The Cross-Quantilogram: Measuring Quantile Dependence and Testing Directional Predictability between Time Series

This paper proposes the cross-quantilogram to measure the quantile dependence between two time series. We apply it to test the hypothesis that one time series has no directional predictability to another time series. We establish the asymptotic distribution of the cross quantilogram and the corresponding test statistic. The limiting distributions depend on nuisance parameters. To construct consistent confidence intervals we employ the stationary bootstrap procedure; we show the consistency of this bootstrap. Also, we consider the self-normalized approach, which is shown to be asymptotically pivotal under the null hypothesis of no predictability. We provide simulation studies and two empirical applications. First, we use the cross-quantilogram to detect predictability from stock variance to excess stock return. Compared to existing tools used in the literature of stock return predictability, our method provides a more complete relationship between a predictor and stock return. Second, we investigate the systemic risk of individual financial institutions, such as JP Morgan Chase, Goldman Sachs and AIG. This article has supplementary materials online

Magnetic field observations near Mercury: Preliminary results from Mariner 10

Results are presented from a preliminary analysis of data obtained near Mercury by the NASA/GSFC Magnetic Field Experiment on Mariner 10. A very well developed, detached bow shock wave, which developed as the super-Alfvenic solar wind interacted with the planet Mercury was observed. A magnetosphere-like region, with maximum field strength of 98 gamma at closest approach (704 km altitude) was also observed, and was contained within boundaries similar to the terrestrial magnetopause. The obstacle deflecting the solar wind flow was global in size, but the origin of the enhanced magnetic field was not established. The most plausible explanation, considering the complete body of data, favored the conclusion that Mercury has an intrinsic magnetic field

An exploratory study of how a Korean chaebol’s learning culture facilitates customer service

This paper explains how the organizational learning concept is used by managers in a global Korean company to promote group work, information sharing and an open communication style in order to produce a high level of customer service. Previously collected data from a set of in-depth personal interviews undertaken with three senior managers in a Korean electronics company were analyzed and interpreted using the grounded theory approach, and a number of propositions are put forward. The research findings show that managers in a chaebol deploy organizational learning to identify skilled and knowledgeable staff, and improve the organization’s capability by placing emphasis on developing harmonious, mutually oriented relationships that permeate throughout the organization. Top management demand that staff identify with government economic objectives and align the organization’s strategy accordingly so that the products produced are marketable. To achieve this, the organization fosters continual interaction among managers throughout the organization’s hierarchy. The chaebol’s organizational learning model encapsulates a “corollary” (continual communication) and “tools” (cultural influence and relationship management), and manifests in a unique strategy that allows management systems to evolve naturally

Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases

Activation of androgen receptor (AR) may play a role in the development of castration resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin, or Gas6 induced AR phosphorylation at Tyr-267; IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. siRNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6, and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we show dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. Dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert anti-tumor activity in prostate cancer through inhibition of Ack1

