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M T Brown

Publications and source records attributed to M T Brown.

At least 19 recordsLinked to original sources
PubMed1996

Regulation, substrates and functions of src.

Src is the best understood member of a family of 9 tyrosine kinases that regulates cellular responses to extracellular stimuli. Activated mutants of Src are oncogenic. Using Src as an example, and referring to other Src family members where appropriate, this review describes the structure of Src, the functions of the individual domains, the regulation of Src kinase activity in the cell, the selection of substrates, and the biological functions of Src. The review concentrates on developments in the last 6-7 years, and cites data resulting from the isolation and characterization of Src mutants, crystallographic studies of the structures of SH2, SH3 and tyrosine kinase domains, biochemical studies of Src kinase activity and binding properties, and the biology of transgenic and knockout mouse strains.

Amino Acid Sequence↗
PubMed1996

Characterization of human adenovirus proteinase activity in disrupted virus particles.

Virus-coded proteinases are attractive targets for antiviral therapy; however, lack of quick, sensitive, quantitative, and selective assays for enzyme activity makes it difficult to characterize these proteinases and to screen large numbers of potential inhibitors. Here we describe new substrates for the adenovirus proteinase, fluorogenic Rhodamine-based substrates containing tetrapeptides corresponding to sequences cleaved in adenovirus precursor proteins. Proteinase activity in as few as 10(9) disrupted virions could be quantitatively detected in a 30-min assay. With the substrate (Leu-Arg-Gly-Gly-NH)2-Rhodamine, the Km was 1.4 microM and the Vmax was 3.24 pmol substrate hydrolyzed/sec/pmol virus. Enzyme activity was stimulated by dithiothreitol and inhibited by several serine-specific as well as cysteine-specific proteinase inhibitors. In a thiol protection experiment, the virion enzyme was shown to have a cysteine residue with an unusually low pKa, a pKa similar to that of the active-site nucleophile of the cysteine proteinase papain. The curve of Vmax as a function of pH is unlike the curve from papain and implied that there are at least three ionizable groups whose protonation state can affect catalysis - one with a pKa of 6.2, another with a pKa of 7.2, and a third with a pKa of 8.3.

2,2'-Dipyridyl↗
PubMed1996

Characterization of three components of human adenovirus proteinase activity in vitro.

Human adenovirus contains a virion-associated proteinase activity essential for the development of infectious virus. Maximal proteinase activity in vitro had been shown to require three viral components: the L3 23-kDa protein, an 11-amino acid cofactor (pVIc), and the viral DNA. Here, we present a quantitative purification procedure for a recombinant L3 23-kDa protein (recombinant endoproteinase (rEP)) expressed in Escherichia coli and the procedure that led to the purification and identification of pVIc as a cofactor. The cofactors stimulate proteinase activity not by decreasing Km, which changes by no more than 2-fold, but by increasing kcat. rEP alone had a small amount of activity, the kcat of which increased 355-fold with pVIc and 6072-fold with adenovirus serotype 2 (Ad2) DNA as well. Curves of Vmax of rEP.pVIc complexes with the substrate (Leu-Arg-Gly-NH)2-rhodamine as a function of pH in the absence and presence of Ad2 DNA indicate that the pKa values of amino acids that affect catalysis are quite different from those that affect catalysis by the cysteine proteinase papain. The pKa values in the absence of Ad2 DNA are 5.2, 6.4, 6.9, 7.5, and 9.4, and those in its presence are 5.2, 6.5, 7.4, and 8.8.

Adenoviruses, Human↗
PubMed1995

Sequence similarities between the yeast chromosome segregation protein Mif2 and the mammalian centromere protein CENP-C.

A short stretch of strong homology between the Saccharomyces cerevisiae chromosome segregation protein Mif2 and the DNA-binding motifs of the Drosophila D1 and mammalian HMGI(Y) chromosomal proteins suggested that Mif2 may act directly on chromosomes. Because this conserved motif is involved in binding A.T DNA, it was proposed that Mif2 may interact with chromosomes at the highly A + T-rich DNA element found in yeast centromeres. Comparison of the Mif2 amino-acid sequence with sequence databases showed that Mif2 shares at least two regions of similarity with the mammalian centromere protein CENP-C, suggesting an evolutionary conservation of centromere protein function from yeast to mammals. The order, spacing and location of these regions are also similar in the two proteins. Sequence analysis of several conditional lethal alleles of MIF2 generated by random mutagenesis revealed mutations in regions homologous to CENP-C, as well as in the highly conserved A.T DNA-binding motif. A potential phosphorylation site for p34cdc2 kinase located adjacent to the A.T DNA-binding motif was also found to be mutated in one of the mutants, suggesting that phosphorylation at this site may be important for Mif2 function and possibly for DNA binding.

