bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular cytogenetic identification of a wheat – Thinopyrum ponticum substitution line with stripe rust resistance
Authors: Zhu Chen , Wang Yanzhen , Chen Chunhuan , Wang Changyou , Zhang Aicen , Peng Nana , Wang Yajuan , Zhang Hong , Liu Xinlun , Ji Wanquan
Published: July 2017

Thinopyrum ponticum (Th. ponticum) (2n = 10x = 70) is an important breeding material with excellent resistance and stress tolerance. In this study, we characterized the derivative line CH1113-B13-1-1-2-1 (CH1113-B13) through cytological, morphological, genomic in situ hybridization (GISH), fluorescence in situ hybridization (FISH), expressed sequence tag (EST), and PCR-based landmark unique gene (PLUG) marker analysis. The GISH analysis revealed that CH1113-B13 contained 20 pairs of common wheat chromosomes and one pair of JSt genomic chromosomes. Linkage analysis of Th. ponticum using seven EST and seven PLUG markers indicated that the pair of alien chromosomes belonged to the seventh homeologous group. Nulli-tetrasomic and FISH analysis revealed that wheat 7B chromosomes were absent in CH1113-B13; thus, CH1113-B13 was identified as a 7JSt (7B) substitution line. Finally, adult-stage CH1113-B13 exhibited immunity to wheat stripe rust. This substitution line is therefore a promising germplasm resource for wheat breeding.
New fermionic dark matters, extended Standard Model and cosmic rays
Authors: Hwang Jae-Kwang
Published: July 2017

Three generations of leptons and quarks correspond to the lepton charges (LCs) in this work. Then, the leptons have the electric charges (ECs) and LCs. The quarks have the ECs, LCs and color charges (CCs). Three heavy leptons and three heavy quarks are introduced to make the missing third flavor of EC. Then the three new particles which have the ECs are proposed as the bastons (dark matters) with the rest masses of 26.121 eV/c2, 42.7 GeV/c2 and 1.9 × 10[Formula: see text] eV/c2. These new particles are applied to explain the origins of the astrophysical observations like the ultra-high energy cosmic rays and supernova 1987A anti-neutrino data. It is concluded that the 3.5 keV X-ray peak observed from the cosmic X-ray background spectra is originated not from the pair annihilations of the dark matters but from the X-ray emission of the Q1 baryon atoms which are similar in the atomic structure to the hydrogen atom. The presence of the 3.5 keV cosmic X-ray supports the presence of the Q1 quark with the EC of −4/3. New particles can be indirectly seen from the astrophysical observations like the cosmic ray and cosmic gamma ray. In this work, the systematic quantized charges of EC, LC and CC for the elementary particles are used to consistently explain the decay and reaction schemes of the elementary particles. Also, the strong, weak and dark matter forces are consistently explained.
Fixator-Norator Pair Based Design of Feedback Networks for Analog Amplifier Circuits
Authors: Krishnan R. Rohith , Krishnakumar S. , Hashemian Reza
Published: July 2017

Feedback is an integral part of many analog circuits. This paper presents a method for the design of feedback networks for analog amplifiers based on Fixator–Norator Pair (FNP). The design process for required transfer function includes inserting proper FNPs to the equivalent small signal model of the target circuit, with norators lying along the feedback path, and helps to design the feedback network components. Care must be taken to ensure that the added feedback should not alter the original DC biasing of the circuit. A number of examples are worked out in this paper using the proposed method and the results are verified. The FNP approach gives a one-step solution for the design problems which otherwise require tedious analysis and calculations. Although the scope of this paper is limited to design of feedback for amplifiers, a skillful designer can extend the proposed method to other areas of analog circuits.
New Topology for Asymmetrical Multilevel Inverter: An Effort to Reduced Device Count
Authors: Thakre Kishor , Mohanty Kanungo Barada , Kommukuri Vinaya Sagar , Chatterjee Aditi
Published: July 2017

Nowadays, multilevel inverters (MLI) are receiving remarkable attention due to salient features like less voltage stress on switches and low total harmonic distortion (THD) in output voltage. However, the required switch count increases with number of voltage levels. This paper presents a new topology for asymmetric multilevel inverter as a fundamental block. Each block generates 13-level output voltage using eight switches and four unequal dc voltage sources. The proposed configuration offers special features such as reduced number of switches, isolated dc sources, cost economy, less complex and modular structure than other similar contemporary topologies. Moreover, significant reduction in voltage stress on the circuit switches can be achieved. Comparative studies of proposed topology with the conventional and recent topologies have been presented in terms of power switches, gate driver circuit requirement, isolated dc voltage sources and total standing voltage. Multicarrier-based sinusoidal pulse width modulation (SPWM) scheme is adopted for generating switching signals using dSPACE real-time controller. In addition, proposed topology offers a fewer number of ON-state switches that lead to reduction in power loss. The proposed topology is validated through simulation and experimental implementation.
Generalized Software Reliability Model Considering Uncertainty and Dynamics: Model and Applications
Authors: Honda Kiyoshi , Washizaki Hironori , Fukazawa Yoshiaki
Published: July 2017

