Eradication of H pylori is known to slow down or even reverse premalignant gastric lesions. COX-2 over-expression may be an important step in H pylori associated gastric carcinogenesis. Although several studies have shown that long-term use of aspirin or non-aspirin NSAIDs can prevent the development of GC, no randomised study of selective COX-2 inhibitor, such as celecoxib, on GC prevention or its precursors has yet been reported. In this issue of Gut Wong et al evaluated the effect of celecoxib alone and combined with H pylori eradication on the evolution of precancerous gastric lesions. They conducted a randomised, placebo controlled trial in Linqu County, Shandong Province, China, an area with a very high incidence of gastric cancer. This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects...]]>
Most epithelial surfaces exposed to a harsh environment protect themselves by means of a multilayered squamous epithelium such as that of the mouth or oesophagus, or by keratinised squamous epithelium such as the skin. Despite the gastric mucosa having to withstand a far harsher chemical environment than any of the above, it consists of only a simple columnar epithelium. It is chilling to think that it is only a single epithelial cell which separates us from our highly corrosive gastric juice. Squamous epithelium may be likened to...]]>
"Hope is a good breakfast but a bad supper"
Francis Bacon (1561–1626)
Functional dyspepsia (FD) has been defined as persistent or recurrent symptoms of unknown cause thought to originate in the proximal gastrointestinal tract. Symptom patterns may vary but usually include epigastric pain or burning. Non-painful dyspeptic symptoms such as early satiation, nausea, postprandial fullness and vomiting suggest an underlying abnormality in gastroduodenal motility. The Rome III consensus committee suggests that FD is subdivided into an epigastric pain syndrome and a postprandial distress syndrome based on symptom patterns.
FD...]]>
Cathepsin B is strongly expressed in pancreatic cancer, and high levels of this protease have been linked to reduced survival in patients after curative resection.
Hepatic stellate cells (HSC) play a pivotal role in the initiation and progression of hepatic fibrosis.
Colorectal cancer comprises a heterogeneous group of diseases that arise through varying molecular carcinogenic pathways, involving complex interactions between tumour cells and the host microenvironment.
In the 1980s, epidemiological and molecular data suggested that cancers arising at different subsites may be biologically disparate, implying different cancer aetiologies or evolutions. These observations prompted the suggestion that the proximal and distal colon should be considered separately in aetiological studies, with the splenic flexure as a demarcation point.
High resolution manometry (HRM) provides a colourful representation of oesophageal motility. Novice and intermediate learners were tested to compare HRM Clouse plots and conventional manometry for accuracy, ease of interpretation and knowledge retention.
36 learners evaluated 60 randomised motility sequences (30 HRM Clouse plots with corresponding line tracings) 4 months apart, following a tutorial. Learners rated prior knowledge of oesophageal pathophysiology and manometry and scored ease and speed of interpretation on 10 cm visual analogue scales (VAS).
Understanding of oesophageal pathophysiology was low in all cohorts (2.9±0.4 on VAS) and knowledge of HRM and conventional motility studies was even lower (1.9±0.4 and 1.8±0.3, respectively, p=NS). After the tutorial, diagnostic accuracy was significantly higher with HRM Clouse plots than with line tracings (p<0.001). HRM gains in diagnostic accuracy were evident over line tracings (43.1%), particularly with aperistalsis (36.1%), oesophageal body hypomotility (25.8%) and relaxation of the lower oesophageal sphincter (21.0%) (p<0.001 for each comparison); these were maintained at the second evaluation. Gains were independent of academic level (F=0.56, p=0.5) and did not correlate with prior experience of learners (r=–0.18, p=0.29). Learners favoured HRM Clouse plots (80.6%) over line tracings and reported faster interpretation (94.4%).
HRM Clouse plots provide ease of interpretation that translates into higher diagnostic accuracy and better knowledge retention in novice and intermediate learners of oesophageal manometry. These results implicate the value of pattern recognition in HRM interpretation, irrespective of academic level and prior understanding of oesophageal motor function.
The authors' goal was to measure pH at the gastric surface (pHo) to understand how acid secretion affects the repair of microscopic injury to the gastric epithelium.
