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Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn's disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials. [ABSTRACT FROM AUTHOR]

Growing evidence supports an important role of the tumor microenvironment (TME) in the pathogenesis of colorectal cancer (CRC). Resident cells such as fibroblasts or immune cells infiltrating into the TME maintain continuous crosstalk with cancer cells and thereby regulate CRC progression. One of the most important molecules involved is the immunoregulatory cytokine transforming growth factor-β (TGFβ). TGFβ is released by various cells in the TME, including macrophages and fibroblasts, and it modulates cancer cell growth, differentiation, and cell death. Mutations in components of the TGF pathway, including TGFβ receptor type 2 or SMAD4, are among the most frequently detected mutations in CRC and have been associated with the clinical course of disease. Within this review, we will discuss our current understanding about the role of TGFβ in the pathogenesis of CRC. This includes novel data on the molecular mechanisms of TGFβ signaling in TME, as well as possible strategies for CRC therapy targeting the TGFβ pathway, including potential combinations with immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances. [ABSTRACT FROM AUTHOR]

• Interleukin-36 cytokines belong to the IL-1 family of cytokines and two antagonists of IL-36 function have been identified (IL-36 receptor antagonist). • Increased levels of IL-36 cytokines are produced by various immune and non-immune cells in numerous inflammatory or neoplastic disorders. • Suppression of IL-36R signaling was effective in murine models of inflammatory disorders of the skin, kidney, lung and gut raising the possibility that blockade of IL-36R signaling events might be relevant for clinical therapy. • Initial studies in patients with generalized pustular psoriasis (GPP) suggested potential efficacy of anti-IL-36R antibody therapy; further clinical studies in other chronic inflammatory disorders are ongoing. IL-36 belongs to the IL-1 family of cytokines and activates target cells by binding to a specific cytokine receptor (IL-36R) followed by activation of intracellular regulators such as MAP kinases and NF-kappaB. Three subforms of IL-36, denoted IL-36alpha, IL-36beta and IL-36gamma, have been described that require N-terminal cleavage for activation. Functional studies have shown that IL-36 may activate a broad spectrum of immune and non-immune cells such as macrophages, T cells, keratinocytes and epithelial cells in an IL-1-independent fashion and thereby controls various inflammatory or oncogenic processes in the skin, the lung, the kidney, the liver and the intestine, respectively. Based on the presence of mutations of the IL-36RN in patients with generalized pustular psoriasis, successful clinical pilot trials with IL-36R blocking antibodies were conducted in these patients and further studies in patients with autoimmune or chronic inflammatory disorders such as inflammatory bowel diseases are under way. Collectively, these findings highlight a crucial regulatory role of IL-36 signaling in driving various inflammatory disorders that provide a rational basis for clinical targeting of this cytokine. [ABSTRACT FROM AUTHOR]

ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development. [ABSTRACT FROM AUTHOR]

While such acute inflammatory processes are usually self-limiting and are followed by tissue repair and healing responses, there are some circumstances in which acute inflammation fails to resolve and is subsequently followed by development of chronic inflammation [[1]]. Studies in recent years have unequivocally shown that resolution of inflammation is an actively controlled process rather than a passive procedure in which the pro-inflammatory immune cascade in inflammation simply fizzles out. SPMs thus may actively reprogram the inflammatory process and favor resolution of inflammation. For instance, while anti-IL-17A blockers such as secukinumab were effective in psoriasis [[20]], they aggravated mucosal inflammation in patients with Crohn's disease [[83]] highlighting the concept of tissue-specific mechanisms affecting resolution of inflammation. [Extracted from the article]

Allogeneic transplantation of hematopoietic stem cells (allo-HCT) represents an increasingly employed therapeutic approach to potentially cure patients suffering from life-threatening malignant and autoimmune disorders. Despite its lifesaving potential, immune-mediated allo-reactivity inherent to the allogeneic transplantation can be observed within up to 50% of all allo-HCT patients regularly resulting in the manifestation of acute and/or chronic graft-versus-host disease (GvHD). Mechanistically, especially donor T cells are assumed to chiefly drive inflammation that can occur in virtually all organs, with the skin, liver, and gut representing as the most frequently affected anatomic sites. Especially in the presence of intestinal manifestations of GvHD, the risk that the disease takes a life-threatening, potentially fatal course is significantly increased. In the light of a rapid gain of knowledge in respect to decode innate and adaptive immunity related mechanisms as, e.g., cytokine networks, intracellular signaling pathways or environmental triggers as, e.g., the intestinal microbiota and the development of novel therapeutic approaches, detailed insight into endogenous mechanisms seeking to counterbalance the proinflammatory machinery or to proactively foster signals promoting the resolution of allo-driven intestinal inflammation is emerging. Here, we seek to highlight the key aspects of those mechanisms involved in and contributing to the resolution of GvHD-associated intestinal inflammation. Concomitantly, we would like to briefly outline and discuss promising future experimental targets suitable to be therapeutically employed to directionally deflect the tissue response from a proinflammatory to an inflammation-resolving type of intestinal GvHD after allo-HCT. [ABSTRACT FROM AUTHOR]