Today’s development environment has changed drastically; the development periods are shorter than ever and the number of team members has increased. Consequently, controlling the activities and predicting when a development will end are difficult tasks. To adapt to changes, we propose a generalized software reliability model (GSRM) based on a stochastic process to simulate developments, which include uncertainties and dynamics such as unpredictable changes in the requirements and the number of team members. We assess two actual datasets using our formulated equations, which are related to three types of development uncertainties by employing simple approximations in GSRM. The results show that developments can be evaluated quantitatively. Additionally, a comparison of GSRM with existing software reliability models confirms that the approximation by GSRM is more precise than those by existing models.
Discovering User Behavioral Features to Enhance Information Search on Big Data
Authors: Cassavia Nunziato , Masciari Elio , Pulice Chiara , Saccà Domenico
Published: July 2017

Due to the emerging Big Data paradigm, driven by the increasing availability of intelligent services easily accessible by a large number of users (e.g., social networks), traditional data management techniques are inadequate in many real-life scenarios. In particular, the availability of huge amounts of data pertaining to user social interactions, user preferences, and opinions calls for advanced analysis strategies to understand potentially interesting social dynamics. Furthermore, heterogeneity and high speed of user-generated data require suitable data storage and management tools to be designed from scratch. This article presents a framework tailored for analyzing user interactions with intelligent systems while seeking some domain-specific information (e.g., choosing a good restaurant in a visited area). The framework enhances a user's quest for information by exploiting previous knowledge about their social environment, the extent of influence the users are potentially subject to, and the influence they may exert on other users. User influence spread across the network is dynamically computed as well to improve user search strategy by providing specific suggestions, represented as tailored faceted features. Such features are the result of data exchange activity (called data posting) that enriches information sources with additional background information and knowledge derived from experiences and behavioral properties of domain experts and users. The approach is tested in an important application scenario such as tourist recommendation, but it can be profitably exploited in several other contexts, for example, viral marketing and food education.
Have You Lost the Thread? Discovering Ongoing Conversations in Scattered Dialog Blocks
Authors: Zanzotto Fabio Massimo , Ferrone Lorenzo
Published: July 2017

Finding threads in textual dialogs is emerging as a need to better organize stored knowledge. We capture this need by introducing the novel task of discovering ongoing conversations in scattered dialog blocks. Our aim in this article is twofold. First, we propose a publicly available testbed for the task by solving the insurmountable problem of privacy of Big Personal Data. In fact, we showed that personal dialogs can be surrogated with theatrical plays. Second, we propose a suite of computationally light learning models that can use syntactic and semantic features. With this suite, we showed that models for this challenging task should include features capturing shifts in language use and, possibly, modeling underlying scripts.
A Geometric Perspective on Minimal Peer Prediction
Authors: Frongillo Rafael , Witkowski Jens
Published: July 2017

Minimal peer prediction mechanisms truthfully elicit private information (e.g., opinions or experiences) from rational agents without the requirement that ground truth is eventually revealed. In this article, we use a geometric perspective to prove that minimal peer prediction mechanisms are equivalent to power diagrams, a type of weighted Voronoi diagram. Using this characterization and results from computational geometry, we show that many of the mechanisms in the literature are unique up to affine transformations. We also show that classical peer prediction is “complete” in that every minimal mechanism can be written as a classical peer prediction mechanism for some scoring rule. Finally, we use our geometric characterization to develop a general method for constructing new truthful mechanisms, and we show how to optimize for the mechanisms’ effort incentives and robustness.
Rethinking m6A Readers, Writers, and Erasers
Authors: Meyer Kate D. , Jaffrey Samie R.
Published: July 2017

In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early concepts regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome.
The Development of Transgender Studies in Sociology
Authors: Schilt Kristen , Lagos Danya
Published: July 2017

The field of transgender studies has grown exponentially in sociology over the last decade. In this review, we track the development of this field through a critical overview of the sociological scholarship from the last 50 years. We identify two major paradigms that have characterized this research: a focus on gender deviance (1960s–1990s) and a focus on gender difference (1990s–present). We then examine three major areas of study that represent the current state of the field: research that explores the diversity of transgender people's identities and social locations, research that examines transgender people's experiences within institutional and organizational contexts, and research that presents quantitative approaches to transgender people's identities and experiences. We conclude with an agenda for future areas of inquiry.
Numerical Study for Time Delay Multistrain Tuberculosis Model of Fractional Order
Authors: Sweilam Nasser Hassan , Al-Mekhlafi Seham Mahyoub , Assiri Taghreed Abdul Rahman
Published: July 2017

