bluuebunny/crossref_metadata_2025 huggingface dataset:
On a Semiclassical Limit of Loop Space Quantum Mechanics
Authors: Mukhopadhyay Partha
Published: May 2013

Following earlier work, we view two-dimensional nonlinear sigma model as single particle quantum mechanics in the free loop space of the target space. In a natural semiclassical limit of this model, the wavefunction localizes on the submanifold of vanishing loops. One would expect that the semiclassical expansion should be related to the tubular expansion of the theory around the submanifold and effective dynamics on the submanifold is obtainable using Born-Oppenheimer approximation. We develop a framework to carry out such an analysis at the leading order. In particular, we show that the linearized tachyon effective equation is correctly reproduced up to divergent terms all proportional to the Ricci scalar. The steps are as follows: first we define a finite dimensional analogue of the loop space quantum mechanics (LSQM) where we discuss its tubular expansion and how that is related to a semiclassical expansion of the Hamiltonian. Then we study an explicit construction of the relevant tubular neighborhood in loop space using exponential maps. Such a tubular geometry is obtained from a Riemannian structure on the tangent bundle of target space which views the zero-section as a submanifold admitting a tubular neighborhood. Using this result and exploiting an analogy with the toy model, we arrive at the final result for LSQM.
Economic Dispatch Using Parameter-Setting-Free Harmony Search
Authors: Geem Zong Woo
Published: May 2013

Economic dispatch is one of the popular energy system optimization problems. Recently, it has been solved by various phenomenon-mimicking metaheuristic algorithms such as genetic algorithm, tabu search, evolutionary programming, particle swarm optimization, harmony search, honey bee mating optimization, and firefly algorithm. However, those phenomenon-mimicking problems require a tedious and troublesome process of algorithm parameter value setting. Without a proper parameter setting, good results cannot be guaranteed. Thus, this study adopts a newly developed parameter-setting-free technique combined with the harmony search algorithm and applies it to the economic dispatch problem for the first time, obtaining good results. Hopefully more researchers in energy system fields will adopt this user-friendly technique in their own problems in the future.
On-Farm Evaluation of Beans Varieties for Adaptation and Adoption in Kigoma Region in Tanzania
Authors: Bucheyeki Tulole Lugendo , Mmbaga Tuaeli Emil
Published: May 2013

On-farm beans research was carried out in Kigoma region, Tanzania. Objectives were to evaluate beans varieties for yield under farmers’ management conditions and to assess farmers’ preferences on beans varieties. Nine farmers from three villages with three farmers per village participated in beans trials. A randomized complete block design with five plots per replications was used to evaluate five bean varieties: Lyamungo 90, Jesca, Uyole 94, Kablanketi, and Kigoma yellow (control). Beans were planted on a 10 m × 2.5 m plot at a spacing of 50 cm × 20 cm. Data was subjected to analysis using ANOVA table in GenStat statistical computer software. Three villages × three seasons resulted in nine environments which were used for stability analysis. Farmers developed their criterion to assess the performance and acceptability of beans varieties. Lyamungo 90 and Jesca ranked high and outyielded other varieties with an average yield of 1430.00 and 1325.67 kg ha−1, respectively. Genotypes sum of squares accounted for the most of the variability (89.12%). Introduction of high yielding bean varieties with the desired farmers’ traits is expected to revamp beans production and contribute to the improved food security in Tanzania.
A Patient Presenting with Bilateral Lung Lesions, Pleural Effusion, and Proteinuria
Authors: Samara Katerina D. , Papadogiannis Giorgos , Nicholson Andrew G. , Magkanas Eleutherios , Stylianou Konstantinos , Siafakas Nikolaos , Antoniou Katerina M.
Published: May 2013

Diagnosis and management of a systemic vasculitis are among the most demanding challenges in clinical medicine. A patient with a past history of cryptogenic organizing pneumonia presents with new bilateral lung lesions, unilateral pleural effusion, and significant proteinuria. The patient tested p-ANCA and anti-MPO positive but c-ANCA negative. A diagnosis of granulomatosis with polyangiitis GPA was reached after performing both renal and lung biopsies. Step-by-step differential diagnosis and management are discussed.
Attitude and Altitude Controller Design for Quad-Rotor Type MAVs
Authors: Wang Wei , Ma Hao , Xia Min , Weng Liguo , Ye Xuefei
Published: May 2013

Micro air vehicles (MAVs) have a wide application such as the military reconnaissance, meteorological survey, environmental monitoring, and other aspects. In this paper, attitude and altitude control for Quad-Rotor type MAVs is discussed and analyzed. For the attitude control, a new method by using three gyroscopes and one triaxial accelerometer is proposed to estimate the attitude angle information. Then with the approximate linear model obtained by system identification, Model Reference Sliding Mode Control (MRSMC) technique is applied to enhance the robustness. In consideration of the relatively constant altitude model, a Linear Quadratic Gaussian (LQG) controller is adopted. The outdoor experimental results demonstrate the superior stability and robustness of the controllers.
Mobile Personal Health System for Ambulatory Blood Pressure Monitoring
Authors: Mena Luis J. , Felix Vanessa G. , Ostos Rodolfo , Gonzalez Jesus A. , Cervantes Armando , Ochoa Armando , Ruiz Carlos , Ramos Roberto , Maestre Gladys E.
Published: May 2013