Ulcerative colitis designates an idiopathic chronic inflammatory bowel disease leading to bloody diarrhea and inflammatory alterations mostly restricted to the large intestine. Many studies continue to unravel important aspects of its etiopathogenesis, and recent pharmaceutical developments broaden the arsenal of therapeutic opportunity. In this review, we delve into the cellular and molecular determinants of successful resolution of ulcerative colitis, describing novel insights in each of the phases of mucosal healing starting from damaging insults to the mucosa, epithelial restitution, and its adaption to inflammation as well as lymphocyte-driven maintenance and resolution of chronic inflammation. Additionally, molecular switches from inflammation to resolution are explored, paving the way for future avenues to resolve ulcerative colitis. [ABSTRACT FROM AUTHOR]

Graphical abstract IL-23 controls activation and cytokine production of various immune cells in colitis such as natural killer (NK) cells, intraepithelial lymphocytes (IEL), innate lymphoid cells (ILCs), and T helper 17 cells (Th17). In contrast, IL-23 blocks activation of regulatory T cells (Tr1, Treg). Highlights • IL-23 production is elevated in patients with inflammatory bowel diseases and colon cancer. • IL-23 target cells comprise T helper 17 cells, innate lymphoid cells type 3, granulocytes, intraepithelial lymphocytes and natural killer cells. • IL-23-induced immune cell activation aggravates gut inflammation and promotes growth of colon cancer. • Suppression of IL-23 or IL-23R function led to suppression of mucosal inflammation in various mouse models of colitis. • Antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn´s disease. Abstract Studies in recent years have identified a pivotal role of the cytokine IL-23 in the pathogenesis of inflammatory bowel diseases (IBD: Crohn´s disease, ulcerative colitis) and colitis-associated colon cancer. Genetic studies revealed that subgroups of IBD patients have single nucleotide polymorphisms in the IL-23R gene suggesting that IL-23R signaling affects disease susceptibility. Furthermore, increased production of IL-23 by macrophages, dendritic cells or granulocytes has been observed in various mouse models of colitis, colitis-associated cancer and IBD patients. Moreover, in several murine models of colitis, suppression of IL-12/IL-23 p40, IL-23 p19 or IL-23R function led to marked suppression of gut inflammation. This finding was associated with reduced activation of IL-23 target cells such as T helper 17 cells, innate lymphoid cells type 3, granulocytes and natural killer cells as well as with impaired production of proinflammatory cytokines. Based on these findings, targeting of IL-23 emerges as important concept for suppression of gut inflammation and inflammation-associated cancer growth. Consistently, neutralizing antibodies against IL-12/IL-23 p40 and IL-23 p19 have been successfully used in clinical trials for therapy of Crohn´s disease and pilot studies in ulcerative colitis are ongoing. These findings underline the crucial regulatory role of IL-23 in chronic intestinal inflammation and colitis-associated cancer and indicate that therapeutic strategies aiming at IL-23 blockade may be of key relevance for future therapy of IBD patients. [ABSTRACT FROM AUTHOR]

