Summary B-cell high-grade lymphomas are heterogeneous in terms of histology, clinical presentation, treatment response and prognosis. As bcl-2 and p53 gene deregulations are frequencly involved in several types of lymphoid malignancies, we aimed our investigation at the study of the relation between bcl-2 and p53 expression and survival probability in a group of 119 patients with B-cell high-grade lymphoma. These were obtained from the Virgen de la Salud Hospital, Toledo, Spain (73 cases), John Radcliffe Hospital, Oxford, UK (31 cases), and the Istituto Nazionale dei Tumori, Milan, Italy (15 cases). The relation between bcl-2 protein expression and survival was small, depending on the primary localisation of the tumour (in lymph node of mucosae), and lacked a significant correlation with overall survival. In contrast with this, p53 expression was related to survival probability in our series, this relation being both significant and independent of histological diagnosis. p53-positive patients showed a sudden decrease in life expectancy in the first months after diagnosis. Multivariant regression analysis confirmed that the only parameters significantly related with survival were extranodal origin, which is associated with a better prognosis, and p53 expression, which indicates a poor prognosis. Simultaneous expression of bcl-2 and p53 was associated with a poorer prognosis than p53 alone. This is particularly significant for large B-cell lymphomas presenting in lymph nodes. The cumulative poor effect of both p53 and bcl-2 in large B-cell lymphomas, which is more significant in nodal tumours, could confirm the existence of a multistep genetic deregulation in non-Hodgkin's lymphoma. This indicates that the genetic mechanisms controlling apoptosis and their disregulation are critical steps in the progression of lymphomas.
Diabetic patients with PDR and ERMs had the highest plasma and vitreous IR-ET-1 levels. ET-1 and its ETA and ETB receptors were present in ERMs. These data suggest that ET-1 is involved in diabetic vitreoretinal disease.
p27 cyclin-dependent kinase inhibitor downregulation is essential for transition to the S phase of the cell cycle. Thus, proliferating cells in reactive lymphoid tissue show no detectable p27 expression. Nevertheless, anomalous high p27 expression has been shown to be present in a group of aggressive B-cell lymphomas with high proliferation index and adverse clinical outcome. This suggests that abnormally accumulated p27 protein has been rendered functionally inactive. We analyzed the causes of this anomalous presence of p27 in a group of aggressive B-cell lymphomas, including 54 cases of diffuse large B-cell lymphomas and 20 Burkitt’s lymphomas. We simultaneously studied them for p27, cyclin D3, cyclin D2, cyclin D1, and cyclin E expression, because it has been stated that high levels of expression of cyclin D1 or E lead to increased p27 levels in some cell types. A statistically significant association between p27 and cyclin D3 expression was found for the group as a whole. Additionally, when dividing the cases according to the level of expression of cyclin D3 by reactive germinal centers, it was observed that cases with stronger cyclin D3 expression also show higher p27 expression. The relationship between both proteins was also shown at a subcellular level by laser confocal studies, showing that in cases with high expression of both proteins there was a marked colocalization. Additional evidence in favor of p27 sequestration by cyclin D3 was provided by coimmunoprecipitation studies in a Burkitt’s cell line (Raji) showing the existence of cyclin D3/p27 complexes and the absence of CDK2/p27 complexes. These results could support the hypothesis that there are cyclin D3/p27 complexes in a subset of aggressive B-cell lymphomas in which p27 lacks the inhibitory activity found when it is bound to cyclin E/CDK2 complexes. This interaction between both proteins could lead to an abnormal nuclear accumulation, detectable by immunohistochemical techniques.
We evaluated the association of nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) in Spanish patients, and studied the expression of EBV products (latent membrane protein-1 [LMP-1] and ZEBRA proteins) by NPC cells and its possible prognostic value. In situ hybridization (ISH) for EBV-encoded nonpolyadenylated RNAs (EBERs) and immunohistochemical expression of LMP-1 and ZEBRA proteins by immunohistochemistry were examined in formalin-fixed, paraffin-embedded NPC specimens from 30 patients, and a survival analysis was done by the Kaplan-Meier method. We detected EBERs by ISH in 96.67% of the NPC cases, and detected expression of LMP-I in 43.33% of the NPC cases and expression of ZEBRA protein in 6.67% of the NPC cases. We conclude that ISH for expression of EBERs is an adequate method for detection of EBV in NPC. LMP-1 is not frequently expressed in NPC cells (43.33%). Most NPC cells carry a latent EBV infection. LMP-1 expression might have worsened the prognosis of NPC in our series.
