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Nature Communications Apr 2023Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell...
Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Metastatic spreading is promoted by cancer cell plasticity, yet its regulation by the microenvironment is incompletely understood. Here, we show that the presence of hyaluronan and proteoglycan link protein-1 (HAPLN1) in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis. Bioinformatic analysis showed that HAPLN1 expression is enriched in the basal PDAC subtype and associated with worse overall patient survival. In a mouse model for peritoneal carcinomatosis, HAPLN1-induced immunomodulation favors a more permissive microenvironment, which accelerates the peritoneal spread of tumor cells. Mechanistically, HAPLN1, via upregulation of tumor necrosis factor receptor 2 (TNFR2), promotes TNF-mediated upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. Extracellular HAPLN1 modifies cancer cells and fibroblasts, rendering them more immunomodulatory. As such, we identify HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.
Topics: Mice; Animals; Peritoneum; Peritoneal Neoplasms; Hyaluronic Acid; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Neoplasm Metastasis; Gene Expression Regulation, Neoplastic; Tumor Microenvironment
PubMed: 37095087
DOI: 10.1038/s41467-023-38064-w -
Ugeskrift For Laeger Mar 2023It is well known that biological treatment increases the risk of opportunistic infections. Guidelines recommend tuberculosis screening prior to treatment. This is a case...
It is well known that biological treatment increases the risk of opportunistic infections. Guidelines recommend tuberculosis screening prior to treatment. This is a case report of a woman who had morbus Crohn and developed peritoneal tuberculosis even though she completed a preventive tuberculosis eradication before initiating treatment with anti-TNF-inhibitor. She appeared with ascites and was examined very thoroughly, and eventually a peritoneal biopsy revealed tuberculosis. Tuberculosis is difficult to diagnose, and eradication is no guarantee that tuberculosis cannot relapse during biological treatment.
Topics: Female; Humans; Tumor Necrosis Factor Inhibitors; Peritonitis, Tuberculous; Tuberculosis; Crohn Disease; Peritoneum
PubMed: 36999296
DOI: No ID Found -
ANZ Journal of Surgery Nov 2022
Topics: Humans; Peritoneal Diseases; Omentum; Infarction
PubMed: 35174609
DOI: 10.1111/ans.17545 -
European Journal of Trauma and... Apr 2022Peritonitis, as a major consequence of hollow visceral perforation, anastomotic disruption, ischemic necrosis, or other injuries of the gastrointestinal tract, often... (Review)
Review
Peritonitis, as a major consequence of hollow visceral perforation, anastomotic disruption, ischemic necrosis, or other injuries of the gastrointestinal tract, often drives acute care in the emergency department, operating room, and the ICU. Chronic critical illness (CCI) represents a devastating challenge in modern surgical critical care where successful interventions have fostered a growing cohort of patients with prolonged dependence on mechanical ventilation and other organ supportive therapies who would previously have succumbed much earlier in the acute phase of critical illness. An important subset of CCI patients are those who have survived an emergency abdominal operation, but who subsequently require prolonged open abdomen management complicated by persistent peritoneal space infection or colonization, fistula formation, and gastrointestinal (GI) tract dysfunction; these patients are described as having tertiary peritonitis (TP).The organ dysfunction cascade in TP terminates in death in between 30 and 64% of patients. This narrative review describes key-but not all-elements in a framework for the coordinate multiprofessional team-based management of a patient with tertiary peritonitis to mitigate this risk of death and promote recovery. Given the prolonged critical illness course of this unique patient population, early and recurrent Palliative Care Medicine consultation helps establish goals of care, support adjustment to changes in life circumstance, and enable patient and family centered care.
Topics: Abdomen; Critical Care; Critical Illness; Humans; Intensive Care Units; Peritonitis
PubMed: 34302503
DOI: 10.1007/s00068-021-01750-9 -
PloS One 2014Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the...
Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r=0.491, p=0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.
Topics: Adult; Aged; Aged, 80 and over; Animals; Case-Control Studies; Cells, Cultured; Chemokines; Cytokine TWEAK; Female; Gene Expression; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Inflammation Mediators; Kidney Failure, Chronic; Macrophages, Peritoneal; Male; Mice, Inbred C57BL; Middle Aged; Peritoneal Dialysis; Peritonitis; Receptors, Tumor Necrosis Factor; TWEAK Receptor; Tumor Necrosis Factors
PubMed: 24599047
DOI: 10.1371/journal.pone.0090399 -
Frontiers in Immunology 2023The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials...
INTRODUCTION
The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting.
METHODS
We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis.
RESULTS AND DISCUSSION
Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia.