Synthetic DNA immunotherapy in biochemically relapsed prostate cancer

Background: INO-5150 (PSA and PSMA) +/- INO-9012 (IL-12), a synthetic DNA immunotherapy, was assessed for safety, immunogenicity and efficacy in biochemically recurrent prostate cancer patients (pts). Methods: Phase I, open-label, multi-center study in the US included pts with rising PSA after surgery and/or RT, PSA doubling time (PSADT) \u3e3 months (mos), testosterone \u3e150 ng/dL and no concurrent ADT. Safety, immunogenicity and efficacy (PSA kinetics, PFS) were evaluated in 4 treatment arms of 15 pts each. Arms A: 2mg INO-5150, B: 8.5 mg INO-5150, C: 2mg INO-5150 + 1mg INO-9012 and D: 8.5mg INO-5150 + 1mg INO-9012. Pts received 4 IM doses of vaccine followed by electroporation on day 0, wks 3, 12 and 24 and were followed for 72 wks. Results: 50/61 (82%) pts completed all visits and treatments were well tolerated with no safety concerns. Median PFS for overall population [N = 61, baseline (D0) PSADT range (mos) 1.5-217.1, median 9.8] and for a subset of pts with D0 PSADT ≤12mos (N = 36) has not yet been reached (FU 3-19 mos). 86% of pts with D0 PSADT ≤12 mos were progression free through 19mos FU. 27 out of 36 (75%) pts with D0 PSADT≤ 12 mos had disease stabilization at wks 27 evidenced by significant improvement in log2PSA change over time (slope) and PSADT from D0 (Slope=0.19 declined to 0.1, PSADT=5.3 improved to 10.1 mos, p = \u3c0.0001). This effect was maintained at wk 72 (Slope=0.09, PSADT=10.6, p = \u3c0.0001). Immunogenicity was observed in 77% (47/61) of pts by multiple immunologic assessments. Patient immunogenicity to INO-5150 as determined by CD38 and Perforin + CD8 T cell immune reactivity correlated with attenuated % PSA rise compared to pts without reactivity (p = 0.05, n = 50). Conclusions: INO-5150 +/- INO-9012 was safe, well tolerated and immunogenic. Clinical efficacy was observed in the patients with D0 PSADT≤ 12 mos as evidenced by a significant dampening of log2PSA change over time and increased PSADT up to 72 weeks FU. Additional genomic analyses are ongoing to further elucidate the correlation of immunologic efficacy and clinical benefit. (NCT02514213)

ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer

Androgen receptor splice variant 7 (AR-V7) is crucial for prostate cancer progression and therapeutic resistance. We show that, independent of ligand, AR-V7 binds both androgen-responsive elements (AREs) and non-canonical sites distinct from full-length AR (AR-FL) targets. Consequently, AR-V7 not only recapitulates AR-FL's partial functions but also regulates an additional gene expression program uniquely via binding to gene promoters rather than ARE enhancers. AR-V7 binding and AR-V7-mediated activation at these unique targets do not require FOXA1 but rely on ZFX and BRD4. Knockdown of ZFX or select unique targets of AR-V7/ZFX, or BRD4 inhibition, suppresses growth of castration-resistant prostate cancer cells. We also define an AR-V7 direct target gene signature that correlates with AR-V7 expression in primary tumors, differentiates metastatic prostate cancer from normal, and predicts poor prognosis. Thus, AR-V7 has both ARE/FOXA1 canonical and ZFX-directed non-canonical regulatory functions in the evolution of anti-androgen therapeutic resistance, providing information to guide effective therapeutic strategies. By cistrome profiling of endogenous androgen receptor (AR) versus an AR splice variant, AR-V7, Cai et al. uncovered non-canonical pathways uniquely targeted by AR-V7 and ZFX, a previously unknown AR-V7 partner. Targeting cofactors (ZFX or BRD4) or non-canonical downstream pathways of AR-V7 provides potential therapeutic ways for treating prostate cancer

Outward expansion of the lunar wake: ARTEMIS observations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95030/1/grl29516.pd

Router-level community structure of the Internet Autonomous Systems

The Internet is composed of routing devices connected between them and organized into independent administrative entities: the Autonomous Systems. The existence of different types of Autonomous Systems (like large connectivity providers, Internet Service Providers or universities) together with geographical and economical constraints, turns the Internet into a complex modular and hierarchical network. This organization is reflected in many properties of the Internet topology, like its high degree of clustering and its robustness. In this work, we study the modular structure of the Internet router-level graph in order to assess to what extent the Autonomous Systems satisfy some of the known notions of community structure. We show that the modular structure of the Internet is much richer than what can be captured by the current community detection methods, which are severely affected by resolution limits and by the heterogeneity of the Autonomous Systems. Here we overcome this issue by using a multiresolution detection algorithm combined with a small sample of nodes. We also discuss recent work on community structure in the light of our results