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D Ross

Publications and source records attributed to D Ross.

At least 145 records · Page 8Linked to original sources
PubMed1996

Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and a potential role for modulation of apoptosis in benzene toxicity.

The role of cell-specific metabolism in benzene toxicity was examined in both murine and human bone marrow. Hemopoietic progenitor cells and stromal cells are important control points for regulation of hemopoiesis. We show that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a high peroxidase/nicotanimide adenine dinucleotide phosphate, reduced [NAD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hydroquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 activity in human stromal cultures vary as a function of time in culture, with peroxidase activity decreasing and NQO1 activity increasing with time. Peroxidase activity and, more specifically, myeloperoxidase, which had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34+ progenitor cells. This provides a metabolic mechanism whereby phenolic metabolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Consequences of a high peroxidase/NQO1 ratio in HL-60 cells were shown to include hydroquinone-induced apoptosis. Hydroquinone can also inhibit proteases known to play a role in induction of apoptosis, suggesting that it may be able to inhibit apoptosis induced by other stimuli. Modulation of apoptosis may lead to aberrant hemopoiesis and neoplastic progression. This enzyme-directed approach has identified target cells of the phenolic metabolites of benzene in bone marrow and provided a metabolic basis for benzene-induced toxicity at the level of the progenitor cell in both murine and human bone marrow.

Animals↗
PubMed1996

Autologous breast reconstruction with endoscopic latissimus dorsi musculosubcutaneous flaps in patients choosing breast-conserving therapy: mammographic appearance.

OBJECTIVE: The objective of this study was to define and evaluate mammographic changes in patients treated with breast-conserving therapy and a new reconstructive technique that uses autologous tissue from a latissimus dorsi musculosubcutaneous flap. MATERIALS AND METHODS: Of 20 patients who underwent either immediate or delayed endoscopic latissimus dorsi muscle flap reconstruction after lumpectomy, 13 also had postsurgery mammograms available for review. Radiographic findings assessed included skin thickening, density or radiolucency at the reconstruction site, density around the flap, fat necrosis, calcifications, and the presence of surgical clips. RESULTS: Mammograms for three patients (23%) revealed thickening that we believed was attributable to radiation therapy. No patient had increased density in the flap itself; all flaps were relatively radiolucent centrally (13/13; 100%). Mammograms revealed density around the rim of the flap in four patients (31%). This density was most likely secondary to latissimus dorsi muscle fibers and did not limit radiographic evaluation. One patient had calcifications, probably secondary to fat necrosis. No oil cysts were seen. In the majority of patients (11/13; 85%), surgical clips were visible. CONCLUSION: Endoscopic latissimus dorsi muscle flap reconstruction, previously used only for mastectomy patients, is now being used for improved esthetic outcome in selected patients who desire breast conservation. Our results indicate that the mammographic findings are predictable. The most common findings are relative radiolucency centrally, with or without density from muscle fibers around the edges of the area of tissue transfer. The transplanted musculosubcutaneous flap does not interfere with mammographic evaluation.

Adult↗
PubMed1996

Immortalisation of a human diploid fibroblast cell strain: a DT-diaphorase paradox.

Transfection of a normal human diploid fibroblast cell strain, GM38, with a simian virus 40 (SV40) large T antigen containing plasmid, yielded an immortal cell line, G38-8X, which had a similar sensitivity as the parental cell strain to the quinone-containing chemotherapeutic agent mitomycin C (MMC), under both aerobic and hypoxic exposure conditions. The activity level of DT-diaphorase was similar in both the parental GM38 and G38-8X cells. Although DT-diaphorase could be detected by Western blot analysis, using two mouse anti-human monoclonal antibodies, in GM38 cells, it was not detected in the G38-8X cells. G38-8X cells have a slightly increased P450R activity (2-fold), and have elevated P-glycoprotein levels compared with the parental GM38 cell strain. The immortal G38-8X cell line is 2-fold more resistant to ionising radiation than the parental GM38 cell strain (D10 approximately 5 Gy). Although these SV40 large T antigen immortalised human diploid fibroblasts behaved similarly to their parental cell strain in terms of MMC sensitivity and DT-diaphorase activity, careful characterisation revealed that these cells had enhanced P-glycoprotein activity and had a decreased sensitivity to ionising radiation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Induction of apoptosis by benzene metabolites in HL60 and CD34+ human bone marrow progenitor cells.