Molecular imaging is based on the labelling of defined molecular targets through the utilization of fluorescently linked probes and their subsequent detection with high‐resolution endoscopic devices, thereby enabling visualization of single molecules including receptors. Whereas early studies have used molecular imaging for improved visualization and detection of early dysplasia and cancer as well as for assessing intestinal inflammation and inflammation‐associated cancer within the gastrointestinal (GI) tract, more recent studies have impressively demonstrated that molecular imaging can also be used to characterize and visualize the molecular fingerprint of cancer and inflammation in vivo and in real time. With this, molecular imaging can be used to guide expression‐tailored individualized therapy. With the rapid expansion and diversification of the repertoire of biological agents utilized in inflammatory bowel disease and cancer, this approach is gaining increasing attention. Within this review, we first summarize the technical components commonly used for molecular imaging and then review preclinical and clinical studies and evolving clinical applications on molecular imaging within the lower GI tract. Molecular imaging has the potential to significantly change endoscopic diagnosis and subsequent targeted therapy of gastrointestinal cancer and chronic gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. The pathophysiological understanding of this disease is limited and no curative therapy is available so far. Therefore, most patients require long-lasting or even life-long immunosuppressive therapies for the suppression of symptoms to improve quality of life and reduction of long-term risks. However, in a relevant subgroup of patients, these therapeutic goals cannot be sufficiently attained. Summary: Clinically established therapies in active CD comprise corticosteroids and immunosuppressants such as azathioprine. After the introduction of anti-TNFα (Tumor necrosis factor alpha) antibodies, other biologicals (e.g., vedolizumab and ustekinumab) have also been approved. New drugs in the pipeline like filgotinib, upadacitinib, risankizumab or rifaximin could improve the therapy of CD in the near future. Thus, an individualized therapy management, based on optimal selection of therapeutic agents will become more important. Additionally, the local application of mesenchymal stem cells might be helpful in the management of fistulas. Key Messages: The targeted biological therapeutic agents (anti-TNFα antibodies, vedolizumab, ustekinumab) are well established for therapy in CD. There are several new substances in the pipeline with promising results in phase II trials (filgotinib, rifaximin, risankizumab, upadacitinib). The upcoming extension of the therapeutic arsenal will require methods for an optimized selection of substances, thus enabling a more individualized therapy. [ABSTRACT FROM AUTHOR]

Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context. [ABSTRACT FROM AUTHOR]

An editorial is presented which discusses about the colorectal polyps during endoscopy, the difference of endoscopists and pathologists, communication between the two departments and the verification of adenomatous polyps by gastroenterologists.

Recent studies have highlighted a crucial regulatory role of the cytokine IL-9 in driving immune responses in chronic inflammatory and autoimmune diseases at mucosal surfaces. IL-9 activates various types of immune and non-immune cells carrying the membrane bound IL-9R. IL-9 signaling plays a pivotal role in controlling the differentiation and activation of these cells by inducing the Jak/STAT pathway. In particular, IL-9 induces activation of T helper cells and affects the function of various tissue resident cells such as mast cells and epithelial cells in the mucosa. Importantly, recent findings suggest that blockade of IL-9 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, allergic disorders such as food allergy and asthma. Thus, blockade of IL-9 and IL-9R signaling emerges as potentially novel approach for therapy of inflammatory diseases in the mucosal immune system. [ABSTRACT FROM AUTHOR]

Interleukin-12 (IL-12) was the first member of the IL-12 family of cytokines to be identified and has therefore become its eponym. It is a heterodimeric protein of two subunits (p35, p40) secreted by phagocytic cells in response to pathogens and mainly acts through STAT4 to induce IFN-γ production in T and NK cells. IFN-γ in turn mediates proinflammatory functions and activates T-bet. As IL-12 engages in T H 1 development, it is believed to represent an important link between innate and adaptive immunity. Following its identification and the finding of its association to T H 1 commitment, great hopes were placed in IL-12 to become a target for therapeutic applications in multiple settings of autoimmunity and cancer. Though, the discovery of the related members of the IL-12 family and several rather disappointing attempts to translate experimental results into clinical practice, have relativized these hopes. Nevertheless, IL-12 remains a cytokine of outstanding importance with lots of unresolved questions. In this review, we will first briefly depict the biochemistry of the cytokine, its receptor and the related signal transduction, before summarizing the regulation of IL-12 production and its biological functions. We will then describe the current knowledge about the implication of IL-12 in different murine disease models as well as in the corresponding human conditions and comment on possible consequences for future clinical applications. [ABSTRACT FROM AUTHOR]

