bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting Semantic Interoperability in Conservation-Restoration Domain
Authors: Niang Cheikh , Marinica Claudia , Markhoff Beatrice , Leboucher Elise , Malavergne Olivier , Bouiller Luc , Darrieumerlou Claude , Laissus Francois
Published: July 2017

In this article, we present a semantic-based approach for dealing with the interoperability issue in the conservation-restoration domain. We first evaluate the context and our observations confirm the critical need for a data integration system taking advantage of data semantics. Our solution consists in: (1) building a domain-specific ontology, to rely on a unified understanding of the conservation-restoration data; (2) mapping the shared ontology to each data source, allowing each participating source to manage its own semantic database, consisting of its original data now associated to the semantic level; and (3) integrating all sources’ data, for querying them in the same homogeneous way. The presented achievements have been conducted as part of the PARCOURS project, whose aim is to develop an information system able to provide a unified access to distinct information sources, related to the cultural heritage field in general and the conservation-restoration processes in particular.
Fixing Faults in C and Java Source Code
Authors: Scanniello Giuseppe , Risi Michele , Tramontana Porfirio , Romano Simone
Published: July 2017

We carried out a family of controlled experiments to investigate whether the use of abbreviated identifier names, with respect to full-word identifier names, affects fault fixing in C and Java source code. This family consists of an original (or baseline) controlled experiment and three replications. We involved 100 participants with different backgrounds and experiences in total. Overall results suggested that there is no difference in terms of effort, effectiveness, and efficiency to fix faults, when source code contains either only abbreviated or only full-word identifier names. We also conducted a qualitative study to understand the values, beliefs, and assumptions that inform and shape fault fixing when identifier names are either abbreviated or full-word. We involved in this qualitative study six professional developers with 1--3 years of work experience. A number of insights emerged from this qualitative study and can be considered a useful complement to the quantitative results from our family of experiments. One of the most interesting insights is that developers, when working on source code with abbreviated identifier names, adopt a more methodical approach to identify and fix faults by extending their focus point and only in a few cases do they expand abbreviated identifiers.
Astrophysical Sources of High-Energy Neutrinos in the IceCube Era
Authors: Mészáros P.
Published: July 2017

High-energy neutrino astrophysics has come of age with IceCube's discovery of neutrinos in the TeV to PeV energy range, attributable to extragalactic sources at cosmological distances. At such energies, astrophysical neutrinos must originate in cosmic-ray interactions, providing information about the sources of high-energy cosmic rays, as well as leading to the coproduction of high-energy γ-rays. The intimate link with these two independently observed types of radiation provides important tools for the quest to identify and understand the nature of the astrophysical sources of the neutrinos. These neutrinos can set important constraints on the cosmic-ray acceleration process, and because they travel essentially unimpeded, they can probe our Universe out to the farthest cosmological distances.
Comparing Dorsal Tangential and Lateral Views of the Wrist for Detecting Dorsal Screw Penetration after Volar Plating of Distal Radius Fractures
Authors: Giugale Juan M. , Fourman Mitchell S. , Bielicka Deidre L. , Fowler John R.
Published: July 2017

Background. The dorsal tangential (DT) view has been shown to improve the detection of dorsal screw perforation during volar distal radius fracture fixation. Here we performed a cadaveric imaging survey study to evaluate if the DT view was uniformly beneficial for all screws. Methods. Standardized placement of fixed-angle volar distal radius plates was performed on two cadavers. Fluoroscopic images depicting variable screw perforation of each of the four screw holes on the plate were generated. A 46-image survey was distributed at a large academic medical center. Respondents were asked to answer if the screw was perforating through the dorsal cortex in each image. Statistical analysis was performed using Fisher’s exact test. A p value < .05 was considered significant. Results. The DT view offered a significantly more reliable determination of dorsal screw penetration than traditional lateral imaging for the radial-most screw at all degrees of perforation and the middle two screws at 2 mm of perforation. Residents and attendings had more accurate screw readings overall using the DT view. Conclusions. The DT view is superior to traditional lateral imaging in the detection of small amounts of dorsal perforation of the radial-most three screws of a fixed-angle volar plate.
Psychometric Properties and Validation of the Arabic Academic Performance Rating Scale
Authors: Quadri M. F. A. Q. , El-Kordy M. S. , Moukhyer M. E. , Mukhayer A. , Ahmad B.
Published: July 2017

Aim. To validate the Arabic version of Academic Performance Rating Scale. Method. Translation and test‐retest reliability were computed. Exploratory factor analysis and Rasch analysis were conducted to report on the validity. EFA factor structures were evaluated using a Scree plot and the standard multiple criteria included eigenvalue greater than 1. Average measures and step measures were ordered and the mean‐square outfit statistic for each category was also evaluated. Results. Cronbach’s Alpha value of 0.90 was obtained. No differences across category of educational levels were seen (P > 0.05). Pattern matrix analysis revealed items to be significantly correlated with each other with a chi square goodness of fit value 0.02. Results supported the interpretation of adequate fit of items, since the infit ZSTD (1.55–0.46), outfit ZSTD (1.59–0.99), infit MNSQ (0.74–1.47), and outfit MNSQ (0.50–1.37) for the items were within acceptable ranges. Conclusion. Valid and reliable A‐APRS‐15 can be used in future studies to see its relation with other variables such as general health and oral health.
3‐Hydroxykynurenine and 3‐Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture
Authors: Ramírez-Ortega Daniela , Ramiro-Salazar Alelí , González-Esquivel Dinora , Ríos Camilo , Pineda Benjamín , Pérez de la Cruz Verónica
Published: July 2017