Two cell types, HL60 human promyelocytic leukemia cells and CD34+ human bone marrow progenitor cells, were used as model systems to explore a possible role for apoptosis in the myelotoxicity of the phenolic metabolites of benzene. HL60 cells were treated with either phenol, catechol, hydroquinone, or 1,2,4-benzenetriol and then stained with Hoechst 33342 and propidium iodide and subjected to fluorescent microscopy. Cells with nuclear condensation and fragmentation were scored as apoptotic, and etoposide (40 microM) was used as a positive control. Catechol, 1,2,4-benzenetriol, and hydroquinone induced marked time- (0-24 hr) and concentration- (25-100 microM) dependent apoptosis, whereas phenol (750 microM) did not. Under these conditions, no significant necrosis was observed. The induction of apoptosis was confirmed by internucleosomal cleavage of DNA, assessed by agarose gel electrophoresis. CD34+ cells treated with etoposide (40 microM) or hydroquinone (50 microM) for 18 hr were stained and subjected to fluorescent microscopy as above. The percentage of cells exhibiting nuclear condensation and/or fragmentation as well as high intensity staining significantly increased in both cases. The induction of apoptosis was confirmed using a terminal deoxynucleotidyl transferase assay. These data show that apoptosis can be induced in both HL60 and CD34+ human bone marrow progenitor cells by benzene metabolites. The ability of phenolic metabolites of benzene to induce apoptosis in human bone marrow progenitor cells may contribute to benzene myelotoxicity.

Adult↗
PubMed1996

Expression of human NAD(P)H: quinone oxidoreductase (DT-diaphorase) in Chinese hamster ovary cells: effect on the toxicity of antitumor quinones.

Previous studies have indicated that NAD(P)H: quinone oxidoreductase [DT-diaphorase (NQO1)] plays an important role in the bioreductive activation of quinone-containing antitumor agents. Although these studies demonstrated that purified NQO1 can reduce these compounds in vitro, the importance of NQO1 in the intracellular activation of quinone-containing antitumor agents remains controversial. In our study, we transfected human NQO1 into Chinese hamster ovary cells that do not normally express NQO1 activity and obtained stable clones that expressed NQO1 activity of 19-3527 nmol of 2,6-dichlorophenolindophenol reduced/min/mg of protein. The level of NQO1 expression correlated with an increased killing by streptonigrin, EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propen ol), and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone, but mitomycin C sensitivity was independent of this activity. NQO1 expression also led to a slight decrease in the sensitivity of cells to menadione. Our data demonstrate that compounds that are efficient substrates for NQO1 in vitro are also bioactivated in cultured mammalian cells when they are transfected with human NQO1. These results are consistent with the relative abilities of mitomycin C, streptonigrin, EO9, and 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone to serve as substrates for bioreduction by human NQO1, and show that NQO1 levels are not necessarily predictive in terms of sensitivity to mitomycin C.

Animals↗
PubMed1996

The pulmonary autograft: history and basic techniques.

The pulmonary autograft introduced in 1967 evolved from the homograft aortic valve, which had been in place 5 years by the time it showed structural deterioration. The strength of the autograft cusps was an initial anxiety, but clinical and experimental studies have shown that they are well able to withstand aortic pressures. The right side reconstruction has been with homografts, first aortic and later pulmonary. Other forms of reconstruction, including autogenous fascia lata and pericardium, have not been satisfactory. Clinical results have been rewarding and suggest a permanent valve replacement. Additionally, there is accumulating evidence that the autograft will grow in young patients. Most surgeons favor root replacement, but there is some anxiety about possible dilatation of the root. This probably relates to technical inadequacies, but subcoronary and inclusion or cylinder insertion remain valid options. There are few contraindications to the use of an autograft, and it has an increasing application in infective and post prosthetic endocarditis.

Aortic Valve↗
PubMed1995

Role of cytochrome P450 in the metabolism and toxicity of hydroperoxides in isolated rat hepatocytes.

The contributions of cytochromes P450 (P450) to the metabolism and toxicity of hydroperoxides in freshly isolated rat hepatocytes were investigated utilizing 2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone (BHTOOH). This hydroperoxide was rapidly degraded in cell suspensions, and the products were identical to those determined previously with subcellular preparations of ferric P450. With 250 microM BHTOOH, the ratio of glutathione peroxidase-mediated:P450-mediated metabolism was estimated to be about 3:1. Surprisingly, BHTOOH was found to be a more potent cytotoxin than cumyl hydroperoxide (CuOOH), despite the fact that it caused substantially less lipid peroxidation than the latter. P450 inhibition enhanced the toxicity of BHTOOH, but lowered the toxicity of CuOOH. These data demonstrate that intracellular ferric P450 can compete with glutathione peroxidase to reduce hydroperoxides by 1- and 2-electron processes. If the alkoxy radical from homolytic cleavage of the O-O bond can undergo facile intramolecular reactions to nontoxic products, as with BHTOOH, the role of P450 is detoxification. On the other hand, if the alkoxy radical preferentially attacks membrane lipids, as with CuOOH, P450 contributes to lipid peroxidation and toxicity. It was determined that the levels of glutathione, protein thiols, and ATP decreased in parallel with BHTOOH-induced cell death, but no conclusions are possible concerning mechanisms underlying the relatively potent toxicity of BHTOOH. Toxicity may be related to the high lipophilicity of this hydroperoxide which, presumably, facilitates its passage into cells and distribution to various intracellular sites. BHTOOH appears to be an excellent model compound for investigating mechanisms of hydroperoxide-mediated cytotoxicity which do not involve lipid peroxidation.