Crohn's disease is a destructive inflammatory bowel disease of unknown origin that may lead to various complications such as strictures, stenosis, fistulas and colitis-associated neoplasias. However, the course of the disease varies substantially among patients and disease behaviour may also change with time. At diagnosis behaviour is inflammatory in the majority of patients, while penetrating or structuring behaviour become more prominent at later time points. Thus, medication in Crohn's disease needs frequent optimization over time. Therefore, new strategies for prediction of response to therapy are urgently needed. Here, recent advantages in imaging techniques for personalized medicine in Crohn's disease are reviewed. Such advantages include ultrasonography, computed tomography, magnetic resonance imaging and new endoscopic approaches such as molecular endoscopy. It is expected that these novel techniques will lead to marked improvements in the assessment of disease behaviour and the prediction of response to clinical therapy with biologicals. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7.Methods: In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28.Results: The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P=0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease.Conclusions: We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo. (Funded by Giuliani; EudraCT number, 2011-002640-27.). [ABSTRACT FROM AUTHOR]

The article presents a study on the effectiveness of mongersen for the treatment of Crohn's disease. Topics covered include the Crohn's Disease Activity Index (CDAI), the reduced activity of the immunosuppressive cytokine transforming growth factor characterizing Crohn's disease-related inflammation, and the gut inflammation tied to Crohn's disease.

A letter to the editor for the article "Multispectral Optoacoustic Tomography for Assessment of Crohn's Disease Activity" that was published in previous issue is presented.

Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD. [ABSTRACT FROM AUTHOR]

The article discusses the safety, importance, and limitations of standard endoscopy for the diagnosis and treatment of inflammatory bowel. The researchers have evaluated the medical appliances used in patients for colonoscopy in colorectal cancer screening, polyp surveillance, and diagnostic evaluation. The findings indicate potential limitations such as non-randomized approach, no comparison in forward viewing, and limited sampling size.

Highlights: [•] IL-6 is a pleiotropic cytokine involved in the regulation of innate and adaptive immunity. [•] IL-6 regulates chronic intestinal inflammation by regulating the balance between pro- and anti-inflammatory T cells. [•] Trans signaling of IL-6 promotes tumor growth in CRC through intracellular STAT3 activation. [•] Various therapeutics targeting IL-6 signaling has been developed for the treatment of human disease during recent years. [•] Initial clinical studies show promising results for IL-6 inhibition in human inflammatory diseases and cancer. [Copyright &y& Elsevier]

This paper reporting on techniques for esophageal evaluation and imaging and drugs for esophageal disease includes commentaries on endoscopy techniques including dye-based high-resolution and dye-less high-definition endoscopy; the shift from CT to MRI guidance in tumor delineation for radiation therapy; the role of functional lumen imaging in measuring esophageal distensibility; electrical stimulation of the lower esophageal sphincter (LES) as an alternative to fundoduplication for treatment of gastroesophageal reflux disease (GERD); the morphological findings of reflux esophagitis and esophageal dysmotility on double-contrast esophagography; the value of videofluoroscopy in assessing protecting mechanisms in patients with chronic reflux or swallowing disorders; targeting visceral hypersensitivity in the treatment of refractory GERD; and the symptoms and treatments of nighttime reflux and nocturnal acid breakthrough (NAB). [ABSTRACT FROM AUTHOR]

Simple Summary: This review describes the role of T cell aging in colorectal cancer development. T cells are important mediators in cancer immunity. Aging affects T cells, leading to various dysfunctions which can impede antitumor immunity. While some hallmarks of T cell aging have been observed in colorectal cancer patients, the functional role of such cells is not clear. Therefore, understanding how aged T cells influence overall patient outcome could potentially help in the pursue to develop new therapies for the elderly. Colorectal cancer (CRC) continues to be one of the most frequently diagnosed types of cancers in the world. CRC is considered to affect mostly elderly patients, and the number of diagnosed cases increases with age. Even though general screening improves outcomes, the overall survival and recurrence-free CRC rates in aged individuals are highly dependent on their history of comorbidities. Furthermore, aging is also known to alter the immune system, and especially the adaptive immune T cells. Many studies have emphasized the importance of T cell responses to CRC. Therefore, understanding how age-related changes affect the outcome in CRC patients is crucial. This review focuses on what is so far known about age-related T cell dysfunction in elderly patients with colorectal cancer and how aged T cells can mediate its development. Last, this study describes the advances in basic animal models that have potential to be used to elucidate the role of aged T cells in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Autophagy is the capability of cells to dismantle and recycle parts of themselves. This process is closely intertwined with other crucial cell functions, such as growth and control of metabolism. Autophagy is oftentimes dysregulated in cancer and offers established and advanced tumors protection against a lack of nutrients and an advantage regarding proliferation. This review will present an overview of the basics of human autophagy, its dysregulation in cancer, and approaches to target autophagy in cancer treatment in recent and current clinical trials as well as new findings of preclinical research. Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles. [ABSTRACT FROM AUTHOR]