The ARVmobile v1.0 is a multiplatform mobile personal health monitor (PHM) application for ambulatory blood pressure (ABP) monitoring that has the potential to aid in the acquisition and analysis of detailed profile of ABP and heart rate (HR), improve the early detection and intervention of hypertension, and detect potential abnormal BP and HR levels for timely medical feedback. The PHM system consisted of ABP sensor to detect BP and HR signals and smartphone as receiver to collect the transmitted digital data and process them to provide immediate personalized information to the user. Android and Blackberry platforms were developed to detect and alert of potential abnormal values, offer friendly graphical user interface for elderly people, and provide feedback to professional healthcare providers via e-mail. ABP data were obtained from twenty-one healthy individuals (>51 years) to test the utility of the PHM application. The ARVmobile v1.0 was able to reliably receive and process the ABP readings from the volunteers. The preliminary results demonstrate that the ARVmobile 1.0 application could be used to perform a detailed profile of ABP and HR in an ordinary daily life environment, bedsides of estimating potential diagnostic thresholds of abnormal BP variability measured as average real variability.
Dynamical Complexity of a Spatial Phytoplankton-Zooplankton Model with an Alternative Prey and Refuge Effect
Authors: Zhang Weiwei , Zhao Min
Published: May 2013

The spatiotemporal dynamics of a phytoplankton-zooplankton model with an alternative prey and refuge effect is investigated mathematically and numerically. The stability of the equilibrium point and the traveling wave solution of the phytoplankton-zooplankton model are described based on theoretical mathematical work, which provides the basis of the numerical simulation. The numerical analysis shows that refuges have a strong effect on the spatiotemporal dynamics of the model according to the pattern formation. These results may help us to understand prey-predator interactions in water ecosystems. They are also relevant to research into phytoplankton-zooplankton ecosystems.
Geographical Flushing of the Children’s Face: A New Clinical Entity?
Authors: Jinnin Masatoshi , Fukushima Satoshi , Inoue Yuji , Ihn Hironobu
Published: May 2013

A lot of skin diseases can occur on children’s faces. We report two children with unique flushing on their faces, sometimes accompanied with headache. Their eruption did not meet various differential diagnoses. Many dermatologists may have seen a similar condition but did not think much about it. Thus, it should be worth regarding such symptom as the benign new clinical entity, which may comfort patients with similar conditions and merit further attention in clinical practice.
High-Accuracy Programmable Timing Generator with Wide-Range Tuning Capability
Authors: Chu Ting-Li , Yu Sin-Hong , Hwang Chorng-Sii
Published: May 2013

In this paper, a high-accuracy programmable timing generator with wide-range tuning capability is proposed. With the aid of dual delay-locked loop (DLL), both of the coarse- and fine-tuning mechanisms are operated in precise closed-loop scheme to lessen the effects of the ambient variations. The timing generator can provide sub-gate resolution and instantaneous switching capability. The circuit is implemented and simulated in TSMC 0.18 μm 1P6M technology. The test chip area occupies 1.9 mm2. The reference clock cycle can be divided into 128 bins by interpolation to obtain 14 ps resolution with the clock rate at 550 MHz. The INL and DNL are within −0.21~+0.78 and −0.27~+0.43 LSB, respectively.
Numerical Analysis of Flow around a Moving Object by an Immersed Boundary Method with the Level Set Method
Authors: Iijima Atsuki , Sato Tomomitsu , Tagawa Toshio
Published: May 2013

We developed a new immersed boundary method which has various advantages, such as accuracy, flexibility, and rapidness combining with the level set method. We numerically demonstrated some typical examples, such as flows around a sphere, an ellipsoid, a flapping ellipsoid, and a windmill. We calculated coefficients of drag in those problems and visualized vortical structures and Powell sound sources for the various Reynolds number and then compared our results with some previous researches.
Detailed Simulation of Complex Hydraulic Problems with Macroscopic and Mesoscopic Mathematical Methods
Authors: Biscarini Chiara , Di Francesco Silvia , Nardi Fernando , Manciola Piergiorgio
Published: May 2013

The numerical simulation of fast-moving fronts originating from dam or levee breaches is a challenging task for small scale engineering projects. In this work, the use of fully three-dimensional Navier-Stokes (NS) equations and lattice Boltzmann method (LBM) is proposed for testing the validity of, respectively, macroscopic and mesoscopic mathematical models. Macroscopic simulations are performed employing an open-source computational fluid dynamics (CFD) code that solves the NS combined with the volume of fluid (VOF) multiphase method to represent free-surface flows. The mesoscopic model is a front-tracking experimental variant of the LBM. In the proposed LBM the air-gas interface is represented as a surface with zero thickness that handles the passage of the density field from the light to the dense phase and vice versa. A single set of LBM equations represents the liquid phase, while the free surface is characterized by an additional variable, the liquid volume fraction. Case studies show advantages and disadvantages of the proposed LBM and NS with specific regard to the computational efficiency and accuracy in dealing with the simulation of flows through complex geometries. In particular, the validation of the model application is developed by simulating the flow propagating through a synthetic urban setting and comparing results with analytical and experimental laboratory measurements.
Synergistic Induction of Adaptive Antitumor Immunity by Codelivery of Antigen with α-Galactosylceramide on Exosomes
Authors: Gehrmann Ulf , Hiltbrunner Stefanie , Georgoudaki Anna-Maria , Karlsson Mikael C. , Näslund Tanja I. , Gabrielsson Susanne
Published: May 2013

