Biomedical subjects

D Ross

Publications and source records attributed to D Ross.

At least 163 records · Page 9Linked to original sources

PubMed1995

Hormonal manipulation and gynaecological cancer: the tamoxifen dilemma.

Tamoxifen has a well established place in the adjuvant therapy of primary carcinoma of the breast. Its effects on breast cancer cells are both anti-oestrogenic and non-oestrogen-receptor mediated. Tamoxifen has oestrogenic effects on non-breast tissues such as liver, bone, the cardiovascular system and the urogenital tract. The effect on the endometrium is to increase the incidence of polyps, hyperplasia and carcinoma. Again, non-oestrogen receptor-mediated actions may be involved. With more widespread use of tamoxifen now being advocated, for instance in the primary prevention of breast cancer, careful assessment of benefit and risk is required.

Breast Neoplasms↗

PubMed1995

Occupational and geographical factors in the epidemiology of malignant mesothelioma.

In most industrialised countries mortality from malignant mesothelioma has risen steeply since about 1950 and is likely to go on doing so well into the next century. This increase, which has lagged behind the level of asbestos use by some 30 or more years, is most evident in men but less clear in women. Amphibole asbestos fibre types, crocidolite in particular, carry the greatest risk and chrysotile the least. Studies in chrysotile miners and millers, in whom the overall frequency of mesothelioma is low suggest the risk is mainly determined by the presence of contamination with amphibole fibres in the tremolite series. There is wide variation in mesothelioma incidence geographically and occupationally. Regions with the highest rates are those where crocidolite is mined; within countries, dockyard areas are most affected, probably because of amphibole use for insulation in naval ships. Occupations at high risk, apart from crocidolite miners and millers, include shipyard and insulation workers and those employed in construction trades. Data on exposure-response are scanty although occupational cohort studies suggest that risk is related to both duration and intensity of exposure. More specific confirmation of an exposure-response relationship has been obtained from lung fibre analysis in a limited number of case-referent studies.

Adult↗

PubMed1994

A role for metals and free radicals in the induction of apoptosis in thymocytes.

Recent reports have implicated a possible but undefined role for reactive oxygen species in the induction and mediation of apoptosis. In the present study, the role of free radicals and metal ions in apoptosis induced in rat thymocytes by dexamethasone and etoposide was examined. Copper chelators, but not iron specific chelators, inhibited apoptosis induced by both these stimuli. Several antioxidants also possessed potent inhibitory effects. We therefore propose that diverse agents may induce apoptosis in thymocytes by a common mechanism involving a copper mediated Fenton reaction, generating site specific hydroxyl radicals, possibly as a result of activation of the redox sensitive transcription factor NF-kappa B.

Animals↗

PubMed1994

Metabolism of bioreductive antitumor compounds by purified rat and human DT-diaphorases.

The metabolisms of two standard electron acceptors and a series of bioreductive antitumor compounds by purified rat and human DT-diaphorases (DTD) were compared. DTD was purified from rat liver cytosol and from Escherichia coli in which rat liver or human lung tumor DTD complementary DNA was expressed. Km and kcat values for menadione and 2,6-dichlorophenolindophenol reduction were similar for the three enzyme preparations except that rat E. coli DTD had 2-3-fold higher kcat values for both menadione and 2,6-dichlorophenolindophenol and a 2-3-fold higher Km for menadione than either rat liver or human E. coli DTD. Reduction of the antitumor compounds was 1.9-4.9 times faster with rat E. coli DTD than with human E. coli DTD. The antitumor compounds were reduced in the following order by rat E. coli DTD: 2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone > streptonigrin > mitomycin A > diaziquone > mitomycin C (MC) > 5-(aziridin-1-yl)-2,4-dinitrobenzamide. The order was the same for human E. coli DTD with one exception; diaziquone was reduced slightly faster than mitomycin A. Metabolism of doxorubicin could not be detected using rat or human E. coli DTD. MC-induced DNA cross-linking was also more efficient using rat E. coli DTD relative to human E. coli DTD. Metabolism of MC by rat and human E. coli DTD was also compared under aerobic and hypoxic conditions. Rates of reduction of MC and metabolite formation were similar under aerobic and hypoxic conditions, and the toxicity of MC to DTD-rich HT-29 cells was also similar in aerobic and hypoxic conditions. In contrast, the toxicity of MC to DTD-deficient BE cells was potentiated markedly under hypoxia. These data show that although small catalytic differences between rat and human E. coli DTD can be observed, compounds such as 2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone and streptonigrin are still excellent substrates for the human enzyme and may be useful in the therapy of tumors high in DTD activity. In addition, metabolism of MC by rat and human E. coli DTD was similar in aerobic and hypoxic conditions; in agreement with these data, cytotoxicity of MC to a DTD-rich cell line was oxygen independent. Increased MC cytotoxicity under hypoxia appears to be mediated by enzymes other than DTD.

