Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity

The four methylated xanthine derivatives, caffeine, theophylline, theobromine and paraxanthine, were tested for their ability to override the mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All four agents were found to partially override the block, ranking in terms of potency at a concentration of 1 mM in the order caffeine greater than theophylline greater than theobromine = paraxanthine. However, the effects of the four agents on the clonal survival of irradiated cells failed to correlate with the extent of override, both in terms of the relative effects of the four agents and the dose-response relationships; at a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override, whilst at higher concentrations all the agents had a significant effect on survival but little or no further influence on the degree of block override. It is therefore concluded that override of a mitotic block is not in itself sufficient to cause the increased killing seen when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect either by directly inhibiting repair of damage in DNA or by causing override of the radiation-induced inhibition of DNA synthesis.     

Silica,compensated silicosis,and lung cancer in Western Australian goldminers

OBJECTIVES: Silica has recently been reclassified as carcinogenic to humans based largely on the observed increase in rates of lung cancer in subjects with silicosis. Other recent reviews have arrived at different conclusions as to whether silicosis or silica itself is carcinogenic. This study aims to examine exposure-response relations between exposure to silica and subsequent silicosis and lung cancer in a cohort of goldminers. METHODS: 2,297 goldminers from Kalgoorlie in Western Australia were examined in 1961, 1974, and 1975. Data were collected on respiratory symptoms, smoking habits, and employment history. Subjects were followed up to the end of 1993. Survival analyses for lung cancer mortality and incidence of compensated silicosis were performed with age and year matched conditional logistic regression analyses. RESULTS: 89% of the cohort were traced to the end of 1993. 84% of the men had smoked at some time and 66% were current smokers. 1386 deaths occurred during the follow up period, 138 from lung cancer, and 631 subjects were compensated for silicosis. A strong effect of smoking on mortality from lung cancer, and a smaller effect on the incidence of compensated silicosis was found. There was a strong effect of duration and intensity of exposure on the incidence of silicosis. The risk of mortality from lung cancer increased after compensation for silicosis. Of all direct measures of exposure to silica, only log cumulative exposure was significantly related to incidence of lung cancer, but this effect disappeared once the onset of silicosis was taken into account. CONCLUSIONS: The incidence of silicosis was clearly related to exposure to silica and the onset of silicosis conferred a significant increase in risk for subsequent lung cancer, but there was no evidence that exposure to silica caused lung cancer in the absence of silicosis.       

Molecular cloning of a mammalian gene involved in the fixation of UV-induced mutations

A mammalian DNA damage tolerance gene has been isolated by DNA transfection and cosmid rescue. Following cotransfection of mouse genomic DNA and pSV2neo into SVM, the UV hypersensitive mutant Indian muntjac cell line, clones with a 1.7 to 2.0-fold greater D₃₇ value for UV killing were isolated. This trait was carried through three rounds of transfection. A neo gene and flanking sequences from a tertiary transfectant were cloned by cosmid rescue. The cosmid clone confers UV resistance to SVM and improves the ability of the cell to replicate UV damaged DNA. This replication appears to be error-prone; UV-induced 6-thioguanine-resistant mutants occur four to fivefold more frequently than in SVM or a wild-type Indian muntjac line. Thus, the gene isolated is not homologous to that defective in SVM. We believe that this is the first mammalian gene to be isolated that is directly involved in mutation fixation.     

Predictors of Ventricular Tachvcardia Inducibility in Programmed Electrical Stimulation and the Effectiveness of Serial Drug Testing: Polish Multicenter Study

WNUK-WOJNAR, A.M., ET AL.: Predictors of Ventricular Tachycardia Inducibility in Programmed Electrical Stimulation and Effectiveness of Serial Drug Testing: Polish Multicenter Study. In 100 patients with IHD and complex ventricular arrhythmias, programmed electrical stimulation was performed using up to three extrastimuli at sinus rhythm, and paced 100, 120, and 140 beats/min delivered from the RV apex, outflow tract or the LV with ventricular mapping to evaluate late potentials (LP) in 41 patients. Sustained monomorphic VT (SMVT) was provoked in 91% of 42 patients with a history of VT/VF, p < 0.001, all five patients had SMVT in 24-hour ECG, p < 0.005, and 91% of 21 patients with LV dyskinesis, p < 0.01. After depolarizations were found in 62% of 21 patients with a history of VT, in 58% of 31 patients with inducible VT, p < 0.01 and in five of six patients with LV dyskinesis. In patients with inducible VT, LP had a higher amplitude (105 ± 35 vs 60 ± 47 µV) and were more delayed (202 ± 96 vs 133 ± 75 msec) than in noninducible patients. In 17 patients, serial drug testing was performed after oral administration using mexilitene, disopyramide, chinidine, propafenone, sotalol, and amiodarone. If one drug was tested, the therapy efficacy was 25% if two drugs-60%, and if three drugs-75%. In eight patients, VT was inducible in all tests, but in only one of these patients chronic antiarrhythmic therapy was not effective. We conclude that the most important predictors of VT inducibility are a history of VT or 24-hour ECG, and LV dyskinesis. Serial drug testing is efficient only when many drugs are tested, but even if VT is inducible, it does not exclude the possibility of a good clinical outcome in chronic therapy.     

