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M R Pincus

Publications and source records attributed to M R Pincus.

118 records · Page 7Linked to original sources
PubMed1976

Prediction of three-dimensional structures of enzyme-substrate and enzyme-inhibitor complexes of lysozyme.

Conformational energy calculations were used to predict the three-dimensional structures of enzyme-substrate and enzyme-inhibitor complexes of lysozyme. A global search method, involving the use of a disaccharide fragment molecule, was used initially to determine all favorable binding regions at the active site. It is shown that the binding of a series of (nonfragmented) oligomers of N-acetylglucosamine is highly specific. The results show further that (a) the enzyme recognizes only one backbone conformation of the oligomer, corresponding to a left-handed helix, and (b) for saccharides containing two or more N-acetylglucosamine residues, two residues bind preferentially to the C and D sites. The calculations also suggest that the chair form of N-acetylglucosamine can bind to the D region. The saccharide residues of tetra-N-acetylglucosamine bind to the A-B-C-D sites, with the residues at the A-B-C sites having essentially the same conformation and orientation as those in the x-ray structure of tetra-N-acetylglucosamine-delta-lactone bound to lysozyme.

Acetylglucosamine↗
PubMedDate not supplied

Thrombocytopenia in a retrovirally-induced murine erythroleukemia.

A variant strain of Rauscher leukemia virus (RLV-A) obtained from a transplantable murine monomyelocytic leukemia causes a disease characterized by frank anemia, wasting, hepatosplenomegaly and erythroblastosis. The involvement of platelets in this disease are reported here. The RLV-A induced a severe thrombocytopenia (25 percent of control level) at the terminal stage of disease. This thrombocytopenia was not associated with disseminated intravascular coagulopathy since the prothrombin times were always within normal limits. The partial thromboplastin time was elevated in the terminal stages of disease and was found to be associated with factor deficiencies, possibly owing to the presence of anti-factor antibodies, in the intrinsic coagulation pathway, especially factor VIII. Further, splenectomy did not abolish the thrombocytopenia, since splenectomized, virally infected animals also developed severe thrombocytopenia (29 percent of control levels). The ensuing splenomegaly during progression of disease was not the cause of the thrombocytopenia. A physiological response to the severe thrombocytopenia was the production of larger size platelets. At terminal stages of the disease, platelet volume increased to 4.2 mu 3 (normal is 3.0 mu 3). An increase in platelet volume was also observed in splenectomized, virally infected animals. Electron microscopy indicated that these circulating platelets contained c-type viral particles. Viral infection was associated with decreased life span of circulating platelets, as measured by 75Se-methionine at mid and terminal stages of the disease. Our results suggest that direct viral infection of platelets and/or megakaryocytes with subsequent cell lysis is a possible cause of the observed thrombocytopenia observed in RLVA-induced disease and may also occur in other retrovirally-induced diseases.

Animals↗
PubMedDate not supplied

Pathways for activation of the ras-oncogene-encoded p21 protein.

The ras-oncogene-encoded p21 protein is known to cause a large number of human tumors. This protein differs from its normal counterpart protein, which is present in all eukaryotic cells, in that it contains a single amino acid substitution at critical positions in the polypeptide chain, such as at Gly 12, Gly 13, Ala 59, and Gln 61. Using computer-based molecular modeling, it has been found that one region of this protein that is a candidate for interacting with other intracellular proteins is the region from residues 35 to 47. In oocyte microinjection experiments, it was found that this peptide strongly inhibits the mitogenic effects of oncogenic (Val 12-containing)p21 but does not inhibit the cellular effects of activation of normal p21 protein. Furthermore, it has been shown that the cellular effects of oncogenic p21 protein can be completely inhibited by selectively blocking protein kinase C (PKC) with a highly specific inhibitor of this protein, CGP 41 251, a staurosporine derivative. This inhibitor, however, only weakly inhibits the effects of normal cellular ras-p21 protein. In addition, a photoaffinity-labeled p21 protein has been microinjected into NIH 3T3 fibroblasts and have isolated intracellular proteins of MW 35, 43 and 61 kda covalently bound to it. The 43 kda protein is the major one and appears to be critical to the functioning of the p21 protein. Our results suggest that oncogenic and normal p21 proteins utilize overlapping but distinct pathways; the oncogenic pathway can be blocked selectively and requires the activation of PKC and the presence of the 43 kda protein.

Amino Acid Sequence↗
PubMedDate not supplied

A peptide from the GAP-binding domain of the ras-p21 protein and azatyrosine block ras-induced maturation of Xenopus oocytes.