Aerobiosis↗

PubMed1994

Defective processing of human adenovirus 2 late transcription unit mRNAs during abortive infections in monkey cells.

Growth of human adenoviruses is severely restricted in monkey cells. We examined the synthesis of mRNAs from the Ad2 late transcription unit (LTU) in abortively infected monkey cells at late times in infection. All L2, L3, and L5 mRNAs were absent or drastically reduced in abortive infections. Most L1 and L4 mRNAs were also greatly decreased in abortive infections; however, a single large messenger was produced from each of the L1 and L4 families, at levels approaching those found in productive infections. The pattern of i-leader containing mRNAs was also changed in abortive infections. These defects could be corrected in monkey cells by the presence of SV40 T antigen or an altered adenoviral DNA binding protein. These defects in late gene expression in abortive infections could not be attributed to differences in transcription along the LTU or levels of DNA replication. In abortively infected cells, nuclear levels of L5 mRNA were decreased 2 to 6 fold, while cytoplasmic levels were decreased over 200-fold. These findings imply a general defect in processing of viral mRNAs, most likely due to defective splicing and/or transport, during abortive infections.

Adenoviruses, Human↗

PubMed1994

Decreased content of the IL1 alpha processing enzyme calpain in murine bone marrow-derived macrophages after treatment with the benzene metabolite hydroquinone.

Benzene is an important industrial chemical known to produce hematotoxicity in mice and humans. Hydroquinone, a major metabolite of benzene, inhibits conversion of the precursor form of IL1 alpha (pre-IL1 alpha) to IL1 alpha in murine bone marrow-derived macrophages in vitro, and a similar effect can be demonstrated in vivo after treatment of mice with benzene. The protease which converts pre-IL1 alpha to IL1 alpha is calpain. We examined decreases in calpain content in bone marrow-derived macrophages as a possible mechanism underlying hydroquinone-induced decreases in pre-IL1 alpha conversion. Hydroquinone, at concentrations which were not overtly cytotoxic, decreased total calpain activity in macrophages by 10-30%. Using immunoblot analysis macrophage calpain II levels were shown to be decreased by approximately 50% after treatment with hydroquinone. Under the same conditions, no changes were observed in calpain I content using immunoblot analysis. These data show that decreased calpain II content represents a potential mechanism of hydroquinone-induced inhibition of pre-IL1 alpha processing, and may contribute to benzene-induced alterations in bone marrow stromal cell function and myelotoxicity.

Animals↗

PubMed1994

Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder.

OBJECTIVE: Previous studies have indicated that patients with panic disorder are more likely than normal subjects to have acute panic attacks during inhalation of CO2, but methodological objections have been raised. In this study the authors attempted to address three of these methodological problems by ensuring that raters who assessed whether panic attacks occurred were blind to subjects' diagnoses, by randomizing the order of administration of 5% CO2 and hyperventilation, and by challenging a greater number of subjects with 7% CO2. METHOD: Patients with panic disorder and normal subjects underwent 20-minute inhalations of 5% CO2 and 7% CO2 and 15 minutes of room-air hyperventilation. Ratings of panic/no panic during each condition were made separately by an assessor blind to diagnosis and by the subject. Scores on four panic rating scales were also recorded before and after each intervention. RESULTS: Room-air hyperventilation caused panic attacks in a small number of patients; the difference in panic rate between patients and comparison subjects was statistically significant by the subjects' but not by the raters' assessment. Panic rates during 5% CO2 and 7% CO2 were significantly greater among the patients by both assessments; the panic rate was greatest during 7% CO2. Order of administration did not significantly affect panic rates for hyperventilation and 5% CO2. CONCLUSIONS: Panic patients were clearly more sensitive to the anxiogenic effects of CO2 than comparison subjects, and CO2 was a more potent anxiogenic stimulus than room-air hyperventilation. Seven percent CO2 discriminated best between patients and comparison subjects and should be the focus of further research.

Administration, Inhalation↗

PubMed1994

Aggressive papillary middle ear tumors: a report of two cases with review of the literature.

