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Cell Reports Jul 2021Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms...
Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-αβ. Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy.
Topics: Animals; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer-Associated Fibroblasts; Cell Differentiation; Cell Proliferation; Humans; Immunotherapy; Lymphocyte Activation; Lymphotoxin beta Receptor; Membrane Glycoproteins; Mice, Inbred C57BL; Neoplasms; Peritoneum; Receptors, Tumor Necrosis Factor; Signal Transduction; Tertiary Lymphoid Structures; Mice
PubMed: 34289373
DOI: 10.1016/j.celrep.2021.109422 -
Indian Journal of Gastroenterology :... Feb 2023Abdominal tuberculosis is an ancient problem with modern nuances in diagnosis and management. The two major forms are tuberculous peritonitis and gastrointestinal... (Review)
Review
Abdominal tuberculosis is an ancient problem with modern nuances in diagnosis and management. The two major forms are tuberculous peritonitis and gastrointestinal tuberculosis (GITB), while the less frequent forms are esophageal, gastroduodenal, pancreatic, hepatic, gallbladder and biliary tuberculosis. The clinicians need to discriminate the disease from the close mimics: peritoneal carcinomatosis closely mimics peritoneal tuberculosis, while Crohn's disease closely mimics intestinal tuberculosis. Imaging modalities (ultrasound, computed tomography, magnetic resonance imaging and occasionally positron emission tomography) guide the line of evaluation. Research in diagnostics (imaging and endoscopy) has helped in the better acquisition of tissue for histological and microbiological tests. Although point-of-care polymerase chain reaction-based tests (e.g. Xpert Mtb/Rif) may provide a quick diagnosis, these have low sensitivity. In such situations, ancillary investigations such as ascitic adenosine deaminase and histological clues (granulomas, caseating necrosis, ulcers lined by histiocytes) may provide some specificity to the diagnosis. A diagnostic trial of antitubercular therapy (ATT) may be considered if all diagnostic armamentaria fail to clinch the diagnosis, especially in TB-endemic regions. Objective evaluation with clear endpoints of response is mandatory in such situations. Early mucosal response (healing of ulcers at two months) and resolution of ascites are objective criteria for early response assessment and should be sought at two months. Biomarkers, especially fecal calprotectin for intestinal tuberculosis, have also shown promise. For most forms of abdominal tuberculosis, six months of ATT is sufficient. Sequelae of GITB may require endoscopic balloon dilatation for intestinal strictures or surgical intervention for recurrent intestinal obstruction, perforation or massive bleeding.
Topics: Humans; Mycobacterium tuberculosis; Ulcer; Sensitivity and Specificity; Tuberculosis, Gastrointestinal; Polymerase Chain Reaction
PubMed: 36899289
DOI: 10.1007/s12664-023-01343-x -
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 -
Immunity Dec 2021Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their...
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNF mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.
Topics: Animals; Cell Movement; Cells, Cultured; Crohn Disease; Disease Models, Animal; Endothelial Cells; Humans; Ileitis; Ileum; Lymph; Lymphangitis; Lymphatic Vessels; Mesentery; Mice; Mice, Knockout; Stress, Mechanical; Tertiary Lymphoid Structures; Tumor Necrosis Factor-alpha
PubMed: 34788601
DOI: 10.1016/j.immuni.2021.10.003 -
Autophagy Jun 2019Macroautophagy/autophagy is a conserved ubiquitous pathway that performs diverse roles in health and disease. Although many key, widely expressed proteins that regulate...
Macroautophagy/autophagy is a conserved ubiquitous pathway that performs diverse roles in health and disease. Although many key, widely expressed proteins that regulate autophagosome formation followed by lysosomal fusion have been identified, the possibilities of cell-specific elements that contribute to the autophagy fusion machinery have not been explored. Here we show that a macrophage-specific isoform of the vacuolar ATPase protein ATP6V0D2/subunit d2 is dispensable for lysosome acidification, but promotes the completion of autophagy via promotion of autophagosome-lysosome fusion through its interaction with STX17 and VAMP8. Atp6v0d2-deficient macrophages have augmented mitochondrial damage, enhanced inflammasome activation and reduced clearance of Salmonella typhimurium. The susceptibility of atp6v0d2 knockout mice to DSS-induced colitis and Salmonella typhimurium-induced death, highlights the in vivo significance of ATP6V0D2-mediated autophagosome-lysosome fusion. Together, our data identify ATP6V0D2 as a key component of macrophage-specific autophagosome-lysosome fusion machinery maintaining macrophage organelle homeostasis and, in turn, limiting both inflammation and bacterial infection. Abbreviations: ACTB/β-actin: actin, beta; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); ATP6V0D1/2: ATPase, H+ transporting, lysosomal V0 subunit D1/2; AIM2: absent in melanoma 2; BMDM: bone marrow-derived macrophage; CASP1: caspase 1; CGD: chronic granulomatous disease; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CTSB: cathepsin B; DSS: dextran sodium sulfate; IL1B: interleukin 1 beta; IL6: interleukin 6; IRGM: immunity-related GTPase family M member; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LC3: microtubule-associated protein 1 light chain 3; LPS: lipo-polysaccaride; NLRP3: NLR family, pyrin domain containing 3; PYCARD/ASC: PYD and CARD domain containing; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP29: synaptosomal-associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TLR: toll-like receptor; TNF: tumor necrosis factor ; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1; VAMP8: vesicle-associated membrane protein 8; WT: wild type; 3-MA: 3-methyladenine.
Topics: Adenosine Triphosphatases; Animals; Autophagosomes; Autophagy; Cells, Cultured; Colitis; HEK293 Cells; Humans; Inflammasomes; Lysosomes; Macrophages; Membrane Fusion; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Peritonitis; Qa-SNARE Proteins; R-SNARE Proteins; Salmonella Infections; Salmonella typhimurium; Vacuolar Proton-Translocating ATPases
PubMed: 30681394
DOI: 10.1080/15548627.2019.1569916 -
ANZ Journal of Surgery Nov 2022
Topics: Humans; Peritoneal Diseases; Omentum; Infarction
PubMed: 35174609
DOI: 10.1111/ans.17545 -
International Journal of Nanomedicine 2022Pancreatitis is an inflammatory reaction of pancreatic tissue digestion, edema, bleeding and even necrosis caused by activation of pancreatin due to various causes. In... (Review)
Review
Pancreatitis is an inflammatory reaction of pancreatic tissue digestion, edema, bleeding and even necrosis caused by activation of pancreatin due to various causes. In particular, patients with severe acute pancreatitis (SAP) often suffer from secondary infection, peritonitis and shock, and have a high mortality rate. Chronic pancreatitis (CP) can cause permanent damage to the pancreas. Due to the innate characteristics, structure and location of the pancreas, there is no effective treatment, only relief of symptoms. Especially, AP is an unpredictable and potentially fatal disease, and the timely diagnosis and treatment remains a major challenge. With the rapid development of nanomedicine technology, many potential tools can be used to address this problem. In this review, we have introduced the pathophysiological processes of pancreatitis to understanding its etiology and severity. Most importantly, the current progress in the diagnosis and treatment tools of pancreatitis based on nanomedicine is summarized and prospected.
Topics: Acute Disease; Humans; Necrosis; Pancreas; Pancreatin; Pancreatitis
PubMed: 36160469
DOI: 10.2147/IJN.S385590 -
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