Amino Acid Sequence↗
PubMed1995

Primary central nervous system lymphoma with systemic metastasis: case report and review.

Primary central nervous system lymphoma (PCNSL) almost always remains confined to the nervous system. We report a patient with well documented PCNSL who responded to treatment, but subsequently developed pathologically confirmed systemic metastases without repeated local failure 35 months after initial diagnosis. In a review of the world's literature we identified 5 other cases of PCNSL with histologically confirmed antemortem systemic metastases and a total of 62 cases of central nervous system (CNS) lymphoma in some way associated with extraneural lymphoma. These cases are classified and discussed. Clinicians caring for PCNSL patients must remain alert to the possibility of systemic metastasis, especially as local control of PCNSL improves.

Aged↗
PubMed1994

Prognostic profile in rectal cancer.

PURPOSE: The purpose of this article was to review the prognostic factors of significance in rectal cancer. METHODS: This is a retrospective review of various reports and an examination of our data. RESULTS: Current imaging techniques with endorectal ultrasound, magnetic resonance imaging with a rectal probe, and possibly tagged monoclonal antibodies allow for presurgical assessment of the invasion of the rectal wall and detection of lymph node involvement. CONCLUSIONS: Tumor penetration of the rectal wall and lymph node metastases are the most important prognostic indicators in rectal cancer and predict local and distant recurrences. When lymph node metastases occur, they are more common in small lymph nodes (< 5 mm). Patients with lymph node metastases always need to be considered for multimodality therapy. Tumors larger than or equal to T3 or with associated lymph node metastases should not be treated with sphincter-saving surgical procedures alone.

Biomarkers, Tumor↗
PubMed1994

Cyclophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy.

The activity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of primary central nervous system lymphoma (PCNSL) prior to radiotherapy was studied in six patients. Primary lesions were reduced by 80% or more on contrast-enhancing cross-sectional area in four patients and to a lesser extent in two others after two cycles of chemotherapy. The primary lesion sites demonstrated no contrast enhancement in the three patients who completed four cycles of therapy. However, concurrent with response at the primary disease sites, multiple lesions occurred at distant, noncontiguous CNS parenchymal sites in five patients after two to four cycles of chemotherapy. Median survival was 8.5 months for the six enrolled patients and 16.5 months for the four patients completing craniospinal radiotherapy. PCNSL is highly responsive to standard systemic non-Hodgkin's lymphoma chemotherapy regimens, but the pattern and rapidity of relapse suggest mechanisms of failure including inherent or rapidly evolving antineoplastic drug resistance and perhaps limited drug delivery to occult sites of disease in the brain.

Aged↗
PubMed1993

Chemotherapy for pilocytic astrocytomas.

BACKGROUND: Although pilocytic astrocytomas (PA) generally are considered benign, a subset of patients with PA have disease progression despite standard treatment with surgery and radiation therapy. The authors report their experience with chemotherapy in this patient group. METHODS: The authors treated 11 patients (4 males and 7 females; median age at diagnosis, 8 years) with pathologically confirmed PA with chemotherapy. In eight patients, tumor progression or recurrence despite prior surgery and radiation therapy led to chemotherapy treatment. In three children younger than 5 years, chemotherapy was given in lieu of radiation therapy immediately after diagnosis (in one patient) or at the time of disease progression after surgery (in two patients). The authors used ten different chemotherapy regimens to treat the 11 patients. RESULTS: Chemotherapy produced clinical and radiographic improvement (R/R) in four (36%) patients, clinical stabilization and radiographic improvement (SD/R) in 1 (9%), clinical and radiographic stabilization (SD/SD) in 3 (27%), and was associated with clinical and radiographic progression (PD/PD) in 3 (27%). Three of the five patients with radiographic improvement had a greater than 75% reduction of maximal cross-sectional tumor area. Hematologic toxicity resulted in dose reductions in 43 of 110 (39%) total courses of chemotherapy. There were three hospitals admissions for fever and neutropenia and one chemotherapy-related death. CONCLUSIONS: The authors conclude that chemotherapy may benefit those with progressive inoperable PA. Chemotherapy may delay the need for radiation therapy in young patients with unresectable PA requiring treatment. PA may be a chemosensitive primary brain tumor.

