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Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of fourteen promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n=192 and =81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n=55 and =92) and DILI patients (n=98, =28, and =143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total keratin 18 (K18), caspase cleaved K18 (ccK18), glutathione S-transferase alpha (GSTα), alpha fetoprotein (AFP), arginase-1 (ARG1), osteopontin (OPN), sorbitol dehydrogenase (SDH), fatty acid binding protein (FABP1), cadherin-5 (CDH5), macrophage colony stimulating factor receptor (MCSFR), paraoxonase 1 (PON1, normalized to prothrombin protein), and leucocyte cell-derived chemotaxin-2 (LECT2). Most candidate biomarkers were significantly altered in DILI cases compared to healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase (ALT) than miR-122 and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among the healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplant within 6 months of DILI-onset. Prediction of prognosis among DILI patients using Model for End-stage Liver Disease (MELD) was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients. K18, OPN and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.

Many patients are reluctant to undergo optical colonoscopy for colorectal cancer screening. The Check-Cap colon imaging system is a non-invasive test that comprises an ingestible imaging capsule that emits and detects ultra-low-dose radiation. The capsule generates a 3D reconstruction of the colonic lumen for detection of polyps and cancer. Preliminary preclinical and clinical testing has demonstrated safety and feasibility. Mean radiation dose is estimated at 0.04 mSv. In conclusion, we describe a novel capsule-based, patient-friendly colorectal test that holds potential for non-invasive screening.

Colorectal cancer (CRC) is a major health concern. It is the third most common type of cancer and cause of death by cancer. Chemoprevention is a promising approach for reducing morbidity and mortality from CRC. The search for a chemoprevention agent with mild side effects has led to particular interest in curcumin. In-vitro and in-vivo studies indicate that curcumin can interfere with multiple cell signaling pathways involved in carcinogenesis, including inhibition of cell cycle progression, induction of apoptosis, slowing of proliferation, and reduction of angiogenesis, invasion, and metastasis formation. Curcumin is also a very potent anti-inflammatory agent and anti-oxidative agent. Curcumin has no adverse effects on normal cells, making it a very promising chemopreventive agent.

Background & Aims The occurrence of drug‐induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid‐binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

CRC development is a multi-step process that spans 10 to 15 years, thereby providing an opportunity for early detection and even prevention. The poor survival rate of advanced CRC has prompted the emphasis on prevention of this disease. CRC screening and removal of adenomas is an effective intervention, and is the cornerstone of prevention. However, screening efforts have had limited impact due to less than optimal compliance with guidelines. Chemoprevention involves the long-term use of a variety of oral agents that can delay, prevent or even reverse the development of adenomas in the large bowel, thus interfering with the multi-step progessing from adenoma to carcinoma. This effect is of particular importance to individuals with a hereditary prediposition to colorectal neoplasia and to those who are especially susceptile to the environmental causes of CRC. NSAIDs have drawn the most attention as chemoprevention agents. Sulindac and celecoxib are effective in promoting poly regression in high risk individuals with Familial Adenomatous Polyposis (FAP). In the more common sporadic setting the APROVe (refecoxib), APC and PreSAP (Celecoxib) trials have shown a significant reduction in adenoma recurrence but important concerns exist regarding cardiovascular toxicity associated with selective COX-2 inhibitors. These landmark studies are very important, as they provide a proof of concept that we can prevent high risk adenomas that can lead to CRC development. The ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Possibly, combinations of agents will maximize effectiveness while limiting drug toxicity. Finally, personalized approaches will include the ability to predict risk and toxicity.

CD24 was first described in the early 1980s and only attributed to scattered publications, referred to as a cell surface molecule in hematopoiesis. Recently, studies are accumulating to show that CD24 conveys a function in cell-to-cell interaction and regulation of proliferation and adhesion. CD24 appears to be highly expressed in a large variety of human cancers and to contribute to the acceleration of tumor growth and metastases shedding by binding to platelet (P)-selectin, L1 and by evoking – to date unknown – intracellular signal pathways. Anti-CD24 monoclonal antibodies thus act as a promising cancer treatment as was shown in the setting of gastrointestinal cancers. Recent articles also correlate CD24 expression with the identification of ‘tumor stem cells’.

The long-term (mean of 16.4±4.2 months) efficacy and safety of rofecoxib (a specific COX-2 inhibitor) in maintaining the colon free of polyps in familial polyposis patients was assessed. Eight patients were treated with rofecoxib 25 mg every day. Sigmoidoscopy/colonoscopy was performed at study entry and every six months. At each endoscopy the number, size, and histological grade of all polyps were assessed, and the polyps were removed. The drug was well tolerated with no significant adverse events throughout the study. A highly significant reduction in the rate of polyp formation (70–100%) was observed in all patients from a mean number of 15.1±11.7 at baseline to 6.0±5.8 at one year and 1.6±1.6 at the end of follow-up (P =0.016 and 0.008, respectively). No patient developed cancer or high-grade adenoma. In conclusion, Long-term use of rofecoxib is well tolerated and effective in inhibiting polyp formation in polyposis patients.