Microscopic gastric damage was induced by laser light, during confocal/two-photon imaging of pH-sensitive dyes (Cl-NERF, BCECF) that were superfused over the mucosal surface of the exposed gastric corpus of anaesthetised mice. The progression of repair was measured in parallel with pHo. Experimental conditions included varying pH of luminal superfusates, and using omeprazole (60 mg/kg ip) or famotidine (30 mg/kg ip) to inhibit acid secretion.
Similar rates of epithelial repair and resting pHo values (~pH 4) were reported in the presence of luminal pH 3 or pH 5. Epithelial repair was unreliable at luminal pH 2 and pHo was lower (2.5±0.2, P <0.05 vs pH 3). Epithelial repair was slower at luminal pH 7 and pHo was higher (6.4±0.1, P<0.001). In all conditions, pHo increased adjacent to damage. At luminal pH 3 or pH 7, omeprazole reduced maximal damage size and accelerated epithelial repair, although only at pH 3 did omeprazole further increase surface pH above the level caused by imposed damage. At luminal pH 7, famotidine also reduced maximal damage size and accelerated epithelial repair. Neither famotidine nor omeprazole raised plasma gastrin levels during the time course of the experiments.
Epithelial repair in vivo is affected by luminal pH variation, but the beneficial effects of acutely blocking acid secretion extend beyond simply raising luminal and/or surface pH.
Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 (COX-2) are associated with gastric cancer and its precursors. To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions, a randomised, placebo-controlled trial was conducted in Linqu County, Shandong Province, China.
A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were randomly assigned in a factorial design to two interventions or placebo: anti-H pylori treatment for 7 days, and a COX-2 inhibitor (celecoxib) for 24 months. The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions.
Of the 1024 participants who received anti-H pylori treatment or placebo, 919 completed a subsequent 24-month treatment with celecoxib or placebo. The H pylori eradication rate by per-protocol analysis was 78.2%. Compared with placebo, the proportions of regression of gastric lesions significantly increased in the celecoxib treatment (52.8% vs 41.2%) and anti-H pylori treatment (59.3% vs 41.2%) group, and OR by per-protocol analysis was 1.72 (95% CI 1.07 to 2.76) for celecoxib and 2.19 (95% CI 1.32 to 3.64) for H pylori eradication. No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions (OR 1.48, 95% CI 0.91 to 2.40).
This population-based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions. No favourable effects were seen for H pylori eradication followed by celecoxib treatment.
HARECCTR0500053 in accordance with WHO ICTRP requirements.
A 56-year-old gentleman presented with a 6-week history of fatigue, drenching night sweats and 6 kg of weight loss. Clinical examination revealed a palpable right iliac fossa mass. He had a history of hypertension. Full blood count, differential white count and blood film were unremarkable. Inflammatory markers were elevated: C reactive protein 66 mg/l (range 0–8 mg/l) and erythrocyte sedimentation rate 36 mm/h. Immunoglobulin G (IgG) was raised at 18.5 g/l (range 6–13 g/l) with a negative autoantibody screen. Contrast-enhanced computerised tomography demonstrated a mass at the ileocaecal junction involving the ascending colon with local and mesenteric lymphadenopathy (
He proceeded to a laparoscopic-assisted resection. This revealed a mesenteric mass extending posteriorly to the serosal surface of the caecum and ascending colon, forming a mesenteric cake around the bowel with no colonic pathology. He underwent a right hemicolectomy to...]]>
To determine the efficacy of acotiamide, an acetylcholinesterase inhibitor, in patients with functional dyspepsia (FD) in a 4-week trial
A multicentre, randomised, placebo-controlled, parallel-group, phase III trial was carried out, in which patients with FD received 100 mg of acotiamide or placebo three times a day for 4 weeks, with 4 weeks post-treatment follow-up. The primary efficacy end points were global assessment of overall treatment efficacy (OTE) and elimination rate of all three meal-related symptoms (postprandial fullness, upper abdominal bloating and early satiation), as derived from daily diaries. Secondary efficacy end points were individual symptom scores and quality of life. Adverse events were monitored.