CONCLUSION
These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
Topics: Animals; Mice; Endotoxemia; Lipopolysaccharides; Mice, Knockout; Peritonitis; Small Ubiquitin-Related Modifier Proteins; Spleen; Tumor Necrosis Factor-alpha; SUMO-1 Protein
PubMed: 37520526
DOI: 10.3389/fimmu.2023.1200939 -
Anaesthesiology Intensive Therapy 2015The abdomen is the second most common source of sepsis and secondary peritonitis. The most common causes of abdominal sepsis are perforation, ischemic necrosis or... (Review)
Review
The abdomen is the second most common source of sepsis and secondary peritonitis. The most common causes of abdominal sepsis are perforation, ischemic necrosis or penetrating injury to the abdominal viscera. Management consists of control of the infection source, restoration of gastrointestinal tract (GI) function, systemic antimicrobial therapy and support of organ function. Mortality after secondary peritonitis is still high. Excluding patient-related factors such as age or co-morbidities that can not be influenced at the time of intervention, delay to surgical intervention and inability to obtain source control are the main determinants of outcome. In patients with severe physiological derangement or difficult intraperitoneal conditions, where a prolonged operation and complete anatomical repair may not be possible or appropriate, it is becoming increasingly popular to utilize a damage control strategy with abbreviated laparotomy and planned reoperations. The main components of damage control laparotomy for secondary peritonitis are postponing the reconstruction of intestinal anastomoses to a second operation (deferred anastomosis) and leaving the abdomen open with some form of temporary abdominal closure (TAC). Advances in the management techniques of the open abdomen and new negative pressure-based TAC-devices have significantly reduced the previously observed prohibitive morbidity associated with open abdomens. These advancements have led to current fascial closure rates after TAC approaching 90%. The cornerstones of appropriate antimicrobial therapy are the timing, spectrum and dosing of antibiotics. Enteral nutrition should be started as soon as possible in hemodynamically stable patients but withheld when the patient is on a significant dose of vasopressors or whenever GI hypoperfusion is suspected. Timely source control with appropriate use of antimicrobial agents and early intensive care offers the best chance of survival for patients with abdominal sepsis. The introduction of the concept of damage control to the management of secondary peritonitis represents a paradigm shift in the same way as in management of major trauma. Although limited and repeated surgical interventions have been shown to be safe, the actual benefits need to be demonstrated in controlled studies.
Topics: Abdomen; Adult; Child; Humans; Intra-Abdominal Hypertension; Laparotomy; Peritonitis; Sepsis
PubMed: 25973662
DOI: 10.5603/AIT.a2015.0026 -
Adipocyte Dec 2019Accumulating evidence highlights the importance of interactions between tumour cells and stromal cells for tumour initiation, progression, and metastasis. In tumours... (Review)
Review
Accumulating evidence highlights the importance of interactions between tumour cells and stromal cells for tumour initiation, progression, and metastasis. In tumours that contain adipocyte in their stroma, adipocytes contribute to modification of tumour microenvironment and affect metabolism of tumour and tumour progression by production of cytokines and adipokines from the lipids. The omentum and bone marrow (BM) are highly adipocyte-rich and are also common metastatic and primary tumour developmental sites. Omental adipocytes exhibit metabolic cross-talk, immune modulation, and angiogenesis. BM adipocytes secrete adipokines, and participate in solid tumour metastasis through regulation of the CCL2/CCR2 axis and metabolic interactions. BM adipocytes also contribute to the progression of hematopoietic neoplasms. Here, we here provide an overview of research progress on the cross-talks between omental/BM adipocytes and tumour cells, which may be pivotal modulators of tumour biology, thus highlighting novel therapeutic targets. MCP-1, monocyte chemoattractant protein 1IL, interleukinSTAT3, signal transducer and activator of transcription 3FABP4, fatty acid binding protein 4PI3K/AKT, phosphoinositide 3-kinase/protein kinase BPPAR, peroxisome proliferator-activated receptorPUFA, polyunsaturated fatty acidTAM, tumour-associated macrophagesVEGF, vascular endothelial growth factorVEGFR, vascular endothelial growth factor receptorBM, bone marrowBMA, bone marrow adipocytesrBMA, regulated BMAcBMA, constitutive BMAUCP-1, uncoupling protein-1TNF-α, tumour necrosis factor-alphaRANKL, receptor activator of nuclear factor kappa-Β ligandVCAM-1, vascular cell adhesion molecule 1JAK2, Janus kinase 2CXCL (C-X-C motif) ligandPGE2, prostaglandin E2COX-2, cyclooxygenase-2CCL2, C-C motif chemokine ligand 2NF-κB, nuclear factor-kappa BMM, multiple myelomaALL, acute lymphoblastic leukemiaAML, acute myeloid leukemiaGDF15, growth differentiation factor 15AMPK, AMP-activated protein kinaseMAPK, mitogen-activated protein kinaseAPL, acute promyelocytic leukemiaCCR2, C-C motif chemokine receptor 2SDF-1α, stromal cell-derived factor-1 alphaFFA, free fatty acidsLPrA, leptin peptide receptor antagonistMCD, malonyl-CoA decarboxylase.
