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Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4-2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.

Drug-drug self-delivery systems serving as both carriers and cargos have been explored as advanced combination chemotherapy strategies to overcome the limitations of the traditional single-drug chemotherapy. However, most known drug-drug self-delivery systems may cause a rapid increase in drug concentration when the single covalent bond is broken, thus leading to high toxicity to organs and low therapeutic efficiency against tumors. To address the above problem, in this study, a novel supramolecular drug-drug complex (SDDC) simultaneously containing both covalent and noncovalent bonds was proposed to realize the sequential release of two drugs in tumor cells for enhanced combination therapy. The SDDC could self-assemble into uniform bilayer supramolecular vesicles (SVs) with a remarkable drug loading capacity and stable drug transport. Notably, the SVs with controlled sequential release ability in tumor cells exhibited a superior synergistic effect and significantly improved therapeutic efficiency with reduced toxicity in

Maximal clique enumeration (MCE) is a fundamental problem in graph theory and is used in many applications, such as social network analysis, bioinformatics, intelligent agent systems, cyber security, etc. Most existing MCE algorithms focus on improving the efficiency rather than reducing the output size. The output unfortunately could consist of a large number of maximal cliques. In this paper, we study how to report a summary of less overlapping maximal cliques. The problem was studied before, however, after examining the pioneer approach, we consider it still not satisfactory. To advance the research along this line, our paper attempts to make four contributions: (a) we propose a more effective sampling strategy, which produces a much smaller summary but still ensures that the summary can somehow witness all the maximal cliques and the expectation of each maximal clique witnessed by the summary is above a predefined threshold; (b) we prove that the sampling strategy is optimal under certain optimality conditions; (c) we apply clique-size bounding and design new enumeration order to approach the optimality conditions; and (d) to verify experimentally, we test eight real benchmark datasets that have a variety of graph characteristics. The results show that our new sampling strategy consistently outperforms the state-of-the-art approach by producing smaller summaries and running faster on all the datasets., Comment: 20 pages, 80 figures

Background: De-regulation of Wnt signaling pathways has been shown to be associated with progression of castration-resistant prostate cancer and more recently, studies indicate that both canonical and non-canonical Wnt pathways may mediate resistance to anti-androgen therapies such as enzalutamide. However, the mechanisms by which Wnt signaling is altered in prostate cancer remain poorly understood. Wnt pathway function begins with Wnt biogenesis and secretion from Wnt signal sending cells. While previous studies have investigated downstream mechanisms of Wnt pathway alterations in prostate cancer, little is known on the role of Wnt secretion mediating proteins. Wntless (WLS) is thought to be essential for the secretion of all Wnts. In this study, we sought to understand the role of WLS in prostate cancer. Methods: RNA-seq and gene set enrichment analysis were used to understand expression profile changes in enzalutamide-resistant C4-2B-MDVR (MDVR) cells versus parental C4-2B cells. Quantitative-PCR and western blot were used to confirm RNA-seq data and to assess expression changes of gene targets of interest. Rv1 cells were used as a separate model of enzalutamide-resistant prostate cancer. RNAi was used to inhibit WLS expression. Cell viability, colony formation, and PSA ELISA assays were used to assess cell growth and survival. Results: Transcriptomic profiling revealed enriched Wnt pathway signatures in MDVR versus parental C4-2B cells. We further show that MDVR cells upregulate Wnt signaling and overexpress WLS. Inhibition of WLS decreases Wnt signaling, markedly attenuates prostate cancer cell viability, induces apoptosis, and re-sensitizes enzalutamide-resistant cells to enzalutamide treatment. Lastly, we show that inhibition of WLS reduces AR and AR-variants expression and downstream signaling. Conclusions: Our findings support a role for WLS in the progression of prostate cancer to a treatment-resistant state. Further efforts to understand Wnt signaling pathway alterations in this disease may lead to the development of novel treatments.

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257-66. ©2017 AACR.