Exosomes and the invariant NKT (iNKT) immune cell ligand α-galactosylceramide (αGC) may offer novel tools for cancer immunotherapy. In this study, we investigated whether exosomes loaded with αGC can activate iNKT cells and potentiate a cancer-specific adaptive immune response. αGC loaded exosomes readily activated iNKT cells both in vitro and in vivo. Exosomes loaded with αGC plus the model antigen ovalbumin (OVA) induced potent NK and γδ T-cell innate immune responses, and they also synergistically amplified T- and B-cell responses that were OVA specific. In contrast to soluble αGC, which anergizes iNKT cells, we found that αGC/OVA-loaded exosomes did not induce iNKT cell anergy but were more potent than soluble αGC + OVA in inducing adaptive immune responses. In an OVA-expressing mouse model of melanoma, treatment of tumor-bearing mice with αGC/OVA-loaded exosomes decreased tumor growth, increased antigen-specific CD8+ T-cell tumor infiltration, and increased median survival, relative to control mice immunized with soluble αGC + OVA alone. Notably, an additional injection of αGC/OVA-loaded exosomes further augmented the treatment effects. Our findings show that exosomes loaded with protein antigen and αGC will activate adaptive immunity in the absence of triggering iNKT-cell anergy, supporting their application in the design of a broad variety of cancer immunotherapy trials. Cancer Res; 73(13); 3865–76. ©2013 AACR.
Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer
Authors: André Fabrice , Bachelot Thomas , Campone Mario , Dalenc Florence , Perez-Garcia Jose M. , Hurvitz Sara A. , Turner Nicholas , Rugo Hope , Smith John W. , Deudon Stephanie , Shi Michael , Zhang Yong , Kay Andrea , Graus Porta Diana , Yovine Alejandro , Baselga José
Published: May 2013

Purpose: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.

Experimental Design: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2–negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).

Results: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway–amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway–amplified breast cancer.

Conclusion: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification. Clin Cancer Res; 19(13); 3693–702. ©2013 AACR.
Abstract A12: Chromatin accessibility reveals insight into androgen receptor activation and transcriptional specificity
Authors: Tewari Alok , Yardimci Galip , Shibata Yoichiro , Sheffield Nathan , Song Lingyun , Taylor Barry , Coetzee Gerhard , Furey Terrence , Crawford Gregory , Febbo Phillip
Published: May 2013

Epigenetic mechanisms such as chromatin accessibility and histone modifications impact transcription factor binding to DNA and transcriptional specificity. The androgen receptor (AR), a master regulator of prostate cancer initiation and progression, acts primarily through ligand-activated transcription of target genes. By combining deep sequencing with DNase I hypersensitivity analysis (DNase-seq) and RNA analysis (mRNA-seq) we assessed genome-wide chromatin structure and transcription and combined this data with publicly available AR chromatin immunoprecipitation data (AR ChIP-seq). We find that 72% of DNase I hypersensitive sites (DHS) overlap each other before and after androgen in LNCaP cells. Interestingly, in regions of increased chromatin accessibility with androgen induction, the canonical AR DNA recognition motif is enriched. Comparing identified DHS to AR binding sites from three different data sets consistently reveals that 50% of AR binding overlaps a DHS in induced cells. Of those sites with both DHS and AR binding, approximately half are available prior to androgen induction (i.e., “primed”) and half open in response to androgen stimulation. This contrasts with the glucocorticoid receptor (GR), which was recently reported to bind to DNA primarily in regions that are accessible to nuclease cleavage prior to ligand activation. Our mRNA-seq analysis discovered 339 genes regulated by AR activation (FDR < 0.05), including 16 of the 19 most commonly identified AR-mediated genes in several other studies. Importantly, we find that regions of increased chromatin accessibility are significantly associated with genes identified as AR-regulated by mRNA-seq. Finally, base pair resolution of the DNase-seq signal reveals distinct footprinting patterns associated with the AR-DNA interaction. Analysis of chromatin structure, AR binding, and transcription prior to and following androgen induction demonstrates that AR activation by ligand induces genome-wide changes in chromatin accessibility, these changes correspond to AR binding to the genome, and they impact AR-mediated transcriptional response. These findings suggest that interaction between the AR and DNA alters chromatin structure and transcriptional specificity.

