Current insights in to the pathophysiology of Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) represents a functional disorder of gastrointestinal tract without the presence of an anatomic defect, in which abdominal pain is relieved with defecation and is associated with altered bowel habits

Metabolic Targets for Improvement of Allogeneic Hematopoietic Stem Cell Transplantation and Graft-vs.-Host Disease

Utilization of the adaptive immune system against malignancies, both by immune-based therapies to activate T cells in vivo to attack cancer and by T-cell therapies to transfer effector cytolytic T lymphocytes (CTL) to the cancer patient, represent major novel therapeutic advancements in oncologic therapy. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is a form of cell-based therapy, which replaces the HSC in the patient's bone marrow but also serves as a T-cell therapy due to the Graft-vs.-leukemia (GVL) effect mediated by donor T cells transferred with the graft. Allogeneic HSCT provides one potentially curative option to patients with relapsed or refractory leukemia but Graft-vs.-Host-Disease (GVHD) is the main cause of non-relapse mortality and limits the therapeutic benefit of allogeneic HSCT. Metabolism is a common cellular feature and has a key role in the differentiation and function of T cells during the immune response. Naïve T cells and memory T cells that mediate GVHD and GVL, respectively, utilize distinct metabolic programs to obtain their immunological and functional specification. Thus, metabolic targets that mediate immunosuppression might differentially affect the functional program of GVHD-mediating or GVL-mediating T cells. Components of the innate immune system that are indispensable for the activation of alloreactive T cells are also subjected to metabolism-dependent regulation. Metabolic alterations have also been implicated in the resistance to chemotherapy and survival of malignant cells such as leukemia and lymphoma, which are targeted by GVL-mediating T cells. Development of novel approaches to inhibit the activation of GVHD-specific naïve T cell but maintain the function of GVL-specific memory T cells will have a major impact on the therapeutic benefit of HSCT. Here, we will highlight the importance of metabolism on the function of GVHD-inducing and GVL-inducing alloreactive T cells as well as on antigen presenting cells (APC), which are required for presentation of host antigens. We will also analyze the metabolic alterations involved in the leukemogenesis which could differentiate leukemia initiating cells from normal HSC, providing potential therapeutic opportunities. Finally, we will discuss the immuno-metabolic effects of key drugs that might be repurposed for metabolic management of GVHD without compromising GVL

The role of circadian rhythm genes in the development of malignant neoplasms of the gastrointestinal track

The circadian rhythm in the intra-cellular level is regulated by a group of genes which interact with each other at the transcriptional and transnational level. It is known that these genes are implicated in the regulation of intra-cellular pathways that are involved in the development and progression of human neoplastic diseases. In the current study we evaluated the impact of the CLOCK, BMAL1, PER1, PER2 and PER3 expression and the frequency of the polymorphisms 311T‹C (rs11801260) in the CLOCK gene, G3853A (rs934945) in the PER2 gene and 4/5 repeats in the PER3 gene in the development and prognosis of colorectal cancer. We compared the expression of the above mentioned genes between colorectal cancer tissues and normal colonic tissues and we found that the CLOCK and BMAL1 genes are up-regulated while PER1 and PER3 genes are down-regulated in the cancerous tissues. We did not identify any correlation between the expression of these genes and the pathology and clinical data or the prognosis of the patients. We also compared the frequency of the above mentioned polymorphisms between patients with colorectal cancer and healthy controls and we found that the allele C and the genotype CC of the 311Τ‹C (rs11801260) in the CLOCK gene is associated with increased risk of colorectal cancer development. These results highlight the role of the circadian rhythm genes in the development and progression of colorectal cancer supporting the conduction of more research in order to introduce these molecules as predictive markers and potential targets for novel therapies.Ο κιρκάδιος ρυθμός σε επίπεδο κυττάρων ρυθμίζεται από μία ομάδα γονιδίων που αλληλοεπιδρούν με το ένα να επηρεάζει την γονιδιακή και πρωτεϊνική έκφραση του άλλου. Είναι γνωστό ότι τα γονίδια αυτά εμπλέκονται στην ρύθμιση ενδοκυττάριων μονοπατιών που συμμετέχουν στην ανάπτυξη και πρόοδο νεοπλασματικών νοσημάτων. Στην παρούσα μελέτη ερευνήσαμε τον επίδραση της έκφρασης των γονιδίων CLOCK, BMAL1, PER1, PER2 και PER3 καθώς και της συχνότητας των πολυμορφισμών 311Τ‹C (rs11801260) στο γονίδιο CLOCK, G3853A (rs934945) στο γονίδιο PER2 και 4/5 επαναλήψεις στο γονίδιο PER3 στην ανάπτυξη και πρόγνωση του καρκίνου παχέος εντέρου. Συγκρίναμε την έκφραση των παραπάνω γονιδίων στους καρκινικούς και φυσιολογικούς ιστούς παχέος εντέρου και βρήκαμε ότι τα γονίδια CLOCK και BMAL1 υπερεκφράζονται ενώ τα γονίδια PER1 και PER3 υποεκφράζονται στους καρκινικούς σε σχέση με τους υγιείς ιστούς. Δεν βρήκαμε κάποια σημαντική συσχέτιση με τα κλινικοπαθολογοανατομικά δεδομένα, την πρόγνωση των καρκίνων και την έκφραση αυτών των γονιδίων. Επίσης συγκρίναμε την συχνότητα των παραπάνω πολυμορφισμών ανάμεσα σε ασθενείς με καρκίνο παχέος εντέρου και υγιείς μάρτυρες. Βρήκαμε ότι η παρουσία του αλληλομόρφου C και ο γονότυπος CC του πολυμορφισμού 311Τ‹C (rs11801260) στο γονίδιο CLOCK σχετίζονται με αυξημένο κίνδυνο ανάπτυξης καρκίνου παχέος εντέρου. Τα αποτελέσματα αυτά υπογραμμίζουν τον ρόλο των γονιδίων του κιρκάδιου ρυθμού στην ανάπτυξη και πρόοδο του καρκίνου παχέος εντέρου και τονίζουν την ανάγκη περαιτέρω μελέτης για την ανάδειξη αυτών των μορίων σε προγνωστικούς δείκτες και πιθανούς στόχους θεραπείας

