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Autophagy May 20223-MA: 3-methyladenine; AIM2: absent in melanoma 2; ATG5: autophagy related 5; BafA1: bafilomycin A; CASP1: caspase 1; CHX: cycloheximide; Co-IP: co-immunoprecipitation;...
3-MA: 3-methyladenine; AIM2: absent in melanoma 2; ATG5: autophagy related 5; BafA1: bafilomycin A; CASP1: caspase 1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; DUBs: deubiquitinases; IL1B/IL-1β: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MARCHF7/MARCH7: membrane associated RING-CH-type finger 7; NFKB/NF-κB: nuclear factor kappa B; Nig.: nigericin; NLRC4: NLR family CARD domain containing 4; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PMN: polymorphonuclear; PMs: peritoneal macrophages; PYCARD/ASC: PYD and CARD domain containing; TLRs: toll like receptors; TNF/TNF-α: tumor necrosis factor; Ub: ubiquitin; USP5: ubiquitin specific peptidase 5; WT: wild type.
Topics: Autophagy; Caspase 1; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 34486483
DOI: 10.1080/15548627.2021.1965426 -
Nutrients Oct 2022While patient care, kidney replacement therapy, and transplantation techniques for chronic kidney disease (CKD) have continued to progress, the incidence of malnutrition... (Review)
Review
While patient care, kidney replacement therapy, and transplantation techniques for chronic kidney disease (CKD) have continued to progress, the incidence of malnutrition disorders in CKD appears to have remained unchanged over time. However, there is now a better understanding of the underlying pathophysiology according to the disease background, disease stage, and the treatment received. In CKD patients, the increased production of proinflammatory cytokines and oxidative stress lead to a proinflammatory milieu that is at least partially responsible for the increased morbidity and mortality in this patient population. New insights into the pathogenic role of innate immunity and the proinflammatory cytokine profile, characterized, for instance, by higher levels of IL-6 and TNF-α, explain some of the clinical and laboratory abnormalities observed in these patients. In this article, we will explore currently available nutritional-inflammatory biomarkers in distinct CKD populations (hemodialysis, peritoneal dialysis, transplantation) with a view to evaluating their efficacy as predictors of malnutrition and their involvement in the common proinflammatory process. Although there is a direct relationship between inflammatory-nutritional status, signs and symptoms [e.g., protein-energy wasting (PEW), anorexia], and comorbidities (e.g., atheromatosis, atherosclerosis), we are in need of clearly standardized markers for nutritional-inflammatory assessment to improve their performance and design appropriate bidirectional interventions.
Topics: Humans; Biomarkers; Interleukin-6; Kidney Failure, Chronic; Malnutrition; Nutritional Status; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha
PubMed: 36296981
DOI: 10.3390/nu14204297 -
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 -
The New England Journal of Medicine Dec 2021Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels.
METHODS
In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25.
RESULTS
A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups.
CONCLUSIONS
Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).
Topics: Aged; Anemia; Barbiturates; Cardiovascular Diseases; Darbepoetin alfa; Epoetin Alfa; Female; Glycine; Hematinics; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Intention to Treat Analysis; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Renal Insufficiency, Chronic; Stroke
PubMed: 34739194
DOI: 10.1056/NEJMoa2113379 -
Autophagy Mar 2023The NLRP3 inflammasome is involved in a diverse range of inflammatory diseases. The activation of inflammasomes must be tightly regulated to prevent excessive...
