Des Winter

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-κB, phosphoinositide 3-kinase/AKT, c-jun-NH2-kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-ϒ). The subcellular location of NR4A “nuclear receptors” is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation. Clin Cancer Res; 18(12); 3223–8. ©2012 AACR.

Emerging role of hydrogen sulfide in colonic physiology and pathophysiology.

&NA; Hydrogen sulfide (H2S) is a toxic gas that is now recognized as an important mediator of many physiological processes. In the colon, H2S is produced both endogenously and by naturally occurring sulfate‐reducing bacteria (SRB). The full arrays of its effects in the gastrointestinal tract are still being elucidated, but they range from motility to carcinogenesis. We examined the evidence relating to H2S as a modulator of colonic function and disease. H2S is implicated in modulation of colonic compliance through its action on smooth muscle. There is also evidence linking H2S to colonic nociception, inflammatory bowel disease (IBD), and colorectal cancer. The exact mechanisms and pathways by which H2S exerts its multitude of effects are not yet fully understood, but its involvement in physiological and pathophysiological conditions of the colon is becoming evident. Elucidating the intricate effects of H2S in the colon and understanding the exact nature of its interactions with the colon makes pharmacological modulation of H2S production and metabolism potential targets for treatment of a multitude of colonic conditions in the future.(Inflamm Bowel Dis 2010)

Berberine inhibits ion transport in human colonic epithelia.

The effects of berberine on ion transport in both human colonic mucosal epithelia and an intestinal epithelial cell line (T84) were examined. Berberine (concentration range 0-500 microM) reduced both basal and stimulated ion transport responses in human colonic mucosae in a manner which was non-specific for Ca2+ -or cAMP-mediated signals. Similarly, in cultured intestinal epithelial monolayers, berberine inhibited Ca2+ -and cAMP-mediated responses indicating an inhibitory activity directly at the level of the epithelium rather than an indirect effect through other mucosal element(s). Berberine did not alter the rate of generation of cAMP by adenylyl cyclase or the activity of protein kinase A, the effector enzyme of the cAMP pathway. Berberine inhibited carbachol-stimulated 86Rb+ efflux from T84 monolayers. Berberine also inhibited K+ conductance in apically-permeabilised re-sected mucosae. These results indicate i) that berberine exerts an anti-secretory action directly upon epithelial cells and ii) the mechanism of action may be at the level of blockade of K+ channels.

Differential protein abundance and function of UT-B urea transporters in human colon

Facilitative UT-B urea transporters enable the passage of urea across cell membranes. Gastrointestinal urea transporters are thought to play a significant role in the urea nitrogen salvaging process that occurs between mammalian hosts and their gut bacteria. This study investigated the expression of UT-B urea transporters in different segments of human colon. Immunoblot analysis showed that human colon expressed a 35-kDa glycosylated UT-B protein in the colonic mucosa. The 35-kDa UT-B transporter was predominantly located in plasma membrane-enriched samples (P < 0.001; n = 6), and its expression was greater in the ascending colon compared with the descending colon (P < 0.01; n = 3). At the cellular level, UT-B transporters were located throughout colonocytes situated in the upper portion of the colonic crypts. Bidirectional trans-epithelial urea transport was significantly greater in the ascending colon than the descending colon (P < 0.05; n = 6). In addition, the facilitative urea transporter inhibitor 1,3,dimethylurea significantly reduced urea transport in the ascending colon (P < 0.05; n = 6) but had no effect in the descending colon (NS; n = 6). These results illustrate differential protein abundance of functional UT-B protein in different sections of the human colon, strongly correlating to regions that contain the largest populations of intestinal bacteria. This study suggests an important role for UT-B urea transporters in maintaining the symbiotic relationship between humans and their gut bacteria.

Radiofrequency Ablation for Neuroendocrine Liver Metastases: A Systematic Review

To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N = 301). Twenty-six percent of RF ablation procedures were percutaneous (n = 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14-27 months. However, recurrence was common (63%-87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery.

