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Biomedical subjects

M Pincus

Publications and source records attributed to M Pincus.

14 recordsLinked to original sources
PubMed1990

Crystal structure of two covalent nucleoside derivatives of ribonuclease A.

Crystal structures of two forms of ribonuclease A with deoxynucleosides covalently bound to respectively His 12 and His 119 have been solved. One form, T-H12-RNase, has a deoxythymidine bound to N epsilon 2 of His 12, while the other one, U-H119-RNase, has a deoxyuridine bound to N delta 1 of His 119. The two crystal forms are nearly isomorphous, with two molecules in the asymmetric unit. However, the modified ribonucleases differ both in their enzymatic activities and in the conformation of the catalytic site and of the deoxynucleoside-histidine moiety. T-H12-RNase is characterized by complete loss of enzymatic activity; in this form the deoxynucleoside completely blocks the catalytic site and forms intramolecular contacts with residues associated with both the B1 and B2 sites. U-H119-RNase retains 1% of the activity of the unmodified enzyme, and in this form His 119 adopts a different orientation, corresponding to the alternate conformation reported for this residue; the deoxynucleoside-histidine moiety points out of the active site and does not form any contacts with the rest of the protein, thus allowing partial access to the catalytic site. On the basis of these structures, we propose possible mechanisms for the reactions of bromoacetamido nucleosides with ribonuclease A.

Binding Sites↗
PubMed1988

Hepatitis B virus markers and persistent antigenemia in adolescents.

Adolescents attending a municipal outpatient adolescent clinic in New York City were evaluated for the prevalence of hepatitis B virus (HBV) markers and persistent antigenemia. Among 313 teenagers tested in 1 year, 11.8% were HBV marker positive, and 4.8% had persistent antigenemia. Hispanic teens had a marker rate of 6.4% and an antigenemia rate of 1.4%. Dominican Republic teens had a significantly higher marker rate than Puerto Rican teens. Among Hispanics, sexual activity status and foreign- vs. U.S.-born status were not significantly related to the presence of HBV markers. Asian teenagers had a 50% marker rate and a 27.2% rate for persistent antigenemia. Marker and antigenemia rates were highest in the most recent immigrants. Unexplained persistent hematuria occurred more frequently in patients with HBV markers than in patients without markers. We recommend routine hepatitis B surface antigen screening in Hispanic and Asian adolescents. The greatest at-risk groups are Asians, especially recent immigrants, immigrants from the Dominican Republic, and probably patients with unexplained persistent hematuria.

Adolescent↗
PubMed1988

Preoperative combined modality therapy for stage III M0 non-small cell lung carcinoma.

More than 1/3 of all non-small cell lung carcinoma (NSCLC) patients present with locally advanced non-metastatic disease. Despite radiation therapy and surgery the survival of these patients remains poor. In an effort to improve upon these results 33 clinical Stage III M0 patients from April 1985 through September 1986 were entered into a Phase II study at Rush-Presbyterian-St. Luke's Medical Center. Treatment included 5-FU by continuous infusion, VP-16, cisplatin and concurrent split course radiation therapy followed by surgical resection when possible. The overall clinical response rate is 74%. Fifty-seven percent of the preoperative group of patients went to surgery with a 100% resectability rate. These patients had a 50% pathologic complete response with no tumor found in the resected specimen. All surgical margins were free of disease and there were no operative deaths. This concurrent combined modality therapy is feasible with the major toxicities being leukopenia, nausea, and vomiting. With an overall median follow-up of 15 months, 36% of the patients remain alive. Overall local control is 71%. Actuarial observed 2 yr. survival is 33% and the median survival is 15 months. Histologic complete response appears to be an early indicator of the efficacy of this treatment regime. With 83% of the resected pathologic complete responders alive without evidence of disease, this preoperative combined modality therapy offers an appealing approach.

Adenocarcinoma↗
PubMed1988

Phase II trial of therapy with etoposide, 5-fluorouracil by continuous infusion, cisplatin, and simultaneous split-course radiation in stage III non-small cell bronchogenic carcinoma.

