Intestinal epithelial layer is an important barrier against antigen invasion. In addition to its barrier function, the immunomodulatory role of intestinal epithelium is attracting considerable attention. The intestinal epithelium may influence underlying immune cells including dendritic cells and lymphocytes and promote tolerogenic and regulatory responses in health. Breakdown of such regulatory influences may result in uncontrolled inflammation and tissue damage. The molecules mediating such regulation derived from intestinal epithelium and their interaction with immune cells may provide novel targets and therapeutic molecules that have translational potential in intestinal inflammation. Understanding the cross-talk between intestinal epithelium and immune cells has progressed from in vitro co-culture models to epithelial cell conditional knockout models.

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

Gastrointestinal (GI) cancers are major health problems, being the most common cancers worldwide. Resistance to apoptosis is closely linked to carcinogenesis and enables malignant cells to evade therapy-induced cell death. In the recent past, the increasing understanding of molecular pathways of apoptosis has provided novel targets in cancer therapy. Several drugs, either inhibiting antiapoptotic signalling or actively inducing apoptosis in cancer cells, have already entered clinical trials. Until now, agents targeting apoptosis pathways are primarily being tested alone or in combination with chemotherapy. In the near future, personalized combination therapies will probably be beneficial for patients with GI cancer. In this review, the current knowledge on defects in apoptosis signalling in GI cancer is summarised and the focus is on the potential clinical efficacy of apoptosis targeting agents.

Heat shock proteins (HSPs) are a highly conserved family of proteins which inhabit almost all subcellular locations and cellular membranes. Depending on their location, these proteins perform a variety of chaperoning functions including folding of newly synthesised polypeptides. HSPs also play a major role in the protection of cells against stressful and injury-inciting stimuli. By virtue of this protective function, HSPs have been shown to prevent acinar cell injury in acute pancreatitis. Also, the levels of HSPs have been shown to be markedly elevated in various forms of cancers when compared with non-transformed cells. Further, inhibition of HSPs has been shown to induce apoptotic cell death in cancer cells suggesting that inhibition of HSPs has a potential to emerge as novel anti-cancer therapy, either as monotherapy or in combination with other chemotherapeutic agents. Several studies have suggested that HSPs can interact with and inhibit both intrinsic and extrinsic pathways of apoptosis at multiple sites. Besides the anti-apoptotic role of HSPs, recent studies suggest that they play a role in the generation of anti-cancer immunity, and attempts have been made to utilise this property of HSPs in the generation of anti-cancer vaccines. The anti-apoptotic function and mechanism of various subtypes of HSPs as well as the current status of anti-HSP therapy are discussed in this review.

Autoimmune pancreatitis (AIP) is distinct from calcifying and obstructive forms of chronic pancreatitis. Clinically and histologically it has two distinct subsets: (i) lymphoplasmacytic sclerosing pancreatitis or type 1 AIP which appears to be a systemic disease characterised by abundant infiltration of affected organs with immunoglobulin G4 (IgG4)-positive plasma cells and (2) duct-centric or type 2 AIP characterised by granulocyte epithelial lesions in the pancreas without systemic involvement. In AIP a marked lymphoplasmacytic infiltrate that responds dramatically to steroid therapy suggests an autoimmune aetiology. However, the target autoantigen(s) and the effector cells in AIP remain speculative. Despite the consistent elevation in serum IgG4 levels and tissue infiltration with IgG4-positive plasma cells in type 1 AIP, the role of IgG4 in its pathogenesis remains unknown. Recent development of animal models of AIP will help improve our understanding of the pathogenesis of these newly described forms of chronic pancreatitis.

Patients with gastro-oesophageal reflux disease (GORD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. Various underlying mechanisms have been shown to contribute to the failure of PPI treatment. These include weakly acidic reflux, duodenogastro-oesophageal reflux, residual acid reflux and functional heartburn, as well as others. Diagnostic evaluation of patients with GORD who have failed PPI treatment may include an upper endoscopy, pH testing and oesophageal impedance with pH monitoring. Commonly, doubling the PPI dose or switching to another PPI will be pursued by the treating physician. Failure of such a therapeutic strategy may result in the addition of a transient lower oesophageal sphincter reducer or pain modulator. Anti-reflux surgery may be suitable for a subset of carefully studied patients.