Citation Format: Alok Tewari, Galip Yardimci, Yoichiro Shibata, Nathan Sheffield, Lingyun Song, Barry Taylor, Gerhard Coetzee, Terrence Furey, Gregory Crawford, Phillip Febbo. Chromatin accessibility reveals insight into androgen receptor activation and transcriptional specificity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A12.
Abstract A34: Critical and reciprocal regulation of SLUG-KLF4 and SLUG-miR-1/miR-200b in TGFβ-initiated prostate cancer EMT
Authors: Liu Yen-Nien , Martin Philip , Kelly Kathleen , Yin Juan Juan , Abou-Kheir Wassim , Hynes Paul , Fang Lei , Casey Orla , Yi Ming , Seng Victoria , Tillman Heather
Published: May 2013

Epithelial-mesenchymal transition (EMT) is implicated in various pathological processes within the prostate, including benign prostate hyperplasia (BPH) and prostate cancer progression. However, an ordered sequence of signaling events initiating carcinoma-associated EMT has not been established. We have used a mouse model of Pten and TP53 null prostate adenocarcinoma, which undergoes progressive TGFβ-dependent EMT leading eventually to sarcomtoid carcinoma formation. Sarcomatoid carcinomas are characterized by various mesenchymal lineages and bone formation.

In this model, SLUG is the dominant regulator of EMT initiation in vitro and in vivo. Depletion of Slug inhibited EMT. We determined that TGFβ-stimulated KLF4 degradation is the mechanism of SLUG induction, and the introduction of a degradation-resistant mutant of KLF4 inhibited EMT. We show that KLF4 and another epithelial determinant, FOXA1, are direct transcriptional inhibitors of SLUG expression in mouse and human prostate cancer cells. In addition, SLUG-dependent binding of polycomb repressive complexes to the Klf4 and Foxa1 promoters was demonstrated to inhibit transcription of these epithelial transcription factors, suggesting that SLUG expression helps to consolidate mesenchymal commitment. Analysis of tissue arrays demonstrated decreased KLF4 and increased SLUG expression in advanced stage primary prostate cancer, substantiating the involvement of the EMT signaling events described in model systems.

As microRNAs are pleiotropic regulators of differentiation and tumorigenesis, we evaluated miR expression associated with tumorigenesis and EMT. Mir-1 and mir-200 were reduced with progression of prostate adenocarcinoma, and we identified Slug as one of the phylogenetically-conserved targets of these miRs. We established that SLUG is a direct repressor of miR-1 and miR-200 transcription. Thus, SLUG and miR-1/miR-200 act in a self-reinforcing regulatory loop leading to amplification of EMT. Depletion of Slug inhibited EMT during tumorigenesis, while forced expression of miR-1 or miR-200 inhibited both EMT and tumorigenesis in human and mouse model systems. Various miR targets were analyzed, and our findings suggest that miR-1 has roles in regulating EMT and mesenchymal differentiation through Slug and functions in tumor-suppressive programs by regulating additional targets.

Citation Format: Yen-Nien Liu, Philip Martin, Kathleen Kelly, Juan Juan Yin, Wassim Abou-Kheir, Paul Hynes, Lei Fang, Orla Casey, Ming Yi, Victoria Seng, Heather Tillman. Critical and reciprocal regulation of SLUG-KLF4 and SLUG-miR-1/miR-200b in TGFβ-initiated prostate cancer EMT [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A34.
Abstract A38: Maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer
Authors: Kuner Ruprecht , Sültmann Holger , Fälth Maria , Pressinotti Nicole Chui , Brase Jan Christoph , Balaguer-Puig Sabrina , Schäfer Georg , Bartsch Georg , Steiner Eberhard , Klocker Helmut
Published: May 2013

Loss of cell cycle control is a prerequisite for cancer onset and progression. In prostate cancer, increased activity of cell cycle proliferating genes has been associated with prognostic parameters such as biochemical relapse and survival. The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop targeted therapy approaches.

We analyzed prostate cancer and corresponding benign tissues (n = 98) using microarrays. The comparison of high and low grade tumors (Gleason score ≥ 4+3 vs. ≤ 3+4) revealed 144 differentially expressed genes (p < 0.05), which are associated with a severe disease course. Out of these, 15 genes are assigned to cell cycle process. The gene maternal embryonic leucine zipper kinase (MELK) was identified to be highly correlated with cell cycle and prostate cancer associated genes like UBE2C, TOP2A, CCNB2 and AURKB, and was therefore further included into validation and functional experiments. The association between MELK gene expression and high-risk prostate cancer was validated in an independent patient cohort (p < 0.005, n = 79). Furthermore, our finding was supported by a public microarray dataset showing a higher MELK expression in prostate cancer patients with biochemical relapse. Immunohistochemical analysis using a tissue microarray (n = 94) revealed increased MELK protein expression in prostate cancer tissues of high Gleason scores. Knockdown of MELK decreased cell viability in PC3 and LNCaP cells. Microarray analysis upon MELK knockdown experiments revealed downstream processes like chromatin modification, embryonic development and cell migration. Our findings indicate that the protein serine/threonine kinase MELK represents a promising marker for advanced prostate cancer disease.

