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Biomedical subjects

J Frank

Publications and source records attributed to J Frank.

At least 343 records · Page 19Linked to original sources
PubMed1985

Phase II trial of cyclophosphamide, doxorubicin, and cisplatin (CAP) versus amsacrine in patients with transitional cell carcinoma of the urinary bladder: a Southwest Oncology Group study.

The combination of cyclophosphamide, doxorubicin, and cisplatin (CAP) was reported to be effective in patients with metastatic transitional cell cancer of the urinary bladder. This study was designed to test the effectiveness of the phase II agent amsacrine (m-AMSA) versus CAP in patients previously untreated with systemic chemotherapy, with crossover if no response occurred or at the time of progression. In 23 patients who were randomized to receive CAP, three achieved complete response, seven achieved partial response, six had stable disease, and seven had disease progression. The responses in the 22 patients who received m-AMSA were: one with complete response, three with partial response, six with stable disease, and 12 with progressive disease. The overall response rate to initial CAP therapy was 43% compared to 19% for initial m-AMSA therapy. The median duration of response to CAP was 28 weeks and to m-AMSA was 21 weeks. There were no statistically significant differences in the durations of response or survival times between the groups. The main side effects of CAP were: nausea and/or vomiting, leukopenia, anemia, thrombocytopenia, and renal toxicity. Leukopenia and anemia were the major toxic effects of m-AMSA. Our study supports the justification for testing phase II agent(s) in previously untreated patients with bladder cancer with systemic chemotherapy, provided adequate crossover to a known active single or combination of agents is built into the design of such a trial.

Aged↗
PubMed1984

Quinoprotein alcohol dehydrogenase from ethanol-grown Pseudomonas aeruginosa.

Cell-free extracts of Pseudomonas aeruginosa strains, grown on ethanol, showed dye-linked alcohol dehydrogenase activities. The enzyme responsible for this activity was purified to homogeneity. It appeared to contain two molecules of pyrroloquinoline quinone per enzyme molecule. In many respects, it resembled other quinoprotein alcohol dehydrogenases (EC 1.1.99.8), having a substrate specificity intermediate between that of methanol dehydrogenases and ethanol dehydrogenases in this group. On the other hand, it also showed dissimilarities: the enzyme was found to be a monomer (Mr 101 000), to need only one molecule of the suicide substrate cyclopropanol to become fully inactivated, and to have a different aromatic amino acid composition.

Alcohol Oxidoreductases↗
PubMed1984

Three-dimensional reconstruction of the 30 S ribosomal subunit from randomly oriented particles.

Electron micrographs show the small (30 S) subunit of Escherichia coli ribosomes lying in a wide range of positions on the specimen support, related by rotation principally around the long axis of the particle. Through correspondence analysis, a multivariate statistical method that distinguishes the major factors accounting for interimage variance, the (aligned) views of the randomly oriented particles were ordered and grouped according to tilt angle. Views so grouped were then averaged and used as input to a three-dimensional reconstruction program. The particle reconstructed from nine averaged projections spanning a 160 degrees rotational range has a resolution of 5 nm in planes perpendicular to the long axis of the particle and approximately 3 nm in the direction of the long axis. It is somewhat asymmetrical and quite compact; its most conspicuous feature is the "platform" that wraps partially around the middle of the subunit.

Escherichia coli↗
PubMed1984

Localization of lipoyl-bearing domains in the alpha-ketoglutarate dehydrogenase multienzyme complex.

The alpha-ketoglutarate dehydrogenase complex from Escherichia coli consists of a core component, dihydrolipoyl transsuccinylase (E2), to which are noncovalently bound 12 polypeptide chains each of alpha-ketoglutarate dehydrogenase and dihydrolipoyl dehydrogenase. E2 exists as a cube-shaped complex comprising 24 identical chains and may be resolved from the other two enzyme components. Limited digestion of E2 with trypsin quantitatively removes domains containing the lipoic acid cofactor while leaving the quaternary structure of the complex intact. Averages of native and trypsin-modified E2 were computed from images of single molecules obtained from electron micrographs of negatively stained specimens. The two averages were very similar and were in general agreement with a model determined previously by X-ray crystallography. However, detailed analysis of the difference image, obtained by subtracting the average of the trypsin-treated E2 from the native E2, showed extra stain-excluding regions along the edges of the native molecule which we interpret as representing the lipoyl-bearing domains. Micrographs of mixtures of native and modified E2 were also analyzed in order to rule out staining or electron-optical artifacts as accounting for the results. On the basis of these results along with other available structural information, we propose that one function of the lipoyl domains is to permit interactions between distantly separated lipoyl moieties in the E2 complex; this proposal also agrees with recent results of modeling studies of biochemical data [Hackert, M.L., Oliver, R.M., & Reed, L.J. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2226-2230].

Acyltransferases↗
PubMed1984

Bovine serum amine oxidase: a mammalian enzyme having covalently bound PQQ as prosthetic group.