52.2% of those receiving acotiamide and 34.8% in the placebo group (p<0.001) were classified as responders according to a global assessment of OTE. Over 4 weeks, the elimination rate for all three meal-related symptoms was 15.3% among patients receiving acotiamide compared with 9.0% in the placebo group (p=0.004). The significant benefit of acotiamide over placebo in OTE and elimination rate was maintained during the 4 week post-treatment follow-up. All other secondary efficacy end points, including quality of life, were significantly improved with 100 mg of acotiamide as compared with placebo. The number needed to treat was 6 for OTE and 16 for symptom elimination rate. The incidence of adverse events was similar between the acotiamide group and placebo group and no significant cardiovascular effects due to treatment were seen.
Over 4 weeks, acotiamide significantly improved symptom severity and eliminated meal-related symptoms in patients with FD.
http://ClinicalTrials.gov number, NCT00761358.
The small intestinal epithelium is highly sensitive to radiation and is a major site of injury during radiation therapy and environmental overexposure.
To examine probiotic bacteria as potential radioprotective agents in the intestine.
8-week-old C57BL/6 wild-type or knockout mice were administered probiotic by gavage for 3 days before 12 Gy whole body radiation. The intestine was evaluated for cell-positional apoptosis (6 h) and crypt survival (84 h).
Gavage of 5x107 Lactobacillus rhamnosus GG (LGG) improved crypt survival about twofold (p<0.01); the effect was observed when administered before, but not after, radiation. Conditioned medium (CM) from LGG improved crypt survival (1.95-fold, p<0.01), and both LGG and LGG-CM reduced epithelial apoptosis particularly at the crypt base (33% to 18%, p<0.01). LGG was detected in the distal ileal contents after the gavage cycle, but did not lead to a detectable shift in bacterial family composition. The reduction in epithelial apoptosis and improved crypt survival offered by LGG was lost in MyD88–/–, TLR-2–/– and cyclo-oxygenase-2–/– (COX-2) mice but not TLR-4–/– mice. LGG administration did not lead to increased jejunal COX-2 mRNA or prostaglandin E2 levels or a change in number of COX-2-expressing cells. However, a location shift was observed in constitutively COX-2-expressing cells of the lamina propria from the villi to a position near the crypt base (villi to crypt ratio 80:20 for control and 62:38 for LGG; p<0.001). Co-staining revealed these COX-2-expressing small intestinal lamina propria cells to be mesenchymal stem cells.
LGG or its CM reduce radiation-induced epithelial injury and improve crypt survival. A TLR-2/MyD88 signalling mechanism leading to repositioning of constitutive COX-2-expressing mesenchymal stem cells to the crypt base is invoked.
Genetic predisposition to cancer in Peutz–Jeghers syndrome (PJS) and the role of germline serine–threonine kinase (LKB1) mutations are poorly understood. The authors studied the effect of germline LKB1 mutations on intestinal stem cell dynamics in unaffected flat PJS mucosa. Recent research has documented that the intestinal crypt houses multiple equipotent stem cell lineages. Lineages continuously compete through random drifts, while somatically inherited methylation patterns record clonal diversity.
To study the effect of germline LKB1 mutations on clonal expansion, the authors performed quantitative analyses of cardiac-specific homeobox methylation pattern diversity in crypts isolated from unaffected colonic mucosa obtained from archival PJS patient material. The authors compared methylation density and methylation pattern diversity in patients with PJS to those in patients with familial adenomatous polyposis and age-matched controls.
The percentage of total methylation is comparable between groups, but the number of unique methylation patterns is significantly increased for patients with familial adenomatous polyposis and patients with PJS compared to control subjects.
Monoallelic LKB1 loss is not silent and provokes a protracted clonal evolution in the crypt. The increased methylation pattern diversity observed in unaffected PJS mucosa predicts that premalignant lesions will arise at an accelerated pace compared to the general population.
Colorectal cancer is typically classified into proximal colon, distal colon and rectal cancer. Tumour genetic and epigenetic features differ by tumour location. Considering a possible role of bowel contents (including microbiome) in carcinogenesis, this study hypothesised that tumour molecular features might gradually change along bowel subsites, rather than change abruptly at splenic flexure.