Citation Format: Ruprecht Kuner, Holger Sültmann, Maria Fälth, Nicole Chui Pressinotti, Jan Christoph Brase, Sabrina Balaguer-Puig, Georg Schäfer, Georg Bartsch, Eberhard Steiner, Helmut Klocker. Maternal embryonic leucine zipper kinase (MELK) is upregulated in highgrade prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A38.
Abstract A44: Practical habit and herbalism knowledge for prostate cancer-related problems among Bangladeshi immigrants to the United States: The experience of Bronx borough in New York City
Authors: Mollik Md. Ariful Haque , Trainor Douglas James
Published: May 2013

In the United States, herbalism use is most prevalent among the immigrants. Very few studies have been conducted in the Bangladeshi immigrants to the United States of America on herbalism knowledge. Therefore a gap in knowledge exists. This study deals with the field observations recorded on the therapeutic applications of the herbalism used in prostate cancer related problems by the Bangladeshi immigrants of Bronx borough in the New York City. Fieldwork was carried out from August 2011 to November 2011. Semi structured interviews and guided field-walk methods were used to gather information on herbalism used by the Bangladeshi immigrants. Along with herbalism, information was also collected on herbalism parts used, formulations, and dosages. Information on phytochemicals as well as pharmacologic activity studies on this herbalism (if any) was obtained from several data bases. The collected information indicates that the following herbalism is used to treat prostate-cancer related problems: Swertia chirata Buch.-Ham. ex Wall., Zingiber officinale Roscoe, Citrus aurantiifolia (Christm.) Swingle, Aloe vera (L.) Burm.f., Plantago major L., Cocos nucifera L., Apis dorsata Fabricius, Allium sativum L., Ocimum gratissimum L., Saccharum officinarum L., Allium cepa L., Momordica charantia L., Areca catechu L., Piper nigrum L., Nigella sativa L., Lactuca sativa L., Ipomoea aquatica Forssk., Persea americana Mill., Panax ginseng C.A.Mey., Carica papaya L., Piper betle L., Bryophyllum pinnatum (Lam.) Oken, Ficus racemosa L., Azadirachta indica A.Juss., Camellia sinensis (L.) Kuntze, Citrullus lanatus (Thunb.) Matsum. & Nakai, Solanum melongena L., Ananas comosus (L.) Merr., Ophicephalus striatus Bloch, Zea mays L., Borassus flabellifer L., Cucumis sativus L., Vigna mungo (L.) Hepper, Brassica napus L., Amaranthus tricolor L., and Aegle marmelos (L.) Corrêa. This study further highlighted the importance of gathering such ethnopharmacology information for effective conservation of the Bangladeshi immigrants' medicinal knowledge and medicinally important herbalism. It is important that modern scientific studies be conducted on this herbalism towards isolation and identification of compounds through which multi-drug resistant prostate cancer related problems can be effectively treated.

Note: This abstract was not presented at the conference because the presenter was unable to attend.

Citation Format: Md. Ariful Haque Mollik, Douglas James Trainor. Practical habit and herbalism knowledge for prostate cancer-related problems among Bangladeshi immigrants to the United States: The experience of Bronx borough in New York City [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A44.
Abstract A70: PTEN loss induces selective upregulation of CXCL8 signaling to modulate survival and resistance to radiation
Authors: Coulter Jonathan , Maxwell Pamela , McKechnie Melanie , Neisen Jessica , Kennedy Richard , Salto-Tellez Manuel , Albanese Chris , Waugh David
Published: May 2013

PTEN is a haplo-insufficient tumor suppressor and the most frequently mutated gene in prostate cancer (CaP). Moreover, loss of PTEN expression arising from allele deletion or promoter methylation is prevalent early disease. The objective of our study was to characterize how the genetic instability and/or stress-induced signaling arising from PTEN loss modulated the expression of clinically-relevant pro-inflammatory chemokines. Transient (siRNA) or prolonged (shRNA) repression of PTEN resulted in increased transcription-mediated increases in expression of CXCL8 and its receptors, CXCR1 and CXCR1 in DU145 and 22Rv1 cells. Stress-induced expression of CXCL8, CXCR1 and CXCR2 was greater in magnitude and duration in PTEN-null PC3 and LNCaP cells, in contrast to the dampened response observed in PTEN-expressing cells. PTEN had no effect on basal or stress-induced expression of CCL2, CXCL12 or their receptors in prostate cancer cells. Moroever, the efficacy of autocrine CXCL8 signaling to induce HIF-1 and NF-κB transcription was also greater in magnitude and duration in PTEN-null prostate cancer cells or following siRNA-mediated PTEN knockdown in DU145 and 22Rv1 cells. Consistent with in vitro data, we observed increased expression of the orthologous murine chemokine KC in atypical cytological features of PTEN+/− prostate tissue relative to normal epithelium in PTENWT glands. Finally, siRNA or shRNA-mediated attenuation of CXCL8 signaling selectively decreased the viability of CaP cells harboring partial or complete PTEN-loss. Furthermore, the knockdown of CXCL8 signaling potentiated the sensitivity of PTEN-depleted prostate cancer cells to clinicallyrelevant doses of ionozing radiation. We conclude that there is a selective upregulation of CXCL8 signaling in PTEN-deficient prostate epithelium, which contributes to the growth, survival and reduced therapeutic sensitivity of these cells.

