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R J Mayer

Publications and source records attributed to R J Mayer.

At least 91 records · Page 5Linked to original sources
PubMed1996

Pathological lesions of Alzheimer's disease and dementia with Lewy bodies brains exhibit immunoreactivity to an ATPase that is a regulatory subunit of the 26S proteasome.

MS73 is one of a family of ATPases that act as regulatory subunits of the 26S proteasome. Localisation of this ATPase in histological sections of hippocampus from Alzheimer's disease (AD) and in cingulate gyrus sections of dementia with Lewy bodies (DLB) brains was examined immunohistochemically. In all cases of AD (n = 10) neurofibrillary tangles (NFT), plaque neurites and neuropil threads were immunoreactive for MS73. In seven out of the nine cases of DLB, distinctive MS73-positive structures were detected within cortical Lewy bodies. The association of MS73 with these neuronal abnormalities provides further evidence that proteolytic processing involving the 26S proteasome occurs in lesions of AD and DLB.

Adenosine Triphosphatases↗
PubMed1996

Specific developmental changes in the regulatory subunits of the 26 S proteasome in intersegmental muscles preceding eclosion in Manduca sexta.

Previously, we have shown extensive reprogramming of the ATPase regulator of the 26S proteasome preceding the programmed destruction of intersegmental muscles (ISM) in the tabacco horn moth Manduca sexta (Dawson et al., J. Biol. Chem, 270, 1850-1858, 1995). We now show that the extensive reprogramming of the regulatory components of the 26S proteasome occurs only in ISM and not in flight muscles (FM), which undergo terminal differentiation at ecdysis. Unlike in ISM, the ATPase regulators, MS73, MSS1, TBP1 and mts2, remain at low levels in 26S proteasomes in FM from developmental Stage-0 to Stage-7. The non-ATPase regulator subunit 5a, which binds to multiubiquitin chains, increased in ISM similarly to the ATPases but not in FM. The ecdysteroid agonist RH-5849 prevented these subunit increases in ISM. These findings show that reprogramming of 26 S proteasomes is involved in the specific elimination of ISM during eclosion and does not occur in FM which are needed for adult moth flight.

Animals↗
PubMed1996

Neurofibrillary tangles of Alzheimer's disease brains contain 14-3-3 proteins.

The localisation of 14-3-3 proteins compared to that of tau and ubiquitin-protein conjugates in sections of hippocampus from Alzheimer's disease (AD) brains was examined by immunohistochemistry. In all cases (n = 10), anti-14-3-3 stained a proportion of neurofibrillary tangles (NFT). In general, NFT stained by anti-14-3-3 were smaller than those stained by anti-tau or anti-ubiquitin-protein conjugates and were more confined to the neuronal cell body. Occasionally, cortical Lewy bodies in cases of Lewy body dementia were also found to be 14-3-3-positive. Since 14-3-3 proteins are central to MAP kinase signalling, the results support the proposal that this pathway is in part responsible for the hyperphosphorylation of tau, which leads to the formation of the paired helical filaments seen in AD brains.

14-3-3 Proteins↗
PubMed1996

Extraction and protein sequencing of immunoglobulin light chain from formalin-fixed cerebrovascular amyloid deposits.

Substantial amounts of a single protein have been extracted into electrophoresis sample buffer from archived formalin-fixed brain blood vessels, taken from a case of cerebral amyloidosis. Cyanogen bromide cleavage and tryptic digestion of the protein on Western blots allowed amino acid sequences from three resultant peptides to be determined. Comparison of these peptides with database sequences identified the extracted protein as being derived from an immunoglobulin light chain. This is the first demonstration of amino acid sequencing of a polypeptide extracted from formalin-fixed tissue. This case also appears to be unique, since primary cerebrovascular amyloidosis involving immunoglobulin light chains has not been previously described. The amyloid protein had clearly resisted formalin fixation; it is possible that this resistance occurred because the protein was deposited in large amounts as insoluble densely packed aggregates, which may exclude infiltration of the formalin. This technique may therefore have applications in the post-mortem diagnosis of amyloidoses and in the purification of other amyloids.

Adult↗
PubMed1996

Endosome-lysosomes, ubiquitin and neurodegeneration.

