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PubMed1999

Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection.

We report three cases of nodal peripheral T-cell lymphoma (PTCL) with Reed-Sternberg-like (RS-like) cells of B-cell pheno- and/or genotype. Histologic analysis in all cases revealed diffuse nodal effacement by atypical lymphoid cells of variable size. Two of the three cases had features of angioimmunoblastic T-cell lymphoma (AILT). Large mononuclear and binucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm resembling classic RS cells and mononuclear variants were scattered throughout all biopsies. The lymphoma cells in the three cases were of T-cell lineage (CD3+, CD43+, and CD45RO+). The RS-like cells from all cases were CD30 and CD15 positive. In contrast to the neoplastic T cells, the RS-like cells lacked all T-cell markers and in two cases were positive for CD20. Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) and EBER 1 (2/2) were detected in the RS-like cells in all cases. The neoplastic T cells were negative for EBV. Polymerase chain reaction (PCR) analysis demonstrated clonal rearrangements of the T-cell receptor gamma chain gene in the three cases. PCR analysis of microdissected RS-like cells for immunoglobulin heavy chain gene rearrangements in cases 1 and 3 showed an oligoclonal pattern. The presence of RS-like cells in PTCL represents a diagnostic pitfall, because in one case this observation led to a misdiagnosis of Hodgkin's disease (HD). The oligoclonal expansion of EBV-infected cells may be related to underlying immunodeficiency associated with T-cell lymphomas and AILT in particular. This phenomenon may provide the basis for some cases of Hodgkin's disease after T-cell lymphomas and suggests that they are clonally unrelated neoplasms. The expression of LMP1 appears to be crucial for the immunophenotype and probably for the morphology of the RS and RS-like cells appearing in diverse lymphoid malignancies, including HD, chronic lymphocytic leukemia, and PTCL.

Aged↗

PubMed2006

Temporally specific proliferation events are induced in the hippocampus following acute focal injury.

In models of global brain injury, such as stroke or epilepsy, a large increase in neurogenesis occurs in the dentate gyrus (DG) days after the damage is induced. In contrast, more focal damage in the DG produces an increase in neurogenesis within 24 hr. To determine how cell proliferation and differentiation differs in the DG after acute injury in the DG, focal electrolytic lesions were made and mitotic activity was assessed at early (1 day) and late (5 day) time points. At the early time point, bromodeoxyuridine (BrdU)-positive cells were diffusely spread throughout the extent of the hippocampus that was ipsilateral to the lesion. No significant increase in the subgranular zone (SGZ) of the DG was observed. When BrdU was administered at the later time point, the number of BrdU+ cells in the SGZ of the DG was significantly increased. This fourfold increase in BrdU+ cells also resulted in a significant increase in neurogenesis, as measured 6 weeks following BrdU administration. This increase in neurogenesis was not observed when BrdU was administered at the early time point. These results indicate that focal injury in the DG activates two temporally specific proliferation events and that enhanced neurogenesis is observed only following a latent period after the lesion is made.

Animals↗

PubMed1989

Expression of the acidic nuclear immediate-early protein (IE1) of human cytomegalovirus in stable cell lines and its preferential association with metaphase chromosomes.

