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41.
Abril N; Luque-Romero FL; Prieto-Alamo MJ; Rafferty JA; Margison GP; Pueyo C 《Carcinogenesis》1997,18(10):1883-1888
Here we confirm and extend our previous studies demonstrating that the
mutagenic potency of 1,2-dibromoethane (DBE) and dibromomethane (DBM) is
markedly enhanced (not prevented) in bacteria expressing the O6-
alkylguanine-DNA alkyltransferase (ATase) encoded by the Escherichia coli
ogt gene. We demonstrate that, in close parallel with mutagenesis, the Ogt
ATase sensitizes the bacteria to the lethal effects of these carcinogens,
suggesting that one or more of the potentially mutagenic lesions induced by
DBE and DBM in the presence of Ogt has additional lethal capacity. We
further demonstrate that the sensitization to both lethality and
mutagenesis by DBE and DBM is a property shared by other DNA
alkyltransferases. This objective was accomplished by quantifying the
induction of mutations and lethal events in ogt- ada- E. coli expressing an
exogenous bacterial or mammalian ATase from a multicopy plasmid. Mammalian
recombinant ATases enhanced the lethal and mutagenic actions of DBE and
suppressed the lack of sensitivity of the vector- transformed bacteria to
DBM. In most cases the order of effectiveness of the ATases ranked: murine
> human > Ogt > rat. Further comparisons included the full-length
Ada ATase from E. coli and a truncated Ada version (T-ada) that retains the
O6-methylguanine binding domain of the protein. The full-length Ada ATase
was effective in enhancing the lethality but not the mutagenicity induced
by DBE and DBM. The T-ada ATase provided less sensitization than Ada to
lethality by DBE, but of the three bacterial ATases T-ada yielded the
highest sensitization to mutagenesis by this compound. T-ada and Ada ATases
were in general less effective than the mammalian versions, with the
exception of the rat recombinant ATase. The effectiveness of the different
mammalian and bacterial ATases in promoting the deleterious actions of
dibromoalkanes was compared with the effectiveness of these proteins in
suppressing the lethal and mutagenic effects induced by
N-nitroso-N-methylurea. The ability to sensitize E. coli to the lethal and
mutagenic effects of DBE and DBM seems restricted to DNA alkyltransferase,
since overexpression of thioredoxin (Trx) or glutaredoxin (Grx1) in ogt-
ada- cells showed no effect, in spite of the reported potential of
bioactive dihaloethane- derived species to alkylate Trx.
相似文献
42.
Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung 总被引:1,自引:0,他引:1
Prahalad AK; Ross JA; Nelson GB; Roop BC; King LC; Nesnow S; Mass MJ 《Carcinogenesis》1997,18(10):1955-1963
Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic
hydrocarbon, is the most potent carcinogen ever tested in mouse skin and
rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction,
tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in
strain A/J mouse lung. Groups of mice received a single i.p. injection of
0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment,
DNA adducts were measured at times between 1 and 28 days, while tumors were
counted at 250 days and analyzed for the occurrence of point mutations in
codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung
induced six major and four minor DNA adducts. Maximal levels of adduction
occurred between 5 and 10 days after injection followed by a gradual
decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti-
and syn-11,12- dihydroxy-13,14-epoxy-
11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both
deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed
by cochromatography. The major adduct was identified as a product of the
reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced
significant numbers of lung adenomas in a dose- dependent manner, with the
highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In
tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based
on the administered dose, DB[a,l]P was more active than other environmental
carcinogens including benzo[a]pyrene. As a function of time-integrated DNA
adduct levels, DB[a,l]P induced lung adenomas with about the same potency
as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar
in carcinogenic potency to other PAHs in the strain A/J mouse lung model.
Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors
revealed the predominant mutations to be G-->T transversions in the
first base of codon 12, A-->G transitions in the second base of codon
12, and A-->T transversions in the second or third base of codon 61,
concordant with the DNA adduct profile.
相似文献
43.
44.
OBJECTIVES: To study the efficacy of otoacoustic emissions (OAEs) as a screening test for hearing impairment in children with acute bacterial meningitis. Hearing tests were performed before discharge from the hospital in an attempt to improve coverage and avoid delays in the diagnosis of postmeningitic hearing loss. METHODS: Children with bacterial meningitis were recruited from 21 centers. In the 48 hours before discharge from the hospital, all patients underwent a thorough audiologic assessment consisting of transient evoked OAEs, auditory brainstem responses (ABRs), otoscopy, and tympanometry. Hearing loss was defined as ABR threshold >/=30 dB. The results of OAE screening were compared with the gold standard of ABR threshold. RESULTS: Of 124 children recruited, we were able to perform both OAEs and ABRs on 110 children. Seven (6.3%) of the 110 children had ABR threshold >/=30 dB; 2 had sensorineural hearing loss and 5 had conductive hearing loss. At follow-up, hearing loss persisted in both cases of sensorineural hearing loss and no new cases were identified. All 7 children with hearing loss failed the OAE screening test. Ninety-four children with normal hearing thresholds passed the test, and 9 failed. Thus, the screening test had a sensitivity of 1.00 (95% confidence interval, 0.59 to 1.00), a specificity of 0.91 (0.85 to 0.97), a positive predictive value of 0. 44 (0.20 to 0.70), and a negative predictive value of 1.00 (0.96 to 1.00). CONCLUSIONS: OAE screening in children recovering from meningitis was found to be feasible and effective. The test was highly sensitive and reasonably specific. Inpatient OAE screening should allow early diagnosis of postmeningitic hearing loss and prompt auditory rehabilitation. 相似文献
45.
