c-MYC is a radiosensitive locus in human breast cells.

Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.

Investigation of chromosome 1q reveals differential expression of members of the S100 family in clinical subgroups of intracranial paediatric ependymoma.

Gain of 1q is one of the most common alterations in cancer and has been associated with adverse clinical behaviour in ependymoma. The aim of this study was to investigate this region to gain insight into the role of 1q genes in intracranial paediatric ependymoma. To address this issue we generated profiles of eleven ependymoma, including two relapse pairs and seven primary tumours, using comparative genome hybridisation and serial analysis of gene expression. Analysis of 656 SAGE tags mapping to 1q identified CHI3L1 and S100A10 as the most upregulated genes in the relapse pair with de novo 1q gain upon recurrence. Moreover, three more members of the S100 family had distinct gene expression profiles in ependymoma. Candidates (CHI3L1, S100A10, S100A4, S100A6 and S100A2) were validated using immunohistochemistry on a tissue microarray of 74 paediatric ependymoma. In necrotic cases, CHI3L1 demonstrated a distinct staining pattern in tumour cells adjacent to the areas of necrosis. S100A6 significantly correlated with supratentorial tumours (P<0.001) and S100A4 with patients under the age of 3 years at diagnosis (P=0.038). In conclusion, this study provides evidence that S100A6 and S100A4 are differentially expressed in clinically relevant subgroups, and also demonstrates a link between CHI3L1 protein expression and necrosis in intracranial paediatric ependymoma.

Effect of evaluator and resident gender on the American Board of Internal Medicine evaluation scores.

OBJECTIVE: To examine the effects of resident and attending physician gender on the evaluation of residents in an internal medicine training program. DESIGN: Cross-sectional study. SETTING: Large urban academic internal medicine residency program. PARTICIPANTS: During their first 2 years of training, 132 residents (85 men, 47 women) received a total of 974 evaluations from 255 attending physicians (203 men, 52 women) from 1989 to 1995. MEASUREMENTS: The primary measurements were the numerical portions of the American Board of Internal Medicine evaluation form. Separate analyses were performed for each of the nine evaluation dimensions graded on a scale of 1 to 9. The primary outcome was the difference in the average scores received by each resident from male versus female attending physicians. RESULTS: Compared with female trainees, male residents received significantly higher scores from male attending physicians than from female attending physicians in six of the nine dimensions: clinical judgment, history, procedures, relationships, medical care, and overall. Similar trends, not reaching conventional levels of statistical significance, were observed in the other three categories: medical knowledge, physical exam, and attitude. These differences ranged from 0.24 to 0.60 points, and were primarily due to higher grading of male residents by male attending physicians than by female attending physicians. CONCLUSIONS: In one academic training program, we found a significant interaction in the grading process between the gender of internal medicine residents and the gender of their attending evaluators. This study raises the possibility that subtle aspects of gender bias may exist in medical training programs.

Endothelium-dependent relaxation to acetylcholine in the rabbit basilar artery: importance of membrane hyperpolarization.

1. Muscarinic stimulation of isolated, preconstricted segments of the basilar artery, with either acetylcholine or carbachol, was followed by endothelium-dependent smooth muscle relaxation and membrane hyperpolarization. 2. Smooth muscle relaxation to acetylcholine was stimulated in the presence of lower concentrations than the associated hyperpolarization (EC50 values 3.2 microM and 31.6 microM, respectively), and was sustained during agonist application, while the hyperpolarization was relatively transient. 3. Repeated exposure to acetylcholine was associated with loss of membrane hyperpolarization, while smooth muscle relaxation was unaltered. Following a second exposure to 100 microM acetylcholine, mean hyperpolarization was markedly depressed from 8.5 to 2 mV, and subsequent exposures failed to induce any hyperpolarization. Relaxations with a similar amplitude and rate of development, were recorded with each subsequent addition of acetylcholine. 4. The competitive substrate inhibitors for nitric oxide synthase, L-NG-monomethyl arginine (100 microM L-NMMA) or L-NG-nitro arginine methyl ester (100 microM L-NAME), modified the form and amplitude of both the relaxation and the hyperpolarization to acetylcholine. In the majority of experiments, both the hyperpolarization and the relaxation were almost totally abolished. 5. Neither nitric oxide, applied directly in physiological salt solution, nor sodium nitroprusside, produced smooth muscle hyperpolarization except in high concentrations. Reproducible, small amplitude (around 2 mV) hyperpolarization followed the application of either NO gas (15 microM) or sodium nitroprusside (100 microM), both of which induced almost maximal smooth muscle relaxation. 6. These data show that muscarinic stimulation of endothelial cells in the rabbit basilar artery is followed by both smooth muscle hyperpolarization and relaxation. They indicate that nitric oxide is involved in both of these responses, but that the smooth muscle hyperpolarization is not an essential component of the relaxation.