Stable DNA-transfected Vero cell lines that express the major immediate-early nuclear antigen (IE68) of HCMV-(Towne) have been established. Immunofluorescence staining with monoclonal antibodies revealed that the protein was distributed either in a uniform diffuse nuclear pattern or as punctate nuclear granules in up to 80% of the cells in these cultures. In addition, 1 to 2% of the positive nuclei gave a distinctive staining pattern suggesting an association with the chromosomes of mitotic cells. Colcemid-blocking studies confirmed that most of the IE antigen was localized in the vicinity of condensed chromosomes in all metaphase cells after methanol fixation. In contrast, the SV40 large T-antigen protein was found to be preferentially excluded from metaphase chromosomes in a similar colcemid-treated human cell line. In transient expression assays, 1 to 2% of IE antigen-positive Vero, 293, or Balb/c3T3 cells also displayed a metaphase chromosome association pattern. Mapping studies using deletion and truncation mutants revealed that the monoclonal antibodies recognized epitopes encoded within the small NH2-terminal exons that are common to both the IE1 and IE2 gene products. However, an intact exon-4 (IE1) region, but not the exon-5 (IE2) region of the HCMV IE gene complex, was required for conferring both the normal diffuse nuclear localization pattern and the chromosome-association properties. Furthermore, removal of the glutamic acid-rich COOH-terminal coding portions of exon-4 resulted in aberrant staining patterns with production of large, phase-dense nuclear globules in all positive cells. An association between the IE68 IE1 protein and metaphase chromosomes was also detected after HCMV-(Towne) infection in a small proportion of both nonpermissive Balb/c3T3 cells and permissive HF cells. We conclude that the IE1 acidic nuclear phosphoprotein displays some properties similar to those of the EBNA-1 protein of Epstein-Barr virus and suggest that it may potentially play a role in maintenance of the latent state of HCMV DNA.

Animals↗

PubMed1997

Role of an immunosuppressive cytokine, interleukin-10, in the development of pyothorax-associated lymphoma.

Malignant lymphoma frequently develops in the pleural cavity of the patients with long-standing pyothorax. Thus, the term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most of PALs are diffuse lymphoma of B cell type and contain Epstein-Barr virus (EBV) DNA. We have established two lymphoma cell lines from the biopsy specimens of PAL cases, OPL-1 and OPL-2. Both cell lines contain EBV DNA, but only OPL-1 expresses Epstein-Barr virus nuclear antigen 2 (EBNA2) that works as a target molecule for cell-mediated immune response. In this study, we examined the expression of immunosuppressive factors in OPLs. Only OPL-1, not OPL-2, expressed interleukin-10 (IL-10) mRNA and secreted IL-10 into culture supernatant. Both OPL-1 and OPL-2 expressed transforming growth factor (TGF) beta 1 mRNA, however, neither expressed latent TGF beta binding protein (LTBP) mRNA at detectable level by Northern blot analysis. Because TGF beta expresses its functions in cooperation with LTBP, the biological functions of TGF beta 1 could be negligible. Neither cell lines expressed EBV BCRF1 mRNA at detectable level, a viral gene product which is partly homologous to human IL-10 and shares biological activities of IL-10. Since OPL-1 shows weaker proliferative activity than OPL-2 and expresses viral antigens, the production of an immunosuppressive cytokine, IL-10, might contribute to the development of overt lymphoma. The present study suggested that immunosuppressive cytokine plays a role in lymphomagenesis of immunocompetent patients.

DNA, Viral↗

PubMed1994

Intravascular lymphomatosis of the CNS: clinicopathologic study and search for expression of oncoproteins and Epstein-Barr virus.

Five cases of intravascular lymphomatosis (IVL) are reported. Diffuse or focal cerebral signs suggestive of vascular disease occurred in four cases, but case 5 presented with symptoms similar to Creutzfeld-Jakob disease. Clinical course ranged from two to eight months and diagnosis was made in all cases by autopsy. Neoplastic lymphoid cells mainly lodged in lumina of small vessels in many organs, but infarction was confined to the CNS. Some extravascular tumor cells were regularly seen. All cases corresponded to high-grade Non-Hodgkin lymphomas of B-cell type and displayed high proliferation indices. Different from findings in primary cerebral and nodal lymphomas, neither p53 nor bcl-2 oncoproteins were detectable. Absence of EBV genome and EBV latent membrane protein from IVL was demonstrated for the first time.

Aged↗

PubMed1978

[Pathomorphology and pathogenesis of radiation sickness in calves and young cattle following whole body roentgen irradiation].