It is a common experience that gastrointestinal symptoms urge us to differentiate inflammatory bowel disease (IBD) from functional disorders. Furthermore, in patients with proven IBD the disease activity has to be accurately monitored. Faecal markers of neutrophil influx into the mucosa are promising indicators of intestinal inflammation. Some neutrophil-derived proteins may be linked to the pathogenesis of IBD due to their functions as damage-associated molecular pattern molecules (DAMPs). Phagocyte-specific DAMPs of the S100 family are released from neutrophils or monocytes, followed by pro-inflammatory activation of pattern recognition receptors. The complex of S100A8/S100A9 was termed "calprotectin" and has been in use as a faecal marker for 10 years. More recently, faecal S100A12 has been reported to be an even more accurate faecal marker of inflammation. We review the biology of this novel group of molecules which can be used as surrogate markers directly linked to the molecular mechanisms of gut inflammation.

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

Probiotics may benefit irritable bowel syndrome (IBS) symptoms, but randomised controlled trials (RCTs) have been conflicting; therefore a systematic review was conducted.

There has been recent progress in the isolation and characterisation of stem/progenitor cells that may differentiate towards the hepatic lineage. This has raised expectations that therapy of genetic or acquired liver disease might be possible by transplanting stem/progenitor cells or their liver-committed progeny. However, it is currently impossible to determine from the many documented studies which of the stem/progenitor cell populations are the best for therapy of a given disease. This is largely because of the great variability in methods used to characterise cells and their differentiation ability, variability in transplantation models and inconsistent methods to determine the effect of cell grafting in vivo. This manuscript represents a first proposal, created by a group of investigators ranging from basic biologists to clinical hepatologists. It aims to define standardised methods to assess stem/progenitor cells or their hepatic lineage-committed progeny that could be used for cell therapy in liver disease. Furthermore standardisation is suggested both for preclinical animal models to evaluate the ability of such cells to repopulate the liver functionally, and for the ongoing clinical trials using mature hepatocytes. Only when these measures have been put in place will the promise of stem/progenitor-derived hepatocyte-based therapies become reality.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. Up to 70% of patients will have persistent infection after inoculation, making this disease a significant cause of morbidity and mortality. The severity of disease varies widely, from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma. Since the discovery of HCV, the treatment of hepatitis C has considerably improved. Recently, combination of pegylated interferons with ribavirin gives a response rate of about 55%. Treatment is indicated in patients with moderate or severe fibrosis. The tolerability of combination treatment is relatively poor, with a frequent flu-like syndrome and an impaired quality of life. In addition to viral and environmental behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in HCV infection. The sequencing of the human genome, together with the development of high-throughput technologies that measure the function of the genome, have afforded unique opportunities to develop profiles that can distinguish, identify and classify discrete subsets of disease, predict the disease outcome or predict the response to treatment. This paper reviews the published literature on gene expression associated with HCV infection (HCV infection, fibrosis progression), and also according to response to treatment.

In the last few decades liver transplantation (LTx) has become a reliable life-saving procedure for patients with chronic end-stage liver diseases. LTx has an outstanding success rate in the first few years after allografting, especially considering that many patients are on the brink of survival at the time of transplantation. The success of LTx is owed to the pioneers who developed the surgical procedures and to researchers who discovered the medications to help prevent immunological rejection of allografts. However, several problems continue to impose serious limits on LTx today, including a shortage of donor livers, recurrence of disease (eg, hepatitis, hepatocellular cancer), preservation of long-term allograft function and the side effects of anti-rejection drugs. While the dilemma of organ shortage is not a focus of this review, we will address the latter issues as they relate to the "oldest" and "newest" approaches to immunosuppression, and discuss the prospect that recipients could potentially be made immunologically tolerant to liver transplants. Due to the critical shortage of organs, new strategies to preserve transplanted liver allografts for the longest possible time are of paramount importance.