A novel mathematical fractional model of multistrain tuberculosis with time delay memory is presented. The proposed model is governed by a system of fractional delay differential equations, where the fractional derivative is defined in the sense of the Grünwald–Letinkov definition. Modified parameters are introduced to account for the fractional order. The stability of the equilibrium points is investigated for any time delay. Nonstandard finite deference method is proposed to solve the resulting system of fractional-order delay differential equations. Numerical simulations show that nonstandard finite difference method can be applied to solve such fractional delay differential equations simply and effectively.
Prescription of Antibiotics to Treat Gonorrhoea in General Practice in Flanders 2009–2013: A Registry-Based Retrospective Cohort Study
Authors: Schweikardt Christoph , Goderis Geert , Elli Steven , Coppieters Yves
Published: July 2017

Background. General practitioners (GPs) as a group have been identified as playing an important role in gonorrhoea management in Flanders. Belgian guidelines recommended ceftriaxone or alternatively spectinomycin from 2008 onwards and azithromycin combination therapy since 2012. Objectives. This study investigates to which extent contemporary gonorrhoea treatment guidelines were followed. Methods. A retrospective cohort study (2009–2013) of antibiotic prescriptions for gonorrhoea cases registered in the Flemish Intego general practice database was carried out. The database is based on electronic health record routine registration by over 90 GPs using the software programme Medidoc. Results. Ninety-one gonorrhoea cases with ten chlamydia and one genital trichomonas coinfections in 90 patients were registered between 2009 and 2013. The proportion of cases with ceftriaxone and/or spectinomycin prescriptions rose from 13% (two of 15 cases) in 2009 to 56% (nine of 16 cases) in 2013. Combination therapy of ceftriaxone and/or spectinomycin together with azithromycin rose from 0 of 15 cases (0%) in 2009 to 7 of 16 cases (44%) in 2013. Conclusion. Although numbers are small, the results suggest that gonorrhoea therapy guideline adherence improved between 2009 and 2013.
Elliptic Function Solutions in Jackiw-Teitelboim Dilaton Gravity
Authors: D’Ambroise Jennie , Williams Floyd L.
Published: July 2017

We present a new family of solutions for the Jackiw-Teitelboim model of two-dimensional gravity with a negative cosmological constant. Here, a metric of constant Ricci scalar curvature is constructed, and explicit linearly independent solutions of the corresponding dilaton field equations are determined. The metric is transformed to a black hole metric, and the dilaton solutions are expressed in terms of Jacobi elliptic functions. Using these solutions, we compute, for example, Killing vectors for the metric.
Forecasting Time Series Movement Direction with Hybrid Methodology
Authors: Waeto Salwa , Chuarkham Khanchit , Intarasit Arthit
Published: July 2017

Forecasting the tendencies of time series is a challenging task which gives better understanding. The purpose of this paper is to present the hybrid model of support vector regression associated with Autoregressive Integrated Moving Average which is formulated by hybrid methodology. The proposed model is more convenient for practical usage. The tendencies modeling of time series for Thailand’s south insurgency is of interest in this research article. The empirical results using the time series of monthly number of deaths, injuries, and incidents for Thailand’s south insurgency indicate that the proposed hybrid model is an effective way to construct an estimated hybrid model which is better than the classical time series model or support vector regression. The best forecast accuracy is performed by using mean square error.
The Optimization of Radiation Protection in the Design of the High Temperature Reactor-Pebble-Bed Module
Authors: Sun Sida , Li Hong , Fang Sheng
Published: July 2017

The optimization of radiation protection is an important task in both the design and operation of a nuclear power plant. Although this topic has been considerably investigated for pressurized water reactors, there are very few public reports on it for pebble-bed reactors. This paper proposes a routine that jointly optimizes the system design and radiation protection of High Temperature Reactor-Pebble-Bed Module (HTR-PM) towards the As Low As Reasonably Achievable (ALARA) principle. A systematic framework is also established for the optimization of radiation protection for pebble-bed reactors. Typical calculations for the radiation protection of radioactivity-related systems are presented to quantitatively evaluate the efficiency of the optimization routine, which achieve 23.3%~90.6% reduction of either dose rate or shielding or both of them. The annual collective doses of different systems are reduced through iterative optimization of the dose rates, designs, maintenance procedures, and work durations and compared against the previous estimates. The comparison demonstrates that the annual collective dose of HTR-PM is reduced from 0.490 man-Sv/a before optimization to 0.445 man-Sv/a after optimization, which complies with the requirements of the Chinese regulatory guide and proves the effectiveness of the proposed routine and framework.
Integrative Medicine for Postoperative Patients: A Survey of Korean Medicine Doctors
Authors: Moon Sun-Young , Shin Kyung-Min , Shin Jae-Young , Kwon O-Jin , Lee Jun-Hwan
Published: July 2017