Here are the most important pathomorphological findings recorded from 14 calves or heads of young cattle following whole-body X-ray treatment (170 R and u50 R median-line dosage): 1. Damage was caused to the haematopoietic system, with the most severe effects on granulopoiesis, thrombocytopoiesis, and lymphopoiesis, but less conspicuous lesion of erythropoiesis. 2. Haemorrhagic diathesis developed together with pneumonia in 86 per cent of all cases, manifested in most of them as severe fibrinous pneumonia and pleuropneumonia (in 75 per cent of the cases) and progressing pericarditis. 3. Liver degeneration occurred to all animals, usually in the form of centrobular liver cell necrobiosis (86 per cent), with most of the cases accompanied by diffuse degenerative hepatoparenchymal damage (80 per cent) as well as by granular degeneration of the myocardium and acute fubulonephrosis, the latter two processes obviously developing only short time before death. 4. Catarrhal as well as fibrinous and circumscribed diphtheroid enteritis developed in 43 per cent of all animals, those which had received a median-line dosage of 170 R. 5. Deficiency in supply was recorded, too, with severe damage to the haematopoietic organs being in the focus of the pathological process. That damage actually was the cause of the haematologically established granulocytopenia or agranulocytosis, thrombocytopenia, and lymphopenia. That was the background against which radiation syndrome of calf could be accompanied by activation of latent or subclinical infection of respiratory organs and the development of severe pneumonia as well as by changes in the intestinal flora leading to the outbreak of enteritis. The collapse of cellular defence mechanisms obviously caused intestinal induction of resorption of bacterial toxins and decomposed tissue products, with the pneumonia-damaged lungs being involved. The results eventually were intoxication with haemodynamic disorders, increase in vascular permeability, and degenerative damage to the parenchyma. Haemorrhagic diathesis was the result of thrombocytopenia and, possibly, endotoxic or toxic damage to the coagulation and blood vessel system. Further pathogenetic aspects relating to the radiation syndrome in calf and young cattle are discussed.

Age Factors↗

PubMed2002

T-cell/histiocyte-rich large B-cell lymphoma: a heterogeneous entity with derivation from germinal center B cells.

T-cell/histiocyte-rich large B-cell non-Hodgkin's lymphoma (THRLBCL) is an unusual morphologic variant of diffuse large B-cell lymphoma. We reviewed 30 cases of THRLBCL to evaluate its heterogeneity based on morphologic, immunophenotypic, and genetic features. Cases were classified according to the appearance of the large neoplastic B cells into three morphologic variants: 1) lymphocytic and histiocytic (L&H-like) (resembling the L&H cells of nodular lymphocyte predominance Hodgkin's lymphoma (14 cases); 2) centroblast (or immunoblast)-like (10 cases), and 3) Reed-Sternberg cell-like (resembling the neoplastic cells of classic Hodgkin's lymphoma) (6 cases). We used a panel of immunohistochemical stains, including those with specificity for germinal center B cells: CD20, CD79a, CD30, CD15, epithelial membrane antigen, BCL-2, BCL-6, and CD10. The /JH polymerase chain reaction assay was further performed to investigate a relationship to follicular lymphoma. The results were correlated with Epstein-Barr virus status as determined by staining for latent membrane protein and EBER-1 in situ hybridization. All cases were of B-cell immunophenotype with strong surface CD20 reactivity in the neoplastic large lymphoid cells, although CD79a was more inconsistently and weakly expressed (10 of 17). Nuclear positivity for the BCL-6 protein was detected in the tumor cells in 26 of 29 (90%) cases. However, differences in expression of other antigens were encountered in the histologic subtypes. Epithelial membrane antigen positivity, a feature often seen in nodular lymphocyte predominance Hodgkin's lymphoma, was observed in 11 of 30 (37%) cases and was most commonly seen in cases with L&H cell morphology (8 of 14; 57%). CD30 expression was observed in 9 of 30 (30%) cases but was most frequent in cases with Reed-Sternberg-like morphology (3 of 6 [50%]). CD10 expression was infrequent overall (3 of 29; 10%), with 2 of 3 positive cases identified in the centroblastic group. The overall rarity of positivity for CD10, BCL-2 (3 of 22; 13%), and -2 JH rearrangement (1 of 28; 4%) indicates a lack of connection to follicular lymphoma for all subtypes. The three cases that were negative for BCL-6 protein were LMP-1 positive and EBER-1 positive by in situ hybridization, and 2 of 3 had neoplastic cells with Reed-Sternberg-like morphology. These results demonstrate that although a large proportion of THRLBCL represent tumors of germinal center B cell derivation, they exhibit a diversity of morphologic and immunophenotypic features. A subset of THRLBCL may be related to nodular lymphocyte predominance Hodgkin's lymphoma. A small percentage show features closely resembling classic Hodgkin's lymphoma and could be considered a variant of grey zone lymphoma.

