N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are a... more N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1(-/-IEC) and AnxA1(-/-) mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expre...
Since the therapeutic use of cannabis and its derivatives is currently rising, the adverse effect... more Since the therapeutic use of cannabis and its derivatives is currently rising, the adverse effects of cannabis and cannabinoids are of special interest. However little is known about the possible effects of long-term use of cannabis on the gastrointestinal motility. Herewith we describe the case of a patient with a rare severe form of intestinal intussusception following long-term cannabis consumption. The case shall raise awareness of possible life threatening complications of the use of cannabis and its derivates.
Introduction: Animal models of intestinal inflammation are extensively employed in research of in... more Introduction: Animal models of intestinal inflammation are extensively employed in research of inflammatory bowel diseases. However histological evaluation can be limited by a degree of subjectivity leading to variable results in the literature. Here we describe an unbiased widely applicable histological[for full text, please go to the a.m. URL]
Robotic surgery offers favorable prerequisites for complex minimally invasive surgeries which are... more Robotic surgery offers favorable prerequisites for complex minimally invasive surgeries which are delivered by higher degrees of freedom, improved instrument stability, and a perfect visualization in 3D which is fully surgeon controlled. In this article we aim to assess its impact on complete mesocolic excision (CME) in colon cancer and to answer the question of whether the current evidence expresses a need for robotic surgery for this indication. Retrospective analysis and review of the current literature on complete mesocolic excision for colon cancer comparing the outcome after open, laparoscopic, and robotic approaches. Complete mesocolic excision results in improved disease-free survival and reduced local recurrence, but turns out to be complex and prone to complications. Introduced in open surgery, the transfer to minimally invasive surgery resulted in comparable results, however, with high conversion rates. In comparison, robotic surgery shows a reduced conversion rate and a ...
Inflammation-induced epithelial injury results in compromised mucosal barrier function. In respon... more Inflammation-induced epithelial injury results in compromised mucosal barrier function. In response to injury, epithelial cells migrate as a sheet to cover denuded surfaces. We have recently reported that a calcium dependent phospholipid binding protein Annexin A1 (AnxA1) is a pro-resolving mediator that signals via epithelial formyl peptide receptors (FPRs) to promote intestinal mucosal wound repair. Analysis of signaling pathways downstream of epithelial FPRs identified intestinal epithelial NADPH oxidase-1 (Nox1) and Rac1 as key elements responsible for generation of reactive oxygen species (ROS). We determined that ROS-induced oxidative modification of phosphatases, in turn, activate proteins involved in controlling focal cell matrix adhesions and epithelial cell migration. Exogenous AnxA1 administration was observed to promote intestinal mucosal wound closure in WT mice but not in mice lacking intestinal epithelial Nox1 (Nox1-/-IEC). Analysis of AnxA1 released from the epitheli...
Purpose Modern non-operative management of diverticulitis consists of a complex therapeutic regim... more Purpose Modern non-operative management of diverticulitis consists of a complex therapeutic regimen and is successful in most cases even of complicated diverticulitis. Still, a certain proportion of patients requires urgent surgery due to failure of the conservative approach. This study aims to identify predictors for failure of conservative treatment of complicated diverticulitis with the need for subsequent urgent resection during the acute episode. Methods A single-centre retrospective cohort study was performed at our tertiary centre including cases of acute complicated diverticulitis (characterized by localized abscess formation and/or pericolic air) between 2007 and 2019 that were treated guideline-conform by multimodal conservative treatment. Radiologic characteristics of disease in CT scans upon admission were analysed by uni- and multivariable logistic regression to determine predictors for resection within 30 days after onset of the conservative therapy approach. Results A...
Background Although in most patients with inflammatory bowel diseases, conservative therapy is su... more Background Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis. Methods Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative r...
Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions ar... more Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as...
Background Anastomotic leakage represents a major complication following resections in colorectal... more Background Anastomotic leakage represents a major complication following resections in colorectal surgery. Among others, intestinal inflammation such as in inflammatory bowel disease is a significant risk factor for disturbed anastomotic healing. Despite technical advancements and several decades of focused research, the underlying mechanisms remain incompletely understood. Animal experiments will remain the backbone of this research in the near future. Here, instructions on a standardized and reproducible murine model of preoperative colitis and colorectal anastomosis formation are provided to amplify research on anastomotic healing during inflammatory disease. Methods We demonstrate the combination of experimental colitis and colorectal anastomosis formation in a mouse model. The model allows for monitoring of anastomotic healing during inflammatory disease through functional outcomes, clinical scores, and endoscopy and histopathological examination, as well as molecular analysis....