The purpose of this survey was to document the experience of Korean Medicine doctors (KMD) who provided postoperative care to patients through integrative medicine and to understand their opinions about integrative medicine utilization. Three researchers (two with a KMD license) of the Korea Institute of Oriental Medicine conducted the survey. The questionnaire was distributed via e‐mail to the 17,041 members of the Association of Korean Medicine in 2015. In total, 487 KMD answered the questionnaires. The majority of respondents worked in a Korean Medicine (KM) clinic, KM hospital, or long‐term care hospitals (94.7%). The respondents mostly treated patients after musculoskeletal (26.7%), spinal (23.7%), or neuropathic surgery (22.2%). Patients predominantly experienced pain (23.0%), fatigue and tiredness (17.4%), delayed scar recovery (13.7%), and paralysis (13.0%). We analyzed subgroups in accordance with institution of employment, specialization, and clinical experience. Most KMD wanted to utilize integrative medicine for postoperative care of patients (92.6%). Moreover, a relatively active collaboration was noted in long‐term care hospitals (mean rate: 60.73% [95% CI: 42.25 to 79.20]). Further studies and clinical trials are needed to determine whether integrative medicine is essential for providing postoperative care to Korean patients.
Malrotation Induced Small Intestine Ischemia in an Adolescent
Authors: Erdem Karadeniz , Sabri Atamanalp Selçuk
Published: July 2017

Intestinal malrotation occurs if midgut does not complete or partially completes its 270° counter-clockwise rotation around the superior mesenteric artery during embryologic life. In general, it frequently manifests with vomiting due to duodenal obstruction and volvulus in the initial months of life, and it is very rare to manifest in the adulthood. A 20-year-old male patient who had severe abdominal pain, nausea, vomiting, and distention for one day was evaluated at the emergency department. On abdominal tomography “swirling appearance of structures around the superior mesenteric artery” was reported. CT appearance was considered compatible with a rotational anomaly. Emergency surgery was planned for the patient. In laparotomy, it was observed that an approximately 100 cm long small intestine segment was rotated around a band (Ladd) and ischemia was developed in this segment due to rotation of its mesentery. The rotation of the small intestinal mesentery was corrected by opening the bands. After the warm application to the intestinal mesenteric ischemia for a while, the color and the peristalsis of the intestines became normal. The patient was discharged on postoperative day 2 with suggestions.
Rapid Onset of B12 Deficiency in the Setting of Worsening Multiple Myeloma: Correlations between B12 Deficiency and Multiple Myeloma
Authors: Seegobin Karan , Maharaj Satish , Nelson Grant , Carlson Jeremy , Baldeo Cherisse , Jacob Rafik
Published: July 2017

A 67-year-old female with a relapse of multiple myeloma after being in remission for approximately 2 years following autologous stem cell transplant presented with worsening pancytopenia, over a three-month period. There were an increase in her monoclonal spike at 3.13 g/dL on serum protein electrophoresis, low serum B12 levels, and positive intrinsic factor antibodies. Three months before, she had normal B12 levels and a significantly lower monoclonal spike of 1.07 g/dL. She was diagnosed with B12 deficiency with pernicious anaemia in the setting of her worsening myeloma. Multiple myeloma (MM) has been linked with B12 deficiency and pernicious anaemia. Several mechanisms have been described regarding the pathogenesis of B12 deficiency in such patients. Increased tumour activity can further perpetuate the development of B12 deficiency in such patients. With regard to our case, the increase in tumour activity and onset of pernicious anaemia could have contributed to the rapid development of B12 deficiency. In contrast to this, rapid development of B12 deficiency could also signify relapse or worsening of the myeloma as seen in our case. Physicians ought to consider B12 deficiency in patients with worsening pancytopenia and myeloma.
Extracts of Salvia‐Nelumbinis Naturalis Ameliorate Nonalcoholic Steatohepatitis via Inhibiting Gut‐Derived Endotoxin Mediated TLR4/NF‐κB Activation
Authors: Shu Xiangbing , Wang Miao , Xu Hanchen , Liu Yang , Huang Jie , Yao Zemin , Zhang Li
Published: July 2017

Nonalcoholic steatohepatitis (NASH) is featured by the presence of hepatic steatosis combined with inflammation and hepatocellular injury. Gut‐derived endotoxin plays a crucial role in the pathogenesis of NASH. Salvia‐Nelumbinis naturalis (SNN), a formula of Traditional Chinese Medicine, has been identified to be effective for NASH, but the mechanisms were not thoroughly explored. In the present study, a NASH model was generated using C57BL/6 mice fed a high fat diet (HFD) supplemented periodically with dextran sulfate sodium (DSS) in drinking water for 12 weeks. Mice fed HFD alone (without DSS) or chow diet were used as controls. The NASH mice were given the SNN extracts in the following 4 weeks, while control mice were provided with saline. Mice fed HFD developed steatosis, and DSS supplementation resulted in NASH. The SNN extracts significantly improved metabolic disorders including obesity, dyslipidemia, and liver steatosis and reduced hepatic inflammation, circulating tumor necrosis factor‐α (TNF‐α), and lipopolysaccharide (LPS) levels. The beneficial effect of the SNN extracts was associated with restoration of intestinal conditions (microbiota, integrity of intestinal barrier) and inhibition of TLR4/NF‐κB activation. These results suggest that the SNN extracts ameliorate NASH progression, possibly through blocking endotoxin related TLR4/NF‐κB activation.
Abstract 1021: Mutations in SWI/SNF chromatin remodeling complex sensitize tumors to OXPHOS inhibition
Authors: Deribe Yonathan Lissanu
Published: July 2017