Adult↗

PubMed1996

Diabetes with the 3243 mitochondrial tRNALeu(UUR) mutation. Characteristic neuroimaging findings.

OBJECTIVE: To investigate the basis of central nervous system dysfunction in diabetes associated with the 3243 mitochondrial tRNA mutation, we studied neuroimaging findings in patients with this disease. RESEARCH DESIGN AND METHODS: We screened 205 diabetic patients. Those patients who had the 3243 mutation in leukocytes or muscle were enrolled. All the subjects underwent computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and N-isopropyl-p-[123I]iodoamphetamine ([123I]IMP) single-photon emission computed tomography (SPECT) of the brain. RESULTS: None of the nine subjects with the 3243 mutation had the typical clinical picture of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, and none had neurological focal signs. CT or MRI revealed diffuse brain atrophy in three patients (33%) and cerebellar atrophy in one (11%). Abnormal high intensity areas were observed on MRI in five patients (56%). The overall prevalence of brain abnormalities was 56% (5 of 9) on CT and 78% (7 of 9) on MRI scans. MRA revealed no stenotic lesions. SPECT showed reduced accumulation of [123I]IMP in the right or left parieto-occipital region in eight patients (89%). CONCLUSIONS: Reduced accumulation of [123I]IMP in the parieto-occipital cortex was found in a high proportion of our subjects on SPECT. This imaging finding might be characteristic of diabetes associated with the 3243 mitochondrial tRNA mutation and may be a sign of latent central nervous system dysfunction.

Adult↗

PubMed1986

A high molecular weight protease in the cytosol of rat liver. I. Purification, enzymological properties, and tissue distribution.

Rat liver cytosol has low hydrolytic activity against [3H]methylcasein at neutrality, but activity increases greatly on addition of various compounds such as poly-L-lysine, N-ethylmaleimide, and sodium dodecyl sulfate, suggesting that it contains latent proteolytic activity. The latent enzyme was found to be stabilized in the presence of 20% glycerol and to be activated by addition of poly-L-lysine. The latent enzyme was purified from a crude extract of rat liver to apparent homogeneity in the presence of 20% glycerol by conventional chromatographic techniques. The purified enzyme showed endoproteolytic activity toward various proteins when it was activated by the compounds listed above. It preferentially degraded N-substituted tripeptide substrates with a basic amino acid at the carboxyl terminus, as well as peptides containing neutral hydrophobic amino acids. It did not require activation for these peptidase activities, in contrast to its activity toward large proteins. Interestingly, a proteinase and a trypsin-like and a chymotrypsin-like peptidase activity could not be separated by customary chromatographic methods but were distinguishable by their sensitivities to various inhibitors, activators, and covalent modifiers, suggesting that the enzyme has three distinct active sites within a single protein. The enzyme seems to be a seryl endopeptidase showing maximal activity at neutral and weakly alkaline pH values. Thus, the enzyme is a unique protease with latent multifunctional catalytic sites. The distribution of the protease in soluble extracts of various rat tissues and cells was examined quantitatively by an enzyme immunoassay. The enzyme level was highest in liver and also in spleen, stomach, lung, small intestine, and kidney, but was low in heart, diaphragm, skeletal muscle, brain, and skin. The concentrations of enzyme in some established cell lines including hepatoma and rat kidney cells were comparable to that in normal liver hepatocytes. The enzyme was found mainly in the cytosol fraction, although a small amount was associated with microsomal membranes, suggesting that it is an extralysosomal protease. Immunohistochemical staining of the liver and skeletal muscles showed that the protease is distributed diffusely in panlobular hepatocytes with slight centrilobar predominance and is present in Kupffer cells, vascular endothelial cells, and bile duct epithelial cells in the liver and also diffusely in the intermyofibrillar spaces and vascular endothelial cells in skeletal muscle. The quantitative data obtained in the present study indicate the presence of the protease in the cytosol fraction of all rat tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1982

Host endocrine status mediates oncogenesis: leukemia virus-induced carcinomas and reticulum cell sarcomas in acyclic or normal mice.