Adolescent↗
PubMed1993

Progressive sensorineural hearing loss in association with distal renal tubular acidosis.

The autosomal recessive inherited syndrome of distal renal tubular acidosis and sensorineural hearing loss may present in one of two distinct fashions. The rare adolescent form is characterized by mild renal tubular acidosis, mild to moderate sensorineural hearing loss, and otherwise normal growth and development. The more common infantile type typically presents in the first year of life with failure to thrive, acidosis, and a more severe sensorineural hearing loss. In this report, progression of sensorineural hearing loss is documented for the first time in two siblings with the infantile variant. This association suggests that all children with distal renal tubular acidosis should undergo sequential audiologic evaluations with the institution of appropriate amplification and educational intervention as needed.

Acidosis, Renal Tubular↗
PubMed1993

MIF2 is required for mitotic spindle integrity during anaphase spindle elongation in Saccharomyces cerevisiae.

The function of the essential MIF2 gene in the Saccharomyces cerevisiae cell cycle was examined by overepressing or creating a deficit of MIF2 gene product. When MIF2 was overexpressed, chromosomes missegregated during mitosis and cells accumulated in the G2 and M phases of the cell cycle. Temperature sensitive mutants isolated by in vitro mutagenesis delayed cell cycle progression when grown at the restrictive temperature, accumulated as large budded cells that had completed DNA replication but not chromosome segregation, and lost viability as they passed through mitosis. Mutant cells also showed increased levels of mitotic chromosome loss, supersensitivity to the microtubule destabilizing drug MBC, and morphologically aberrant spindles. mif2 mutant spindles arrested development immediately before anaphase spindle elongation, and then frequently broke apart into two disconnected short half spindles with misoriented spindle pole bodies. These findings indicate that MIF2 is required for structural integrity of the spindle during anaphase spindle elongation. The deduced Mif2 protein sequence shared no extensive homologies with previously identified proteins but did contain a short region of homology to a motif involved in binding AT rich DNA by the Drosophila D1 and mammalian HMGI chromosomal proteins.

Alleles↗
PubMed1993

Pilocytic astrocytoma: correlation between the initial imaging features and clinical aggressiveness.

OBJECTIVE: Astrocytomas are classified as either fibrillary or pilocytic on the basis of their histologic appearance. The imaging features of the fibrillary astrocytoma correlate closely with the tumor's clinical aggressiveness and are, therefore, useful in predicting prognosis. Correlation between the imaging features and the clinical aggressiveness of the pilocytic astrocytoma, however, is not well established. Accordingly, we compared the initial MR and CT appearances of the lesion with tumor aggressiveness as seen clinically to determine if a correlation exists. MATERIALS AND METHODS: We retrospectively evaluated the initial MR images or CT scans of 32 consecutive patients who had a histologic diagnosis of pilocytic astrocytoma. The lesions were evaluated with regard to location, size, calcification, morphology, and degree of contrast enhancement. These initial imaging features were correlated with the aggressiveness of the tumor as seen clinically. Tumors were classified as aggressive or nonaggressive on the basis of their clinical manifestations. Patients with clinically aggressive lesions had progressive symptoms and radiologic evidence of tumor progression or recurrence within an unusually short period. Patients with clinically nonaggressive lesions had a more indolent course, either improving or remaining stable, on both clinical and radiologic evaluations. In 12 patients, the tumor was classified as aggressive clinically, either progressing or recurring within a median time of 7.5 months (range, 2.5-118 months) from the initial diagnosis. The remaining 20 patients had a clinically nonaggressive course. RESULTS: In our series of patients, lesion size and location were not significantly different between the nonaggressive and aggressive tumors, as noted clinically. Furthermore, the aggressive and nonaggressive tumors were similar with regard to the presence or absence of calcium. Most tumors in both groups showed either moderate or marked enhancement and were multilobular. CONCLUSION: The initial CT and MR features of pilocytic astrocytoma are unreliable for predicting which lesions will behave in a more aggressive manner clinically and have a poor prognosis.

Adolescent↗
PubMed1987

Ultrasound findings in children with cystic fibrosis.

The results of a prospective study using ultrasound to assess abdominal complications in 76 children with proven cystic fibrosis are reported. Fifty-six patients (74%) had normal liver ultrasound scans. The most striking abnormality was an irregular, inferior edge to the liver occurring in 85% of abnormal liver scans and in 70% there was corresponding clinical and biochemical evidence of abnormal liver function. This finding has been only briefly mentioned before. Increased reflectivity in abnormalities of the pancreas and gallbladder is also described.

Adolescent↗