Recent large-scale cancer genomic studies have established a framework in which biological functions and genetic interactions of established and novel cancer genes can be explored. One of the major findings of these studies has been the discovery of frequent genetic alterations in chromatin and epigenetic regulators including inactivating mutations in components of the SWI/SNF chromatin remodeling complex. In lung adenocarcinoma in particular, a quarter of tumors have inactivating mutations in the SWI/SNF components Smarca4, ARID1A or the histone modifier SETD2. With the aim of understanding the mechanism of tumor development and identifying potential vulnerabilities of SWI/SNF mutant tumor, we developed a genetically engineered mouse model (GEMM) of lung adenocarcinoma by selectively ablating Smarca4 in the respiratory epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss. Cross species integrative gene expression analyses revealed signatures of enhanced oxidative phosphorylation and reactive oxygen species (ROS) response in Smarca4 mutant murine and human lung tumors. We further show that Smarca4 mutant cells have increased oxygen consumption, enhanced basal and maximal respiratory capacity and production of ROS. This is primarily driven by activation of the mitochondrial master regulator, PGC1alpha. Finally, we show that Smarca4 and other SWI/SNF mutant lung cancer cell lines have exquisite sensitivity to inhibition of oxidative phosphorylation using a novel small molecule that is under development. These findings provide a mechanistic basis for further development of OXPHOS inhibitors as therapies in SWI/SNF mutant tumors.

Citation Format: Yonathan Lissanu Deribe. Mutations in SWI/SNF chromatin remodeling complex sensitize tumors to OXPHOS inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1021. doi:10.1158/1538-7445.AM2017-1021
Abstract 1024: Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation
Authors: Lareau Caleb , Aryee Martin
Published: July 2017

INTRODUCTION:

The organization of chromatin within the nucleus into hierarchical three-dimensional (3D) structures plays a key role in the regulation of gene expression. Differences in 3D architecture, such as the presence or absence of “loops” between specific enhancers and their target genes, are a major driver of transcriptional and phenotypic variation. By determining the accessibility of genes to transcriptional machinery and distal regulatory regions, mechanisms mediating oncogene activation can be discerned. Recent studies have implicated pathogenic alterations in genome topology with the activation of proto-oncogenes in a multitude of cancers.

METHODS:

To characterize the topological changes associated with different cancer states, we developed a computational suite of tools that facilitates the systematic discovery, annotation, and visualization of features in chromatin topology and assigns statistical confidence estimates to regions with variability between cellular phenotypes. Our framework facilitates the integration of heterogeneous genomic data, including gene expression, histone modification, DNA methylation, open chromatin, and genetic variation, to further characterize changes in 3D genome. Ultimately, we propose a joint model that functionalizes the effect of epigenetic modifications on transcription as mediated through hierarchical chromatin structure.

RESULTS:

We identify regions of topological variation unique to breast cancer, cervical cancer, glioblastomas with and without an IDH1 mutation, melanoma, and leukemia. Patterns of disrupted insulation and subsequent localization of enhancers to proto-oncogenes can be attributed to variation in the epigenome, including variation in DNA methylation and open chromatin, at distal regulatory regions. These 3D alterations provide a mechanism for activation of specific oncogenic pathways, including signaling mediated by p38, PLK3, and BRCA.

CONCLUSIONS:

Variable patterns of chromatin topology provide a unique signature and mechanism of oncogenes for the cancer phenotypes considered. Additionally, our framework provides a novel means for interpreting epigenetic variability, particularly at distal regulatory regions, and explaining transcriptional variation associated with cancer phenotypes as mediated through structural changes in the DNA.