NCT00141193/ www.clinicaltrials.gov ) were studied to determine effi cacy and safety at a year 5 assessment. METHODS: In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colo- rectal adenomas removed within 3 months of the study ' s initiation were assessed after ~ 3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratifi ed by cardioprotective aspirin use and randomized to receive orally 400 mg celecoxib (933 subjects) or placebo (628 subjects) once daily. Effi cacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment. RESULTS: At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically signifi cantly lower in the celecoxib group (51.4 % ) than in the placebo group (57.5 % ; P < 0.001). Similarly, the cumulative rate of new advanced adenomas was signifi cantly lower in the celecoxib group (10.0 % ) than in the placebo group (13.8 % ; P = 0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0 % ) was 1.66 times more likely to have new adenomas than the placebo group (16.3 % ; P < 0.0001). Similarly, the percentage of patients with new advanced adenomas was signifi cantly higher in the celecoxib group (5.0 % ) than in the placebo group (3.8 % ) ( P = 0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95 % confi dence interval (CI) 1.01 - 2.73), selected renal / hypertension events (RR 1.35; 95 % CI 1.09 - 1.68), and general vascular (RR 1.34; 95 % CI 1.08 - 1.68) and cardiac disorders (RR 1.59; 95 % CI 1.12 - 2.26) were higher in those taking celecoxib than in those on placebo. CONCLUSIONS: The year 5 cumulative measures of the incidence of new and advanced adenomas were signifi cantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were sig- nifi cantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxyge- nase-2 inhibition. Consistent with what has been previously reported, increased risk of renal / hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Background & Aims Effective and selective treatment options are needed for patients with colorectal cancer (CRC). The CD24 mucin-like glycoprotein is overexpressed in CRCs; monoclonal antibodies (mAbs) against CD24 inhibit tumor cell growth in vitro and in vivo. Based on the tumor-specific expression of CD24, we investigated the potential of anti-CD24 SWA11 mAb, to deliver a cytotoxic agent into CRC cells. Methods We conjugated SWA11 to a Pseudomonas exotoxin derivative (PE38) via an Fc-binding ZZ domain from Staphylococcal protein A (which binds the Fc domain of mouse IgG2a immunoglobulins) to generate the immunotoxin SWA11-ZZ-PE38; IgG-ZZ-PE38 was used as control. Human HT-29 and COLO320 (CD24-positive) and HCT116 (CD24-negative) CRC cell lines were assayed for immunotoxin binding, cytotoxicity, viability, and apoptosis. Toxicity and antitumor efficacy were tested in mice. Results The immunotoxin preserved the affinity and specificity of SWA11, bound and selectively killed CD24-expressing CRC cells via apoptosis. IC 50 values ranged from 20 to 50 ng/mL—several orders of magnitude lower than that of the mAb alone. The immunotoxins were not toxic to mice at the maximum dose of 0.75 mg/kg. Growth of HT-29 xenograft tumors was significantly reduced in mice given SWA11-ZZ-PE38 (by 78%) compared to untreated mice. Conclusions Anti-CD24 SWA11 mAb can deliver a PE exotoxin derivative to CRC cells and cause them to undergo apoptosis, without toxicity to normal tissues. This immunotoxin might be developed as a therapeutic treatment for patients with CRC.

Sixty male adult rats weighing between 250 and 300 g were divided in two equal experimental groups. The first experiment was designed to evaluate hepatocyte streaming. Animals were injected with 0.5 microCi [3H]thymidine and 1 hour later received one intraperitoneal injection of bromobenzene (3.8 mmol/kg, dissolved in corn oil). The animals were then killed in groups of five at 1 hour and 2, 4, 7, 14, and 30 days. The aim of the second experiment was to evaluate labeling index changes with time. Animals received one intraperitoneal injection of bromobenzene and were killed in groups of five at 1, 2, 3, 4, 7, and 14 days. They received [3H]thymidine 1 hour before killing. Bromobenzene induced a necrosis in the third acinus zone that disappeared within a week. On day 0 the labeling index of hepatocytes and littoral cells was 0.3% +/- 0.04% and 0.4% +/- 0.05%, respectively. On the second day, it reached 14.6% +/- 2.6% and 10.1% +/- 3.1% and returned to its initial value after 1 week. Dead cells in the third zone were replaced by inflowing cells from the intact zones. Hepatocytes and littoral cells streamed at the same velocity of 6 +/- 0.5 micron/day, faster than in untreated animals with velocity of 3.2 microns/day. Parenchyma and stroma responded to injury in a coordinated fashion. From the functional point of view, hepatocytes and littoral cells operate as a unit that is called proliferon. The maximal proliferon life span was 57 days after bromobenzene treatment and 108 days in controls.