Utilising 1443 colorectal cancers in two US nationwide prospective cohort studies, the frequencies of molecular features (CpG island methylator phenotype (CIMP), microsatellite instability (MSI), LINE-1 methylation and BRAF, KRAS and PIK3CA mutations) were examined along bowel subsites (rectum, rectosigmoid junction, sigmoid, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon and caecum). The linearity and non-linearity of molecular relations along subsites were statistically tested by multivariate logistic or linear regression analysis.
The frequencies of CIMP-high, MSI-high and BRAF mutations gradually increased from the rectum (<2.3%) to ascending colon (36–40%), followed by falls in the caecum (12–22%). By linearity tests, these molecular relations were significantly linear from rectum to ascending colon (p<0.0001), and there was little evidence of non-linearity (p>0.09). Caecal cancers exhibited the highest frequency of KRAS mutations (52% vs 27–35% in other sites; p<0.0001).
The frequencies of CIMP-high, MSI-high and BRAF mutations in cancer increased gradually along colorectum subsites from the rectum to ascending colon. These novel data challenge the common conception of discrete molecular features of proximal versus distal colorectal cancers, and have a substantial impact on clinical, translational and epidemiology research, which has typically been performed with the dichotomous classification of proximal versus distal tumours.
Early detection of colon adenomas at high risk of progression and early-stage colorectal cancer (CRC) is an effective approach to reduce CRC death rates. Current screening methods lack specificity as they detect many adenomas that will never progress to CRC. The authors aimed to identify cell surface protein biomarkers with extracellular domains that could be targeted for molecular imaging and discriminate low-risk adenomas and normal colon from high-risk adenomas and CRC.
Cell surface proteins of five CRC cell lines were biotinylated, isolated and analysed by in-depth proteomics using gel electrophoresis and nanoliquid chromatography coupled to tandem mass spectrometry. Differential expression in adenomas and CRCs was based on mRNA expression and verified by immunohistochemical staining of tissue microarrays.
In total, 2609 proteins were identified in the cell surface fractions. Of these, 44 proteins were selected as promising cell surface candidate biomarkers for adenoma-to-carcinoma progression based on the following criteria: protein identification in at least four out of five cell lines, a predicted (trans)membrane location and increased mRNA expression in CRCs compared to adenomas. Increased protein expression in high-risk adenomas and CRCs compared to low-risk adenomas was confirmed by immunohistochemistry for glucose transporter type 1 (gene symbol SLC2A1; p<0.00001) and prion protein (gene symbol PRNP; p<0.005).
This study revealed glucose transporter type 1, prion protein and 42 other cell surface candidate biomarkers for adenoma-to-carcinoma progression that could potentially serve as targets for emerging molecular imaging modalities like optical imaging, 19F-MRI and positron emission tomography.
The selection of patients for genetic testing to rule out Lynch syndrome is currently based on fulfilment of at least one of the revised Bethesda criteria followed by mismatch repair (MMR) status analysis. A study was undertaken to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC).
2093 patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumour tissue. Germline MLH1 and MSH2 mutation analysis was performed in patients whose tumours showed loss of MLH1 or MSH2 staining, respectively. MSH6 genetic testing was done in patients whose tumours showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have MSH2 mutations. PMS2 genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumours and normal or not available MMR protein expression, all four MMR genes were studied.
A total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not.
Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.
To evaluate the suggested association between tetracycline and acute pancreatitis in a large pharmacoepidemiological study.
The use of tetracycline in relation to the risk of acute pancreatitis was examined in a nationwide case–control study of people aged 40–84 years between 2006 and 2008 in Sweden. The Swedish Patient Register was used to identify 6161 cases of first-episode acute pancreatitis. The Register of the Total Population was used to randomly select 61 637 control subjects from the general population using frequency-based density sampling, matched for age, sex, and calendar year. Tetracycline use was defined as ‘current’, ‘recent’, ‘past’ or ‘former’ if the drug had been dispensed 0–30 days, 31–180 days, 181–365 days or 1–31/2 years before the index date, respectively. The risk of acute pancreatitis was estimated by unconditional logistic regression, providing ORs with 95% CIs, adjusted for potential confounding factors.