Citation Format: Caleb Lareau, Martin Aryee. Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1024. doi:10.1158/1538-7445.AM2017-1024
Abstract 1026: Identify BRD4 as a facilitator of replication stress response signaling
Authors: Zhang Jingwen , Willis Brandon , Hattersley Maureen , Lau Alan , Reimer Corinne , Zinda Michael , Fawell Stephen , Mills Gordon , Dulak Austin , Chen Huawei
Published: July 2017

BRD4 is a member of the BET (bromodomain and extraterminal domain) family of chromatin readers that recognize acetylated-lysines on histones and nuclear proteins. Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. However, whether BRD4 contributes to cancer malignancy through other mechanisms has not been extensively evaluated. Here, we show that BRD4 is important for maintaining an intact DNA replication checkpoint in cancers. Displacement of BRD4 by BET bromodomain inhibitor AZD5153 in cell lines under intrinsic or exogenous replication stress led to a time-dependent reduction in phospho-Chk1 first detected within 30 minutes, and reaching maximum phospho-Chk1 inhibition (~85%) at an hour after AZD5153 treatment in U2OS cells. The decrease in Chk1 phosphorylation was observed without a concomitant decrease in total Chk1, and this was not replicated by treatment with pan-transcriptional inhibitors, suggesting a non-transcriptional mechanism linked to BRD4. Furthermore, BRD4 interacts with the DNA pre-replication complex and inhibition of BRD4 leads to hyperactivation of the pre-replication complex and aberrant DNA replication re-initiation under replication stress conditions. Consistent with a role in S-phase signaling, BETi treatment sensitizes replicating cells to replication stress-inducing agents. Finally, we observed that ovarian cancer cell lines are highly-sensitive to the combined inhibition of BRD4 and ATR. Coadministration of AZD5153 and AZD6738 (ATR inhibitor) significantly inhibited tumor growth in OVCAR3 ovarian xenograft model (TGI after 21 day dosing: AZD5153, 52%; AZD6738, 46%; Combo, 84%). Sustained tumor growth delay was observed after combination treatment cessation. Together, our study uncovered a novel function for BRD4 in regulating DNA replication stress response, and provide mechanistic rational for combining BETi with DNA damage-targeted agents for cancer therapies.

Citation Format: Jingwen Zhang, Brandon Willis, Maureen Hattersley, Alan Lau, Corinne Reimer, Michael Zinda, Stephen Fawell, Gordon Mills, Austin Dulak, Huawei Chen. Identify BRD4 as a facilitator of replication stress response signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2017-1026
Abstract 1048: Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine
Authors: Pluchino Lenora A. , Wang Hwa-Chain R.
Published: July 2017

Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States and is often associated with induction of oncogenic H-Ras. Long-term survival of patients is suboptimal with the current chemotherapeutic regimen of combined cisplatin and gemcitabine and others due to acquired drug resistance and recurrence. Thus, it is urgent to develop new regimens effective in control of tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We used our cellular system, consisting of human urinary bladder cancer J82 cells paired with its derived oncogenic H-Ras-expressing J82-Ras cells, to investigate the efficacy of a novel combination regimen in treating bladder cancer cells. Our studies revealed, for the first time, the ability of a combination of cisplatin and romidepsin with gemcitabine to synergistically and preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. The Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species (ROS), leading to enhanced caspase activation, DNA damage, and DNA oxidation, as well as reduced glutathione, to synergistically increased cell death and reduced drug resistance in cells treated with combined romidepsin, cisplatin, and gemcitabine. Preferentially induced Ras-ERK-Nox-ROS pathway, caspase

activation, and DNA damage/oxidation, as well as reduced glutathione, contributed to the preferentially induced cell death and reduced drug resistance in J82-Ras versus J82 cells. Synergistically induced death and reduced drug resistance were also detected in human bladder cancer SW780 cells treated with combined romidepsin, cisplatin, and gemcitabine. Hence, our results lead us to suggest that a combination of romidepsin, cisplatin, and gemcitabine should be seriously considered as a new therapeutic regimen for controlling the development and recurrence of human urinary bladder cancer, especially Ras-ERK-activated cancers.

Citation Format: Lenora A. Pluchino, Hwa-Chain R. Wang. Reactive oxygen species-mediated synergistic and preferential induction of cell death and reduction of drug resistance in oncogenic H-Ras-expressing bladder cancer cells by combined romidepsin and cisplatin with gemcitabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1048. doi:10.1158/1538-7445.AM2017-1048
Abstract 1051: Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer
Authors: Oba Takaaki , Ito Ken-ichi
Published: July 2017

Purpose:

There is an urgent need to develop novel therapeutic strategies for triple negative breast cancer (TNBC). To explore the antitumor effect of combination of eribulin (ERI) and paclitaxel (PTX) for TNBC, we conducted preclinical experiments.

Materials & methods:

Combinational effects of ERI and PTX were analyzed both in vitro and in vivo using two TNBC cell lines (MDA-MB-231, Hs578T).