Animals↗
PubMed1995

Echocardiographic assessment of aortic valve replacement with stentless porcine xenografts.

Stentless porcine xenografts (SPXs) implanted in the aortic position have potential hemodynamic advantages over traditional valve prostheses because of the lack of a rigid stent. Twenty-four patients (mean age 59 years) who underwent aortic valve replacement with SPXs were studied by echocardiography early after and 26 +/- 10 months (range 8 to 40) after operation. Peak and mean gradients, as well as aortic valve area, did not change significantly from baseline (16.3 +/- 8 and 9.8 +/- 5.6 mm Hg, and 1.78 +/- 0.63 cm2, respectively) to follow-up study (12.5 +/- 5 and 7.7 +/- 3 mm Hg, and 1.8 +/- 0.65 cm2, respectively). At baseline, color flow Doppler imaging showed aortic valve regurgitation where the leaflets coapted centrally in 17 of 24 patients (trivial, n = 14; mild, n = 3). Besides the central leak, paravalvular regurgitation was seen in 4 patients (trivial, n = 3; mild, n = 1). At follow-up, 18 of 24 patients had aortic valve regurgitation (trivial, n = 11; mild, n = 6; and moderate, n = 1). New valvular regurgitation (graded as trivial, n = 2; mild, n = 2; and moderate, n = 1) was detected in 5 patients, and new paravalvular regurgitation (graded as mild) developed in 1 patient. Two patients underwent repeat operation for valve-related complications: (1) rupture of a valve cusp with acute pulmonary edema, and (2) fibrotic stenosis of the left coronary ostium with unstable angina. In conclusion, this study demonstrates good hemodynamic performance of the SPX in the aortic position.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Outbreaks of foodborne infectious intestinal disease in England and Wales: 1992 and 1993.

We have analysed data from the surveillance scheme of general foodborne outbreaks of infectious intestinal disease in England and Wales reported to, or otherwise identified by, the PHLS Communicable Disease Surveillance Centre in 1992 and 1993. Data were available about 458 outbreaks, 197 (43%) in commercial catering premises (restaurants, cafés, hotels, public houses, and canteens), 77 (17%) associated with food prepared in private houses, and 58 (13%) in hospitals and residential institutions. Salmonellas and Clostridium perfringens were responsible for 340 outbreaks (74%) and no pathogen was identified in 55 outbreaks (12%). Organisms associated with the highest mean attack rates were Staphylococcus aureus (66%) and C. perfringens (53%). Eleven thousand people were reported to be il and 362 were admitted to hospital. There were 15 deaths, 13 of which were associated with salmonellosis. A specified food was suspected to be the vehicle of infection in 204 outbreaks (45%). Possible contributory factors were identified in 277 (61%), most commonly inappropriate storage, cross contamination, and inadequate heat treatment. Reducing the incidence of food poisoning will depend on concerted action on farms, in abattoirs and food processing plants, in wholesale and retail outlets, and in kitchens.

Disease Outbreaks↗
PubMed1995

Metabolism of 1,3-butadiene to butadiene monoxide in mouse and human bone marrow cells.

1,3-Butadiene (BD), a gas used in the production of rubber and plastics, induces a high incidence of leukemias and lymphomas in B6C3F1 mice. Because of the potential involvement of the hematopoietic system in response to BD, we have examined metabolism of BD by B6C3F1 mouse and human bone marrow and by purified human myeloperoxidase (MPO), an enzyme rich in bone marrow. BD was metabolized to butadiene monoxide (BMO) by MPO and by mouse and human bone marrow cells. In all of these systems metabolism was stimulated by hydrogen peroxide suggesting a peroxidase-mediated process. In B6C3F1 mouse bone marrow cell lysates, hydrogen peroxide but not NADPH stimulated metabolism suggesting that cytochrome P450 was not involved in BMO formation. Metabolism of BD to BMO in hydrogen peroxide-fortified mouse bone marrow cell lysates was more than two orders of magnitude lower than in either NADPH-fortified rat or mouse hepatic microsomes. Experiments using both mouse and human bone marrow cells showed that cells from both sources could generate BMO from BD. These data show that BD can be converted to BMO in a target organ of BD carcinogenicity.