Survival of patients who have clinical stage IIIM0 non-small cell bronchogenic carcinoma remains relatively short despite treatment with either surgery or radiation. Results from a phase II study of simultaneous continuous infusion of 5-fluorouracil, cisplatin, and split-course radiation with or without surgery indicate that median survival duration in patients treated with this combined modality approach may be better than the median survival for patients treated with radiation alone. Etoposide has been added to this regimen, and 32 stage IIIM0 non-small cell lung cancer patients have been treated with the 3-drug regimen resulting in a 73% clinical partial remission rate. No residual tumor was found in 6 of 12 patients who had pulmonary resection after 4 courses of chemotherapy and radiation. The sites of failure in 8 patients with recurrent disease are as follows: local only, 3; distant only, 4; and local and distant, 1. The major toxicities have been leukopenia, nausea, and vomiting. The median leukocyte nadir was 2,400/mm3. A leukocyte count less than 1,000/mm3 was observed in 2 patients (7%), 1 of whom died of progressive pneumonia. All patients experienced nausea, vomiting, and anorexia. Severe esophagitis, dermatitis, and pneumonitis were not observed. Survival analysis has not been done because median follow-up time (326 days) is relatively short.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Bilirubin in cerebrospinal fluid: an indicator of blood-brain barrier disruption in asphyxiated rats.

To evaluate the relationship of serum cerebrospinal fluid (CSF) and brain total bilirubin levels in asphyxia, an experiment was designed with 5 to 6-week-old Sprague-Dawley rats. The rats were randomized into control and experimental groups. All rats received intravenously 30 mg/kg of bilirubin. Four hours later the experimental group was asphyxiated. Forty-eight hours after asphyxiation, the bilirubin concentrations in blood, CSF, and brain were measured in both study groups. Mean CSF and brain bilirubin levels were significantly higher in the experimental compared to the control group; however, mean serum bilirubin levels were not different. Moreover, in the experimental group a significant correlation existed between CSF and brain bilirubin concentrations. In conclusion, an asphyxiatic insult resulted in disruption of both the blood-brain and the blood-CSF barriers.

Animals↗
PubMed1984

Sex- and age-related differences in bilirubin concentrations in serum.

The relation between age and sex and the concentration of bilirubin in serum was evaluated in 6740 men and 11 215 women, ages 13 to 96 years. Mean serum bilirubin concentrations in the men significantly exceeded values in the women over all age groups examined. Further, mean serum bilirubin concentrations were greatest both in males and females in the 19-24 years age group and then declined to former values, which persisted throughout life. Pearson correlation coefficients for bilirubin with liver function indices (albumin and total protein) and with hemoglobin were low in all ages and in both sexes, suggesting that bilirubin concentrations do not correlate with those liver functions not directly concerned with bile pigment processing.

Adolescent↗
PubMed1982

Cancer of the gallbladder: a review of forty-three cases.

This study presents the clinicopathologic findings 43 cases of cancer of the gallbladder. Particular attention was paid to the classification of various histologic types along with their distribution by age, sex, race, the presenting symptoms, the presence of gallstones, the occupational history, and the sites of metastases. The most common type was found to be differentiated adenocarcinoma, and the bulk of the cases occurred in elderly white females. Of note was the fact that in 79 per cent of the cases it was possible to identify underlying predisposing circumstances, either cholelithiasis or a positive occupational history. In light of the dismal prognosis associated with this malignant tumor, the identification of such predisposing factors provides an important avenue for the future investigation and prevention of this disease. In addition, in this series, a high rate of multiple primary malignant tumors of different tissues was note. This was attributable to the age and sex distribution of the cases, that is, their being primarily elderly and female. However, this subpopulation of multiple cancers was significantly different with regard to etiologic factors, and this may provide further clues for future preventive measures for this cancer.

Adenocarcinoma↗
PubMed1975

The kinetics and specificity of the reaction of 2'(3')-O-bromoacetyluridine with bovine pancreatic ribonuclease A.

2'(3')-O-Bromoacetyluridine reacts rapidly and selectively with bovine pancreatic ribonuclease A at pH 5.5 and 25 degrees. Under conditions of high molar ratios of nucleoside derivative to enzyme, the only derivative is N-3-carboxymethylhistidine-12 ribonuclease A. The reaction occurs almost exclusively with the histidine-12 residue at the active site inactivation of the enzyme is accompanied by the stoichiometric disappearance of unmodified ribonuclease A and appearance of the product, N-3-carboxymethylhistidine-12 ribonuclease A. Kinetic studies indicate a mechanism involving saturation of the enzyme by the nucleoside derivative. The inhibitor constant, Kb, is 0.087 M and k3 is 35.1 times 10(-4) sec minus 1. The reaction of 2'(3')-O-bromoacetyluridine with the enzyme occurs at a rate approximately 3100 times greater than that corresponding to the reaction with L-histidine. The alkylation reaction is inhibited competitively by uridine with a Ki of 0.013 M. 2'(3')-O-Bromoacetyluridine inactivates ribonuclease A 4.5 times faster than bromoacetic acid and the specificity for alkylation of active-site histidine residues is different. 2'(3')-O-Bromoacetyluridine reacts 1000 times more rapidly with ribonuclease A than iodoacetamide. The contribution of nucleoside binding to the overall rate of alkylation is discussed.

Amino Acids↗