Results:

When ERI was added simultaneously with PTX to TNBC cells, the sensitivity to PTX was increased synergistically. On the other hand, synergistic increase of sensitivity to ERI was observed in the presence of PTX. When the TNBC cells were treated with each drug subsequently, pretreatment with ERI for 96 hours enhanced the sensitivity to PTX administrated subsequently. In contrast, pretreatment of TNBC cells with PTX enhanced the sensitivity to the subsequently administrated ERI. When the TNBC cells were treated with ERI, the expression of epithelial marker, E-cadherin was increased, while the expression of mesenchymal markers, pSmad2, ZEB1, Slug, and vimentin were decreased. In contrast, when the cells were treated with PTX, the expressions of mesenchymal markers were increased. When epithelial-mesenchymal transition (EMT) was induced by TGF-β in the TNBC cells, the sensitivity to ERI was enhanced, while TGF-β receptor inhibitor (LY2157299) reduced the sensitivity to ERI. Furthermore, knockdown of ZEB1 by small interfering RNA conferred resistance to ERI in both TNBC cell lines. In the mouse xenograft model bearing MDA-MB-231, ERI plus PTX combination therapy significantly inhibited tumor growth compared with either PTX or ERI monotherapy. Furthermore, prior treatment with ERI significantly enhanced the antitumor activity of PTX in the mouse xenograft model.

Conclusions:

Our findings demonstrate an EMT-mediated synergistic antitumor effect by combination of two tubulin inhibitors. This combination therapy may serve as a novel therapeutic strategy for TNBC.

Citation Format: Takaaki Oba, Ken-ichi Ito. Preclinical analyses of synergistic effect of eribulin and paclitaxel for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1051. doi:10.1158/1538-7445.AM2017-1051
Abstract 1054: Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway
Authors: Kato Kazunori , Yamazaki Takumi , Honma Masaaki
Published: July 2017

Nobiletin is a citrus polymethoxy flavonoid that suppresses cell proliferation, angiogenesis and metastatic properties in various cancer cells. In this study, we investigated the combined effects of nobiletin and various chemotherapeutic agents on the cytotoxicity of human colon and esophageal cancer cells. We cultured cancer cells at serial dilution of chemotherapeutic agents with or without nobiletin and assessed cell cytotoxicity at 5 days after drug treatment. The addition of a suboptimal dose of nobiletin did not alter the growth of cancer cells, however cytotoxic effect of antimetabolites (gemcitabine and 5-FU) and DNA-platinating agent (cisplatin) were markedly attenuated by nobiletin. By contrast, nobiletin markedly enhanced antitumor effect of antimicrotubule agents such as docetaxel, paclitaxel, vincristine and MMAE. Moreover, enhanced cytotoxicity by nobiletin was also verified in the combination with MMAE- or DM1-conjugated antibodies to EpCAM and EphA2. We found the inhibition of phosphorylation and nuclear translocation of Pin1 (peptidyl-prolyl isomerase) by nobiletin, suggesting a rational molecular target of nobiletin is Pin1. Overall, these data suggest that nobiletin might useful for the chemotherapeutic treatment of microtubule inhibitors.

Citation Format: Kazunori Kato, Takumi Yamazaki, Masaaki Honma. Nobiletin synergizes cytotoxicity of antimicrotubule agents by inhibiting Pin1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1054. doi:10.1158/1538-7445.AM2017-1054
Abstract 1061: Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas
Authors: An Yi , Sun Lillian , Derakhshan Adeeb , Carlson Sophie , Das Rita , Chen Zhong , Waes Carter Van
Published: July 2017

Head and neck squamous cell carcinomas (HNSCC) induced by human papilloma virus (HPV) have increased recently in the US, and exhibit a different prognosis and response to therapies from HPV(-) cancers. Analysis of HNSCC TCGA datasets provide evidence for distinct alterations in expression of components of the NF-κB and death pathways in HNSCC with different HPV status. Previously, we have found that birinipant, a novel SMAC mimetic that inhibits inhibitor of apoptosis proteins (IAPs), sensitizes a subset of HPV(-) HNSCC cell lines to death agonists like TNF-α and TRAIL. In this study, we have observed that birinipant also sensitizes most HPV(+) cell lines to TRAIL and TNF-α in vitro. The IC50 of birinipant was under 50nM for HPV(+) UPCI-SCC-90 and UM-SCC-47 cell lines, when combined with TNF-α or TRAIL. To explore the therapeutic potential of enhancing TRAILR mediated death signaling in HPV(+) HNSCC cells, we investigated the effects of an agonistic polyclonal TRAILR2 antibody. Treatment of cells with TRAILR2 antibody alone shows little or no inhibitory effect on UPCI-SCC-90 and UM-SCC-47 cells in vitro. However, a combination of birinipant and TRAILR2 antibody, or triple combination of birinipant, TRAIL, and TRAILR2 antibody shows additive or synergistic effects to inhibit cell proliferation and induce cell death in a dose dependent manner. In addition, our preliminary data suggested that the non-canonical NF-κB pathway is predominately activated in HPV(+) HNSCC cells, and that NF-κB inducing kinase (NIK) is a key component of this pathway. When we tested the NIK inhibitor 4H-isoquinoline-1,3-dione in UPCI-SCC-90 cells, we found it reduced cell proliferation in a dose-dependent manner (IC50 =1.5 μM). Taken together, these results indicate that TNF-α, TRAIL, and TRAILR2 agonist antibody sensitized birinipant anti-tumor activity, and triple combination exhibited synergistic effects in HPV(+) HNSCC cell lines. NIK inhibitor alone inhibits cell proliferation of HPV(+) cells, supporting the hypothesis of aberrant activation of alternative pathway in HPV(+) HNSCC cells. (Supported by NIDCD intramural projects ZIA-DC-000016, 73, 74).