Combined CA125 and mesothelin levels for the diagnosis of malignant mesothelioma

BACKGROUND: Malignant mesothelioma is an aggressive, uniformly fatal tumor. Serum markers would be useful for the diagnosis of this disease. One potential marker is mesothelin. The purpose of this study was to study the mesothelin biomarker in a large patient cohort and to determine if another biomarker, CA125, improves on the sensitivity of mesothelin in the diagnosis of mesothelioma. METHODS: Serum levels of mesothelin and CA125 were determined by commercially available assays in 117 samples obtained at diagnosis from patients with pleural malignant mesothelioma, 33 healthy, asbestos-exposed individuals, 53 patients with asbestos-related lung or pleural disease, and 30 patients presenting with benign pleural effusions. Cross-validated sensitivities were determined, and receiver operator characteristic curves were generated to compare the diagnostic accuracy of the biomarkers. RESULTS: CA125 had a cross-validated sensitivity of 27% for mesothelioma patients at a specificity of 95% relative to asbestos-exposed individuals, or 50% relative to individuals with benign pleural effusions. Mesothelin had a cross-validated sensitivity of 52% for mesothelioma patients, at a sensitivity of 95% relative to individuals with benign lung or pleural disease. CA125 and mesothelin levels were discordant in > 50% of mesothelioma patients. Combining the data from the two biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone. CONCLUSION: Combining mesothelin and CA125 data does not improve the sensitivity of mesothelioma diagnosis over mesothelin alone. The use of both markers potentially increases the number of patients who can be monitored.     

Early recognition of heart failure in patients with diabetes type 2 in primary care. A prospective diagnostic efficiency study. (UHFO-DM2)

Background  

We hypothesize that the prevalence of unknown heart failure in diabetic patients aged 60 years and over is relatively high (15% or more) and that a cost-effective strategy can be developed to detect heart failure in these patients. The strategy is expected to include some signs and symptoms (such as dyspnoea, orthopnoea, pulmonary crepitations and laterally displaced apical beat), natriuretic peptide measurements (Amino-terminal B-type natriuretic peptide) and possibly electrocardiography. In a subset of patients straightforward echocardiography may show to be cost-effective. With information from our study the detection of previously unknown heart failure in diabetic patients could be improved and enable the physician to initiate beneficial morbidity and mortality reducing heart failure treatment more timely.     

Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0–3, 7–10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4⁺ and CD8⁺ T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.     

High-resolution array CGH clarifies events occurring on 8p in carcinogenesis

Background  

Rearrangement of the short arm of chromosome 8 (8p) is very common in epithelial cancers such as breast cancer. Usually there is an unbalanced translocation breakpoint in 8p12 (29.7 Mb – 38.5 Mb) with loss of distal 8p, sometimes with proximal amplification of 8p11-12. Rearrangements in 8p11-12 have been investigated using high-resolution array CGH, but the first 30 Mb of 8p are less well characterised, although this region contains several proposed tumour suppressor genes.     

Respiratory symptoms and lung-function changes with exposure to five substances in aluminium smelters

OBJECTIVES: To determine whether exposure to five different occupational substances contributes to respiratory symptoms in aluminium smelter workers. METHODS: A cross-sectional survey of 1,615 male employees of two Australian aluminium smelters was conducted in 1995. Subjects underwent spirometry and were asked about respiratory symptoms and the relationship of those symptoms to work. Their job histories were combined with a task exposure matrix to produce individual quantitative measures of cumulative exposure to fluoride, sulphur dioxide, inspirable dust, the benzene-soluble fraction of coal tar pitch volatiles (BSF), and oil mist. RESULTS: After adjusting for smoking and age, we found that subjects with the highest cumulative exposure to fluoride (>0.16 mg/m(3) years) and inspirable dust (>2.9 mg/m(3) years) were two to four times more likely to report work-related wheeze and chest tightness than were unexposed subjects. Lower prevalence ratios for the same symptoms were seen with sulphur dioxide and BSF. Levels of lung function decreased slightly with exposure to oil mist, but not with cumulative exposure to other substances. CONCLUSIONS: This study suggests that the relevant causative agents for respiratory symptoms in aluminium smelters are fluoride and inspirable dust.