In addition to the metal ion, copper-containing amine oxidases possess an organic prosthetic group, the nature of which has long been controversial. We show here that in the case of bovine plasma amine oxidase, this second prosthetic group is covalently bound pyrroloquinoline quinone ( PQQ ). Until now the coenzyme PQQ has been found in several bacterial dehydrogenases. Thus the finding reported here is the first example of a quinoprotein oxidoreductase discovered in a eukaryotic organism.

Amine Oxidase (Copper-Containing)↗
PubMed1984

Inactivation of quinoprotein alcohol dehydrogenases with cyclopropane-derived suicide substrates. .

Quinoprotein alcohol dehydrogenases can be inactivated by cyclopropanol, cyclopropanone hydrate, and, depending on whether they can oxidize secondary alcohols, also by cyclopropanone ethyl hemiketal. Only enzyme molecules containing the oxidized coenzyme (PQQ), but not those with the coenzyme in the semiquinone form (PQQH), become inactivated with these compounds. The inactivation process proceeds without proton production or electron acceptor consumption and free radical is not observed in the inactivated enzyme. It could be demonstrated that a stoichiometric relationship exists between enzyme inactivation, PQQ converted, PQQ adduct formed, and cyclopropanol added. Thus the dimeric and monomeric enzyme become fully inactivated with two and one molecule of cyclopropanol, respectively, indicating that the dimeric enzyme contains two independently acting catalytic sites. Inactivation of the enzyme by cyclopropanol and cyclopropanone hydrate produces chromatographically different PQQ adducts. Since cyclopropanemethanol, cyclobutanol and cyclohexanol are not suicide substrates, the inactivation presumably proceeds via a ring opening such as proposed for the metal-ion-catalysed degradation of cyclopropane derivatives. The results are in accordance with our view on the reaction mechanism of these enzymes but not with that of others [Mincey et al. (1981) Biochemistry 20, 7502-7509]. The reasons why their model has to be refuted are discussed.

Alcohol Oxidoreductases↗
PubMed1984

NAD-dependent, PQQ-containing methanol dehydrogenase: a bacterial dehydrogenase in a multienzyme complex.

Cell-free extracts of methanol-grown Nocardia sp. 239 only show significant dye-linked methanol-oxidizing activity when NAD+ is added to the assay mixture. This activity resides in a multienzyme complex which could be resolved into 3 components, namely the methanol dehydrogenase, NAD-dependent aldehyde dehydrogenase and NADH dehydrogenase. In its dissociated form, the methanol dehydrogenase no longer shows dye reduction and although rises in the absorbance values around 340 nm are seen on addition of methanol plus NAD+ to the enzyme, this is not due to NADH production. However, dye reduction (NAD dependent) could be restored on incubating methanol dehydrogenase with the corresponding NADH dehydrogenase, obtained from the enzyme complex. It is concluded that this novel methanol dehydrogenase transfers the reducing equivalents, derived from methanol, directly to its associated NADH dehydrogenase via a mechanism in which NAD+ and PQQ are involved.

Alcohol Oxidoreductases↗
PubMed1984

Combination chemotherapy plus levamisole in the treatment of disseminated malignant melanoma. A Southwest Oncology Group study.

Two hundred-eighty patients were randomized to receive either BCNU, hydroxyurea and imidazole carboxamide (BHD), BHD plus levamisole, or high-dose DTIC plus actinomycin D. There was no difference in response rate in the three groups (24%, 25% and 22%). Females responded better than males and, as expected, those with a better performance status responded more favorably than those with poor performance status. Patients whose primary site of melanoma was on the extremities did significantly better than those melanomas originating on the trunk or head and neck. Patients with lymphocyte counts greater than 2000/mm3 fared better than those with lymphopenia. Those responders who received high-dose DTIC plus actinomycin D had a significantly longer length of response than those receiving the immunotherapy limb. This was also true in those patients who had a prior disease-free interval of greater than 6 months before being placed in this study. Although there was no difference in survival from the start of treatment in all patients, those patients receiving high-dose DTIC plus actinomycin D and who had a prior disease-free interval of greater than 6 months, had significantly superior survival when compared to the immunotherapy limb. It is concluded that the addition of Levamisole to BHD does not improve response rate and may in certain subsets be detrimental to disease-free response and survival. High-dose DTIC plus actinomycin D is equally effective to BHD.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study.

Over a 24-month period, the Southwest Oncology Group (SWOG) conducted a randomized prospective chemotherapeutic trial in 158 patients with advanced prostatic cancer. Patients were initially randomized to receive either a combination of Adriamycin and cyclophosphamide (AC) or a single agent, hydroxyurea (H), and then crossed over to the other treatment on failure. Of the 137 evaluable patients, 43 (31%) had classically measurable metastatic disease in the lymph nodes, skin, chest, or liver. Focusing their efforts on this subset of patients with measurable disease, the authors of this report found the combination AC to have a superior response rate to the single agent, hydroxyurea. Objective response to AC was seen in 6 of 19 (32%) and in only one of 24 (4%) patients randomized to hydroxyurea (P = 0.06, Fisher's exact test). However, in the larger group of 137 evaluable patients, a survival advantage was not seen for those individuals treated with AC. Failure to demonstrate a survival advantage for an objectively superior drug combination would suggest the need for more active phase II agents in this disease.