There was a 60% increased risk of acute pancreatitis among current users of tetracycline after adjustment for potential confounders (OR=1.6, 95% CI 1.2 to 2.1). There was no increased OR for any category of previous use.
Current use of tetracycline is associated with an increased risk of acute pancreatitis, verifying previous case reports.
The lysosomal protease cathepsin B is upregulated in human pancreatic ductal adenocarcinoma (PDA) and represents a potential therapeutic target. Loss of cathepsin B delays tumour progression in mouse models of islet, mammary and intestinal carcinoma and decreases invasion and metastasis. This study examines the role of cathepsin B in the initiation, progression and metastasis of PDA.
Cathepsin B germline knockout mice were crossed with animals expressing an endogenous KrasG12D allele in the pancreas, and mice were aged to evaluate the role of cathepsin B in pancreatic intraepithelial neoplasia (PanIN). A survival study was also performed with mice carrying an additional heterozygous conditional Trp53R172H allele. Cell lines derived from tumours were used to investigate the role of cathepsin B in vitro, and subcutaneous allografts investigated the cell autonomous and non-cell autonomous roles of cathepsin B in pancreatic cancer.
Constitutive cathepsin B loss resulted in delayed progression of both PanIN and PDA and a significant survival advantage in mice. Cathepsin B-deficient PDA cells and PanIN showed decreased proliferation and mitogen-activated protein (MAP) kinase signalling. The reconstitution of deficient cells with cathepsin B reversed these findings, which correlated with decreased levels of the active forms of the related protease cathepsin L. Conversely, acute ablation of cathepsin L activated the MAP kinase cascade in PDA cells.
These results confirm that cathepsin B plays an important cell autonomous role in the progression of PDA and suggest that the regulation of cathepsin L by cathepsin B may be a means of stimulating cell proliferation in neoplasia.
Liver fibrosis, which involves activation of hepatic stellate cells (HSC), is a major health problem and is the end outcome of all chronic liver diseases. The liver is populated with lymphocytes, among which are natural killer (NK) cells, whose activity is controlled by inhibitory and activating receptors. NKp46, one of the major NK activating receptors expressed by NK cells, is also a specific NK marker that discriminates NK cells from all other lymphocyte subsets. It recognises viral haemagglutinins and unknown cellular ligands.
The anti-fibrotic activity of the NKp46 receptor was assessed in vivo and in vitro using NKp46-deficient mice (NCR1gfp/gfp), the carbon tetrachloride model and in vitro NK killing assays. Primary murine and human HSC were stained for the expression of the NKp46 ligand using fusion proteins composed of the extracellular portions of the murine and human NKp46 receptors fused to human IgG1.
It was shown that murine HSC express a ligand for the murine orthologue of the NKp46 receptor, NCR1. NCR1 inhibited liver fibrosis in vivo; in vitro, murine HSC were killed in an NCR1-dependent manner. In humans it was shown that human HSC also express a ligand for the human NKp46 receptor and that the killing of human HSC is NKp46 dependent.
In addition to NKG2D, NKp46/NCR1 play an important role in inhibition of liver fibrosis. This suggests that fibrosis can be better controlled through the manipulation of NKp46 activity.
There is increasing interest in the therapeutic potential of human mesenchymal stem cells (hMSCs), especially in diseases such as acute hepatic failure (AHF) that are predominantly caused by a variety of drugs and viruses. In previous studies, a distinct population termed human spindle-shaped MSCs were isolated and expanded from second trimester amniotic fluid (AF-MSCs) and characterised based on their phenotype, pluripotency and differentiation potential.
AF-MSCs, hepatic progenitor-like (HPL) cells and hepatocyte-like (HL) cells derived from AF-MSCs were transplanted into CCl4-injured NOD/SCID mice with the AHF phenotype in order to evaluate their therapeutic potential. Conditioned medium (CM) derived from AF-MSCs or HPL cells was then delivered intrahepatically in order to determine whether the engraftment of the cells or their secreted molecules are the most important agents for liver repair.
