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Biomedical subjects

H A Hill

Publications and source records attributed to H A Hill.

At least 19 recordsLinked to original sources
PubMed1995

Determinants of black/white differences in colon cancer survival.

BACKGROUND: Blacks have lower survival rates for colon cancer than whites, possibly related to more advanced stages of disease at diagnosis and to socioeconomic differences between blacks and whites. While the black/white difference in colon cancer survival is well documented, the few studies that have investigated this difference have been limited by the modest number and type of explanatory factors that were considered. PURPOSE: We analyzed data from the National Cancer Institute Black/White Cancer Survival Study to determine 1) what characteristics might contribute to the racial difference in colon cancer survival and 2) if a survival disparity remained between black and white patients after adjustment was made for these characteristics. METHODS: This prospective study included 454 blacks and a stratified random sample of 521 whites, aged 20-79 years, with cancer of the colon diagnosed from January 1, 1985, through December 31, 1986, and who were residents of the metropolitan areas of Atlanta, New Orleans, and San Francisco/Oakland. Follow-up was truncated on December 31, 1990. Cox proportional hazards regression was used to estimate the death rate among blacks relative to that among whites after adjustment for potential explanatory factors, including sociodemographic factors, concurrent (comorbid) medical conditions, stage at diagnosis, tumor characteristics, and treatment. All P values were calculated from two-tailed tests of statistical significance. RESULTS: After adjustment for age, sex, and geographic area, the black-to-white mortality hazard ratio (HR) was 1.5 (95% confidence interval [CI] = 1.2-1.9), indicating that the risk of death among black patients was 50% higher than that among white patients. Further adjustment for stage reduced the excess cancer mortality to 20% (HR = 1.2; 95% CI = 1.0-1.5), decreasing the overall racial difference in excess mortality from 50% to 20% or to a 60% reduction in excess mortality. Although adjustment for poverty reduced the excess mortality by 20%, adjusting for both stage and poverty did not further reduce the racial difference. Among patients with stages II and III disease, blacks had lower survival rates than whites (HR = 1.8; 95% CI = 1.0-3.1 and HR - 1.5; 95% CI = 1.0-2.3, respectively). Among those patients with metastatic disease (stage IV), survival was similar for whites and blacks. CONCLUSIONS: Stage at diagnosis accounted for more than half of the excess colon cancer mortality observed among blacks. Poverty and other socioeconomic conditions, general health status, tumor characteristics, and general patterns of treatment did not further explain the remaining survival disadvantage among blacks. IMPLICATIONS: Because the racial disparity was confined to earlier stages, future studies should investigate whether blacks have more advanced disease at diagnosis and whether less aggressive treatment is provided because of understanding.

Adult↗
PubMed1995

Racial differences in tumor grade among women with endometrial cancer.

Black women with endometrial cancer have more advanced disease and less favorable tumor grade than do white women. This study evaluated whether racial differences in tumor grade could be explained by hormone-related factors and other putative determinants of grade. Subjects included 207 white and 81 black postmenopausal women diagnosed with primary cancer of the uterine corpus between 1985 and 1987. Blacks had poorer tumor grade than whites (odds ratio for FIGO grade 2 versus grade 1 is 1.8; odds ratio for grade 3 versus grade 1 is 2.8). Over 75% of the excess of poorly differentiated tumors versus well-differentiated tumors among blacks could be explained by racial differences in use of replacement estrogens, age at first pregnancy, history of oophorectomy, poverty, stage of disease, use of screening, and access to health care. The most prominent factor was estrogen therapy, which was associated with favorable tumor grade and was used much less frequently by blacks. Although not statistically significant, a moderate racial difference in tumor grade remained after control of the potential explanatory explanatory variables. This may reflect true biologic variation between blacks and whites and may explain, in part, the observation that blacks with endometrial cancer have a worse prognosis.

Black or African American↗
PubMed1995

Endometrial cancer: stage at diagnosis and associated factors in black and white patients.