Abstract: Non-small cell lung cancer (NSCLC) is among the most frequent types of cancer and associated with significant mortality. Recent studies suggest that tumor infiltrating T lymphocytes and their immunoregulatory cytokines play a fundamental role in controlling tumor growth and metastasis. Whereas T helper 1 cells and their master transcription factor T-bet have been identified as important regulators of IFN-gamma driven anti-tumoral immune response, IL-17 producing T helper 17 cells expressing RORA/C transcription factors have been found to augment tumor growth and cell proliferation in NSCLC. Furthermore, regulatory T cells were shown to impair immune responses against lung cancer. As modulation of T cell cytokines such as IL-17A has been recently shown to suppress tumor growth in experimental models, anti-cytokine agents emerge as a promising new approach for treatment of lung cancer. [Copyright &y& Elsevier]

Recent studies have identified mucosal healing on endoscopy as a key prognostic parameter in the management of inflammatory bowel diseases (IBD), thus highlighting the role of endoscopy for monitoring of disease activity in IBD. In fact, mucosal healing has emerged as a key treatment goal in IBD that predicts sustained clinical remission and resection-free survival of patients. The structural basis of mucosal healing is an intact barrier function of the gut epithelium that prevents translocation of commensal bacteria into the mucosa and submucosa with subsequent immune cell activation. Thus, mucosal healing should be considered as an initial event in the suppression of inflammation of deeper layers of the bowel wall, rather than as a sign of complete healing of gut inflammation. In this systematic review, the clinical studies on mucosal healing are summarised and the effects of anti-inflammatory or immunosuppressive drugs such as 5-aminosalicylates, corticosteroids, azathioprine, ciclosporin and anti-TNF antibodies (adalimumab, certolizumab pegol, infliximab) on mucosal healing are discussed. Finally, the implications of mucosal healing for subsequent clinical management in patients with IBD are highlighted. [ABSTRACT FROM AUTHOR]

Recent advances in endoscopic imaging techniques have revolutionized the diagnostic approach of patients with inflammatory bowel disease (IBD). New, emerging endoscopic imaging techniques visualized a plethora of new mucosal details even at the cellular and subcellular level. This review offers an overview about new endoscopic techniques, including chromoendoscopy, magnification endoscopy, spectroscopy, confocal laser endomicroscopy and endocytoscopy in the face of IBD. [ABSTRACT FROM AUTHOR]

Recent advances in endoscopic imaging techniques have revolutionized the diagnostic approach of patients with inflammatory bowel disease (IBD). New, emerging endoscopic imaging techniques visualized a plethora of new mucosal details even at the cellular and subcellular level. This review offers an overview about new endoscopic techniques, including chromoendoscopy, magnification endoscopy, spectroscopy, confocal laser endomicroscopy and endocytoscopy in the face of IBD. [ABSTRACT FROM AUTHOR]

Recent advances in endoscopic imaging techniques have revolutionized the diagnostic approach of patients with inflammatory bowel disease (IBD). New, emerging endoscopic imaging techniques visualized a plethora of new mucosal details even at the cellular and subcellular level. This review offers an overview about new endoscopic techniques, including chromoendoscopy, magnification endoscopy, spectroscopy, confocal laser endomicroscopy and endocytoscopy in the face of IBD. [ABSTRACT FROM AUTHOR]

Abstract: IL-6 activates various cell types carrying the membrane bound IL-6R (classical IL-6 signaling) as well as IL-6R− gp130+ cells via the soluble IL-6R (IL-6 trans-signaling). IL-6 signaling plays a pivotal role in controlling the differentiation and activation of T lymphocytes by inducing the Jak/STAT-3 and the Ras/Erk/C/EBP pathways. In particular, IL-6 modulates the resistance of T cells against apoptosis, induces activation of T helper cells and controls the balance between regulatory T cells and Th17 cells. Importantly, recent findings suggest that blockade of IL-6 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, diabetes, multiple sclerosis, asthma and rheumatoid arthritis as well as models of inflammation-associated cancer. Thus, anti-IL-6/anti-IL-6R strategies emerge as promising novel approaches for therapy of inflammatory diseases in humans. In this review article, we discuss the latest findings on the role of IL-6 in experimental models of autoimmunity and cancer, as well as clinical perspectives. [Copyright &y& Elsevier]