A highly selective leukemogenic virus obtained from thymic lymphosarcomas (LS) of C57BL/6 mice was inoculated intraperitoneally into normal or gonadectomized C57BL/6 male mice and into normal or masculinized, acyclic, Charles River (CR) outbred female mice. This virus induced early onset of LS in both normal and gonadectomized C57BL/6 mice. The same virus induced a relatively late onset of many mammary adenocarcinomas in the normal CR mice and ovary adenocarcinomas and systemic neoplasms (LS and reticulum cell neoplasms) in the acyclic females. Topography, histopathology and the average latent period of the tumors were completely different between the normal and the acyclic females. This is consistent with the idea that a leukemia virus can induce tumors other than leukemia and that permanent alterations of the physiological hormonal cyclicity plays a major role in determining whether or on which target cells the ubiquitous virus will exert its carcinogenic action.

Adenocarcinoma↗

PubMed2004

Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model.

Infection with Mycobacterium tuberculosis is a major world health problem. An estimated 2 billion people are presently infected and the disease causes approximately 3 million deaths per year. After bacteria are inhaled into the lung, a complex immune response is triggered leading to the formation of multicellular structures termed granulomas. It is believed that the collection of host granulomas either contain bacteria resulting in a latent infection or are unable to do so, leading to active disease. Thus, understanding granuloma formation and function is essential for improving both diagnosis and treatment of tuberculosis. Granuloma formation is a complex spatio-temporal system involving interactions of bacteria, specific immune cells, including macrophages, CD4+ and CD8+ T cells, as well as immune effectors such as chemokine and cytokines. To study this complex dynamical system we have developed an agent-based model of granuloma formation in the lung. This model combines continuous representations of chemokines with discrete agent representations of macrophages and T cells in a cellular automata-like environment. Our results indicate that key host elements involved in granuloma formation are chemokine diffusion, prevention of macrophage overcrowding within the granuloma, arrival time, location and number of T cells within the granuloma, and an overall host ability to activate macrophages. Interestingly, a key bacterial factor is its intracellular growth rate, whereby slow growth actually facilitates survival.

Chemokines↗

PubMedDate not supplied

Platelet accumulation in regions of low blood flow during the postischemic period.

Various studies indicate that after a latent interval, a progressive focal deterioration of microvascular perfusion can develop in zones of acute damage to the central nervous system (CNS). In order to obtain reliable information concerning the possibility of platelet participation in this phenomenon, platelet deposition was investigated by means of 111Indium-labeled platelets, and compared with local cerebral blood flow (CBF) and cortical sensory evoked response (CSER). Studies were performed with a model of focal ischemia in which small volumes of air were injected selectively into one internal carotid artery of dogs anesthetized with alpha chloralose throughout the experiment. The ischemic period was followed by a 10-min, 60-min or 4-hr recovery period. The main result was a prominent and diffuse accumulation of platelets in zones of low CBF in dogs subjected to 4 hr recovery.

Animals↗

PubMed1993

Epstein-Barr virus and CD30+ malignant lymphomas.

Phenotypic, genotypic, and karyotypic analyses have indicated that Hodgkin's disease and CD30+ anaplastic large cell lymphoma may be conceived as malignancies derived from activated, cytokine-producing lymphoid cells, in many instances with an immature genotype. Most recently, Epstein-Barr virus (EBV) genomes and gene products, most notably the transformation-associated latent membrane protein (LMP), have been detected in approximately 50 and 20% of the cases, respectively. These findings suggest that EBV may superimpose an activated phenotype on an immature lymphoid cell, contributing to the pathoetiology of sizable proportions of these CD30+ malignancies.