Before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. The application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including Alzheimer's disease (AD), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD) and scrapie) are related by some form of intraneuronal inclusion which contains ubiquitin protein conjugates. In addition, disorders such as Alzheimer's disease, CJD and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins which may be associated with cytoskeletal reorganisation. Although our knowledge about these diseases is increasing, they remain largely untreatable. Recently, attention has focused on the mechanisms of production of different types of amyloid and the likely involvement within cells of the endosome-lysosome system, organelles which are immuno-positive for ubiquitin protein conjugates. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials or their precursors which subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Such common features of the disease processes give new direction to therapeutic intervention.

Animals↗
PubMed1996

Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French-American-British criteria: a Cancer and Leukemia Group B Study.

PURPOSE: To determine the treatment outcome of standard acute myeloid leukemia (AML)-type chemotherapy in a subset of patients with newly diagnosed myelodysplastic syndromes (MDS) compared with that of patients with de novo AML as defined using French-American-British (FAB) criteria. In addition, to determine the pretreatment variables having prognostic significance for treatment outcome in patients with MDS. PATIENTS AND METHODS: Nine hundred seven newly diagnosed patients with no history of cytopenias having a local institutional de novo AML successfully karyotyped and treated on Cancer and Leukemia Group B (CALGB) protocols for AML from 1984 to 1992. Thirty-three of the 907 patients were reclassified as having MDS on central pathology review using FAB criteria and form the basis of this analysis. RESULTS: The treatment outcomes for patients with MDS and AML were similar; the complete remission (CR) rate was 79% and 68%, respectively (P = .37); median CR duration was 11 and 15 months, respectively (P = .28); and median survival was 13 and 16 months, respectively (P = .72). For the MDS patients, there were no prognostic variables for CR rate identified. For CR duration, only the Sanz classification had prognostic value. The prognostic factors for survival in a univariate analysis included age, WBC count, Sanz classification, and percent blood blasts. In a proportional hazards analysis of survival, age greater than 60 years and WBC less than 2.6 x 10(9)/L were adverse prognostic factors. CONCLUSION: In patients with no known history of cytopenias who are treated intensively at diagnosis, the FAB distinctions between MDS (refractory anemia with excess blasts and refractory anemia with excess blasts in transformation) and AML appear to have little therapeutic relevance.

Acute Disease↗
PubMed1996

Inhibitors of coenzyme A-independent transacylase induce apoptosis in human HL-60 cells.

ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine) is an antiproliferative agent, blocking the growth of cancer cells both in vitro and in vivo. However, there is controversy regarding the mechanism leading to its antiproliferative effects. CoA-independent transacylase (CoA-IT) is an enzyme that remodels arachidonate between specific phospholipid donor and acceptor molecules in a variety of mammalian cells. ET-18-O-CH3 was found to be a potent inhibitor of CoA-IT (IC50, 0.5 microM), and kinetic analysis revealed that its inhibition was competitive with the lyso-phospholipid substrate. The goal of the current study was to explore the connection between inhibition of CoA-IT and antiproliferative effects using several structurally distinct inhibitors of CoA-IT. ET-18-O-CH3 and other inhibitors of CoA-IT were found to inhibit cell proliferation and thymidine incorporation into the DNA, as well as to induce apoptosis in human HL-60 monocytic leukemia cells. The mechanism of apoptosis induced by ET-18-O-CH3 appeared to be different from that induced by tumor necrosis factor; the former failed to activate NF-kappa B, whereas tumor necrosis factor did. Closer examination of the pharmacology of apoptosis in this model revealed that compounds that were structurally related to CoA-IT inhibitors, but lacked CoA-IT inhibitory activity, also failed to induce apoptosis. In addition, compounds that inhibited other enzymes that participate in arachidonic acid metabolism, cyclooxygenase, 5-lipoxygenase and phospholipase A2, did not induce apoptosis. Taken together, these results demonstrate that inhibition of CoA-IT can be linked to blockade of proliferation and the induction of apoptosis in HL-60 cells.

Acyltransferases↗
PubMed1995

Related organelles of the endosome-lysosome system contain a different repertoire of ubiquitinated proteins in Sf9 insect cells.

Two components of the endosomal/lysosomal compartment of Sf9 cells, multivesicular bodies (MVB) and light vacuoles with membrane complexes (LVMC) have been isolated and probed for ubiquitin protein conjugates with a specific antibody. Immunogold electron microscopy indicates that whereas ubiquitin-protein conjugates are localised to electron dense areas of MVB they are associated with the membranes of LVMC. Five ubiquitinated polypeptides are revealed in MVB by immunoblotting while numerous ubiquitinated species forming a smear following electrophoresis are present in LVMC. We suggest two possible routes for entry of ubiquitin-protein conjugates into these organelles, via the cell surface and via primary lysosomes.