Recent advances in endoscopic imaging techniques have revolutionized the diagnostic approach of patients with inflammatory bowel disease (IBD). New, emerging endoscopic imaging techniques visualized a plethora of new mucosal details even at the cellular and subcellular level. This review offers an overview about new endoscopic techniques, including chromoendoscopy, magnification endoscopy, spectroscopy, confocal laser endomicroscopy and endocytoscopy in the face of IBD. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn’s disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today’s differentiated clinical therapy and describes mechanisms of promising future medicinal approaches. [ABSTRACT FROM AUTHOR]

Abstract: Although colorectal cancer (CRC) is still one of the leading causes of cancer related death in the western hemisphere, new therapeutic options have increased the overall survival rate of advanced disease from 10 to 18–24months during the past decade. The new therapeutics include biological agents as bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor (VEGF), and cetuximab (Erbitux), an inhibitor of epithelial growth factor receptor (EGFR). Although these biologicals have entered clinical routine due to their encouraging results, their effect has been shown to be limited due to adaptation or previously existing resistance of tumor cells. This has been clearly shown in the case of patients with mutations of K-ras, which lead to resistance against cetuximab. Therefore, several new pathways are currently investigated for therapeutic targeting in CRC. These include WNT-signaling, downstream mediators of EGFR as the mitogen-activated protein kinase (MAPK)- or the phosphatidylinositol 3-kinase (PI3K)-pathway, the hypoxia response system involving hypoxia inducible factor-1 (HIF-1), mechanisms of tumor development following chronic inflammation, and many others. This article will review new molecular targets for the treatment of CRC and discuss possible implications for clinical therapy. [Copyright &y& Elsevier]

Several cytokines have been identified as critical mediators of chronic inflammation in inflammatory bowel disease (IBD) and biological therapies that target these molecules have been developed during recent years. Thereby, anti-TNF agents have noticeably improved the treatment of patients with IBD in comparison to conventional therapy. Furthermore, initial clinical trials showed promising results with anti-IL-6 and anti-IL-12/IL-23 agents. In addition to these well-known mediators of IBD, various novel cytokines have been described as critical during the pathogenesis of IBD in recent experimental studies and therapeutic targeting of these cytokines could provide new strategies for human disease. [Copyright &y& Elsevier]

Recent studies have provided important insights into the pathogenesis of inflammatory bowel disease (IBD). The development of new therapeutic agents has been triggered by basic research and studies in mouse models of IBD. It is expected that improved translational research will lead to optimized therapy and new individualized treatment options. [Copyright &y& Elsevier]

Chronic inflammation severely increases the risk for cancer development as seen in patients with inflammatory bowel disease (IBD). Although the exact mechanisms of inflammation-associated tumor development remain to be shown, a role for the adaptive immune system has been implicated in colitis-associated cancer (CAC). In fact, CD4+ effector T cells, which promote chronic inflammation in IBD, create a tumor convenient environment, which can lead to cancer initiation, promotion, and progression. Thereby, the cytokines interleukin-6 and tumor necrosis factor-α constitute an important link between inflammation and tumor growth. Furthermore, cytotoxic CD8+ T cells, which usually are protective as part of the host antitumor immune response in sporadic cancer, can contribute to the aggravation of chronic inflammation and thereby support tumor development. In contrast, regulatory T cells, which have been shown to attenuate tumor immunosurveillance, act as potent suppressors of chronic inflammation and thus can have protective effects in CAC. This review discusses the role of the adaptive immune response and especially T cells in the pathogenesis CAC and possible implications for the therapeutic applications. [ABSTRACT FROM AUTHOR]

Interleukin-12p70 (IL-12p70) induces T-helper-1-cell responses and IL-23, a related cytokine, is the master switch in several T-cell-mediated inflammatory disorders. IL-27, another member of the IL-12 family, regulates innate and adaptive immune responses. Recently, distinct combinations of transcription factors have been shown to regulate the expression of the genes that encode these three cytokines. Toll-like receptor ligands, in association with other microbial products and endogenous mediators, tip the balance between the expression of IL-12 family members and thereby may control the outcome of T-cell-mediated inflammation. On this basis, we present a novel perspective on the pathogenesis and regulation of inflammatory disorders. [ABSTRACT FROM AUTHOR]

