigms. Although data are accumulating that the earlier use of immunomodulators and anti-tumor necrosis factor agents are more effective than the standard "step-up" pyramidal treatment algorithm, patients may not be comfortable with this more intensive therapeutic approach. The process of shared decision making engages patients in treatment decisions to optimize the chance that a chosen therapy matches their personal preferences for care. Decision aids are standard shared decision making tools, which are used to present evidence-based data in a patient-friendly manner to help patients with preference- sensitive decisions. Not all care decisions are preference-sensitive, and not all patients are interested in being part of a shared medical decision. The responsibility of the provider is to identify how much of a role patients want, and then determine which decisions need their input to provide the best patient-centered care. The overall goal is to involve patients in decisions so that they are educated about their options, confident in the plan, adherent to chosen therapy and ultimately have a better quality of life.
Siegel, C. A.
Shared decision making in inflammatory bowel disease: helping patients understand the tradeoffs between treatment options
Date de mise en ligne : Vendredi 03 février 2012 Hammer GE, Turer EE, Taylor KE, et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 2011;12:1184–93. doi:10.1038/ni.2135 Dendritic cells (DCs) are known to play a key role in innate immune activation, but may also regulate immune homeostasis. This recent paper from Averil Ma and colleagues at the University of California, San Francisco, examined the role of the ubiquitin-editing protein A20 within DCs to identify how A20-dependent DC functions are implicated in intestinal homeostasis. A20 is a potent anti-inflammatory protein that negatively regulates the transcription factor nuclear factor kappa B by restricting signalling through several molecules including tumour necrosis factor (TNF), toll-like receptors and Nod proteins. Single nucleotide polymorphisms (SNPs) in the human A20 locus (TNFAIP3 or A20) have already been associated with several autoimmune...
McLean, M. H.
GI highlights from the literature
Date de mise en ligne : Vendredi 03 février 2012 We refer to two articles by Duijvestein et al and Ciccocioppo et al We wish to report our experience of allogeneic MSCT in seven patients with IBD. Infused allogeneic MSCs were obtained from the bone marrow or umbilical cord. Bone marrow was aspirated from healthy relatives of three patients. Umbilical cords were obtained from local maternity hospitals after normal deliveries. The isolated MSCs were given by intravenous infusions as 1x106 cells per kilogram of body weight. Four of the included seven patients had CD and three had ulcerative colitis (UC).
Liang, J., Zhang, H., Wang, D., Feng, X., Wang, H., Hua, B., Liu, B., Sun, L.
Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease
Date de mise en ligne : Vendredi 03 février 2012 We have read the recently published article by de Sablet et al with great interest. The article is well structured and has important findings about the ancestral origin of Helicobacter pylori, which can be used as a predictor of gastric cancer risk. First, there was insufficient data about other virulence factors of H pylori. We examined the association between virulence factors, including cag pathogenicity island, vacA, babA, iceA and OipA, of H pylori strains isolated from Columbian subjects and clinical outcomes.
Shiota, S., Matsunari, O., Watada, M., Yamaoka, Y.
Virulence factors or ancestral origin of Helicobacter pylori: which is a better predictor of gastric cancer risk?
Date de mise en ligne : Vendredi 03 février 2012 We thank Dr Ben-Horin for his comments published in the February 2012 issue of Gut
Rhodes, J. M.
Authors' response
Date de mise en ligne : Vendredi 03 février 2012 I read with great interest the two reports by Boparai and coworkers in Gut on the increased risk of colorectal carcinoma (CRC) in 77 hyperplastic/serrated polyposis syndrome (HPS) patients during follow-up Nevertheless, there are some points to be explained:
Orlowska, J.
Hyperplastic polyposis syndrome and the risk of colorectal cancer
Date de mise en ligne : Vendredi 03 février 2012 Patients with hyperplastic polyposis syndrome (HPS) harbour multiple colorectal hyperplastic polyps and are at risk of developing colorectal cancer (CRC).
Boparai, K. S., Reitsma, J. B., Dekker, E.
Authors' response
Date de mise en ligne : Vendredi 03 février 2012 We were interested to read the paper by Morris et al demonstrating significant variation in 30-day postoperative mortality following major colorectal cancer surgery in National Health Service hospitals in England.
Whistance, R. N., Blencowe, N. S., Blazeby, J. M.
The need for standardised outcome reporting in colorectal surgery
Date de mise en ligne : Vendredi 03 février 2012 Benamouzig R, Uzzan B, Deyra J, et al. Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial. There are two numerical errors in the last sentence of the "Results" paragraph of the Abstract of this paper. This sentence should be read as follows: "Also, the proportion of patients with at least one advanced adenoma did not differ (10/102 (10 %) in the aspirin group vs 7/83 (8.4 %) in the placebo group; NS)."
Correction