Animals↗
PubMed1995

Gastric carcinoma.

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Antineoplastic Agents↗
PubMed1995

Inhibitors of CoA-independent transacylase block the movement of arachidonate into 1-ether-linked phospholipids of human neutrophils.

The enzyme CoA-independent transacylase (CoA-IT) has been proposed to mediate the movement of arachidonate between phospholipid subclasses and influence the formation of arachidonic acid metabolites and platelet-activating factor. To substantiate the critical role of CoA-IT, we have developed two structurally diverse inhibitors of CoA-IT activity, SK&F 98625 [diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydro-imidazole-1-yl)heptane phosphonate] and SK&F 45905 [2-[2-(3-4-chloro-3-(trifluoromethyl)phenyl)-ureido]-4- (trifluoromethyl)phenoxy]-4,5-dichlorobenzenesulfonic acid]. These compounds were tested for their capacity to block microsomal CoA-IT activity using two assay systems, the transacylation of 1-alkyl-2-lyso-sn-glycero-3-phosphocholine (GPC) and the transfer of [14C]arachidonate from 1-acyl-2-[14C]arachidonoyl-GPC to lyso-PE. Both SK&F 98625 and SK&F 45905 inhibited CoA-IT activity (IC50s 6-19 microM) in these two assays. In contrast, SK&F 98625 or SK&F 45905 had little or no effect on other lipid-modifying activities, including CoA-dependent acyltransferase or acetyltransferase. Kinetic analysis revealed that both SK&F 98625 and SK&F 45905 interact directly with the enzyme and prevented the acylation of lysophospholipids in a competitive manner. In intact human neutrophils, both SK&F 98625 and SK&F 45905 completely blocked the movement of [3H]arachidonate from 1-acyl-linked phospholipids into 1-alkyl-2-arachidonoyl-GPC and 1-alk-1'-enyl-2-arachidonoyl-GPE. In contrast, these compounds did not inhibit the incorporation of free arachidonic acid into cellular lipids indicating that they did not alter CoA-dependent acyl transferase activities in the intact cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyltransferases↗
PubMed1995

Developmental changes of the 26 S proteasome in abdominal intersegmental muscles of Manduca sexta during programmed cell death.

cDNA clone MS73 codes for an ATPase that is a regulatory subunit of the 26 S proteasome. Reverse transcriptase polymerase chain reaction analysis demonstrates that the expression of the gene dramatically increases in the pre-eclosion period. Western analyses show increases in other related. ATPases including MS73, MSS1, and mts2 but not TBP1. A similar increase in the 30-kDa subunit of the 20 S proteasome occurs. There are accompanying large changes in the peptidase activities of the 26 S proteasome. Relative to the 30-kDa subunit, there is no change in MSS1 and MS73, a 3-fold increase in mts2, and a 5-fold decline in TBP1. A large increase in the concentration of 26 S proteasomes together with extensive regulatory reprogramming may facilitate rapid muscular proteolysis.

Algorithms↗
PubMed1995

Morphologic characteristics of erythroleukemia (acute myeloid leukemia; FAB-M6): a CALGB study.