Antigens, CD↗

PubMed1997

Differential expression of the immediate-early and early antigens in neuronal and glial cells of developing mouse brains infected with murine cytomegalovirus.

Brain disorders induced by congenital cytomegalovirus (CMV) infection may appear at a later time after birth as a consequence of persistent infection and/or the activation of a latent infection of the neural cells. We have analyzed the infection dynamics of the neural cells in the neonatal mouse brains infected with murine CMV (MCMV) in the late stage of gestation. First we prepared a rat monoclonal antibody to the major immediate-early (IE)-89K antigen and then used the antibody for comparison of the expression of early and late viral genes in the developing mouse brains. The cells expressing the IE-89K antigen were mostly localized in the ventricular and subventricular zones and were preferentially double stained with anti-glial fibrillary acidic protein and anti-nestin antibodies. In contrast, the cells expressing the early nuclear antigen, detected by the monoclonal antibody D5, were diffusely distributed in the cortex and the hippocampus and were mostly double labeled with anti-neuron-specific enolase antibody. In neonatal mouse brains infected congenitally with recombinant MCMV, which expressed lacZ as a late gene, the number of the early nuclear antigen-positive cells was much higher than that of the beta-galactosidase-expressing cells, the number of which was almost the same as that of the IE-89K antigen-positive cells. In addition, the distribution of viral DNA-rich cells detected by DNA-DNA hybridization was similar to that of the IE-89K antigen-positive cells. These results suggest that CMV may persistently infect neuronal cells, whereas lytic infection may preferentially occur in the glial cells in the developing brain.

Aging↗

PubMed1994

Immunohistochemical detection of Epstein-Barr virus-encoded latent membrane protein in Reed-Sternberg cells and variants of Hodgkin's disease.

A total of 186 specimens of Hodgkin's disease of various histologic types (127 nodular sclerosis, 39 mixed cellularity, 14 lymphocyte predominance, 3 lymphocyte depleted, and 3 unclassified) were evaluated for the presence of latent membrane protein (LMP) and Epstein-Barr virus nuclear antigen-2, two Epstein-Barr virus encoded gene products that appear to play important roles in cell transformation and oncogenesis. Immunoreactivity for LMP was observed in Reed-Sternberg cells and variants of 27/39 (69%) cases of mixed cellularity type, 18/127 (14%) of nodular sclerosis type, 2/3 cases of lymphocyte depleted type, and 1/3 cases of unclassified type. All cases of lymphocyte predominance Hodgkin's disease were nonreactive for LMP. In cases that were reactive for LMP, staining was restricted to Reed-Sternberg cells and variants. Other cells within the proliferation, e.g., lymphocytes, histiocytes, eosinophils, fibroblasts, etc., were nonreactive. The pattern of immunoreactivity for LMP was characterized by strong diffuse cytoplasmic staining, occasionally with membrane accentuation and/or paranuclear staining. Reactivity for LMP was demonstrated in cryostat sections and was also well preserved in paraffin sections of B5- or formalin-fixed tissues. Five of six specimens of Hodgkin's disease (4 mixed cellularity and 2 nodular sclerosis type) that occurred in HIV-positive patients exhibited immunoreactivity for LMP in Reed-Sternberg cells and variants. Cryostat section studies for Epstein-Barr virus nuclear antigen-2 using monoclonal antibody PE-2 failed to reveal staining for 43 cases (26 nodular sclerosis, 12 mixed cellularity, and 5 lymphocyte predominance) after a 2-h incubation with primary antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

PubMed1992

Hodgkin's disease and Epstein-Barr virus.

Seroepidemiological and molecular biological studies have established an association of Hodgkin's disease with Epstein-Barr virus (EBV). Recently, EBV genomes and gene products, most notably the latent membrane protein (LMP), have been detected in approximately 50% of the cases. The findings suggest that EBV may contribute to the pathoetiology of a sizable proportion of Hodgkin's disease cases.