OBJECTIVE: This study examined the relationship of clinicopathologic, health status, medical system, and socioeconomic factors to differences in stage at diagnosis of endometrial cancer in black and white patients. STUDY DESIGN: A population-based study of 130 black and 329 white patients with invasive endometrial cancer was conducted as part of the National Cancer Institute's Black/White Cancer Survival Study. Logistic regression was used to determine the relative importance of factors thought to be related to stage at diagnosis after age and geographic location were adjusted for. RESULTS: High-grade (poorly differentiated) lesions increased the risk for stage III or IV disease (odds ratio 8.3, 95% confidence interval 3.4 to 20.3), as did serous histologic subtype (odds ratio 3.5, 95% confidence interval 1.4 to 8.8) and no usual source of care (odds ratio 5.5, 95% confidence interval 1.4 to 20.9). In the final statistical model these three factors also accounted for the majority of the excess risk of advanced stage for blacks. CONCLUSIONS: Black-white racial disparities in stage at diagnosis appear to be related to higher-grade lesions and more aggressive histologic subtypes occurring more frequently in black patients with endometrial cancer.

Adult↗
PubMed1994

Kinetics of the reduction of wild-type and mutant cytochrome c-550 by methylamine dehydrogenase and amicyanin from Thiobacillus versutus.

To elucidate the kinetic properties of the methylamine dehydrogenase (MADH) redox chain of Thiobacillus versutus the reduction of cytochrome c-550 by MADH and amicyanin has been studied. Under steady state conditions, the rate constants of the reactions have been determined as a function of the ionic strength, both for wild type cytochrome c-550 and for mutants in which the conserved residue Lys14 has been replaced as follows: Lys14-->Gln (mutant [K14Q]cytochrome c-550) and Lys14-->Glu (mutant [K14E]cytochrome c-550). The second-order rate constant of the reduction of cytochrome c-550 by MADH shows a biphasic ionic-strength dependence. At low ionic strength the rate constant remains unchanged (wild type) or increases ([K14Q]cytochrome c-550) with increasing ionic strength, while at high salt concentrations the rate constant decreases monotonically as the ionic strength increases. It is suggested that conformational freedom exists in the association complex and that this is favourable for electron transfer. [K14Q]cytochrome c-550 and [K14E]cytochrome c-550 are reduced at rates 20-fold and 500-fold slower than wild-type cytochrome c-550 by MADH, due to a lower association constant. It is concluded that MADH possesses a negative patch with which cytochrome c-550 associates. Lys14 plays an important role in the formation of the reaction complex. The midpoint potentials of wild-type and mutant cytochrome c-550 have been determined by using cyclic voltammetry. [K14Q]cytochrome c-550 and [K14E]cytochrome c-550 show an increase in E0 of only 2 mV and 8 mV, respectively, compared to wild-type cytochrome c-550 (241 mV at pH 8.1). [K14Q]cytochrome c-550 and [K14E]cytochrome c-550 cytochrome c-550 are reduced by amicyanin at rates that are only slightly faster than for wild-type cytochrome c-550. The difference is partly attributable to the change in E0. High ionic strength results in a threefold increase in the rate in all three cases. These results indicate that charge interactions do not play a major role in the formation of the amicyanin/cytochrome c-550 reaction complex, suggesting an interaction at the hydrophobic patch of amicyanin. The reduction of cytochrome c-550 by MADH can be inhibited by Zn(2+)-substituted amicyanin. Ag(+)-amicyanin, however, has little effect on the reduction rate. These results suggest that MADH has a much higher affinity for Cu(2+)-amicyanin (substrate) than for Cu(+)-amicyanin (product). On the basis of these findings the roles of the components of the MADH redox chain are discussed.

Amino Acid Sequence↗
PubMed1991

Direct electrochemistry of proteins. Investigations of yeast cytochrome c mutants and their complexes with cytochrome b5.

Direct electrochemistry of site-specific mutants of yeast iso-1-cytochrome c (cyt c) and their complexes with bovine cytochrome b5 (cyt b5) has been investigated at edge-plane pyrolytic graphite (EPG) and bis(4-pyridyl)-disulphide-modified gold electrodes. Structure/function relationships have been investigated with the particular aim of clarifying the factors controlling the interactions of proteins at electrode/electrolyte interfaces and the determinants for direct electrochemistry in ternary protein/protein/electrode adducts, e.g. cyt c/cyt b5/EPG. Investigations of the cyt c mutants alone revealed a variety of electrochemical responses: all the mutants show similar voltammetric reversibility at modified gold electrodes, whereas at EPG electrodes the reversibility follows the order: Asn52Ile-Cys102Thr greater than Cys102Thr greater than Asn52Ala-Cys102Thr. Mid-point potentials follow the order: Arg13Ile (+60 +/- 5 mV vs. standard calomel electrode) greater than Cys102Thr (+40 +/- 5 mV) greater than Lys27Gln (+30 +/- 5 mV) approximately Lys72Asp (+30 +/- 5 mV) greater than Asn52Ala-Cys102Thr (+15 +/- 5 mV) greater than Asn52Ile-Cys102Thr (-10 +/- 5 mV). The structural basis for these differences is briefly discussed. When these mutants are bound to cyt b5, the differences in electrochemical response are greatly enhanced in the ternary cyt c/cyt b5/EPG adducts. A minimal analysis of these differences supports a model of multiple overlapping binding and recognition domains on cyt c which may be finely tuned to allow ternary complex formation so that a single-site variation could modify or abolish direct electrochemistry in the ternary adduct.