Aged↗
PubMed1984

Randomized trial of radiotherapy versus radiotherapy plus metronidazole for the treatment metastatic cancer to brain. A Southwest Oncology Group study.

One hundred sixteen eligible patients with metastatic cancer to the brain were randomized to receive either radiotherapy 3000 rad/10 fractions (treatment 1) or the same radiotherapy plus metronidazole 6 gm/m2 (treatment 2). One hundred eleven patients were either fully or partially evaluable. The response rates (CR + PR) and survival showed no significant differences between treatments. Treatment 1: CR + PR 24%, median survival 14 weeks, Treatment 2: CR + PR 27%, median survival 12 weeks. There were no differences observed in response rates based on primary tumor site, neurologic performance status, or extent of metastatic disease. Metronidazole therapy was associated with substantial nausea and vomiting but no neurotoxicity was observed. Oral metronidazole given every other day during radiation therapy provided no clinical benefit for patients with brain metastases compared to radiotherapy alone.

Age Factors↗
PubMed1984

An electron-nuclear double-resonance study of methanol dehydrogenase and its coenzyme radical.

Proton as well as deuteron ENDOR (electron-nuclear double resonance) spectroscopy were performed of methanol dehydrogenase and pyrrolo-quinoline semiquinone (PQQH). Samples were examined in H2O- and 2H2O-containing buffers at 4.2 degrees K with Ka-band (33.5 GHz) frequency. Measurements of the enzyme in 2H2O revealed that the signals observed around the proton free-precession frequency belong to exchangeable protons. Therefore, our earlier assumption (R. de Beer et al. (1979) J. Chem. Phys. 70, 4491-4495) that these signals originate from protons in the aromatic ring of PQQH is incorrect. The proton matrix signal of the enzyme in H2O and 2H2O are nearly similar, while a deuteron matrix signal is not observed in the latter case. It is concluded, therefore, that the coenzyme is situated in a hydrophobic site of the enzyme.

Alcohol Oxidoreductases↗
PubMed1984

Negative staining characteristics of arrays of mitochondrial pore protein: use of correspondence analysis to classify different staining patterns.

Fourier-filtered images of negatively stained arrays of mitochondrial pore protein have been classified by correspondence analysis of their diffraction patterns. The most significant component of interpattern variation is an isotropic shift in reflection intensities between high- and low-order reflections. This corresponds in the images to the presence or absence of high resolution detail (stain minima). Experimentally the loss of detail in images correlates with the use of highly dissociated heavy metal salts as negative stains. It is proposed that such stains yield poorer negative-contrast images due to electrostatic binding of heavy-metal complex ions to fixed charge groups on the protein. Results with surface-modified protein arrays are consistent with this hypothesis.

Crystallography↗
PubMed1984

Nucleosome mass distribution using image averaging.

Scanning transmission electron microscopy has been used to obtain mass distribution data for unstained, randomly oriented dinucleosomes. These data were then subjected to computer analysis to increase the signal/noise ratio, and define the major sources of image variation within the population. Average images of groups of similar particles have a mass distribution consistent with current models of nucleosome structure, and a resolution approaching 3 nm. The potential value of this method for analyzing structural variants of nucleosomes is discussed.

Animals↗
PubMed1984

Statistical significance of molecule projections by single particle averaging.

A statistical test based on a multiple comparison of Friedman's rank sums has been developed to determine the statistical significance of molecule projections obtained by non-crystallographic averaging techniques. The test, applied to electron microscope images of the acetylcholine receptor molecule, confirms the significance and quoted resolution of averages by Zingsheim et al. (1980, 1982a, b).

Chemical Phenomena↗
PubMed1984

Representation of three-dimensionally reconstructed objects in electron microscopy by surfaces of equal density.

A surface representation algorithm has been developed to visualize the results of three-dimensional reconstructions from projections in electron microscopy. It produces an easily recognizable image of the reconstructed particle and facilitates comprehension of the three-dimensional structure. Thus building of physical models can be avoided in many cases. If such a model is needed the algorithm can be used to establish the correct particle boundary in advance. Some further effort has been made to represent long fibres and visualize inner structures of objects, which are obscured by outer high-density regions. Shading may be used to enhance the depth perception from single views.

Animals↗
PubMed1984

[Results of anorectal manometry for the determination of age- and sex-dependent pressure differences].

Manometric findings in 88 anorectal healthy probands are reported. Basal (PAC) and maximal squeeze (PAC max) pressures in the anal canal as well as rectal pressure at rest (PAR) and the pressure increase in the anal canal after dilatation of the ampulla recti (delta PAC) were registered with a 2 balloon catheter and statistically analysed in the 52 male and 36 female probands, divided in three age groups (group I under 40 years, group II 40-60 years and group III over 60 years). PAC showed for all three groups a statistically significant difference for men and women as well as a statistically significant decrease with age in both sex groups. PAC max, PAR and PAC decreased statistically significantly with age in both sex groups whereas in the three age groups, men and women showed nearly equal values. These age- and sex correlated differences in the anorectal pressure profile must be considered in the evaluation of the continence function.

Adolescent↗