Citation Format: Jonathan Coulter, Pamela Maxwell, Melanie McKechnie, Jessica Neisen, Richard Kennedy, Manuel Salto-Tellez, Chris Albanese, David Waugh. PTEN loss induces selective upregulation of CXCL8 signaling to modulate survival and resistance to radiation [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A70.
Abstract B29: A meta-analysis of racial disparities in the association between 8q24 and prostate cancer risk
Authors: Price Douglas K. , Troutman Sarah M. , Sissung Tristan M. , Cropp Cheryl , Venzon David J. , Spencer Shawn D. , Figg William D.
Published: May 2013

Purpose: The aim of this meta-analysis was to elucidate potential racial disparities in the association between single nucleotide polymorphisms (SNPs) and prostate cancer risk.

Background: Racial disparities in the incidence of prostate cancer exist but remain unexplained. Recent studies implicate SNPs within the 8q24 region as risk factors for prostate cancer and the frequency of variant alleles at these SNPs appear to differ by race.

Methods: Twenty-nine studies of seven SNPs and one microsatellite marker located within the 8q24 region were included in the meta-analyses. Allelic odds ratio (OR) values and confidence intervals were calculated using the Mantel-Haenszel test. This test assumes homogeneity so the Breslow-Day test was first used to determine whether or not the assumption of homogeneity was valid in each population.

Results: Prostate cancer risk was associated with the following SNPs in all included races: rs6983267, rs1447295, rs6983561, rs7837688, rs16901979, and DG8S737(-8). However, race-dependent differences were detected in (1) baseline allele frequencies, (2) degree of risk conferred, and (3) predictive power relative to the other SNPs.

Conclusions: The inheritance of 8q24 polymorphisms may in part account for racial disparities in the incidence of prostate cancer.

Citation Format: Douglas K. Price, Sarah M. Troutman, Tristan M. Sissung, Cheryl Cropp, David J. Venzon, Shawn D. Spencer, William D. Figg. A meta-analysis of racial disparities in the association between 8q24 and prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B29.
Abstract B32: Evaluating genetic risk for prostate cancer among Japanese Americans and Latinos: The Multiethnic Cohort Study
Authors: Cheng Iona C. , Stram Daniel O. , Kolonel Laurence N. , Henderson Brian E. , Marchand Loïc Le , Haiman Christopher A. , Chen Gary K. , He Jing , Wan Peggy , Sheng Xin , Pooler Loreall C. , Wilkens Lynne R. , Monroe Kristine R.
Published: May 2013

Prostate cancer displays dramatic differences in incidence rates across racial/ethnic groups. The genetic basis of prostate cancer may depend in part on race/ethnicity, which may partially account for the variability in prostate cancer rates across racial/ethnic groups. To search for novel risk variants for prostate cancer, within the Multiethnic Cohort Study we conducted a genome-wide association study of men of Japanese and Latino ancestry, two populations that have a lower burden of this disease. In addition, we tested established risk variants for prostate cancer and utilized these variants to develop genetic risk models of prostate cancer. For Japanese Americans (case/controls=1,033/1042), we identified 69 SNPs associated with prostate cancer risk at P < 1.0×10-4 outside of known risk regions. The most notable association was seen with rs1093117 at chromosome 2 (P=1.23×0-7). For 57 of the established risk variants for prostate cancer, 20 variants were significantly associated with prostate cancer in Japanese Americans. The cumulative effect of these risk alleles resulted in a 12% increased risk of disease for each additional allele (P=2.08×10-25), with Japanese American men in the top quartile of the risk allele distribution having a 3.2-fold increased risk of prostate cancer compared to those in the lowest quartile (P = 8.47×10-20). For Latinos (cases/controls=1,043/1,057), outside of known risk regions, 56 SNPs were associated with prostate cancer risk at P < 1.0×10-4 and rs4240731 at chromosome 12 was most strongly associated with disease (P = 2.60×10-6). For the 57 risk variants for prostate cancer, 19 variants were significantly associated with disease in Latinos. The cumulative effect of prostate cancer risk alleles resulted in a 9% increased risk of prostate cancer for each additional risk allele (P=2.67×10-6) and those in the highest risk quartile had a 2.7-fold increased risk of prostate cancer in comparison to men in the lowest risk quartile (P=1.55×10-13). In summary, our findings suggest established risk variants for prostate cancer significantly contribute to disease susceptibility and future work will examine replication of genome-wide association findings in independent panels of Japanese and Latino men.

