Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation

© 2016 Macmillan Publishers Limited.Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)-and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers

A DAG-based comparison of interventional effect underestimation between composite endpoint and multi-state analysis in cardiovascular trials

Abstract Background Composite endpoints comprising hospital admissions and death are the primary outcome in many cardiovascular clinical trials. For statistical analysis, a Cox proportional hazards model for the time to first event is commonly applied. There is an ongoing debate on whether multiple episodes per individual should be incorporated into the primary analysis. While the advantages in terms of power are readily apparent, potential biases have been mostly overlooked so far. Methods Motivated by a randomized controlled clinical trial in heart failure patients, we use directed acyclic graphs (DAG) to investigate potential sources of bias in treatment effect estimates, depending on whether only the first or multiple episodes are considered. The biases first are explained in simplified examples and then more thoroughly investigated in simulation studies that mimic realistic patterns. Results Particularly the Cox model is prone to potentially severe selection bias and direct effect bias, resulting in underestimation when restricting the analysis to first events. We find that both kinds of bias can simultaneously be reduced by adequately incorporating recurrent events into the analysis model. Correspondingly, we point out appropriate proportional hazards-based multi-state models for decreasing bias and increasing power when analyzing multiple-episode composite endpoints in randomized clinical trials. Conclusions Incorporating multiple episodes per individual into the primary analysis can reduce the bias of a treatment’s total effect estimate. Our findings will help to move beyond the paradigm of considering first events only for approaches that use more information from the trial and augment interpretability, as has been called for in cardiovascular research

Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes

BACKGROUND Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes. METHODS We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. RESULTS During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group. CONCLUSIONS In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease

Novel Statistical Methods for Cost-Effectiveness Analysis

The hardware used in the computational studies is part of the UMBC High Performance Computing Facility (HPCF). The facility is supported by the U.S. National Science Foundation through the MRI program (grant nos. CNS–0821258 and CNS–1228778) and the SCREMS program (grant no. DMS–0821311), with additional substantial support from the University of Maryland, Baltimore County (UMBC). See www.umbc.edu/hpcf for more information on HPCF and the projects using its resources.http://hpcf-files.umbc.edu/research/posters/Mathew_poster2015.pd