Adenomatous tumors of the middle ear are rare, with only approximately 100 cases reported. A distinct subclass of this tumor demonstrates microscopic papillary architecture and has a propensity to erode the petrous bone and extend intracranially. The term "aggressive papillary middle ear tumor" has recently been proposed to describe this more invasive type of middle ear tumor. Thirty-seven cases of aggressive papillary middle ear tumors have been reported. We present two additional cases and discuss the clinical, radiologic, histologic, and operative features of this locally aggressive neoplasm. The tumor affects adults of both sexes. The clinical prodrome is prolonged. Presenting signs and symptoms most often relate to the involvement of cranial nerves V-VIII. Imaging studies reveal large, enhancing, destructive tumors with a generous vascular supply. Intraoperatively, the tumors are bloody, fibrous, and adherent to surrounding structures. Various surgical approaches in combination or in series may be used. Preoperative embolization may be helpful. The role of adjunctive radiation is unclear. Aggressive papillary middle ear tumors are histologically benign tumors with clinically destructive behavior. However, it appears that aggressive surgical management affords prolonged survival with minimal worsening of cranial nerve deficits.

Adenoma↗

PubMed1994

Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies.

Because of the elevated DT-diaphorase (DTD) activity in certain tumors such as human nonsmall cell lung cancer (NCSLC), DTD is a potential target on which to base the development of new antitumor compounds. Mitomycin C is the most effective single agent used for the therapy of NSCLC and is metabolized and bioactivated by DTD. Mitomycin C is a poor substrate for DTD, however, and its metabolism is pH-dependent. We have therefore focused on identifying more efficient substrates for DTD. We have developed a metabolic and cytotoxicity screen that identifies compounds which are efficiently bioactivated by DTD. This screen utilizes both aerobic and hypoxic conditions and cell lines with both elevated and deficient DTD activity as an index of selectivity. Using the screen described above, we have identified [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)-prop-be ta-en- alpha-ol] (E09), 2,5-diaziridinyl-1,4-benzoquinone (MeDZQ), and streptonigrin as compounds that are most efficiently bioactivated by DTD and exert selective cytotoxicity. Although certain tumors such as NSCLC have elevated DTD activity, we have characterized a point mutation at position 609 in the DTD cDNA, which codes for a proline to serine change in the protein and leads to a loss of enzyme activity. We have characterized this mutation in both BE human colon carcinoma cells and H596 human NSCLC cells. This mutation and resulting lack of DTD activity complicates the use of agents designed to target DTD in tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Mitomycin C.

Explore the source record for details and available documents.

Animals↗

PubMed1994

Denton, Brock, and I.

Explore the source record for details and available documents.

Cardiac Surgical Procedures↗

PubMed1994

Peroxidase activity in murine and human hematopoietic progenitor cells: potential relevance to benzene-induced toxicity.

Peroxidases may be important in the mechanism of toxicity of a number of compounds including benzene, a chemical that has been associated with bone marrow toxicity and leukemia after chronic exposure. The major peroxidase in bone marrow is myeloperoxidase (MPO), which has been previously thought to be expressed at the promyelocytic stage of differentiation. Hematopoietic progenitor cells are important potential cellular targets of bone marrow toxins and leukemogens. We therefore examined peroxidase activity in both murine and human progenitor cells. Murine progenitor populations were purified as lineage-negative cells (> 99% enriched) and human progenitor populations were purified as CD34+ cells (> 95% enriched). Using conventional biochemical assays for peroxidase activity, murine and human progenitor cells were found to have 30% and 11% of the peroxidase activity of murine and human unpurified marrow, respectively. Peroxidase activity was confirmed in purified murine and human progenitor populations by flow cytometry using a 2,7-dichlorofluorescein assay, adapted to measure peroxidase activity. In addition, two-color flow cytometry of murine whole marrow using phycoerythrin-conjugated antibodies to lineage markers confirmed the peroxidase activity of the murine progenitor cell population. A reverse transcription-polymerase chain reaction assay was developed for MPO mRNA, which was detected in murine progenitor cells. These data show that MPO mRNA is expressed in murine progenitor cells and that both murine and human progenitor cells have marked peroxidase activity. These data may have relevance for studies of hematopoietic cell differentiation and for the examination of mechanisms underlying cell-specific toxicity in bone marrow.

Animals↗

PubMed1993

Foodborne disease surveillance in England and Wales: 1989-1991.