The current first-line treatment for advanced metastatic prostate cancer, i.e. docetaxel-based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti-prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase-I Clinical Trial. Human metastatic, androgen-independent C4-2 prostate cancer cells and NOD-SCID mice bearing PTEN-deficient, metastatic and PSA-secreting, patient-derived subrenal capsule LTL-313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4-2 cell replication in a dose-dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti-tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel-based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.

PurposeUse of enzalutamide has improved the treatment of advanced prostate cancer. However, resistance to enzalutamide can develop frequently in initial responders. This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide.Experimental designSensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, ELISA, and Western blotting were performed to detect expression levels of IL-6, c-Myc, survivin, and AR. Expression of Stat3 was downregulated using siRNA specific to Stat3. ChIP assay was performed to examine recruitment of AR to the PSA promoter.ResultsProstate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes. Down regulation of Stat3 led to an increase in sensitivity of prostate cancer cells to enzalutamide. Overexpression of constitutively active Stat3 in prostate cancer cells induced resistance to enzalutamide treatment. Constitutively active Stat3 also enhanced the recruitment of AR to PSA promoter which could not be disrupted by enzalutamide. The Stat3 inhibitor AG490 reversed enzalutamide resistance in prostate cancer cells, while combination treatment with enzalutamide and AG490 significantly inhibited cell growth and induced cell apoptosis.ConclusionsThis study demonstrates that the autocrine IL-6 pathway induces enzalutamide resistance in prostate cancer cells via the constitutive activation of Stat3. Co-targeting IL6-Stat3 pathway with enzalutamide may be utilized for treatment of advanced prostate cancer.

IntroductionTreatment of primary prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually progresses to grow in a castration-resistant state due to aberrant activation of androgen receptor (AR). Understanding the mechanisms leading to the aberrant activation of AR is critical to develop effective therapy. We have previously identified Rho GDP Dissociation Inhibitor alpha (GDIα) as a novel suppressor in prostate cancer. In this study, we examine the effect of GDIα on AR signaling in prostate cancer cells.MethodsGDIα was transiently or stably transfected into several prostate cancer cell lines including LNCaP, C4-2, CWR22Rv1, and DU145. The regulation of AR expression by GDIα was analyzed by qRT-PCR and Western blot. AR activity was measured by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Immunofluorescence assay was performed to study AR nuclear translocation. The interaction between GDIα and AR was examined by co-immunoprecipitation assays.ResultsIn this study, we have identified GDIα as a negative regulator of AR signaling pathway. Overexpression of GDIα downregulates AR expression at both mRNA and protein levels. Overexpression of GDIα is able to prevent AR nuclear translocation and inhibit transactivation of AR target genes. Co-immunoprecipitation assays showed that GDIα physically interacts with the N-terminal domain of AR.ConclusionsGDIα suppresses AR signaling through inhibition of AR expression, nuclear translocation, and recruitment to androgen-responsive genes. GDIα regulatory pathway may play a critical role in regulating AR signaling and prostate cancer growth and progression.

While keyword query empowers ordinary users to search vast amount of data, the ambiguity of keyword query makes it difficult to effectively answer keyword queries, especially for short and vague keyword queries. To address this challenging problem, in this paper we propose an approach that automatically diversifies XML keyword search based on its different contexts in the XML data. Given a short and vague keyword query and XML data to be searched, we firstly derive keyword search candidates of the query by a classifical feature selection model. And then, we design an effective XML keyword search diversification model to measure the quality of each candidate. After that, three efficient algorithms are proposed to evaluate the possible generated query candidates representing the diversified search intentions, from which we can find and return top-$k$ qualified query candidates that are most relevant to the given keyword query while they can cover maximal number of distinct results.At last, a comprehensive evaluation on real and synthetic datasets demonstrates the effectiveness of our proposed diversification model and the efficiency of our algorithms.