Citation Format: Yi An, Lillian Sun, Adeeb Derakhshan, Sophie Carlson, Rita Das, Zhong Chen, Carter Van Waes. Modulation of death pathways by TRAILR2 agonist antibody and NF-κB pathway by NIK inhibitor in HPV-positive head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1061. doi:10.1158/1538-7445.AM2017-1061
Abstract 1069: Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells
Authors: Chi Ru-pin , Wei Wei , Birrer Michael , Leaner Virna D.
Published: July 2017

Elevated expression of members of the nuclear transport protein family has been reported in multiple cancers and presents as novel anticancer therapeutic targets. Using a cervical cancer model system, we have previously shown that inhibition of the nuclear import receptor, KpnB1 by siRNA and a novel small molecule, Inhibitor of Nuclear Import (INI-43) resulted in cancer cell death via apoptosis. In this study, we investigated the cancer cell killing effects of KpnB1 inhibition in combination with Cisplatin (CDDP), a first-line chemotherapeutic agent used in the treatment of many cancers. KpnB1 siRNA and INI-43 treatment at sub-lethal concentrations enhanced cancer cells' sensitivity to CDDP. Our data shows that the combination treatment of INI-43 and CDDP significantly decreases CDDP IC50 compared to CDDP treatment alone. Increased PARP-cleavage was observed in combination treated cells and this correlated with increased γH2A.X, indicating increased apoptosis and DNA damage. Furthermore, INI-43 treatment reduced the nuclear import of NFκB, a stress-regulated response transcription factor known to be a KpnB1 cargo protein that promotes cancer cell survival. Decreased levels of downstream pro-survival and DNA-repair targets of NFκB were observed, including cyclinD1, c-Myc and XIAP, which correlated with increased DNA damage and apoptosis. Taken together, results suggest increased Cisplatin sensitivity of cervical cancer cells when nuclear import via KpnB1 is inhibited.

Citation Format: Ru-pin Chi, Wei Wei, Michael Birrer, Virna D. Leaner. Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1069. doi:10.1158/1538-7445.AM2017-1069
Abstract 109: Effects of trifluoperazine analogue on A549 human lung cancer cells
Authors: Jeong Joo Yeon , Ryu Jinhyun , Yoon Nal Ae , Kang Seokmin , Seong Hyemin , Fudhaili Ahmad , Park Juyeong , Sim Jimin , Lee Jiyeon , Hwang Soohyun , Kang Sang Soo
Published: July 2017

Although there have been great advancement in technology, molecular diagnosis, therapeutics, lung cancer is still the leading cause of cancer related mortality all over the world. Recently, some antipsychotic drugs have been shown to possess the anticancer activity. Thus the present study was designed to evaluate the anticancer effects of trifluoperazine (TFP), a commonly used antipsychotic drug, and its synthetic analogs on human lung cancer cell lines. To this end, effects of TFP and its selected analog on A549 cells were investigated in vitro as well as in vivo experiments. Synthetic TFP analogs were evaluated by the viability of A549 cells following drug treatment and compared to TFP. KCFC51, a selected TFP analog, significantly inhibited the proliferation of A549 cells. Further experiment showed that TFP and KCFC51 had activities to inhibit the migration, and anchorage dependent/independent colony formation of A549 cells. Western blot analysis revealed that TFP and KCFC51 affect the protein expression levels related to cell apoptosis and cell cycle. KCFC51 showed stronger anticancer effects in all the experiment than TFP. Flow cytometric analysis showed that KCFC51 induced sub-G1 population and reduced cell population in S and G2/M phase. In addition, the two in vivo experimental models, KCFC51 also showed powerful anticancer effect in skin xenograft tumor growth and orthotropic lung cancer development than TFP. Thus present study demonstrates that a synthetic TFP analog has anti-lung cancer activity and provides a potential therapeutic candidate for lung cancer.

Citation Format: Joo Yeon Jeong, Jinhyun Ryu, Nal Ae Yoon, Seokmin Kang, Hyemin Seong, Ahmad Fudhaili, Juyeong Park, Jimin Sim, Jiyeon Lee, Soohyun Hwang, Sang Soo Kang. Effects of trifluoperazine analogue on A549 human lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 109. doi:10.1158/1538-7445.AM2017-109