Both HPL cells and AF-MSCs were incorporated into CCl4-injured livers; HPL cell transplantation had a greater therapeutic effect. In contrast, HL cells failed to engraft and contribute to recovery. In addition, HPL-CM was found to be more efficient than CM derived from AF-MSCs in treatment of the liver. Proteome profile analysis of HPL-CM indicated the presence of anti-inflammatory factors such as interleukins IL-10, IL-1ra, IL-13 and IL-27 which may induce liver recovery. Blocking studies of IL-10 secretion from HPL cells confirmed the therapeutic significance of this cytokine in the AHF mouse model.
Human spindle-shaped AF-MSCs or HPL cells might be valuable tools to induce liver repair and support liver function by cell transplantation. More importantly, the factors they release may also play an important role in cell treatment in diseases of the liver.
Reports on the effects of bone marrow-derived cells on hepatic fibrosis are contradictory. Impaired fibrosis but increased inflammation has recently been demonstrated 10 weeks after bone marrow transplantation (BM-Tx) in Abcb4–/– mice. It is hypothesised that BM-Tx might have long-term therapeutic potential by altering the immunological and matrix remodelling processes leading to hepatic regeneration.
After lethal irradiation of recipient mice, BM cells from GFP+ donor mice (allogeneic Tx) or Abcb4–/– mice (syngeneic Tx) were transplanted via tail vein injection. Readouts were performed 2, 10 and 20 weeks after Tx. Liver integrity was assessed serologically and histologically. Surrogate markers for fibrogenesis, T helper (Th) response, inflammation, graft-versus-host disease and fibrolysis were analysed by quantitative real-time PCR, zymography and immunohistology.
20 weeks after syngeneic and allogeneic BM-Tx, hepatic grading and staging were significantly improved. In contrast, 2 weeks after BM-Tx inflammatory grading, expression of inflammatory cell markers and associated chemokines and their receptors were increased and subsequently declined. In parallel, CD8+/GFP+ donor-derived T cells infiltrated the liver 2 weeks after BM-Tx. The Th1 cyokine interferon was increased 2 and 10 weeks after BM-Tx whereas the Th2 associated interleukin 13 was not altered. The gene expression of matrix metalloproteinases MMP-2, MMP-7, MMP-9 and MMP-13 was transiently upregulated and MMP-9 protein remained elevated 20 weeks after BM-Tx with enhanced gelatinase activity located within the fibrotic areas. Neutrophils were identified as major sources of MMP-9.
These results show that BM-Tx causes an antifibrotic Th1 response combined with transient inflammatory effects and subsequently upregulated MMP activity. Antifibrotic Th polarisation and prolonged proteolytic activity, especially of MMP-9, might be responsible for long-term amelioration of hepatic fibrosis.
There have been many recent advances in the aetiopathogenesis and management of chronic pancreatitis (CP). It is now well recognised that genetic mutations play an important role in this complex disease with strong gene-environment interaction. Mutations in cationic trypsinogen (PRSS1) gene are associated with hereditary pancreatitis; those in CFTR and SPINK1 genes have been associated with idiopathic CP. Such mutations are also likely to play a role in pancreatitis associated with other factors such as pancreas divisum, and hyperparathyroidism. Oxidative stress is also implicated in the pathophysiology of CP. Abdominal pain is the predominant symptom of CP. Although medical therapy has generally been considered ineffective, recent studies have shown that antioxidants might be effective in decreasing oxidative stress and in alleviating abdominal pain. Endoscopic...]]>
Singh A, Sweeney MF, Yu M, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 2012;148:639–50.
Mutation of KRAS is common in the pathogenesis of colorectal cancer and predicts resistance to epidermal growth factor receptor inhibition as a treatment strategy. The cellular effect of mutated KRAS is complex and is known to be linked to both the Wnt and TGFβ signalling pathways. Studies in colorectal cancer cell lines suggest that only around half of KRAS-mutated cell lines are dependent on KRAS expression for survival. Cellular effectors of KRAS dependency remain largely undetermined. Using KRAS-dependent and -independent colorectal cancer cell lines, Singh and colleagues identified a KRAS dependency gene expression set by microarray. Hierarchical clustering and ontology analyses demonstrated enrichment for kinases and Wnt signalling components in KRAS-dependent cells. Selected kinases were targeted for disrupted expression in two...]]>
In order to relate this classification to in-hospital mortality, we conducted...]]>