Animals↗
PubMed1995

Noncovalent binding of a mitomycin C metabolite, 2,7-diaminomitosene, to duplex DNA.

The major metabolite of mitomycin C, 2,7-diaminomitosene (DAM), interacts noncovalently with DNA. This was supported by ultraviolet-visible spectrum changes upon mixing with DNA and ethidium bromide displacement from DNA, measured as fluorescence changes. Moreover, DAM bound to DNA sufficiently strongly to hold DNA in a double stranded conformation under denaturing gel electrophoresis conditions commonly used to measure mitomycin C cross-links. These data show that generation of DAM and interaction with DNA represent a potential additional mechanism of DNA damage induced by mitomycin C.

Alkylation↗
PubMed1995

3D laser scanning for image guided stereotactic neurosurgery.

While this work is in its very early stages, the 3D laser scanner shows significant promise as a surgical localization device with advantages over other sensing methods. Accurate 3D surface extraction and matching, a central problem in computer vision, is the key to frameless stereotaxic neurosurgery using this technique.

Brain↗
PubMed1995

Legislation.

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Humans↗
PubMed1995

Defective repair of O6-methylguanine-DNA in primary Sjögren's syndrome patients predisposed to lymphoma.

OBJECTIVE: To investigate a role for mutation in the aetiogenesis of autoimmune disease by examining levels of repairing enzyme for the promutagenic DNA base lesion, O6-methylguanine, in lymphocyte extracts from patients with autoimmune diseases. We included primary Sjögrens syndrome (PSS) patients because of the additional relevance of their being at increased risk (> 40-fold) of developing lymphoma. METHODS: Lymphocytes were prepared from patients with PSS (n = 22) (12 with parotid gland enlargement, an indicator of extensive lymphoproliferation), rheumatoid arthritis (n = 12), primary biliary cirrhosis (n = 11), osteoarthritis (n = 12), and healthy individuals (n = 11). MGMT amounts were determined in lymphocyte extracts by direct enzyme assay and expressed in relation to total extract DNA, protein, or cell number. RESULTS: We found no defect in the repairing methyltransferase enzyme between any of the groups, except in PSS patients at increased risk of developing lymphoma (those with enlarged parotid glands): p < 0.0001 and p = 0.0056, compared with healthy controls and PSS patients without parotid gland swelling, respectively. CONCLUSIONS: Our findings implicate persistence of O6-methylguanine-DNA in the aetiology of lymphoma associated with PSS, and raise the possibility that an alternative repair process for O6-methylguanine-DNA, nucleotide excision repair, might be defective in autoimmune disease.

Aged↗
PubMed1995

Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines.

Bioreductive antitumor quinones require reductive metabolism to produce their cytotoxic effects. A series of these compounds was screened for relative rates of reduction by the two-electron reductase, NAD(P)H:quinone oxidoreductase (DTD). The antitumor quinones streptonigrin (SN), 2,5-diaziridinyl-3-phenyl-1,4-benzoquinone (PDZQ), 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinine (MeDZQ), and [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H-indole-4,7-dione)-propen ol] (EO9) were all excellent substrates for recombinant rat and human DTD. All four compounds were reduced by DTD at least 100 times faster than the clinically important bioreductive alkylating agent, mitomycin C (MC). Reduction of the antitumor quinones was generally 4-5 times more efficient by rat DTD than by human DTD. The exception was EO9, which, surprisingly, was reduced 23 times faster by rat DTD than by human DTD. The rate of reduction of each individual quinone was similar under either aerobic or anaerobic conditions, suggesting that DTD may be an important activating enzyme in the hypoxic fraction of solid tumors. The cytotoxicity of MeDZQ and MC was examined in a panel of human breast and lung cancer cell lines. The data showed good correlations between DTD activity and toxicity for both MeDZQ (r = 0.57, p = 0.054) and MC (r = 0.69, p = 0.020), confirming biochemical data that both compounds are bioactivated by DTD. In addition, IC50 values were in general lower for MeDZQ than for MC in cell lines containing elevated DTD, a finding that was consistent with metabolic data that indicated that MeDZQ was a better substrate for DTD than MC. SR, defined as the ratio of the IC50 value for the H596 NSCLC cell line (undetectable DTD activity) to the IC50 value for the H460 NSCLC cell line (high DTD activity), were determined for all five antitumor quinones. SN was the most selective (SR = 86) followed by EO9 (SR = 62), MeDZQ (SR = 17), and MC (SR = 11). Surprisingly, PDZQ, an excellent substrate for DTD, was toxic to both cell lines (SR = 1.8). These data suggest that antitumor quionones that are substrates for DTD may be selectively toxic to tumors with high DTD activity and may be useful in the treatment of those tumors.

Animals↗