Quality of Life After Laparoscopic Colectomy for Cancer

Background and Objectives: This review focuses on health-related quality-of-life (HRQoL) assessment questionnaires and the influence of various parameters on HRQoL at distinct time points after laparoscopic colectomy for cancer. Methods: A PubMed electronic database literature search was conducted. Results: Twenty studies (7 prospective randomized, 5 nonrandomized, 2 retrospective, 1 matched, and 3 observational studies) used the following HRQoL tools: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (8 studies), EORTC QLQ-CR38 (6 studies), EORTC QLQ-CR29 (1 study), Short Form 36 (8 studies), Gastrointestinal Quality Life Index (2 studies), EuroQoL-5D (1 study), Symptoms Distress Scale (2 studies), Quality of Life Index (2 studies), and global quality of life (1 study). Long-term beneficial effects on patient HRQoL after laparoscopic colectomy for cancer have not been clearly shown compared with “open” resections. A physical function deterioration and emotional function improvement are observed during the first month. Most patients have recovered at 12 months. Distinct HRQoL domains may be affected in older, female, and chemotherapy-treated patients. HRQoL-related parameters of pain and cosmesis have been assessed in few of the current studies on hand-assisted and single-incision laparoscopic colectomy. Conclusion: Studies’ heterogeneity in terms of assessment tools and time points remains as the main obstacle to establish robust conclusions. The addition of more patients and extension of the follow-up period will improve our knowledge on HRQoL changes after laparoscopic colectomy for cancer

Regulation of T cell differentiation and function by EZH2

The enhancer of zeste homologue 2 (EZH2), one of the polycomb group (PcG) proteins, is the catalytic subunit of Polycomb-repressive complex 2 (PRC2) and induces the trimethylation of the histone H3 lysine 27 (H3K27me3) promoting epigenetic gene silencing. EZH2 contains a SET domain promoting the methyltransferase activity while the three other protein components of PRC2, namely EED, SUZ12 and RpAp46/48 induce compaction of the chromatin permitting EZH2 enzymatic activity. Numerous studies highlight the role of this evolutionary conserved protein as a master regulator of differentiation in humans involved in the repression of the homeotic (Hox) gene and the inactivation of X-chromosome. Through its effects in the epigenetic regulation of critical genes, EZH2 has been strongly linked to cell cycle progression, stem cell pluripotency and cancer biology. Most recently, EZH2 has been associated with hematopoietic stem cell proliferation and differentiation, thymopoiesis and lymphopoiesis. Several studies have evaluated the role of EZH2 in the regulation of T cell differentiation and plasticity as well as its implications in the development of autoimmune diseases and graft versus host disease (GvHD). In this review we will briefly summarize the current knowledge regarding the role of EZH2 in the regulation of T cell differentiation, effector function and homing in the tumor microenvironment and we will discuss possible therapeutic targeting of EZH2 in order to alter T cell immune functions

Extracellular Vesicles in Myeloid Neoplasms

Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into the extracellular space and involved in intercellular communication. Recent studies have described RNA and protein alterations in EVs isolated from myeloid neoplasm patients compared to healthy controls. The altered expression of various micro-RNAs is the best-described feature of EVs of these patients. Some of these micro-RNAs induce growth-related pathways such as AKT/mTOR and promote the acquisition of stem cell-like features by malignant cells. Another well-described characteristic of EVs in myeloid neoplasms is their ability to suppress healthy hematopoiesis either via direct effect on healthy CD34+ cells or via alteration of the differentiation of BMM cells. These results support a role of EVs in the pathogenesis of myeloid neoplasms. mainly through mediating the interaction between malignant and BMM cells, and warrant further study to better understand their biology. In this review, we describe the reported alterations of EV composition in myeloid neoplasms and the recent discoveries supporting their involvement in the development and progression of these diseases

Probiotics, Prebiotics, Synbiotics: Is There Enough Evidence to Support Their Use in Colorectal Cancer Surgery?

Background/Aims: Pro-/pre-/synbiotics supplementation seems to provide beneficial effects in various aspects of abdominal pathology. Skepticism exists with respect to their effects on colorectal cancer (CRC) patients. This review presents the potential clinical applications of pro-/pre-/synbiotics in CRC surgery. Methods: A literature search of electronic databases was conducted and all studies published on ‘probiotics’, ‘prebiotics’ and ‘synbiotics’ were collected. Among them, the ones referring to CRC and which had any clinical relevance offering information on perioperative parameters were used. Results: Incorporation of pre-/pro-/syn biotic formulations in the preoperative mechanical bowel preparation cannot be supported by the current evidence. Limited clinical studies may be promising in supporting their potentially protective role against postoperative infectious complications. Encouraging are the results on their protective role against adjuvant (chemo)radiation-induced diarrhea. Such supplementation may also hold promise to improve postcolectomy gastrointestinal related quality of life. Conclusions: Despite the positive results and plethora of agents, bacterial combinations and concentrations, the inconsistency in administration, the inhomogeneity of comparison groups and lack of stringent clinical endpoints remain obstacles in the effort to establish a definitive clinical strategy at this time. Further work is warranted to gain a keen understanding of their clinical value in CRC patients. Copyright (C) 2012 S. Karger AG, Base