We have reviewed the clinical, morphologic, immunophenotypic, and cytogenetic features of 52 patients with erythroleukemia (FAB Cooperative Group; AML-M6) studied by the Cancer and Leukemia Group B (CALGB). The purpose of this study was to correlate morphology with the clinical features, immunophenotypes, and karyotypes of neoplastic cells, and with the response to therapy of patients with AML-M6. Thirty-three patients (63%) were male, median age 59 (range 16-81) years, 47 patients (90%) were white, and 42 patients (81%) had a performance status of < 2. Myelodysplastic changes were observed in at least 1 cell lineage in all cases, and in 2 cell lineages in 45 of 52 (86%) cases. Fifty percent or more of cases studied were positive for CD11b, CD13, CD15, CD33, glycophorin-A, and HLA-DR markers. Fourteen of 27 cases (52%) in whom karyotypic analyses were conducted had cytogenetic abnormalities. Five (19%) were simple (< 3 karyotypic abnormalities), while 9 (33%) were complex (> or = 3 abnormalities). We observed either a complete or partial loss of chromosomes 5, 7, or 12p, or the presence of trisomy 8, in 11 of 27 (41%) patients. Cases of AML-M6 were divided into group 1 (14 patients with bone marrow proerythroblasts and basophilic erythroblasts > 25% of all erythroblasts) and group 2 (38 patients with proerythroblasts and basophilic erythroblasts < or = 25% of all erythroblasts). We observed no significant differences between groups 1 and 2 in regard to sex, age, race, performance status, percentage of blood erythroblasts or myeloblasts, percentage of bone marrow erythroblasts, and periodic acid-Schiff (PAS) or myelodysplasia scores. Six of 6 (100%) patients of group 1, and 7 of 21 (33%) patients of group 2, had normal karyotypes (P = .006). Nine of 13 (69%) patients of group 1 and 15 of 33 (45%) patients of group 2 had a complete remission (CR) (P = .2). Eight of 11 (73%) cytogenetically normal patients achieved CR: 5 of 6 (83%) in group 1, and 3 of 5 (60%) in group 2. Five of 12 (42%) cytogenetically abnormal patients achieved CR. No difference in duration of survival (group 1, median = 4.6 months vs. group 2, median = 10.2 months; P = .93) was observed between the 2 groups. We conclude that AML-M6 is typified by multilineage involvement of hematopoietic cells. The morphology of erythroblasts in patients with AML-M6 may correlate with cytogenetic abnormalities and rate of CR.

Adolescent↗
PubMed1995

The abnormal isoform of the prion protein accumulates in late-endosome-like organelles in scrapie-infected mouse brain.

The prion encephalopathies are characterized by accumulation in the brain of the abnormal form PrPsc of a normal host gene product PrPc. The mechanism and site of formation of PrPsc from PrPc are currently unknown. In this study, ME7 scrapie-infected mouse brain was used to show, both biochemically and by double-labelled immunogold electron microscopy, that proteinase K-resistant PrPsc is enriched in subcellular structures which contain the cation-independent mannose 6-phosphate receptor, ubiquitin-protein conjugates, beta-glucuronidase, and cathepsin B, termed late endosome-like organelles. The glycosylinositol phospholipid membrane-anchored PrPc will enter such compartment for normal degradation and the organelles may therefore act as chambers for the conversion of PrPc into infectious PrPsc in this murine model of scrapie.

Animals↗
PubMed1995

Immunohistochemical localization of ubiquitin cross-reactive protein in human tissues.

Ubiquitin cross-reactive protein (UCRP) is an interferon-inducible ubiquitin homologue which is constitutively present in cells and can be conjugated to other proteins. Using a characterized polyclonal antiserum to UCRP, immunohistochemical localization of UCRP was performed on paraffin-processed normal human tissues and in human tissues known to contain ubiquitinated intracellular inclusions. The antibody to UCRP immunostained lymphoid cells, striated and smooth muscle, several epithelia, and neurons. The level of staining varied greatly between tissues but was in a consistent punctate pattern. Localization to neuromuscular junctions and striations is similar to that described for antisera to ubiquitin-protein conjugates. Inclusion bodies characterized by immunoreactivity to anti-ubiquitin were not detected by the antibody to UCRP. Importantly, because UCRP may also be detected by antisera to conjugated ubiquitin, future studies on the distribution of ubiquitin in tissue sections must now take account of possible cross-reactivity with UCRP.

Cross Reactions↗
PubMed1995

Summary of the Second International Conference on Biology, Prevention and Treatment of Gastrointestinal Malignancies.

R. Mayer (U.S.A.) in summarizing the data presented at the three day conference, raised several general issues. Therapeutic benefit in the past has been measured by the criterion of 'objective response'; the latter term most likely should be replaced by 'quality of life' and 'overall survival time' since they appear to be more biologically meaningful. It appears that few new cytotoxic drugs have been developed in recent years, and , as yet, none has an established role in the management of patients with gastrointestinal cancers. Of those currently under investigation, CPT-11 seems to represent the most promising, since its mode of action is something other than inhibition of thymidylate synthase. It seems that too many small, uncontrolled studies examining a give concept (e.g. neoadjuvant therapy) have been performed prior to initiating definitive, phase III trials; a greater degree of collaboration seems necessary so that new treatment principles may be objectively assessed in an efficient manner. Finally, it seems clear that economic realities are increasingly affecting choices in patient care and clinical research and this trend will undoubtedly increase in the future.

Adenocarcinoma↗