Abstract: Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and Ulcerative colitis, the idiopathic forms of inflammatory bowel disease in humans. The clinical appearance of human IBD is heterogeneous, a fact that is also reflected by the steadily increasing number of mouse strains displaying IBD like intestinal alterations. The analysis of these models together with genetic studies in humans greatly enhanced our insights into immunoregulatory processes in the gut and led to the generally accepted hypothesis that a deregulated immune response against components of the intestinal microbiota is critically involved in IBD pathophysiology. In this article we provide a brief overview of selected mouse models of IBD and discuss their contribution to the current understanding of disease mechanisms that contribute to IBD. [Copyright &y& Elsevier]

BACKGROUND: Mitomycin C–associated thrombotic microangiopathy (TMA) has a poor prognosis with limited therapeutic options. Most patients die within 4 months of diagnosis due to pulmonary or renal failure. Here, a patient resistant to total plasma exchange (TPE) and immunosuppressive therapy with glucocorticoids, rituximab, vincristine, and splenectomy who was successfully treated with protein A immunoadsorption is described. CASE REPORT: A 29-year-old woman developed a TMA after chemotherapy with mitomycin C. She presented with thrombocytopenia, pulmonary edema, hemolytic anemia with presence of schistocytes, and renal failure. Immediate TPE (>120 times) and immunosuppressive therapy with glucocorticoids, however, did not improve her clinical situation. Furthermore, she was refractory to subsequent immunosuppressive therapy with rituximab and vincristine and laparoscopic splenectomy. Finally, after 12 cycles of extracorporeal protein A immunoadsorption with a commercially available immunoadsorption system (Immunosorba, Fresenius AG), platelet counts increased with disappearance of hemolytic syndromes. CONCLUSION: Extracorporeal protein A immunoadsorption with the Immunosorba system emerges as a potentially effective and safe treatment for refractory mitomycin C–associated TMA with only moderate side effects. This therapeutic option may be considered at an early state of the disease to prevent extensive immunosuppression. [ABSTRACT FROM AUTHOR]

Background: Stenoses and fistulas are frequent complications in patients with Crohn's disease (CD). They represent a major diagnostic and therapeutic challenge and surgical intervention is often required. The availability of novel, anti-TNF strategies for therapy has raised the question as to what extent these new treatment options have impact on the clinical decision-making process regarding the necessity for surgery. Discussion: A short overview of the current pathophysiological understanding of CD, focusing on the immunology of the intestinal mucosa, is given. Then the problems of proper clinical management of stenoses and fistulas are addressed. With regard to symptomatic stenoses, attention will be given to novel diagnostic tools for the distinction between inflammatory and fibrotic stenoses, and our clinical experience with the treatment of symptomatic inflammatory stenoses with infliximab will be discussed. With regard to fistulizing CD, the data that are currently available for medical therapy are summarized with special reference to the studies on the efficacy of anti-TNF treatment. Conclusion: With regard to moderately and severe inflammatory stenoses, medical treatment with infliximab may be an option after careful assessment of the inflammatory nature of the stenosis and exclusion of a septic focus. With regard to fistulas, anti-TNF treatment is a valuable option that is likely to improve the clinical outcome. Based on the available data, however, anti-TNF treatment cannot yet replace surgical intervention when necessary. Prospective trials of medical therapy and a combination of medical and surgical therapy for complex fistulas and internal fistulas are needed to define the potential and the limitations of these novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus-induced gene 3 (EBI3) is a widely expressed IL-12p40-related protein that associates as a heterodimer with either IL-12p35 or an IL-12p35 homologue, p28, to create a new cytokine (IL-27). To define the function of EBI3 in vivo, we generated knockout mice in which the ebi3 gene was targeted by homologous recombination. EBI3[sup -/-] mice exhibited normal numbers of both naive and mature CD4[sup +] and CD8[sup +] T cells and B cells, but markedly decreased numbers of invariant natural killer T cells (iNKT) as defined by staining with an α-galactosylceramide (αGalCer)-loaded CD1d-tetramer. iNKT cells from EBI3[sup -/-] mice exhibited decreased IL-4 and, to a lesser extent, IFN-γ production after αGalCer stimulation in vitro. A sustained decrease in IL-4 production was also observed in EBI3[sup -/-] mice after αGalCer stimulation in vivo in contrast to IFN-γ production, which was only transiently decreased under such stimulation. Notably, EBI3[sup -/-] mice were resistant to the induction of immunopathology associated with oxazolone-induced colitis, a colitis model mediated primarily by T helper (Th) 2-type cytokine production by iNKT cells. In contrast, trinitrobenzene sulfonic acid-induced colitis, a predominantly Th1-mediated colitis models was unaffected. Thus, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of iNKT cell function. [ABSTRACT FROM AUTHOR]