The NLRP3 inflammasome is involved in a diverse range of inflammatory diseases. The activation of inflammasomes must be tightly regulated to prevent excessive inflammation, and the protein ubiquitination system is reported to be one of the ways in which inflammasome activation is regulated. However, the deubiquitination regulatory mechanisms of inflammasome activation remain elusive. Here, we demonstrated that USP22 (ubiquitin specific peptidase 22) promotes NLRP3 degradation and inhibits NLRP3 inflammasome activation. USP22 deficiency or in vivo silencing significantly increases alum-induced peritonitis and lipopolysaccharide-induced systemic inflammation. Mechanistically, USP22 inhibits NLRP3 inflammasome activation via the promotion of ATG5-mediated macroautophagy/autophagy. USP22 stabilizes ATG5 via decreasing K27- and K48-linked ubiquitination of ATG5 at the Lys118 site. Taken together, these findings reveal the role USP22 plays in the regulation of NLRP3 inflammasome activation and suggest a potential therapeutic target to treat NLRP3 inflammasome-related diseases. ATG5: autophagy related 5; ATP: adenosine triphosphate; CASP1: caspase 1; IL18: interleukin 18; IL1B/IL-1β: interleukin 1 beta; LPS: lipopolysaccharide; NLRC4: NLR family, CARD domain containing 4; NLRP3: NLR family, pyrin domain containing 3; PYCARD/ASC: PYD and CARD domain containing; TNF/TNF-α: tumor necrosis factor; USP22: ubiquitin specific peptidase 22.
Topics: Humans; Animals; Mice; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Autophagy; Lipopolysaccharides; Inflammation; Caspase 1; Ubiquitin-Specific Proteases; Interleukin-1beta; Mice, Inbred C57BL; Autophagy-Related Protein 5; Ubiquitin Thiolesterase
PubMed: 35900990
DOI: 10.1080/15548627.2022.2107314 -
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 -
Scandinavian Journal of Surgery : SJS :... Jun 2021Acute mesenteric venous thrombosis accounts for up to 20% of all patients with acute mesenteric ischemia in high-income countries. Acute mesenteric venous thrombosis is...
BACKGROUND AND AIMS
Acute mesenteric venous thrombosis accounts for up to 20% of all patients with acute mesenteric ischemia in high-income countries. Acute mesenteric venous thrombosis is nowadays relatively more often diagnosed with intravenous contrast-enhanced computed tomography in the portal phase than at explorative laparotomy No high-quality comparative studies between anticoagulation alone, endovascular therapy, or surgery exists. The aim of the present systematic review was to offer a contemporary overview on management.
MATERIALS AND METHODS
Eleven relevant published original studies with series of at least ten patients were retrieved from a Pub Med search between 2015 and 2020 using the Medical Subject Heading term "mesenteric venous thrombosis."
RESULTS
When MVT is diagnosed early, immediate anticoagulation with either unfractionated heparin or subcutaneous low-molecular-weight heparin should commence. Surgeons need to be aware of the importance to scrutinize the computed tomography images themselves for assessment of secondary intestinal abnormalities to mesenteric venous thrombosis and the risk of bowel resection and worse prognosis. Progression toward peritonitis is an indication for explorative laparotomy and assessment of bowel viability. Frank transmural small bowel necrosis should be resected and bowel anastomosis may be delayed for several days until second look. Meanwhile, intravenous full-dose unfractionated heparin should be given at the end of the first operation. Postoperative major intra-abdominal or gastrointestinal bleeding occurs rarely, but the heparin effect can instantaneously be reversed by . Patients who do not improve during conservative therapy with anticoagulation alone but without developing peritonitis may be subjected to endovascular therapy in expert centers. When the patient's intestinal function has recovered, with or without bowel resection, switch from parenteral unfractionated heparin or low-molecular-weight heparin therapy to oral anticoagulation can be performed. There is a trend that direct oral anticoagulants are increasingly used instead of vitamin K antagonists. Up to now, direct oral anticoagulants have been shown to be equally effective with the same rate of bleeding complications. Patients with no strong permanent trigger factor for mesenteric venous thrombosis such as intra-abdominal cancer should undergo blood screening for inherited and acquired thrombophilia.
CONCLUSION
Early diagnosis with emergency computed tomography with intravenous contrast-enhancement and imaging in the portal phase and anticoagulation therapy is necessary to be able to have a succesful non-operative succesful course.
Topics: Anticoagulants; Heparin; Humans; Mesenteric Ischemia; Mesenteric Veins; Venous Thrombosis
PubMed: 33118463
DOI: 10.1177/1457496920969084