46.
47.
Cutaneous manifestations of malignancy are not uncommon, especially in advanced disease. They may also occur early in malignant disease or they may even signify recurrence particularly if they are paraneoplastic in nature. Clinical diagnosis can be difficult because of the wide spectrum of appearance of these lesions, and, in many cases, because of the lack of an identifiable underlying primary. Presented here is the case of a 65-year-old woman with multiple inflammatory cutaneous metastases, which were sclerodermoid in nature. These appeared 14 months after initial diagnosis of adenocarcinoma of unknown primary (ACUP) and signified the beginning of a rapid deterioration in her condition. The coexistence of limited systemic sclerosis (scleroderma) and ACUP initially raised several interesting diagnostic possibilities. Adenocarcinoma of unknown primary and the sclerodermoid reaction in malignancy are discussed. 相似文献
48.
49.
Characteristics and outcomes of older patients presenting to the emergency department after a fall: a retrospective analysis 总被引:2,自引:0,他引:2
OBJECTIVES: To study older patients presenting to the emergency department after a fall--factors associated with the fall, injuries sustained and outcome. DESIGN: A retrospective analysis using the Emergency Department Information System (EDIS), the Trauma Registry and the patient information database (CCIS), in addition to the patient's emergency and inpatient medical records. SETTING: Emergency department of a major inner city teaching hospital, 1 June-30 November 1997. PATIENTS: All patients over 65 years presenting to the emergency department (ED) after a fall, for whom complete medical records were available. RESULTS: Of 803 patients over 65 years presenting to the ED after a fall, complete records were available for 733 (91.3%) (283 men and 450 women). Extrinsic (accidental) causes were implicated in more than a third of falls (313 patients [42.7%]). A high proportion of the patients were living at home (520; 70.9%) and walking unaided (389; 53.1%). Although absolute numbers of women increased with age, men were as likely as women to present after a fall. Many patients had fallen before--39% of the men (111/283) and 24% of the women (110/450). In 78 patients (10.6%), alcohol misuse may have been a direct cause of the fall. The overall injury rate was 70.5% (517/733 patients), the most common injury being an isolated fracture (269/517 patients; 52.0%). In all, 419 patients (57.2%) were admitted to hospital, 48% (200/419) with a fracture and 52% (219/419) for investigation of the medical cause of the fall. The median length of hospital stay was 6 days (mean, 10.4 days; range, 1-129 days); 35% (146/419) of patients were in hospital for more than 10 days. CONCLUSION: Older patients presenting to the ED after a fall had high injury rates, high admission rates and often prolonged hospitalisation. About a third had fallen before. Patients at risk can be identified in the ED and referred to falls prevention programs. 相似文献
50.
B T Hennessy A M Gauthier L B Michaud G Hortobagyi V Valero 《Annals of oncology》2005,16(8):1289-1296
BACKGROUND: Capecitabine is active against anthracycline- and taxane-pretreated metastatic breast cancer. Post-marketing use of capecitabine at the FDA-approved dose (2500 mg/m2/day) leads to unacceptable toxicity in many patients. Dose reductions anecdotally improve tolerability without compromising efficacy. This retrospective analysis was designed to verify these anecdotal reports. Patients and methods: We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999. Responses were defined as clinical improvement (ID), stabilization of disease (SD) for 6 weeks or longer, or progression (PD). Patients were grouped according to the starting dose level of capecitabine: A=2500+/-5% (dose range 2385-2560) mg/m2/day; B=2250+/-5% (range 2130-2350) mg/m2/day; C < or = 2000+5% (range 1000-2100) mg/m2/day. We also reviewed the safety profile of capecitabine at these doses and performed a safety review of capecitabine in phase II and III metastatic breast and colorectal cancer trials. RESULTS: Clinical data were available for 113 patients (105 for response, 106 for toxicity). The median age was 52.5 years and the mean number of prior metastatic chemotherapy regimens was 2 (range 0-7). The mean capecitabine starting dose was 2220 mg/m2/day and the median number of cycles administered was 4 (range 1-19). The mean tolerated dose was 2040 mg/m2/day (range 960-2670). Grade 3/4 toxic effects at dose levels A, B and C, respectively, included palmar-plantar erythrodysesthesia (33%, 63%, 20%), diarrhea (13%, 12%, 3%), stomatitis (8%, 0%, 3%), and nausea/vomiting (4%, 6%, 5%). Forty per cent of all patients required capecitabine dose reductions; fewer patients treated with 2000 mg/m2/day required dose modification (28%). Five per cent of the patients required discontinuation of capecitabine owing to toxicity. Patients started at the lowest doses of capecitabine did not have poorer response rates or shorter time to progression. CONCLUSIONS: This retrospective analysis supports a starting dose of 2000 mg/m2/day because of its superior therapeutic index; however, patients may still have toxic effects and individualization of dosing is necessary. A phase III, multicenter, randomized study to establish the safety and efficacy of different doses of capecitabine is urgently needed. 相似文献