Corrigendum: Methotrexate in Chronic Active Crohn's Disease: A Double-Blind, Randomized, Israeli Multicenter Trial

The role of screening colonoscopy for colorectal (CR) neoplasia in average-risk population, remains to be determined.To evaluate the prevalence and anatomic location of CR adenoma and carcinoma and the morbidity of colonoscopy in individuals at average risk for CR cancer (CRC).A retrospective prevalence study of subjects aged 40-80 yr, with no cancer-related symptoms, personal or family history of CR neoplasia, who underwent a colonoscopy.Enrolled were 1,177 persons; 183 aged 40-49 yr (young), 917 aged 50-75 yr, and 77 aged 76-80 yr (elderly). The prevalence of overall CR neoplasia, advanced neoplasia, and cancer was 20.9%, 6.3%, and 1.1%, respectively. In the 50-75 age group, the prevalence of overall adenoma, advanced neoplasia, and cancer was 21.3%, 6.7%, and 1.2%, respectively. Of the 206 neoplasia cases, 21-43% harbored proximal neoplasia beyond the reach of sigmoidoscopy, without distal lesions. Among the elderly, the prevalence of overall adenoma, advanced neoplasia, and cancer reached 26.0%, 14.3%, and 2.6%, respectively. In the young group, 9.8% had overall neoplasia, 1.1% had advanced adenoma, and none had CRC. Procedure-related morbidity rate was 0.1%, with no perforations, bleedings, or mortality.Screening colonoscopy in average-risk subjects demonstrated a considerable prevalence of CR neoplasia and proximal lesions beyond the reach of sigmoidoscopy. The morbidity rate was negligible. Primary screening colonoscopy should be considered in health programs for the average-risk population, beginning at the age of 50 yr. The significantly high rate of advanced and proximal neoplasia in the elderly, encourages the inclusion of healthy subjects aged 76-80 yr in future prospective studies.

Background & Aims: The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines. Methods: Gene expression array analysis ([RG-U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase-2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas). Human cancer cell lines were tested for their response to anti-CD24 monoclonal antibodies. Results: A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6%). Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose- and time-dependent manners. These results were repetitive for 3 different antibodies. Conclusions: CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy.

Background & Aims: Endoscopic screening of the colon with available instruments requires considerable training, is often painful, and carries a risk of perforation. New instrument platforms for endoscopic screening could be useful. The aim of this study was to evaluate the extent of colonic intubation by using a novel self-propelled, self-navigating endoscope (the Aer-O-Scope; GI View Ltd, Ramat Gan, Israel). Methods: Twelve young healthy volunteers underwent complete bowel preparation followed by a nonsedated examination using the novel device. Each examination was followed by a standard colonoscopy for safety evaluation. Cecal intubation was confirmed by endoscopic landmarks and fluoroscopy. Results: In 10 out of 12 subjects (83%) the cecum was successfully reached, whereas in 2 cases the Aer-O-Scope advanced to the hepatic flexure. The time to complete advancement to cecum averaged 14.0 ± 7 minutes, and the driving pressures averaged 34 ± 2.3 milibar. Two subjects requested analgesics during the procedures (in both cases the cecum was reached). Four subjects experienced sweating and a bloating sensation that resolved spontaneously. All subjects were followed up to 48 hours and then for 30 days postprocedure, and no complications were observed. Conclusions: In a preliminary pilot feasibility study of this new instrument, the Aer-O-Scope effectively intubated all or most of the colon. Further clinical studies are warranted.

Chronic inflammation is associated with increased erythrocyte adhesiveness/aggregation. This might have deleterious effects on the microcirculatory flow and tissue oxygenation. We aimed to determine the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of individuals with inflammatory bowel disease (IBD). Fifty-two patients (24 women and 28 men) with ulcerative colitis (UC) at a mean age of 44.0 ± 16.8 years and 96 patients (44 women and 52 men) with Crohn’s disease (CD) at a mean age of 38.0 ± 15.5 years, with various degrees of disease activity, were matched to normal controls. A simple slide test and image analysis were used to determine the degree of erythrocyte adhesiveness/aggregation. CD activity index (CDAI) was determined in patients with CD, while clinical colitis activity index was applied for patients with UC. A significant (P < 0.0005) increment in the degree of erythrocyte adhesiveness/aggregation was noted in both groups of IBD patients compared with matched control groups. This increment was evident even in individuals with a low index of disease activity and during remission. The highly significant correlation with the concentrations of fibrinogen suggests that the degree of erythrocyte adhesiveness/aggregation is an inflammation-related phenomenon. An enhanced state of erythrocyte adhesiveness/aggregation was noted in the peripheral blood of patients with IBD. This might have a deleterious effect on intestinal microcirculatory flow and tissue oxygenation.