Citation Format: Iona C. Cheng, Daniel O. Stram, Laurence N. Kolonel, Brian E. Henderson, Loïc Le Marchand, Christopher A. Haiman, Gary K. Chen, Jing He, Peggy Wan, Xin Sheng, Loreall C. Pooler, Lynne R. Wilkens, Kristine R. Monroe. Evaluating genetic risk for prostate cancer among Japanese Americans and Latinos: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B32.
Abstract B34: IKKalpha regulation of mTORC1 and modulation of prostate tumorigenesis through phosphorylation of mTOR
Authors: Dan Hancai , Baldwin Albert S.
Published: May 2013

The mammalian target of rapamycin (mTOR) is a critical mediator of cell growth, cell proliferation, survival, and energy metabolism. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the I kappa B kinase (IKK) pathway, associated with nuclear factor-kappaB activation, in controlling mTOR activity. The experiments show that IKK alpha controls mTOR activity in Akt-active, PTEN-null prostate cancer cells by directly phosphorylation of mTOR at Serine 1415. In these cells, IKK alpha associates with mTORC1 and weaken the association between mTOR and Raptor, an important component of mTORC1, to increase mTORC1 kinase activity by phosphorylation in an Akt-dependent manner. Additionally, IKKalpha phosphorylation of mTOR is required for efficient induction of cell proliferation downstream of constitutively active Akt in these cells. The results indicate a novel role for IKKalpha in controlling mTOR function in protate cancer cells with loss of PTEN and constitutive Akt activity.

Citation Format: Hancai Dan, Albert S. Baldwin. IKKalpha regulation of mTORC1 and modulation of prostate tumorigenesis through phosphorylation of mTOR [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B34.
Abstract B48: Integrin α6 S-nitrosylation induces prostate cancer cell migration by loss of adhesion to laminin-1
Authors: Isaac Jared , Lam Ying Wai , Tarapore Pheruza , Ho Shuk-mei
Published: May 2013

Prostate cancer is the second most common cancer in American males. Elevated nitric oxide and nitric oxide synthase levels are associated with the progression of prostate tumors. S-nitrosylation, a reversible nitric oxide post-translational modification of cysteines, was investigated here. This report showed that low dose nitric oxide and inducible nitric oxide synthase induced the migration of prostate cancer cells, which was blocked using selective integrin alpha 6 and inducible nitric oxide synthase inhibitors. Furthermore, both nitric oxide donor and inducible nitric oxide synthase targeted integrin alpha 6 for S-nitrosylation on cysteine 86 in prostate cancer cells. Nitric oxide reduced prostate cancer cell adhesion to laminin-1 and integrin alpha 6 binding to laminin beta 1 but theses effects were not seen after mutation of cysteine 86 in integrin alpha 6. S-nitrosylation of integrin alpha 6 cysteine 86 ultimately led to increased migration of prostate cancer cells, which is a potential mechanism of prostate cancer metastasis.

Citation Format: Jared Isaac, Ying Wai Lam, Pheruza Tarapore, Shuk-mei Ho. Integrin α6 S-nitrosylation induces prostate cancer cell migration by loss of adhesion to laminin-1 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B48.
Abstract B68: The microenvironment decides how prostate tumors respond to castration treatment
Authors: Bergström Sofia Halin , Rudolfsson Stina , Scherdin Tove Dahl , Bergh Anders
Published: May 2013

Although androgen deprivation is the standard therapy for metastatic prostate cancer the mechanisms for the initial response and subsequent relapse are largely unknown. The stroma and vasculature are necessary for castration-induced involution of the normal prostate, and androgen-independent tumors respond to castration when surrounded by normal prostate tissue. This suggests that the microenvironment is highly important for the therapeutic effect of castration.

To further explore this, androgen-sensitive rat prostate tumor cells (Dunning G) were injected into the rat prostate and/or bone marrow (to simulate bone metastasis) and analyzed for response to castration. Tumors in the prostate responded well to castration with decreased tumor size, both in already established tumors and when tumor cells were injected in castrated animals. The size of bone metastases was, however, unaffected by castration. Both groups developed lung metastasis but castration tended to increase rather than decrease pulmonary tumor burden.

To further explore the mechanisms behind this we have established in vitro cell lines from bone metastasis of both castrated and control rats. In our ongoing experiments we are examining if these cells are responsive to castration if instead placed within the prostate environment or if the resistance to therapy has become stable. The response to castration is also further explored in lung metastasis. Our results suggest that the metastatic environment is highly important for the establishment of castration resistant prostate cancer and that the mechanisms behind this need to be further explored.

Citation Format: Sofia Halin Bergström, Stina Rudolfsson, Tove Dahl Scherdin, Anders Bergh. The microenvironment decides how prostate tumors respond to castration treatment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B68.
Abstract C10: Tumor necrosis factor is necessary but not sufficient for castration-induced prostate regression
Authors: Davis Jennifer S. , Nastiuk Kent L.
Published: May 2013

TNF, a pro-inflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. There are few examples of a physiologic role for TNF induced apoptosis in vivo, but here we describe a novel role for TNF in prostate epithelial cell apoptosis following androgen withdrawal. We demonstrate, using high resolution serial MRI (magnetic resonance imaging) to measure mouse prostate volume changes over time, that castration induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes, but not mice deficient for TRAIL or Fas signaling. Wild type mice treated with soluble TNFR2 (to bind TNF and block signaling) prior to castration showed a similar reduction. Additionally, consistent with a paracrine role for TNF in prostate regression, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate following castration.

Injection of soluble TNF restores normal levels of prostate regression of Tnf −/− mice. Together, these data indicate that uniquely among these extrinsic death signals, TNF is required for castration induced prostate regression. However, wild type mice receiving soluble TNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient, but acts in the context of additional castration induced signals. A preliminary investigation using ALK5 inhibitors prior to castration suggests that TGFβ signaling may also be important. Understanding the physiologic role for TNF, and the interaction with other signaling pathways active in prostate regression following androgen withdrawal may lead to novel therapies for prostate cancer.