Antigens, CD↗

PubMed2000

Overexpression of BCL-2, BCL-X, and BAX in primary central nervous system lymphomas that occur in immunosuppressed patients.

In contrast to primary central nervous system lymphomas (PCNSLs) that occur in immunocompetent patients, most of those that occur in immunosuppressed patients are associated with Epstein-Barr virus (EBV). BCL-2-related proteins either block or promote cell death, forming homo- or heterodimers with each other. LMP-1, EBV latent protein, has been shown to upregulate BCL-2 and BCL-XL. This observation suggests that these proteins may be involved in the transformation process of EBV-infected cells. Twenty-three cases of PCNSLs were studied: 12 of the patients were immunosuppressed, and 11 were immunocompetent. For all cases, we collected clinical information, histologic data, and immunophenotype and tested for the presence of EBV (EBER-1, LMP-1). Apoptosis was assessed by the TdT-mediated dUTP-biotin nick-end labeling method and quantified by image analysis. In three cases, electron microscopy was performed. The BCL-2 family proteins (BCL-2, BCL-X, MCL1, and BAX) and p53 expression were studied by immunohistochemistry on paraffin slides. All cases were classified as diffuse large B-cell lymphomas. PCNSLs in immunosuppressed patients were characterized by EBV association, necrosis, important gliosis, and numerous macrophages. There was no significant difference between the two groups regarding the TdT-mediated dUTP-biotin nick-end labeling staining (P = .08). In contrast, PCNSLs in immunosuppressed patients were shown to express high levels of BCL-2, BCL-X, and BAX in more than 80% of tumor cells in 7, 10, and 11 cases, respectively. In immunocompetent patients, only one case showed a high level of BCL-2 expression in more than 80% of the cells, whereas BCL-X and BAX were overexpressed in two cases. These differences are significant (P < .05). In contrast, there was no significant difference between the two groups in MCL-1 expression. Besides EBV association and necrosis, PCNSLs related to immunosuppression are characterized by an overexpression of BCL-2-related proteins, without dramatically modifying their susceptibility for apoptosis.

Adult↗

PubMed1988

Proteasomes (multi-protease complexes) as 20 S ring-shaped particles in a variety of eukaryotic cells.

Latent multicatalytic protease complexes, named proteasomes, were purified to apparent homogeneity from various eukaryotic sources, such as human, rat, and chicken liver, Xenopus laevis ovary, and yeast (Saccharomyces cerevisiae), and their functional and structural properties were compared. They showed latency in breakdown of [methyl-3H]casein, but were greatly activated in various ways, such as by addition of polylysine. They all degraded three types of fluorogenic oligopeptides at the carboxyl side of basic, neutral, and acidic amino acids, and the three cleavage reactions showed different spectra for inhibition, suggesting that they had three distinct active sites. The proteasomes all seemed to be seryl endopeptidases with similar pH optima in the weakly alkaline region. Their physiochemical properties, such as their sedimentation coefficients (19 S to 22 S), diffusion coefficients (2.0-2.6 X 10(-7) cm2 s-1), molecular masses (700-900 kDa), and circular dichroic spectra, were similar. Their amino acid compositions were also very similar. Electron microscopy showed that they had similar well-defined symmetrical morphology, appearing to be ring-shaped particles with a small hole in the center. All the proteasomes seemed to be multisubunit complexes consisting of 15-20 polypeptides with molecular masses of 22-33 kDa and isoelectric points of pH 3-10, but they showed species-specific differences in subunit multiplicity. Moreover, they differed immunologically, as shown by Ouchterlony tests and immunoblotting analyses, although cross-immunoreactivities of some subunits or domains were observed. These results indicate that the sizes and shapes of these proteasomes have been highly conserved during evolution, but that they show species-specific differences in immunoreactivities and subunit structures. Thus proteasomes with similar structure and function seem to be ubiquitously distributed in eukaryotic organisms ranging from man to yeast. This distribution implies the general importance of these proteasomes for proteolysis.

Amino Acids↗