Animals↗
PubMed1991

Subunit interactions change the heme active-site geometry in p-cresol methylhydroxylase.

The enzyme p-cresol methylhydroxylase [4-cresol: (acceptor) oxidoreductase (methyl-hydroxylating), EC 1.17.99.1] contains two subunits: a cytochrome c (electron transfer) subunit (cytochrome cpc) and a flavin (catalytic) subunit. When these subunits are separated by isoelectric focusing, a stable cytochrome subunit is obtained. Significant differences are observed between the one-dimensional NMR spectra of oxidized cytochrome cpc and of oxidized p-cresol methylhydroxylase. Analysis of the two-dimensional nuclear Overhauser enhancement and exchange spectroscopy (NOESY) spectrum of reduced cytochrome cpc suggests that the axial ligand, Met-50, of the stable subunit reorients by a rotation about the C gamma-S delta bond when cytochrome cpc binds to the flavin subunit. This reorientation must result in a change in bonding at the heme, which is reflected both in the para-magnetically shifted resonances and in the redox potential. p-Cresol methylhydroxylase thereby provides an interesting example of the coupling of subunit interactions to active-site structure and reactivity.

Allosteric Regulation↗
PubMed1991

Direct electrochemistry of two genetically distinct flavodoxins isolated from Azotobacter chroococcum grown under nitrogen-fixing conditions.

Two genetically distinct flavodoxins, designated AcFldA and AcFldB, were isolated from Azotobacter chroococcum (MCD1155) grown under nitrogen-fixing conditions. AcFldA and AcFldB differ in their midpoint potentials for the semiquinone-hydroquinone couple (Em -305 mV and -520 mV respectively). Only AcFldB was competent to act as an electron donor to the Mo-containing nitrogenase of A. chroococcum. The N-terminal amino acid sequence (20 residues) of AcFldB was identical with that predicted from the nifF DNA sequence of A. vinelandii OP [Bennett, Jacobsen & Dean (1988) J. Biol. Chem. 263, 1364-1369], suggesting that AcFldB is the nifF gene product of A. chroococcum (MCD1155). Direct fast reversible electrochemistry of these flavodoxins has been achieved at a polished edge-plane graphite electrode using the aminoglycoside neomycin as a promoter. The heterogeneous rates of electron transfer between the graphite electrode and AcFldA and AcFldB were determined to be 1.2 x 10(-3) cm.s-1 and 2.0 x 10(-3) cm.s-1 respectively. The natures of two minor species of flavodoxin designated AcFldC and AcFldD, which were resolved by f.p.l.c., are also discussed.

Amino Acid Sequence↗
PubMed1991

Direct electrochemistry of the enzyme, methylamine dehydrogenase, from bacterium W3A1.

The electrochemical response of methylamine dehydrogenase from bacterium W3A1 at edge-plane-oriented pyrolytic graphite (epg) and modified gold electrodes has been investigated. Quasi-reversible electron transfer has been observed. Variations in concentration of different cations and anions gave rise to both promotion and inhibition of the direct response. A catalytic response of the enzyme in the presence of methylamine has been observed at both an epg electrode and a 2,2'-dithiodiglycolic-acid-modified gold electrode surface, and the effects of various cations and anions on the catalytic peak current have been investigated. The spectroelectrochemical results obtained at an optically transparent thin-layer electrode, modified with 2,2'-dithiodiglycolic acid, are also reported. In the presence of 1,1'-dimethylferrocene-3-(1-ethanol-2-amine) (14.8 microM), the results reveal a midpoint potential of -148 mV for methylamine dehydrogenase from bacterium W3A1. This is in very close agreement to the value obtained in the cyclic voltammetric investigations of -140 mV.