This review summarises reports of food poisoning, salmonellosis, campylobacteriosis and other acute foodborne illness to the PHLS Communicable Disease Surveillance Centre, and notifications of food poisoning collated by the Office of Population Censuses and Surveys, in the period 1989-1991. During this period there were continuing rises in notifications of food poisoning and reports of salmonellosis and campylobacteriosis. There was considerable success in the control of foodborne listeriosis. Newly emerging pathogens, such as Vero cytotoxin producing Escherichia coli, became more important. There was unprecedented scrutiny of the salmonella data by experts and politicians, reflecting continuing concern over the role of eggs as well as poultry meat in the increase of Salmonella enteritidis phage type 4 infection. This concern, along with advances in information technology, has led to developments in the collection and dissemination of information which continue to be implemented.

Adolescent↗

PubMed1993

Sequence-selective alkylation and cross-linking induced by mitomycin C upon activation by DT-diaphorase.

Aerobic reduction of MMC by DTD, an obligate two-electron reductase, or chemical reduction by sodium borohydride results predominantly in monoalkylation of DNA at the guanine N7 position within 5'-GG-3' and 5'-GTC-3' sequences. The level of guanine N7 alkylation after DTD reduction increased as the pH was decreased from 7.8 and was optimal at pH 6.6. A similar profile of alkylation was obtained when the major metabolite of DTD-mediated MMC metabolism, 2,7-diaminomitosene, was further reduced by DTD. The sequence preference for DNA interstrand cross-linking (ISC) was also determined using singly end-labeled oligonucleotide duplexes. Reduction of MMC by DTD induced DNA cross-links which were resistant to piperidine cleavage. Exposure of cross-linked DNA to dimethyl sulfate or formic acid and subsequent piperidine cleavage displayed a discontinuity in band pattern which suggested a 5'-CG-3' preference for DNA ISC. Major groove alkylation is proposed to occur via generation, and subsequent metabolism by DTD, of 2,7-diaminomitosene. Cross-linking of DNA, at 5'-CG-3' sequences, is proposed to require the formation of either the protonated leucomitomycin C or the leucoaziridinomitosene during DTD-mediated metabolism of MMC.

Aerobiosis↗

PubMed1993

Activity of mouse liver glutathione S-transferases toward trans,trans-muconaldehyde and trans-4-hydroxy-2-nonenal.

This study investigated the catalytic activities of hepatic glutathione S-transferase (GST) isoenzymes isolated from CD-1 mice toward two activated alkenals of toxicological relevance: trans,trans-muconaldehyde (MA), a putative myelotoxic metabolite of benzene, and trans-4-hydroxy-2-nonenal (HNE), a highly reactive lipid peroxidation product. The activity toward 1-chloro-2,4-dinitrobenzene (CDNB) was also determined. Four isoenzymes with pI values of 9.8, 8.7, 6.4, and 5.7 were each isolated from male and female mice. The isoenzymes with pI values of 8.7 and 6.4 are pi and mu class GSTs, respectively, whereas the pI 9.8 and 5.7 GSTs are both alpha class isoenzymes. CDNB activity was greatest in the pi (pI 8.7) isoenzyme of both sexes. In addition, the CDNB activity of the pi (pI 8.7) isoenzyme from males was markedly greater than the corresponding GST from female mouse liver. In contrast to CDNB, both MA and HNE were better substrates for the acidic alpha (pI 5.7) and mu (pI 6.4) GSTs, whereas minimal activity toward either alkenal was detected in the pi (pI 8.7) and alpha (pI 9.8) isoenzymes. Maximum activity toward MA and HNE was exhibited by the alpha (pI 5.7) isoenzyme of both sexes. The level of HNE activity observed with the alpha (pI 5.7) isoenzyme was five- to sixfold greater than that reported previously for any mouse GST isoenzyme. Moreover, the specific activities of the female alpha (pI 5.7) isoenzyme toward both HNE and MA were markedly greater than those of the corresponding isoenzyme from males. A similar gender-specific difference was noted in the activity of the mu (pI 6.4) isoenzyme toward HNE, but not toward MA. These results show that both MA and HNE are substrates for the alpha (pI 5.7) and mu (pI 6.4) GSTs of murine liver, with maximum activity toward both activated alkenals exhibited by the alpha (pI 5.7) isozyme. In addition, evidence is presented that demonstrates a female-dominant sex difference in the activity of the alpha (pI 5.7) isoenzyme toward MA and HNE, which contrasts sharply with the male-dominant activity of pi class GSTs toward CDNB. These results are consistent with the hypothesis that alpha and mu class GSTs are critical detoxication enzymes in female mouse liver, whereas pi-class GST isozymes predominate in the liver of male mice.

