ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types.

Purpose: Histone deacetylase inhibitors (HDACi) are epigenome-targeting small molecules approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma. They have also demonstrated clinical activity in acute myelogenous leukemia, non-small cell lung cancer, and estrogen receptor-positive breast cancer, and trials are underway assessing their activity in combination regimens including immunotherapy. However, there is currently no clear strategy to reliably predict HDACi sensitivity. In colon cancer cells, apoptotic sensitivity to HDACi is associated with transcriptional induction of multiple immediate-early (IE) genes. Here, we examined whether this transcriptional response predicts HDACi sensitivity across tumor type and investigated the mechanism by which it triggers apoptosis.Experimental Design: Fifty cancer cell lines from diverse tumor types were screened to establish the correlation between apoptotic sensitivity, induction of IE genes, and components of the intrinsic apoptotic pathway.Results: We show that sensitivity to HDACi across tumor types is predicted by induction of the IE genes FOS, JUN, and ATF3, but that only ATF3 is required for HDACi-induced apoptosis. We further demonstrate that the proapoptotic function of ATF3 is mediated through direct transcriptional repression of the prosurvival factor BCL-XL (BCL2L1) These findings provided the rationale for dual inhibition of HDAC and BCL-XL, which we show strongly cooperate to overcome inherent resistance to HDACi across diverse tumor cell types.Conclusions: These findings explain the heterogeneous responses of tumor cells to HDACi-induced apoptosis and suggest a framework for predicting response and expanding their therapeutic use in multiple cancer types. Clin Cancer Res; 23(18); 5573-84. ©2017 AACR.

Effects of age, step direction, and reaction condition on the ability to step quickly.

BACKGROUND: The ability to take a step quickly is important for balance maintenance during activities of daily living. The purpose of this study was to investigate the effects of age, reaction condition, and step direction on the ability to take a volitional step as fast as possible. METHODS: The performance of a voluntary step task was measured in young adult (mean age 20, SD 0.9 years), young-old adult (mean age 67, SD 3.7 years), and old adult (mean age 78, SD 2.3 years) healthy female participants. Each participant stepped as fast as possible in eight directions in response to a visual cue in a simple or choice reaction time condition. The effects of age, reaction condition, and step direction and their interactions on the primary outcome variables of response time, step liftoff, and step landing time were examined. RESULTS: The normal aging process progressively increased the response, liftoff, and landing times. The choice reaction time condition, compared to the simple, had significantly increased response, liftoff, and landing times. Step direction significantly affected the liftoff and landing times, with lateral, diagonal, and anterior and posterioir (A-P) times increasing, respectively. CONCLUSIONS: We found substantial declines in the ability to step rapidly in healthy adults as age increased. When a decision was required regarding the step direction, the step performance also declined. Step direction also significantly affected step performance. The assessment of voluntary step performance, which may be an indicator of balance ability, should include dimensions of both direction and the choice condition.

Activating transcription factor 3 contributes to Toll-like receptor-mediated macrophage survival via repression of Bax and Bak.

Macrophages play an essential role in the innate immune response to infection and tissue injury. However, excessive macrophage activation may also significantly contribute to chronic inflammatory diseases. The Toll-like receptor (TLR) family are key regulators of innate immune responses in macrophages, and they are able to promote their survival and resistance against apoptosis. We, and others, have shown that the adaptive response gene, activating transcription factor 3 (ATF3), acts as a negative regulator of TLR signaling by repressing transcription of pro-inflammatory cytokines in primary mouse macrophages. Here, we describe a novel role for ATF3 as a component of TLR-mediated survival in macrophages. ATF3-deficient bone marrow macrophages show reduced survival in response to a range of TLR ligands and significantly higher apoptotic rates were observed in response to lipopolysaccharide, indicating that ATF3 is required to suppress apoptosis in macrophages. Furthermore, we show that ATF3 lies downstream of JNK signaling after TLR engagement, resulting in repression of pro-apoptotic Bak and Bax transcription.

Rounds reports: Early experiences of using printed summaries of electronic medical records in a large teaching medical hospital.

This article describes the rationale, processes, technology, and results of creating of a paper-based rounds report that is now used by our entire institution for efficient inpatient work rounds and checkout rounds that are routinely done in virtually every hospital, both academic and private, in the US. The results of a survey of clinicians suggests that printed rounds reports have markedly improved rounding efficiency, saved substantial amounts of physician time, standardized checkout processes, and improved patient safety.

ATF3 transcription factor and its emerging roles in immunity and cancer.

Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding (ATF/CREB) family of transcription factors. It is an adaptive-response gene that participates in cellular processes to adapt to extra- and/or intracellular changes, where it transduces signals from various receptors to activate or repress gene expression. Advances made in understanding the immunobiology of Toll-like receptors have recently generated new momentum for the study of ATF3 in immunity. Moreover, the role of ATF3 in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.