Anions↗
PubMed1990

Evidence for fast and discriminatory electron transfer of proteins at modified gold electrodes.

The electrochemistry of the redox proteins, cytochrome c, cytochrome b5, plastocyanin and ferredoxin at modified gold electrodes has been examined on the basis that electron transfer takes place at electroactive sites which are microscopic in size. Using this model, it is now proposed that electrochemistry of these proteins occurs at suitably modified sites with fast rates at potentials near the standard redox potential. The microscopic model implies that redox proteins and enzymes take part in fast electron transfer at specific sites on the electrode, other sites being completely ineffective. This form of molecular recognition, i.e. the ability to discriminate between the different sites on an electrode surface, mimics homogeneous redox reactions wherein redox active proteins 'recognize' their biological partners in a very specific sense. Previously, protein electrochemistry has been interpreted via use of a macroscopic model in which the proteins are transported to the electrode surface by linear diffusion followed by quasi-reversible or irreversible electron transfer to the electrode surface. The microscopic model, which assumes that the movement of the protein occurs predominantly by radial diffusion to very small sites, would appear to explain the data more satisfactorily and be consistent with biologically important, homogeneous redox reactions which are known to be fast.

Cytochrome c Group↗
PubMed1990

Electron transfer reactions of metalloproteins at peptide-modified gold electrodes.

The electron transfer reactions of four small redox proteins, cytochrome c. ferredoxin, plastocyanin and azurin, have been investigated at novel peptide-modified gold electrodes. These proved to be effective and selective in facilitating electron transfer. Good, quasi-reversible electron transfer was achieved selectively at different peptide-protein configurations by changing the pH or the ionic strength of the solution. The use of peptides as promoters for protein electrochemistry opens up the possibility of designing very specific electrode surfaces for larger molecules like enzymes.

Azurin↗
PubMed1990

Direct electrochemistry of protein-protein complexes involving cytochrome c, cytochrome b5, and plastocyanin.

The direct electrochemistry of the cytochrome c/cytochrome b5 and cytochrome c/plastocyanin complexes has been investigated at edge-plane graphite and modified gold electrode surfaces, which are selective for one of the two components of the complex. Electrochemical response of one protein at an otherwise electrostatically unfavorable electrode surface was achieved in the presence of the other protein, and the calculated heterogeneous electron-transfer rate constant and diffusion coefficient were found to be in good agreement with the values determined previously from the electrochemistry of the individual proteins [Armstrong, F. A., Hill, H. A. O., & Walton, N. J. (1988) Acc. Chem. Res. 21, 407 and references therein]. A dynamic model of the protein-protein-electrode ternary complex is proposed to explain the promotion effect, and this model is supported by a study comparing the electrochemical responses of covalent and electrostatic cytochrome c/plastocyanin complexes. It is also suggested that the behavior of protein-protein complexes at electrode surfaces could be related to that of the complexes associated with biological membranes.

Cytochrome c Group↗
PubMed1990

The complex formed between plastocyanin and cytochrome c. Investigation by NMR spectroscopy.

Spinach plastocyanin and horse heart cytochrome c have been shown, by monitoring the behaviour of the hyperfine-shifted heme resonances of Fe(III) cytochrome c on titration with Cu(II) plastocyanin, to form a 1:1 complex with a dissociation constant of 67 mM (D2O, pH* 7.0, 300 K). The interaction sites on the plastocyanin surface have been investigated in one- and two-dimensional NMR experiments involving competition for plastocyanin between cytochrome c and the paramagnetic cation Cr(NH3)(3+)6. The plastocyanin resonances which are paramagnetically broadened in the spectrum of plastocyanin alone are also broadened in the spectrum of the mixture of the two proteins. This shows that, on the NMR time scale, no plastocyanin residues are hidden from Cr(NH3)(3+)6 by complexation with cytochrome c. [It has been shown that Cr(NH3)(3+)6 does not disrupt formation of the complex between the two proteins.] It appears that initial complexation of cytochrome c takes place at the acidic east site of plastocyanin, and that the extensive negative electrostatic surface of plastocyanin accommodates the paramagnetic probe and cytochrome c simultaneously in a dynamic ternary complex. The location of the electron transfer site on plastocyanin is discussed.

