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Small molecule inhibitors of aurora kinases are currently being investigated in oncology clinical trials. The long-term effects of these inhibitors on proliferating euploid cells have not been adequately studied. We examined the effect of the reversible pan-aurora kinase inhibitor VX-680 on p53-competent human euploid cells. Circumscribed treatment with VX-680 blocked cytokinesis and arrested cells in G1 or a G1-like status. Approximately 70% of proliferatively arrested cells had 4N DNA content and abnormal nuclei. The remaining 30% of cells possessed 2N DNA content and normal nuclei. The proliferative arrest was not due to the activation of the tumor suppressor Rb and was instead associated with rapid induction of the p53–p21 pathway and p16. The induction was particularly evident in cells with nuclear abnormalities but was independent of activation of the DNA damage response. All of these effects were correlated with the potent inhibition of aurora kinase B. After release from VX-680, the cells with normal nuclei robustly resumed proliferation whereas the cells with abnormal nuclei underwent senescence. Irrespective of their nuclear morphology or DNA content, cells pre-treated with VX-680 failed to grow in soft agar or form tumors in mice. Our findings indicate that an intermittent treatment strategy might minimize the on-target side effects of Aurora Kinase B (AURKB) inhibitory therapies. The strategy allows a significant fraction of dividing normal cells to resume proliferation. [ABSTRACT FROM AUTHOR]

A synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug's inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic or epigenomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases, ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC. [ABSTRACT FROM AUTHOR]

Introduction We develop a multidomain model to predict progression of Alzheimer's disease dementia (AD). Methods Data from the US National Alzheimer's Coordinating Center (n = 3009) are used to examine change in symptom status and to estimate transition probabilities between health states described using cognitive function, functional ability, and behavior. A model is used to predict progression and to assess a hypothetical treatment scenario that slows mild to moderate AD progression. Results More than 70% of participants moved state over 12 months. The majority moved in domains other than cognitive function. Over 5 years, of those alive more than half are in severe AD health states. Assessing an intervention scenario, we see fewer years in more severe health states and a potential impact (life years saved) due to mortality improvements. Discussion The model developed is exploratory and has limitations but illustrates the importance of using a multidomain approach when assessing impacts of AD and interventions. [ABSTRACT FROM AUTHOR]

This paper investigates the statistical properties of human motion-based harvested power, and provides models for the distribution, auto-correlation and cross-correlation of harvested power at different body locations, namely left wrist, right wrist, left ankle and waist. The models are developed based on empirical acceleration measurements while the subjects perform unscripted daily tasks. The measured accelerations are converted to harvestable power by assuming a velocity-damped resonant harvesting generator. The provided models enable realistic analysis and simulation of wearable communication systems with motion-based energy harvesting. [ABSTRACT FROM AUTHOR]

Energy harvesting is one of the promising solutions to the problem of limited battery capacity in many wireless devices. This paper addresses the problem of system design of energy harvesting capable wireless devices in terms of the required sizes for energy and data buffers, as well as the size of the harvester, for given delay and loss requirements. We analyze the performance of an energy harvesting node, considering a stochastic model that takes into account energy harvesting and event arrival processes. We derive closed-form expressions for the probability of event loss and the average queueing delay. Our event-driven continuous time simulations validate our analytical results. Employing these results, we provide a near-optimal approach to the design of the system in terms of sizing the energy harvesting device, the energy storage, and the event queue capacity. [ABSTRACT FROM PUBLISHER]

Abstract: Shading devices, such as venetian blinds, are widely used to eliminate glare and maintain a comfortable working environment for occupants. This paper proposes an open-loop control of blind height and slat angle based on an analytic model of solar position, and geometry of venetian blinds and the windows. The algorithm enables completely blocking direct sunlight from entering the room beyond a certain user specified interior distance from the window while enhancing daylight utilization. We derive closed-form solutions for blind height and angle which are easily implemented in practice. Moreover, the proposed blind control algorithm is simulated with favorable performance. The algorithm has also been implemented and verified in real-time test-beds. [Copyright &y& Elsevier]

This article examines the dynamics of the linkages between Shanghai and Hong Kong stock indices. While the volatility linkage is analysed by a Multivariate Generalized Autoregressive Conditional Heteroscedasticity (MVGARCH) framework, the dependence of returns is examined by a copula approach. Eight different copula functions are applied in this study including two time-varying ones which capture the dynamics of the linkage. The result shows significant tail dependence of the returns in the two markets. [ABSTRACT FROM AUTHOR]

Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by conferring more or less potency in the killing of tumor cells. To identify such modifiers, isogenic cell lines were utilized to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoptosis. It was found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a pan-aurora kinase inhibitor, VX-680. Suppression was show to stem from the inhibition of autophagy, specifically in multinucleated cells, rather than a general inhibition of apoptosis. The anti-autophagic activity of Bcl-2 also impacted polyploid cell recovery in colony-forming assays, suggesting a route of escape from MYC-VX-680 synthetic lethality that may have clinical consequences. These findings expand on previous conclusions that autophagic death of VX-680-induced polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs. Image 1 • The aurora kinase inhibitor, VX-680, induces early apoptosis and late polyploidy. • Bcl-2 and Bcl-xL do not inhibit VX-680-induced apoptosis, but instead enable polyploid cell survival. • This pro-survival function requires localization to the endoplasmic reticulum and inhibition of autophagy. • The findings describe a novel mode by which drug resistance might occur. [ABSTRACT FROM AUTHOR]

Plants are a rich source for bioactive compounds. However, plant extracts can harbor a mixture of bioactive molecules that promote divergent phenotypes and potentially have confounding effects in bioassays. Even with further purification and identification, target deconvolution can be challenging. Corynoline and acetylcorynoline, are phytochemicals that were previously isolated through a screen for compounds able to induce mitotic arrest and polyploidy in oncogene expressing retinal pigment epithelial (RPE) cells. Here, we shed light on the mechanism by which these phytochemicals can attack human cancer cells. Mitotic arrest was coincident to the induction of centrosome amplification and declustering, causing multi-polar spindle formation. Corynoline was demonstrated to have true centrosome declustering activity in a model where A549 cells were chemically induced to have more than a regular complement of centrosomes. Corynoline could inhibit the centrosome clustering required for pseudo-bipolar spindle formation in these cells. The activity of AURKB, but not AURKA or polo-like kinase 4, was diminished by corynoline. It only partially inhibited AURKB, so it may be a partial antagonist or corynoline may work upstream on an unknown regulator of AURKB activity or localization. Nonetheless, corynoline and acetylcorynoline inhibited the viability of a variety of human cancer derived cell lines. These phytochemicals could serve as prototypes for a next-generation analog with improved potency, selectivity or in vivo bioavailability. Such an analog could be useful as a non-toxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired. [Display omitted] • Corynoline, a benzophenanthridine alkaloid phytochemical, disrupts cell division. • Mitotic arrest, apoptosis and polyploidy are coincident with centrosome defects. • Corynoline definitively induces centrosome declustering in cancer cells. • AURKB activity, but not AURKA, is diminished by corynoline treatment. [ABSTRACT FROM AUTHOR]

To identify novel bioactive compounds, an image-based, cell culture screening of natural product extracts was conducted. Specifically, our screen was designed to identify phytochemicals that might phenocopy inhibition of the chromosomal passenger protein complex in eliciting mitotic and cytokinetic defects. A known alkaloid, scoulerine, was identified from the rhizomes of the plant Corydalis decumbens as being able to elicit a transient mitotic arrest followed by either apoptosis induction or polyploidy. In examining the mitotic abnormality further, we observed that scoulerine could elicit supernumerary centrosomes during mitosis, but not earlier in the cell cycle. The localization of NUMA1 at spindle poles was also inhibited, suggesting diminished potential for microtubule recruitment and spindle-pole focusing. Polyploid cells emerged subsequent to cytokinetic failure. The concentration required for scoulerine to elicit all its cell division phenotypes was similar, and an examination of related compounds highlighted the requirement for proper positioning of a hydroxyl and a methoxy group about an aromatic ring for activity. Mechanistically, scoulerine inhibited AURKB activity at concentrations that elicited supernumerary centrosomes and polyploidy. AURKA was only inhibited at higher concentrations, so AURKB inhibition is the likely mechanism by which scoulerine elicited division defects. AURKB inhibition was never complete, so scoulerine may be a suboptimal AURK inhibitor or work upstream of the chromosomal passenger protein complex to reduce AURKB activity. Scoulerine inhibited the viability of a variety of human cancer cell lines. Collectively, these findings uncover a previously unknown activity of scoulerine that could facilitate targeting human cancers. Scoulerine, or a next-generation analogue, may be useful as a nontoxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.

Introduction: We develop a multidomain model to predict progression of Alzheimer's disease dementia (AD)., Methods: Data from the US National Alzheimer's Coordinating Center (n = 3009) are used to examine change in symptom status and to estimate transition probabilities between health states described using cognitive function, functional ability, and behavior. A model is used to predict progression and to assess a hypothetical treatment scenario that slows mild to moderate AD progression., Results: More than 70% of participants moved state over 12 months. The majority moved in domains other than cognitive function. Over 5 years, of those alive more than half are in severe AD health states. Assessing an intervention scenario, we see fewer years in more severe health states and a potential impact (life years saved) due to mortality improvements., Discussion: The model developed is exploratory and has limitations but illustrates the importance of using a multidomain approach when assessing impacts of AD and interventions., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)