We studied the effect of fibronectin (FN) on aggregates at 30 minutes (mean 2 SD 15 f 1.7%) than did the normal rats (T, 1.5 f 0.2 minutes, 22 f 2.870, respectively; P < 0.0005). Both parameters were within normal limits in the FN-treated rats (Tn 1.6 +-0.4 minutes, 22 +-6%. respectively). In vitro, FN induced a significant increase in aggregated IgC catabolism by Kupffer cells and peritoneal macrophages from normal rats. These results show that FN reduces the proteinuria and histologic lesions of chronic nephritis in rats. These beneficial effects of FN could be due to the improved clearance of immune complexes, decreased glomerular deposition, and perhaps, to better renal processing of immune complexes.Fibronectin ( F N ) is a high molecular weight glycoprotein (440 kd) composed of 2 similar polypeptide chains that are connected by 2 disulfide bonds (1). It is present both in a soluble form in extracellular fluids and in an insoluble form in connective tissue and basement membranes. where it acts as a binding or attachment protein. FN manifests a high affinity for native and denatured collagen, DNA, fibrin, hyaluronic acid, heparin. and several bacterial species ( 2 ) . This protein also mediates cell adhesion, migration, and mobility. and functions as an opsonic probe for fibrin. collagen, and cytoskeletal debris, preventing excessive localization in highly vascular organs such as the lungs and kidneys (3).The mononuclear phagocyte system plays a major role in the clearance of circulating immune complexes (CIC). Kupffer cells represent the predominant mononuclear phagocytic cells that clear foreign material from the blood (4.5). The removal of CIC is mediated by the Fc and CRI receptors on these cells. When large amounts of immune complexcs saturate
The aim of this study was to optimise conditions for mRNA detection by nonisotopic in situ hybridisation (NISH) using biotinylated and digoxigenin labelled riboprobes. Because graphy is avoided; and labelled riboprobes are easily produced. NISH also provides more precise cellular resolution than autoradiography.Biotinylated probes have been used extensively to label DNA probes but endogenous biotin produces background noise in some organs.5 Since the introduction of digoxigenin labelled probes for NISH,67 the general experience has been that background is less of a problem with this reporter5: it is a plant alkaloid and, unlike biotin (vitamin H), it is not a physiological tissue constituent and is uncharged at neutral pH. The improved methodology for digoxigenin detection makes this the reporter of choice in most NISH DNA experiments.5Lysozyme mRNA in archival clinical gut biopsy specimens was chosen as a model system to optimise NISH procedures for identification of gene transcription in archival clinical biopsy specimens. This protein8 and mRNA9 are present in appreciable quantities in well defined cell populations, such as Paneth cells and lamina propria mononuclear cells. We analysed the following NISH variables for mRNA localisation by digoxigenin and biotin labelled riboprobes: (i) unmasking conditions for mRNA; (ii) prehybridisation requirements; (iii) hybridisation conditions; (iv) optimisation of detection systems; and (v) the efficacy of RNAse inhibitors. MethodsAll reagents were obtained from Sigma (UK) or BDH (UK) unless otherwise stated. Sixteen routine formalin fixed, paraffin wax embedded endoscopic biopsy specimens of histopathologically normal small or large bowel were obtained from our diagnostic archival file: these included two rectal biopsy specimens of Crohn's colitis. Four small bowel surgical resection specimens were also studied after various fixation times. Sections (4 gum thick)were mounted on multi-well slides with four wells (12 mm in diameter) per slide (Henley, Essex) that had been previously coated with aminopropyl-triethoxysilane, and baked at 75'C for 60 minutes and overnight at 60°C.'0 Slides were heated at 75°C (10 minutes) and immediately transferred while still hot, to xylene in which they were gently washed with shaking at 22°C twice for 10 minutes each wash to remove the wax. Slides were immersed in Martinez-Montero, Herrington, Stickland, Sawyer, Evans, Flannery, McGee methanol for 10 minutes, twice, and quickly rinsed (three times) in double distilled water (ddH2O). Sections were warmed in ddH2O at 37°C while the proteases were prepared (see below). RIBOPROBESThe lysozyme probe was a 642 base pair human lysozyme cDNA, subcloned in both orientations into the Hinc II site of pGEM-3 (Promega Biotec, Madison, Wisconsin, USA).9 The recombinant plasmids were purified, linearised with Hind III, and transcribed with T7 RNA polymerase to generate anti-sense RNA probes. For sense RNA probes, the plasmids were linearised with EcoRI and transcribed with SP6 polymerase. An...
In both groups IHC profiles of proteins involved in G1/S transition regulation significantly differed from normal PT glands. The results support partial reversion to normal IHC profile in post-transplantation HPT.
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