N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are a... more N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1(-/-IEC) and AnxA1(-/-) mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expre...
Since the therapeutic use of cannabis and its derivatives is currently rising, the adverse effect... more Since the therapeutic use of cannabis and its derivatives is currently rising, the adverse effects of cannabis and cannabinoids are of special interest. However little is known about the possible effects of long-term use of cannabis on the gastrointestinal motility. Herewith we describe the case of a patient with a rare severe form of intestinal intussusception following long-term cannabis consumption. The case shall raise awareness of possible life threatening complications of the use of cannabis and its derivates.
Introduction: Animal models of intestinal inflammation are extensively employed in research of in... more Introduction: Animal models of intestinal inflammation are extensively employed in research of inflammatory bowel diseases. However histological evaluation can be limited by a degree of subjectivity leading to variable results in the literature. Here we describe an unbiased widely applicable histological[for full text, please go to the a.m. URL]
Robotic surgery offers favorable prerequisites for complex minimally invasive surgeries which are... more Robotic surgery offers favorable prerequisites for complex minimally invasive surgeries which are delivered by higher degrees of freedom, improved instrument stability, and a perfect visualization in 3D which is fully surgeon controlled. In this article we aim to assess its impact on complete mesocolic excision (CME) in colon cancer and to answer the question of whether the current evidence expresses a need for robotic surgery for this indication. Retrospective analysis and review of the current literature on complete mesocolic excision for colon cancer comparing the outcome after open, laparoscopic, and robotic approaches. Complete mesocolic excision results in improved disease-free survival and reduced local recurrence, but turns out to be complex and prone to complications. Introduced in open surgery, the transfer to minimally invasive surgery resulted in comparable results, however, with high conversion rates. In comparison, robotic surgery shows a reduced conversion rate and a ...
Inflammation-induced epithelial injury results in compromised mucosal barrier function. In respon... more Inflammation-induced epithelial injury results in compromised mucosal barrier function. In response to injury, epithelial cells migrate as a sheet to cover denuded surfaces. We have recently reported that a calcium dependent phospholipid binding protein Annexin A1 (AnxA1) is a pro-resolving mediator that signals via epithelial formyl peptide receptors (FPRs) to promote intestinal mucosal wound repair. Analysis of signaling pathways downstream of epithelial FPRs identified intestinal epithelial NADPH oxidase-1 (Nox1) and Rac1 as key elements responsible for generation of reactive oxygen species (ROS). We determined that ROS-induced oxidative modification of phosphatases, in turn, activate proteins involved in controlling focal cell matrix adhesions and epithelial cell migration. Exogenous AnxA1 administration was observed to promote intestinal mucosal wound closure in WT mice but not in mice lacking intestinal epithelial Nox1 (Nox1-/-IEC). Analysis of AnxA1 released from the epitheli...
Purpose Modern non-operative management of diverticulitis consists of a complex therapeutic regim... more Purpose Modern non-operative management of diverticulitis consists of a complex therapeutic regimen and is successful in most cases even of complicated diverticulitis. Still, a certain proportion of patients requires urgent surgery due to failure of the conservative approach. This study aims to identify predictors for failure of conservative treatment of complicated diverticulitis with the need for subsequent urgent resection during the acute episode. Methods A single-centre retrospective cohort study was performed at our tertiary centre including cases of acute complicated diverticulitis (characterized by localized abscess formation and/or pericolic air) between 2007 and 2019 that were treated guideline-conform by multimodal conservative treatment. Radiologic characteristics of disease in CT scans upon admission were analysed by uni- and multivariable logistic regression to determine predictors for resection within 30 days after onset of the conservative therapy approach. Results A...
Background Although in most patients with inflammatory bowel diseases, conservative therapy is su... more Background Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis. Methods Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative r...
Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions ar... more Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as...
Background Anastomotic leakage represents a major complication following resections in colorectal... more Background Anastomotic leakage represents a major complication following resections in colorectal surgery. Among others, intestinal inflammation such as in inflammatory bowel disease is a significant risk factor for disturbed anastomotic healing. Despite technical advancements and several decades of focused research, the underlying mechanisms remain incompletely understood. Animal experiments will remain the backbone of this research in the near future. Here, instructions on a standardized and reproducible murine model of preoperative colitis and colorectal anastomosis formation are provided to amplify research on anastomotic healing during inflammatory disease. Methods We demonstrate the combination of experimental colitis and colorectal anastomosis formation in a mouse model. The model allows for monitoring of anastomotic healing during inflammatory disease through functional outcomes, clinical scores, and endoscopy and histopathological examination, as well as molecular analysis....
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