Topics: Adipocytes; Adipokines; Animals; Bone Marrow Cells; Carcinogenesis; Humans; Lipid Metabolism; Omentum; Tumor Microenvironment
PubMed: 31334678
DOI: 10.1080/21623945.2019.1643189 -
European Review For Medical and... Feb 2023We aimed to present our experience with the management of 17 patients with ascites who underwent diagnostic laparoscopy or laparotomy, and histologic confirmation of wet...
OBJECTIVE
We aimed to present our experience with the management of 17 patients with ascites who underwent diagnostic laparoscopy or laparotomy, and histologic confirmation of wet ascitic type of peritoneal tuberculosis (TB).
PATIENTS AND METHODS
Between January 2008 and March 2019, 17 patients whose ascites were investigated by a gastroenterologist and who were thought to have non-cirrhotic ascites were referred to our Surgery clinic for peritoneal biopsy. The clinical, biochemical, radiological, microbiological, and histopathological data of the patients who underwent diagnostic laparoscopy or laparotomy were analyzed retrospectively. Histopathological examination of peritoneal tissue samples in hematoxylin-eosin-stained preparations revealed necrotizing granulomatous inflammation with caseous necrosis and Langhans type giant cells. Ehrlich-Ziehl-Neelsen (EZN) staining was studied with the suspicion of TB. Acid-fast bacilli (AFB) were detected in EZN stained slide. Histopathological findings were also considered.
RESULTS
Seventeen patients aged 18 to 64 years were included in this study. The most common symptoms were ascites and abdominal distention, weight loss, night sweats, fever and diarrhea. Radiological examination revealed peritoneal thickening, ascites, omental cacking, and diffuse lymphadenopathy. Histopathologically, necrotizing granulomatous peritonitis consistent with peritoneal TB were detected. While direct laparoscopy was preferred in sixteen patients, laparotomy was preferred in the remaining one due to previous surgical procedures. However, seven were converted to open laparotomy.
CONCLUSIONS
Diagnosis of abdominal TB requires high index of suspicion, and the treatment should be prompt to reduce the morbidity and mortality associated with delay in treatment.
Topics: Humans; Ascites; Retrospective Studies; Peritonitis, Tuberculous; Peritoneum; Laparoscopy
PubMed: 36808343
DOI: 10.26355/eurrev_202302_31192 -
Pharmacology Research & Perspectives Oct 2020Acute peritonitis is an acute inflammatory response of the peritoneal cavity to physical injury and chemical stimulation. Timely resolution of this response is critical...
Acute peritonitis is an acute inflammatory response of the peritoneal cavity to physical injury and chemical stimulation. Timely resolution of this response is critical to prevent further damage to the body, which can eventually lead to more severe chronic inflammation. Arctigenin (ATG) is the main active ingredient of the Chinese medicine Arctium lappa. In recent years, there have been an increasing number of studies on the anti-inflammatory effect of ATG, but there have been few studies on the effect of ATG on acute inflammation, especially in acute peritonitis, which has not been reported. In this study, a mouse model of experimental acute peritonitis induced by thioglycolate (TG) solution was used to study the protective anti-inflammatory effect of ATG against acute peritonitis and the relevant mechanism. Our results showed that, after 12 hours of TG treatment, ATG significantly reduced inflammatory cell infiltration in mouse tissues and inhibited the secretion and expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in mice. ATG significantly reduced the percentage of CD11b Ly6G neutrophils and F4/80 macrophages in the spleen and peritoneal exudate. In addition, ATG significantly inhibited the expression of the chemokines CCL3 and CCL4 and the adhesion molecule CD62L on the surface of CD11b-positive monocytes. ATG was observed to inhibit the phosphorylation of p65 and p38 in LPS-stimulated RAW264.7 cells. In conclusion, ATG can improve the symptoms of TG-induced acute peritonitis through immune regulation. ATG can reduce the inflammatory response in TG-induced acute peritonitis in mice.
Topics: Animals; Anti-Inflammatory Agents; Chemokines; Disease Models, Animal; Female; Furans; Gene Expression Regulation; Interleukin-6; L-Selectin; Lignans; Lipopolysaccharides; Macrophages; Mice; Neutrophils; Peritonitis; RAW 264.7 Cells; Thioglycolates; Tumor Necrosis Factor-alpha
PubMed: 32960513
DOI: 10.1002/prp2.660