Combination of eribulin and aurora a inhibitor MLN8237 prevents metastatic colonization and induces cytotoxic autophagy in breast cancer

© 2016 American Association for Cancer Research.Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubuletargeting drug eribulin on different stages of metastasis in triplenegative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors

3-Dimensional Mapping and Radiofrequency Ablation of Atrial Flutter in a Patient with Interrupted Inferior Vena Cava

The presence of isolated interrupted inferior vena cava (IVC) is very rare. Though the occurrence of typical atrial flutter in this setting has recently been described, the use of 3-dimensional activation mapping to aid the management of such patients has not yet been described. We report the successful ablation of this arrhythmia in a 63-year-old woman using the superior route through the internal jugular vein with the help of a mapping system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46349/1/10840_2005_Article_4512.pd

Hsf1 Activation Inhibits Rapamycin Resistance and TOR Signaling in Yeast Revealed by Combined Proteomic and Genetic Analysis

TOR kinases integrate environmental and nutritional signals to regulate cell growth in eukaryotic organisms. Here, we describe results from a study combining quantitative proteomics and comparative expression analysis in the budding yeast, S. cerevisiae, to gain insights into TOR function and regulation. We profiled protein abundance changes under conditions of TOR inhibition by rapamycin treatment, and compared this data to existing expression information for corresponding gene products measured under a variety of conditions in yeast. Among proteins showing abundance changes upon rapamycin treatment, almost 90% of them demonstrated homodirectional (i.e., in similar direction) transcriptomic changes under conditions of heat/oxidative stress. Because the known downstream responses regulated by Tor1/2 did not fully explain the extent of overlap between these two conditions, we tested for novel connections between the major regulators of heat/oxidative stress response and the TOR pathway. Specifically, we hypothesized that activation of regulator(s) of heat/oxidative stress responses phenocopied TOR inhibition and sought to identify these putative TOR inhibitor(s). Among the stress regulators tested, we found that cells (hsf1-R206S, F256S and ssa1-3 ssa2-2) constitutively activated for heat shock transcription factor 1, Hsf1, inhibited rapamycin resistance. Further analysis of the hsf1-R206S, F256S allele revealed that these cells also displayed multiple phenotypes consistent with reduced TOR signaling. Among the multiple Hsf1 targets elevated in hsf1-R206S, F256S cells, deletion of PIR3 and YRO2 suppressed the TOR-regulated phenotypes. In contrast to our observations in cells activated for Hsf1, constitutive activation of other regulators of heat/oxidative stress responses, such as Msn2/4 and Hyr1, did not inhibit TOR signaling. Thus, we propose that activated Hsf1 inhibits rapamycin resistance and TOR signaling via elevated expression of specific target genes in S. cerevisiae. Additionally, these results highlight the value of comparative expression analyses between large-scale proteomic and transcriptomic datasets to reveal new regulatory connections

Radiomics Features in Contrast‐Enhanced and Nonenhanced Magnetic Resonance Imaging Images Are Associated With High Intracranial Aneurysmal Risk

Background Aneurysm wall enhancement is a potential imaging biomarker for risk stratification of intracranial aneurysms (IAs). Variations in the texture of the magnetic resonance imaging (MRI) signal could shed light on the underlying pathobiology of the aneurysm wall. Radiomics can help quantify the textural complexity in MRI images, which could lead to better understanding and risk stratification of IAs. Herein, we investigated the potential use of radiomics derived from nonenhanced and contrast‐enhanced MRI to identify high‐risk IAs and evaluated their performance on different data sets. Methods We obtained 126 IAs from different centers and extracted radiomics features from nonenhanced and contrast‐enhanced MRI for each aneurysm. We then built a random forest model from a part of the 3‐T data set to identify high‐risk IAs based on the 5‐year population, hypertension, age, size of aneurysm, earlier SAH from another aneurysm, site of aneurysm (PHASES) score. We then tested the performance of this model on a part of the same 3‐T data set, a 7‐T data set, and an external 3‐T data set. We also performed multivariate analysis to understand the significance of radiomics features. Results We found that 75 radiomics features were significantly different between high‐ and low‐risk IAs. The radiomics model had good performance when tested on the 3‐T data set (accuracy, 90%; sensitivity, 86%; and specificity, 92%); however, when tested on external data sets, it had a moderate performance (accuracy, 88%; sensitivity, 50%; and specificity, 95% for external 3‐T data set; and accuracy, 62%; sensitivity, 27%; and specificity, 100% for 7‐T data set). Conclusions Radiomics derived from nonenhanced and contrast‐enhanced MRI show high accuracy in identifying high‐risk aneurysms from the same data set and could be used as a tool for quantifying aneurysm wall enhancement

Combination of eribulin and aurora a inhibitor MLN8237 prevents metastatic colonization and induces cytotoxic autophagy in breast cancer

© 2016 American Association for Cancer Research.Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubuletargeting drug eribulin on different stages of metastasis in triplenegative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process, including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells, providing foundation for the combination therapy. Mechanistically, AURKA inhibition induces cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. These preclinical data provide a new understanding of the mechanisms by which MLN8237 mediates its antimetastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early-stage solid tumors