Aldehydes↗

PubMed1993

DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C.

A role of DTD in the bioreductive activation of mitomycin C was supported by indirect evidence utilizing enzyme inhibitors in cellular systems. Using a cell-free system, we have confirmed that DTD can bioactivate mitomycin C using both purified rat and human DTD. Metabolism and bioactivation of mitomycin C by DTD is pH-dependent. At pH 7.8 alkylation of DTD leading to enzyme inhibition and DTD crosslinking occurs whereas at pH values of 7.4 and below metabolite formation, preservation of catalytic activity of DTD and sequence-selective DNA crosslinking occurs. Bioactivation of mitomycin C by DTD and the cytotoxicity of this drug in DTD-rich cell lines is oxygen-independent. Mitomycin C induces greater DNA crosslinking, even after chemical reduction, at lower pH values. This suggests that if mitomycin C is used in tumors with elevated DTD activity, greater therapeutic activity may be obtained by lowering intratumoral pH. Human NSCLC has elevated DTD activity relative to SCLC and normal lung and may be a target for the development of drugs which can be efficiently bioactivated by DTD. Because of the pH-dependent inactivation of DTD by mitomycin C, however, other drugs which are efficiently metabolized and bioactivated by DTD may be better candidates for the therapy of tumors high in DTD such as NSCLC.

Animals↗

PubMed1993

Metabolism and cytotoxicity of trans,trans-muconaldehyde and its derivatives: potential markers of benzene ring cleavage reactions.

trans,trans-Muconaldehyde (MA) has been proposed to be a myelotoxic metabolite of benzene, although it has not been isolated from benzene administration in vivo. Since the reactivity and further metabolism of MA may preclude its isolation, we have examined the metabolism of MA by: (a) mixtures of yeast alcohol and aldehyde dehydrogenases, (b) mouse liver cytosol, and (c) isolated rat hepatocytes. In all three systems, MA was metabolized rapidly and the major stable end-product of metabolism was the hydroxy/acid (OH/COOH) derivative of MA. The major route of metabolism involved initial reduction to the hydroxy/aldehyde (OH/CHO) derivative. trans,trans-Muconic acid (COOH/COOH), which is used as a marker of benzene ring cleavage reactions in vivo, was also formed from MA albeit to a much lesser extent compared to the OH/COOH. The thiol reactivity, metabolism, and cytotoxicity of MA and its different redox forms (i.e., OH/OH, OH/CHO, COOH/CHO, COOH/COOH, OH/COOH) were also investigated. MA was found to react most rapidly with reduced glutathione (GSH) in a cell-free system and was also the most cytotoxic to rat hepatocytes. Apart from MA, only the OH/CHO demonstrated GSH-reactivity and cytotoxicity. The OH/CHO was a major initial metabolite in all three systems and, thus, could represent a less reactive but more diffusible derivative of MA. These studies define the metabolism and cytotoxicity of MA and its redox derivatives and suggest that the OH/COOH metabolite of MA may have relevance as a marker of ring cleavage reactions of benzene in vivo.

Alcohol Dehydrogenase↗

PubMed1993

Changes in psychopathology and dyskinesia after neuroleptic withdrawal in a double-blind design.

The goal of this study was to assess the time course of change in psychopathology and dyskinesia after neuroleptic withdrawal. Fifteen DSM-III schizophrenic patients were abruptly withdrawn in a double-blind fashion from stable haloperidol treatment. Weekly ratings of dyskinesia and psychopathology were performed for 4 weeks post-withdrawal. There was an overall increase in dyskinesia ratings over the 4-week period (p < 0.05) beginning in week 2, with dyskinetic movements of the fingers showing the most significant increase (p < 0.001). There were no overall changes in psychopathology, though the group appeared to be bimodal with 6 of the 15 patients showing a significant relapse in psychotic symptoms. Neither baseline TD nor psychotic relapse significantly interacted with change in TD over time. These schizophrenic patients showed an increase in global dyskinesia rating early within four weeks of neuroleptic withdrawal. This time course did not appear to be associated with reemergence of psychopathology which occurred later. A significant minority of patients relapsed within this time period. This suggests the relative safety of brief periods of neuroleptic withdrawal for carefully selected patients in a controlled setting with specific goals (e.g., for evaluation or in preparation for clozapine) and the need to further understand who is at risk for rapid relapse.

Adolescent↗