The ras-oncogene-encoded p21 protein causes malignant transformation of NIH 3T3 cells and maturation of Xenopus oocytes when microinjected into these cells. P21 is known to interact with GTPase activating protein (GAP) intracellularly. Residues 32-45 of p21 have been implicated in interacting with GAP. In a previous study, we demonstrated that a synthetic peptide containing residues 35-47 from the GAP-binding region of p21 could block in vivo the effects of oncogenic p21 protein. It has also been found that an antibiotic, azatyrosine, blocks ras-initiated cell transformation. We now demonstrate that both of these agents inhibit the ras-p21 protein-induced maturation of Xenopus oocytes in a dose-related manner when microinjected into oocytes. The effects of each of these agents is specific. Both agents block insulin-induced maturation of oocytes, a process which is known to involve activation of endogenous normal p21 protein. On the other hand, neither agent inhibited oocyte maturation induced by progesterone, which is known to initiate oocyte maturation by ras-independent pathways. The inhibitory effects of the peptide were not mimicked by a control peptide from the CD4 receptor protein. Furthermore, the effect of azatyrosine was not mimicked by L-tyrosine. These results suggest that both the peptide and azatyrosine have potent anti-ras effects intracellularly.

3T3 Cells↗
PubMedDate not supplied

erbB-2 and myc oncoproteins in sera and tumors of breast cancer patients.

This study compares the prevalence of elevated serological levels of erbB-2 and myc proteins in 36 breast cancer patients and 25 healthy, ambulatory female controls. The controls were frequency matched to the cases by age and ethnicity. Oncoprotein levels were determined blind to the "case-control status" of the individual from whom the specimen was derived. Corresponding tissue levels were examined in tumors of the 13 cases from whom sufficient tissue was available. Serum oncoproteins were elevated as follows: erbB-2 in one control (4%) compared with nine cases (25%; PFisher's exact = 0.03); myc in no control (0%) compared with seven cases (19%; PFisher's exact = 0.02). Elevated serum levels of erbB-2 or myc oncoproteins were detected in four of the seven cases (57.1%) of in situ cancer without evidence of infiltration. In all cases with elevated serum oncoproteins where tumor tissue was available, the corresponding protein was elevated in the tumor. The three cases who had elevated preoperative serum oncoprotein levels and from whom it was possible to procure postoperative specimens had normal postoperative serum oncoprotein levels. We conclude that (a) erbB-2 and myc oncoproteins are elevated in a proportion of breast cancer patients, (b) the tumor seems to be the source of the serum elevation, and (c) these proteins may be useful as part of a panel of biomarkers of early malignant disease.

Adult↗
PubMedDate not supplied

Primary lupus-associated protein-losing enteropathy.

A 79-year-old native American female with a history of diabetes mellitus, but no history of hepatic or renal disease, presented with anasarca and hypoalbuminemia. Laboratory tests for fecal alpha 1-antitrypsin and an indium III-labeled plasma transferrin nuclear scan revealed a protein-losing enteropathy. A serological test was positive for antinuclear antibody in a titer of 1:1250 with a homogeneous pattern. This finding combined with low normal serum complement levels suggested the diagnosis of systemic lupus erythematosus (SLE). This case is unusual in that protein-losing enteropathy was the only presenting symptoms. The late onset of this disease is also unusual.

Aged↗
PubMedDate not supplied

Acute severe rhabdomyolysis in an human immunodeficiency virus-seropositive patient associated with rising anti-coxsackie B viral titers.

Very recently there have been sporadic reports of polymyositis in patients who are positive for human immunodeficiency virus (HIV). The cause of this condition has not been documented. Recent evidence has been presented which indicates that the Coxsackie B virus may be a causative factor. Presentation is made of a patient, a drug abuser who was found to be HIV-positive with severe polymyositis manifested by generalized muscle weakness and a total serum creatinine kinase that reached the unusually high level of > 600,000 U/L. This patient was found to have a rise in titer of Coxsackie B-4 virus antibodies. He was negative for a variety of possible infectious causes of this condition and was negative for both antinuclear antibodies (ANA) and rheumatoid factor (RF). It is concluded that a polymyositis may indeed be associated with immunosuppressed states and that Coxsackie B-4 virus may be an important causative factor.

Adult↗
PubMedDate not supplied

Diffuse large cell lymphoma of B-cell type associated with reactive hemophagocytosis.

Some lymphomas, virtually all phenotypically of the T-cell type, have been associated with the phenomenon of hemophagocytosis. Only two B-cell lymphomas, one T-cell-rich and the other an angiocentric lymphoma, have been observed to exhibit this phenomenon. A case is reported of a diffuse large cell lymphoma of the B-cell type associated with reactive hemophagocytosis. Cytokines or other humoral factors produced by the lymphoma are a possible cause, and their effect is probably systemic. There is some evidence suggesting correlation of hemophagocytosis with tumor aggressiveness.

Adult↗
PubMedDate not supplied

Direct identification of unexpected serum antibodies against red cell antigens.

A new method to detect the identity of unexpected antibodies in the sera of prospective transfusion recipients is presented. The method is based on a macroscopic hemagglutination inhibition assay. In this assay, incubation of phenotypically defined test red blood cells with patient sera containing non-agglutinating antibodies to one or more specific antigen systems block monoclonal IgM induction of red cell agglutination. Since the specificities of the IgM antibodies are known, the identity of the patient's antibody(ies) can be directly determined. This method, which uses only reagents that are commercially available, is specific and eliminates the use of the indirect antiglobulin test (IAT) and the use of elimination panels.

Antibodies↗