In this paper, a new high precision focused word sense disambiguation (WSD) approach is proposed, which not only attempts to identify the proper sense for a word but also provides the probabilistic evaluation for the identification confidence at the same time. A novel Instance Knowledge Network (IKN) is built to generate and maintain semantic knowledge at the word, type synonym set and instance levels. Related algorithms based on graph matching are developed to train IKN with probabilistic knowledge and to use IKN for probabilistic word sense disambiguation. Based on the Senseval-3 all-words task, we run extensive experiments to show the performance enhancements in different precision ranges and the rationality of probabilistic based automatic confidence evaluation of disambiguation. We combine our WSD algorithm with five best WSD algorithms in senseval-3 all words tasks. The results show that the combined algorithms all outperform the corresponding algorithms.

Workflow-based web applications are important in workflow management systems as they interact with users of business processes. With the Model-driven approach, user interfaces (UIs) of these applications can be partially generated based on functional and data requirements obtained from underlying process models. In traditional activity-centric modelling approaches, data models and relationships between tasks and data are not clearly defined in the process model; thus, it is left to UI modellers to manually identify data requirement in generated UIs. We observed that artifact-centric approaches can be applied to address the above problems. However, it brings in challenges to automatically generate UIs due to the declarative manner of describing the processes. In this paper, we propose a model-based automatic UI generation framework with related algorithms for deriving UIs from process models.

Au/TiO2 nanocomposite particles were synthesized by a method based on intense X-ray irradiation without adding any reducing agent or stabilizer. The nanocomposite exhibits promising photocatalytic and biological properties at physiologically relevant concentration ([Au] = 0.028 mM, [TiO2] = 0.5 mM). The structure and photocatalysis were examined by X-ray diffraction, electron microscopy and ultraviolet-visible spectroscopy demonstrating that gold nanoparticles of 2-5 nm size were successfully deposited on TiO2 nanoparticle surfaces. The nanocomposite exhibited good colloidal stability within a typical cellular environment and was nontoxic to cancer cell according to evaluations under controlled conditions. The Au/TiO2 nanoparticles were also found to enhance the photocatalytic efficiency of UV radiation and even more that of X-ray radiation. In vitro studies indicated that the cell-killing effect under X-ray irradiation is more pronounced with the addition of Au/TiO2 nanoparticles than of bare TiO2 nanoparticles. (C) 2009 Elsevier B.V. All rights reserved.

Using reputation system to help determine trust worthiness of online entities is a widely adopted method in the current web environment. Reputation bootstrapping, known as determining a default reputation value for a newcomer, is an important issue which currently is short of a proper solution. In this paper, we introduce a new concept, marginal reputation utility, based on which we discuss the relationship between trust and reputation and construct a reputation boot strapping framework that is universally applicable to different reputation models and systems. We use experiments to test the effectiveness of the proposed framework upon different reputation models, which shows satisfactory results. Refereed/Peer-reviewed

In this paper, we study the problem how to efficiently evaluate a set of contained rewritings on materialized views. Previous works focused on how to find a set of contained rewritings given a view and a query, but did not address how to evaluate the rewritings on materialized views. To evaluate a potential exponential number of contained rewritings, we design two algorithms, a basic algorithm and an optimized algorithm. Both algorithms are built on the observation that the exponential number of contained rewritings are actually composed by a linear number of component patterns. In the optimized algorithm, we further design four important pruning rules and several heuristic rules that can effectively reduce the number of component patterns we need to evaluate. The experiments demonstrate the efficiency of our algorithms. Refereed/Peer-reviewed

Substantial improvements in the nanofabrication and characteristics of gold Fresnel zone plates yielded unprecedented resolution levels in hard-x-ray microscopy. Tests performed on a variety of specimens with 8-10keV photons demonstrated a first-order lateral resolution below 40nm based on the Rayleigh criterion. Combined with the use of a phase contrast technique, this makes it possible to view features in the 30nm range; good-quality images can be obtained at video rate, down to 50ms/frame. The important repercussions on materials science, nanotechnology, and the life sciences are discussed.