Hereditary mixed polyposis syndrome due to a BMPR1A mutation

The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)‐β signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF‐β pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

Estrogen and its role in gastrointestinal health and disease

IntroductionWhile the concept of a role of estrogen in gastrointestinal (in particular, colonic) malignancy has generated excitement in recent years, no review has examined the role of this potent and omnipresent steroid hormone in physiological states or its contribution to the development of benign pathological processes. Understanding these effects (and mechanisms therein) may provide a platform for a deeper understanding of more complex disease processes.MethodsA literature search was conducted using the PubMed database and the search terms were “estrogen,” “estrogen AND gastrointestinal tract,” “estrogen AND colon,” “estrogen AND esophagus,” “estrogen AND small intestine,” “estrogen AND stomach,” “estrogen AND gallbladder,” and “estrogen AND motility.” Bibliographies of extracted studies were further cross-referenced. In all, 136 full-text articles were selected for review. A logical organ-based approach was taken to enable extraction of data of clinical relevance and meaningful interpretation thereof. Insight is provided into the hypotheses, theories, controversies, and contradictions generated over the last five decades by extensive investigation of estrogen in human, animal, and cell models using techniques as diverse as autoradiographic studies of baboons to human population analysis.ConclusionsEffects from esophagus through to the colon and rectum are summarized in this first concise collection of data pertaining to estrogenic actions in gastrointestinal health and disease. Mechanisms of these actions are discussed where possible. Undoubtedly, this hormone exerts many actions yet to be elucidated, and its potential therapeutic applications remain, as yet, largely unexplored.

Modern Concepts in Diverticular Disease

Over the last decade there has been a striking shift in our understanding of the epidemiology, pathology, and management of diverticular disease. Indeed, many of the guidelines published in the late nineties and early 2000s are now redundant. High-fiber diets, avoidance of nuts and seeds, antibiotic treatment for mild diverticulitis, elective resection after 2 attacks of diverticulitis, Hartmanns procedure (HP), and aggressive management of young patients are all open to question. The more we challenge our understanding of diverticulitis it becomes apparent how little we know about this disease entity. This review aims update the reader on current hypotheses and evidencebased modern management strategies in diverticular disease.

Laparoscopic Spigelian Hernia Repair: A Series of 40 Patients.

Spigelian hernias are a rare abdominal wall hernia. The aim of this study was to assess the efficacy and outcomes of patients who underwent a laparoscopic spigelian hernia repair. A retrospective study was performed reviewing all patients who had a laparoscopic spigelian hernia repair. We assessed the success of the procedure including conversion rates, postoperative morbidities, and recurrence rates. Forty patents had a laparoscopic repair. Two thirds (n=25) had an intraperitoneal repair. There was no conversion to open repair. Four patients had postoperative morbidities. At 6-month follow-up all patients were pain free, with 1 recurrence. There is considerable evidence supporting the opinion that laparoscopic repair offers excellent outcomes. This report is the largest series to date, and we advocate that this approach should become the standard of care.

Iatrogenic common bile duct injuries: Increasing complexity in the laparoscopic era: A prospective cohort study

PURPOSE Iatrogenic bile duct injury (BDI) is the most significant associated complication to laparoscopic cholecystectomy (LC). Little is known about the evolution of the pattern of BDI in the era of laparoscopy. The aim of the study is to assess the pattern of post-LC BDIs managed in a tertiary referral centre. METHODS Post-LC BDI referred over two decades were studied. Demographic data, type of BDI (classified using the Strasberg System), clinical symptoms, diagnostic investigations, timing of referral, post-referral management and morbidity were analysed. The pattern of injury, associated vascular injuries rate and their management were compared over two time periods (1992-2004,2005-2014). RESULTS 78 BDIs were referred. During the second time period Strasberg A injuries decreased from 14% to 0 and Strasberg E1increased from 4% to 23%, the rate of associated vascular injury was six time higher (3.6% versus 22.7%), more patients had an attempted repair at the index hospital (16% versus 35%) sand fewer patients could be managed without surgical intervention at the referral hospital (28% versus 4%). CONCLUSION Complexity of referred BDIs and rate of associated vascular injuries have increased over time. These findings led to more patients managed requiring surgical intervention at the referral hospital.