Citation Format: Jennifer S. Davis, Kent L. Nastiuk. Tumor necrosis factor is necessary but not sufficient for castration-induced prostate regression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C10.
Abstract C3: Receptor tyrosine kinase(s) modulate androgen receptor signaling in castrate-resistant prostate cancer
Authors: Sharma Ankur , Balk Steven P.
Published: May 2013

This study is designed to investigate the mechanisms underlying effects of receptor tyrosine kinase(s) on androgen receptor (AR) in castrate resistant prostate cancer (CRPC). Hormone ablation therapies remain the mainstay of treatment for metastatic prostate cancer, but disease eventually reoccurs as CRPC where AR has been reactivated despite castrate androgen levels. Amongst ways that facilitate restoration of AR activity in CRPC, receptor tyrosine kinases (RTKs) have been reported to activate AR and induce CRPC growth through as of yet unclear mechanisms. Our investigative studies revealed that lapatinib (inhibits Her2/Her3 heterodimer and EGFR) treatment inhibited endogenous AR expression and activity in C4-2 CRPC cells. Lapatinib induced destabilization and proteosomal degradation of the AR with minimal effect on AR mRNA transcript levels. To further investigate if this effect was dependent on Her2/Her3 or EGFR, an EGFR inhibitor erlotinib was used. It produced modest effects on AR, indicating that effects of lapatinib are predominantly through Her2/Her3. As AKT, a serine/threonine kinase, functions downstream of Her2/Her3, we then directly investigated the effects of AKT on AR in CRPC cells. Our studies revealed that inhibition of AKT decreased endogenous AR expression through proteosomal degradation. Moreover AKT inhibition decreased endogenous AR activity and C4-2 cell survival, indicating that AKT positively regulates AR and CRPC growth. As many groups have previously reported conflicting effects of AKT on AR, we are now focused on the molecular basis for this positive effect of AKT on AR expression and function in CRPC. Preliminary studies indicate that AKT inhibition may be decreasing levels of heat shock proteins (Hsp70, Hsp90) that serve as chaperones for cytoplasmic AR, and may by another mechanism be decreasing AR accumulation in the nucleus. We anticipate that these studies will provide a clear mechanistic view of effects of RTKs and AKT on AR in CRPC and highlight molecules that may be targeted for novel therapeutic interventions.

Citation Format: Ankur Sharma, Steven P. Balk. Receptor tyrosine kinase(s) modulate androgen receptor signaling in castrate-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C3.
Abstract C31: NAMPT inhibition combined with radiation enhances cell death in a prostate cancer model
Authors: Zerp Shuraila , Triest Baukelien Van , Floot Ben , Vens Conchita , Verheij Marcel
Published: May 2013

Background and purpose: Prostate cancer patients with localized disease can be treated with radiotherapy. In the present study we investigated the complementary effect of NAMPT inhibitor APO866, on the combination with radiation treatment with respect to prostate tumor cell death. APO866 is a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the regulation of NAD+ biosynthesis. Inhibition of NAMPT could deplete cellular NAD+. According to literature NAMPT may have a prominent role in prostate cancer development and progression. Interestingly for research purposes, prostate cancer cell lines PC3 and LNCaP solely depend on the NAMPT synthesis route for their NAD recovery. Treatment of prostate cancer cells with a combination of ionizing radiation and APO866 shows an enhancement of cell death in vitro as well as in vivo.

Results: APO866, in nanomolar concentrations, induces a time- and dose-dependent depletion of cellular NAD+ levels in a panel of human tumor cell lines (U937, J16, LNCaP, PC3 and A431). In vitro, under APO866-mediated reduced NAD+ conditions, solid tumor cell lines PC3 and LNCaP show besides a cytotoxic effect also a decrease in clonogenic survival in combination with ionizing radiation (Dose enhancement factor at 10% survival: 1.34 and 1.45 resp.), which was not caused by radiation-induced enhancement of dsDNA breaks as determined by γ-H2AX nuclear foci formation, nor by induction of apoptosis. In vivo experiments with PC3 xenografts, treated with the APO866/radiation combination, show the combination is more effective than APO866 or radiation treatment alone. The time to reach 300% of the initial tumor volume was in the control group 9.5 days, for APO866 treatment 28.6 days, radiation treatment 51.4 days and for the combined APO866/radiation treatment 76.6 days. Only the combination treatment caused complete initial growth regression. No significant toxicity was observed after any of these treatments. Tumors from animals treated with APO866 showed significant reduced NAD+ levels.

Conclusion: NAMPT inhibition through APO866 treatment enhances cell death in combination with radiation in a prostate cancer model. Targeting NAD+ biosynthesis is a promising strategy in combined modality therapy with radiation.

Citation Format: Shuraila Zerp, Baukelien Van Triest, Ben Floot, Conchita Vens, Marcel Verheij. NAMPT inhibition combined with radiation enhances cell death in a prostate cancer model [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C31.