Rush University Medical Center

About: Rush University Medical Center is a healthcare organization based out in Chicago, Illinois, United States. It is known for research contribution in the topics: Population & Dementia. The organization has 13915 authors who have published 29027 publications receiving 1379216 citations. The organization is also known as: Rush Presbyterian St. Luke's Medical Center.

Cross-talk between Notch and the Estrogen Receptor in Breast Cancer Suggests Novel Therapeutic Approaches

Abstract: High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor alpha-negative (ERalpha(-)), Her2/Neu nonoverexpressing cells. In ERalpha(+) cells, estradiol inhibited Notch activity and Notch-1(IC) nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERalpha(-)) cells, Notch-1 knockdown or gamma-secretase inhibition decreased cyclins A and B1, causing G(2) arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERalpha(+)) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, gamma-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers.

Relation of cognitive activity to risk of developing Alzheimer disease

Abstract: Background: Frequent cognitive activity in old age has been associated with reduced risk of Alzheimer disease (AD), but the basis of the association is uncertain. Methods: More than 700 old people underwent annual clinical evaluations for up to 5 years. At baseline, they rated current and past frequency of cognitive activity with the current activity measure administered annually thereafter. Those who died underwent a uniform postmortem examination of the brain. Amyloid burden, density of tangles, and presence of Lewy bodies were assessed in eight brain regions and the number of chronic cerebral infarctions was noted. Results: During follow-up, 90 people developed AD. More frequent participation in cognitive activity was associated with reduced incidence of AD (HR 0.58; 95% CI: 0.44, 0.77); a cognitively inactive person (score 2.2, 10th percentile) was 2.6 times more likely to develop AD than a cognitively active person (score 4.0, 90th percentile). The association remained after controlling for past cognitive activity, lifespan socioeconomic status, current social and physical activity, and low baseline cognitive function. Frequent cognitive activity was also associated with reduced incidence of mild cognitive impairment and less rapid decline in cognitive function. Among 102 persons who died and had a brain autopsy, neither global nor regionally specific measures of neuropathology were related to level of cognitive activity before the study, at study onset, or during the course of the study. Conclusion: Level of cognitively stimulating activity in old age is related to risk of developing

A Double-Strand Break Repair Defect in ATM-Deficient Cells Contributes to Radiosensitivity

Abstract: The ATM protein, which is mutated in individuals with ataxia telangiectasia (AT), is central to cell cycle checkpoint responses initiated by DNA double-strand breaks (DSBs). ATM's role in DSB repair is currently unclear as is the basis underlying the radiosensitivity of AT cells. We applied immunofluorescence detection of gamma-H2AX nuclear foci and pulsed-field gel electrophoresis to quantify the repair of DSBs after X-ray doses between 0.02 and 80 Gy in confluence-arrested primary human fibroblasts from normal individuals and patients with mutations in ATM and DNA ligase IV, a core component of the nonhomologous end-joining (NHEJ) repair pathway. Cells with hypomorphic mutations in DNA ligase IV exhibit a substantial repair defect up to 24 h after treatment but continue to repair for several days and finally reach a level of unrepaired DSBs similar to that of wild-type cells. Additionally, the repair defect in NHEJ mutants is dose dependent. ATM-deficient cells, in contrast, repair the majority of DSBs with normal kinetics but fail to repair a subset of breaks, irrespective of the initial number of lesions induced. Significantly, after biologically relevant radiation doses and/or long repair times, the repair defect in AT cells is more pronounced than that of NHEJ mutants and correlates with radiosensitivity. NHEJ-defective cells analyzed for survival following delayed plating after irradiation show substantial recovery while AT cells fail to show any recovery. These data argue that the DSB repair defect underlies a significant component of the radiosensitivity of AT cells.