Mucosal immunity relies on the delicate balance between antigen responsiveness and tolerance. The polarization of T helper cells plays a key role in maintaining or disrupting this equilibrium. [ABSTRACT FROM AUTHOR]

Gut-related diseases like ulcerative colitis, Crohn's disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers new opportunities in finding novel ways to interfere with and apply new pharmaceuticals. Memory T cells (mT cells) and their pro-inflammatory properties have been proven to play an important role in gastrointestinal diseases and are therefore increasingly spotlighted. This review focuses on mT cells and their subsets in the context of disease pathogenesis and maintenance. It illustrates the network of regulatory proteins and metabolites connecting mT cells with other cell types and tissue compartments. Furthermore, the crosstalk with various microbes will be a subject of discussion. Characterizing mT cell interactions will help to further elucidate the sophisticated molecular and cellular networking system in the intestine and may present new ideas for future research approaches to control gut-related diseases. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion We assessed and compared molecular tissue changes at the entheses in patients with psoriasis (PsO) and psoriatic arthritis (PsA) and in healthy controls (HCs) in vivo using multispectral optoacoustic tomography (MSOT) and described their relationship with clinical and ultrasound findings of enthesitis.A cross‐sectional study (MSOT and Arthrosonography in PsA) in biologic disease‐modifying antirheumatic drug–naïve patients with PsA and PsO and HCs was performed. Participants underwent clinical, ultrasonographic, and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, and Achilles tendon attachment). MSOT‐measured hemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified, and mean differences between groups were calculated using linear mixed effects models. MSOT‐measured analytes were compared between entheses with and without clinical and ultrasound anomalies.Ninety participants were included (30 PsO, 30 PsA, and 30 HCs), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Patients with PsA and PsO showed increased oxygenated Hb (PsA: P = 0.003; PsO: P = 0.054) and SO2 (PsA: P < 0.001; PsO: P = 0.001) levels and decreased collagen signals (PsA: P < 0.001; PsO: P < 0.001) compared with HCs, with more pronounced changes in PsA. Significantly lower collagen levels (P = 0.01) and increased lipids (P = 0.03) were recorded in tender entheses compared with nontender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (P = 0.014) and lipid signals (P = 0.020), respectively.Patients with PsA and PsO exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immunometabolic tissue changes. [ABSTRACT FROM AUTHOR]

Monocytes, as well as downstream macrophages and dendritic cells, are essential players in the immune system, fulfilling key roles in homeostasis as well as in inflammatory conditions. Conventionally, driven by studies on reporter models, mouse monocytes are categorized into a classical and a non-classical subset based on their inversely correlated surface expression of Ly6C/CCR2 and CX3CR1. Here, we aimed to challenge this concept by antibody staining and reporter mouse models. Therefore, we took advantage of Cx3cr1GFP and Ccr2RFP reporter mice, in which the respective gene was replaced by a fluorescent reporter protein gene. We analyzed the expression of CX3CR1 and CCR2 by flow cytometry using several validated fluorochrome-coupled antibodies and compared them with the reporter gene signal in these reporter mouse strains. Although we were able to validate the specificity of the fluorochrome-coupled flow cytometry antibodies, mouse Ly6Chigh classical and Ly6Clow non-classical monocytes showed no differences in CX3CR1 expression levels in the peripheral blood and spleen when stained with these antibodies. On the contrary, in Cx3cr1GFP reporter mice, we were able to reproduce the inverse correlation of the CX3CR1 reporter gene signal and Ly6C surface expression. Furthermore, differential CCR2 surface expression correlating with the expression of Ly6C was observed by antibody staining, but not in Ccr2RFP reporter mice. In conclusion, our data suggest that phenotyping strategies for mouse monocyte subsets should be carefully selected. In accordance with the literature, the suitability of CX3CR1 antibody staining is limited, whereas for CCR2, caution should be applied when using reporter mice. [ABSTRACT FROM AUTHOR]