1,721,037 research outputs found
Histogenesis and natural history of gut neuroendocrine tumors: present status
No full textImportant progress has been made during the last decade in the histopathologic characterization and overall prognostic evaluation of gut neuroendocrine tumors. However, some issues like tumor histogenesis, typing, functional characterization, and preferred site of origin deserve further clarification. This is a survey of the present status of the matter outlining some of the open points. In particular, careful comparison of normal gut endocrine cell types with related endocrine tumors so far identified shows an unexplained lack of neoplasms involving upper small intestine cells like secretin, cholecystokinin, motilin, and GIP cells, as well as the equally unexplained concentration of serotonin EC cell tumors in the ileum and appendix or of somatostatin cell tumors in the duodenal papillary region, despite their wide distribution in the normal gut, not to mention gastrinomas arising in the pancreas, normally devoid of gastrin cells. Special functional (e.g., achlorhydria-driven hypergastrinemia) or pathologic (as chronic inflammation) conditions may locally influence the proliferative and differentiation state of the endocrine cells thus promoting tumor growth. Tumor histologic structure, differentiation level, and proliferative index as well as gastrointestinal wall barriers to tumor diffusion may account for most prognostic parameters, with considerable changes, however, according to the tumor type and site. Thus, further work is needed to develop tumor- and site-adjusted prognostic parameters
Nonfunctioning pancreatic neuroendocrine neoplasms (including PP-producing and calcitonin-producing tumors)
No full textAccumulation of Helicobacter pylori products, NOD1, ubiquitinated proteins and proteasome in a novel cytoplasmic structure of human gastric epithelial cells in vivo.
No full textEvidence for transepithelial dendritic cells in human H. pylori active gastritis.
No full textBackground: Despite extensive experimental investigation stressing the importance of bacterial interaction with dendritic cells (DCs), evidence regarding direct interaction of H. pylori or its virulence products with DCs in the human gastric mucosa is lacking.
Methods: Human gastric mucosa biopsies, with or without H. pylori infection and active inflammation, were investigated at light and electron microscopy level with immunocytochemical tests for bacterial products (VacA, urease, outer membrane proteins) and DC markers (DC-SIGN, CD11c, CD83) or with the DC-labeling ZnI2-OsO4 technique. Parallel tests with cultured DCs were carried out.
Results: Cells reproducing ultrastructural and cytochemical patterns of DCs were detected in the lamina propria and epithelium of heavily infected and inflamed (but not of normal or moderately inflamed) mucosa, where DC luminal endings directly contact H. pylori and take up their virulence products. Cytotoxic changes (mitochondrial swelling, cytoplasmic vacuolation, autophagy) were observed in intraepithelial DCs and reproduced in cultured DCs incubated with H. pylori broth culture filtrates to obtain intracellular accumulation of VacA and urease. Granulocytes were also seen to contact and heavily phagocytose luminal H. pylori, while macrophages remained confined to basal epithelium, though taking up bacteria and bacterial products.
Conclusion: Human DCs can enter H. pylori-infected gastric epithelium, in association with other innate immunity cells, to take up bacteria and their virulence products. This process is likely to be important for bacterial sensing and pertinent immune response, however it may also generate DC cytotoxic changes potentially hampering their function
In vivo accumulation of Helicobacter pylori products, NOD1, ubiquitinated proteins and proteasome in a novel cytoplasmic structure.
No full textCell internalization and intracellular fate of H. pylori products/virulence factors in vivo by human gastric epithelium, the main target of H. pylori-induced pathologies (i.e., peptic ulcer and cancer), are still largely unknown. Investigating gastric endoscopic biopsies from dyspeptic patients by means of ultrastructural immunocytochemistry, here we show that, in human superficial-foveolar epithelium and its metaplastic or dysplastic foci, H. pylori virulence factors accumulated in a discrete cytoplasmic structure characterized by 13-nm-thick cylindrical particles of regular punctate-linear substructure resembling the proteasome complex in size and structure. Inside this particle-rich cytoplasmic structure (PaCS) we observed colocalization of VacA, CagA, urease and outer membrane proteins with NOD1 receptor, ubiquitin-activating enzyme E1, polyubiquitinated proteins, proteasome components and potentially oncogenic proteins like SHP2 and ERKs in human gastric epithelium. By means of electron and confocal microscopy, we demonstrate that the in vivo findings were reproduced in vitro by incubating human epithelial cell lines with H. pylori products/virulence factors. PaCSs differed from VacA-induced vacuoles, phagosomes, aggresomes or related bodies. Our data suggest that PaCS is a novel, proteasome-enriched structure arising in ribosome-rich cytoplasm at sites of H. pylori products accumulation. As a site of selective concentration of bacterial virulence factors, the ubiquitin-proteasome system and interactive proteins, PaCS is likely to modulate immune-inflammatory and proliferative responses of the gastric epithelium of potential pathologic relevance
Proteasome-Rich PaCS as an Oncofetal UPS Structure Handling Cytosolic Polyubiquitinated Proteins. In Vivo Occurrence, in Vitro Induction, and Biological Role
No full textIn this article, we outline and discuss available information on the cellular site and mechanism of proteasome interaction with cytosolic polyubiquitinated proteins and heat-shock molecules. The particulate cytoplasmic structure (PaCS) formed by barrel-like particles, closely reproducing in vivo the high-resolution structure of 26S proteasome as isolated in vitro, has been detected in a variety of fetal and neoplastic cells, from living tissue or cultured cell lines. Specific trophic factors and interleukins were found to induce PaCS during in vitro differentiation of dendritic, natural killer (NK), or megakaryoblastic cells, apparently through activation of the MAPK-ERK pathway. Direct interaction of CagA bacterial oncoprotein with proteasome was shown inside the PaCSs of a Helicobacter pylori-infected gastric epithelium, a finding suggesting a role for PaCS in CagA-mediated gastric carcinogenesis. PaCS dissolution and autophagy were seen after withdrawal of inducing factors. PaCS-filled cell blebs and ectosomes were found in some cells and may represent a potential intercellular discharge and transport system of polyubiquitinated antigenic proteins. PaCS differs substantially from the inclusion bodies, sequestosomes, and aggresomes reported in proteinopathies like Huntington or Parkinson diseases, which usually lack PaCS. The latter seems more linked to conditions of increased cell proliferation/differentiation, implying an increased functional demand to the ubiquitin−proteasome system
Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion pathway and budding of outer membrane vesicles. Uptake of released toxin and vesicles by gastric epithelium
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K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions
No full textHigh cell sensitivity to Helicobacter pylori VacA toxin depends on a GPI-anchored protein and is not blocked by inhibition of the clathrin-mediated pathway of endocytosis
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