Animals↗
PubMed1990

Direct voltammetry of the Chromatium vinosum enzyme, sulfide:cytochrome c oxidoreductase (flavocytochrome c552).

The electrochemistry of the enzyme, sulfide:cytochrome c oxidoreductase, also known as flavocytochrome c552 from the purple sulfur bacterium, Chromatium vinosum, has been studied using several modified electrodes. Direct electron transfer between the heme of the flavocytochrome and an electrode is observed in the presence of a redox-inactive cationic species which promotes the voltammetry of the enzyme. Quasi-reversible electron transfer was achieved using the aminoglycoside, neomycin, as a promoter at either a modified gold or polished edge-plane graphite electrode. Further evidence for direct electron transfer is provided by the catalytic response of the enzyme at the electrode in the presence of substrate. Also reported is the direct spectroelectrochemistry of flavocytochrome c552 at an optically transparent thin layer gold electrode modified with Cys-Glu-Cys in the presence of neomycin.

Chromatium↗
PubMed1988

Direct and indirect electron transfer between electrodes and redox proteins.

The direct electrochemistry of redox proteins has been achieved at a variety of electrodes, including modified gold, pyrolytic graphite and metal oxides. Careful design of electrode surfaces and electrolyte conditions are required for the attainment of rapid and reversible protein-electrode interaction. The electron transfer reactions of more complex systems, such as redox enzymes, are now being examined. The 'well-behaved' electrochemistry of redox proteins can be usefully exploited by coupling the electrode reaction to enzymes for which the redox proteins act as cofactors. In systems where direct electron transfer is very slow, small electron carriers, or mediators, may be employed to enhance the rate of electron exchange with the electrode. The organometallic compound ferrocene and its derivatives have proved particularly effective in this role. A new generation of electrochemical biosensors employs ferrocene derivatives as mediators.

Electrodes↗
PubMed1988

Direct electrochemical probes of redox protein and redox enzyme structure and function.

The direct electrochemistry of redox proteins has been achieved at a variety of electrodes, including modified gold and pyrolytic graphite. Careful design of electrode surfaces and electrolyte conditions are required for the attainment of rapid and reversible protein-electrode interaction. Protein-protein complexes can be studied by using selective electrode surfaces. The "well-behaved" electrochemistry of redox proteins can be exploited by coupling the electrode reaction to enzymes for which the redox proteins act as cofactors. The electron-transfer reactions of more complex systems, such as redox enzymes, are now being examined.

Cytochromes↗
PubMed1987

1H-NMR sequential assignments and cation-binding studies of spinach plastocyanin.

The essentially complete assignment of the 1H-NMR spectrum of the Cu(i) form of spinach plastocyanin has been achieved using two-dimensional NMR techniques and sequence-specific resonance assignment procedures. A variety of pH and temperature conditions was utilised to overcome the problems of resonance overlap in the spectrum, degeneracy of C alpha H and solvent H2O chemical shifts, and cross-saturation of labile NH resonances. A qualitative analysis of the long-range nuclear Overhauser effects observed indicates that the backbone fold of spinach plastocyanin is very similar to that of poplar plastocyanin, whose structure has been solved by X-ray crystallography and differs in 22 of its 99 amino acid residues. The assignments provide a basis for further investigations into the structural and ion- and protein-binding properties of plastocyanin in solution.

Binding Sites↗
PubMed1987

Electron-transfer biosensors.

The electrochemistry of redox proteins is now well established. Conditions exist which allow electron-transfer reactions of all simple proteins to proceed rapidly and reversibly at electrodes. Coupling of the electrode reaction to enzymes, for which the redox proteins act as cofactors, allows exploitation of this good electrochemistry. This is well illustrated by the enzyme-catalysed electrochemical oxidation of p-cresol to p-hydroxybenzaldehyde, which has been shown to proceed along with coupling to the electrode via the copper protein, azurin, or the organometallic compound ferroceneboronic acid. Ferrocene derivatives, in general, show a degree of versatility, coupling the electron-transfer reactions of many enzymes. Thus derivatives of the ferricinium ion act as excellent electron-transfer reagents from the enzyme glucose oxidase. The system is capable of detecting glucose in blood. Similar procedures, in conjunction with the appropriate enzyme, have yielded assays for, among others, H2O2 and cholesterol.

Biotechnology↗