Copper is an integral component of various enzymes, necessary for mitochondrial respiration and other biological functions. Excess copper is related with neurodegenerative diseases as Alzheimer and is able to modify cellular redox environment, influencing its functions, signaling, and catabolic pathways. Tryptophan degradation through kynurenine pathway produces some metabolites with redox properties as 3‐hydroxykynurenine (3‐HK) and 3‐hydroxyanthranilic acid (3‐HANA). The imbalance in their production is related with some neuropathologies, where the common factors are oxidative stress, inflammation, and cell death. This study evaluated the effect of these kynurenines on the copper toxicity in astrocyte cultures. It assessed the CuSO4 effect, alone and in combination with 3‐HK or 3‐HANA on MTT reduction, ROS production, mitochondrial membrane potential (MMP), GHS levels, and cell viability in primary cultured astrocytes. Also, the chelating copper effect of 3‐HK and 3‐HANA was evaluated. The results showed that CuSO4 decreased MTT reduction, MMP, and GSH levels while ROS production and cell death are increasing. Coincubation with 3‐HK and 3‐HANA enhances the toxic effect of copper in all the markers tested except in ROS production, which was abolished by these kynurenines. Data suggest that 3‐HK and 3‐HANA increased copper toxicity in an independent manner to ROS production.
Extraction of Illegal Dyes from Red Chili Peppers with Cholinium-Based Deep Eutectic Solvents
Authors: Zhu Shuqiang , Liu Dongling , Zhu Xinyue , Su Along , Zhang Haixia
Published: July 2017

Deep eutectic solvents (DESs) as a new kind of green solvents have been used to extract bioactive compounds but there are few applications in extracting chrysoidine dyes. In this study, we developed an ultrasonic-assisted extraction method with choline chloride/hydrogen bond donor (ChCl/HBD) DES for the extraction of chrysoidine G (COG), astrazon orange G (AOG), and astrazon orange R (AOR) in food samples. Some experimental parameters, such as extraction time, raw material/solvent ratio, and temperature, were evaluated and optimized as follows: the ratio of ChCl/HBD, 1 : 2 (v/v); the ratio of sample/DES, 1 : 10 (g/mL); extraction time, 20 min; extraction temperature, 50°C. Under the optimized conditions, the limits of detection (μg/mL) were 0.10 for COG and 0.06 for AOG and AOR. The relative standard deviations were in the range of 1.2–2.1%. The recoveries of the three dyes were in the range of 80.2–105.0%. By comparing with other commonly used solvents for extracting chrysoidine dyes, the advantages of DESs proved them to be potential extraction solvents for chrysoidine G, astrazon orange G, and astrazon orange R in foods.
Characteristics of Water Vapor in the UTLS over the Tibetan Plateau Based on AURA/MLS Observations
Authors: Sun Yi , Chen Quanliang , Gui Ke , Dong Fangyou , Feng Xiao , Long Qichao
Published: July 2017

Water vapor (WV) has a vital effect on global climate change. Using satellite data observed by AURA/MLS and ERA-Interim reanalysis datasets, the spatial distributions and temporal variations of WV were analyzed. It was found that high WV content in the UTLS over the southern Tibetan Plateau is more apparent in summer, due to monsoon-induced strong upward motions. The WV content showed the opposite distribution at 100 hPa, though, during spring and winter. And a different distribution at 121 hPa indicated that the difference in WV content between the northern and southern plateau occurs between 121 and 100 hPa in spring and between 147 and 121 hPa in winter. In the UTLS, it diminishes rapidly with increase in altitude in these two seasons, and it shows a “V” structure in winter. There has been a weak increasing trend in WV at 100 hPa, but a downtrend at 147 and 215 hPa, during the past 12 years. At the latter two heights, the WV content in summer has been much higher than in other seasons. Furthermore, WV variation showed a rough wave structure in spring and autumn at 215 hPa. The variation of WV over the Tibetan Plateau is helpful in understanding the stratosphere-troposphere exchange (STE) and climate change.
Implementation of a Low-Cost Energy and Environment Monitoring System Based on a Hybrid Wireless Sensor Network
Authors: Kim Dong Sik , Chung Beom Jin , Son Sung-Yong
Published: July 2017

A low-cost hybrid wireless sensor network (WSN) that utilizes the 917 MHz band Wireless Smart Utility Network (Wi-SUN) and a 447 MHz band narrow bandwidth communication network is implemented for electric metering and room temperature, humidity, and CO2 gas measurements. A mesh network connection that is commonly utilized for the Internet of Things (IoT) is used for the Wi-SUN under the Contiki OS, and a star connection is used for the narrow bandwidth network. Both a duty-cycling receiver algorithm and a digitally controlled temperature-compensated crystal oscillator algorithm for frequency reference are implemented at the physical layer of the receiver to accomplish low-power and low-cost wireless sensor node design. A two-level temperature-compensation approach, in which first a fixed third-order curve and then a sample-based first-order curve are applied, is proposed using a conventional AT-cut quartz crystal resonator. The developed WSN is installed in a home and provides reliable data collection with low construction complexity and power consumption.
Effect of Efavirenz on Endogenous Progesterone Concentrations and Contraceptive Outcomes among Ugandan HIV Infected Women Coadministering Ethinylestradiol/Levonorgestrel
Authors: Munkwase Grant , Bisaso Kuteesa R. , Kakaire Othman , Nanzigu Sarah
Published: July 2017

This study assessed the effect of efavirenz mid-dose plasma concentrations on mid-luteal endogenous progesterone concentrations and contraceptive outcomes among 49 HIV infected women coadministering ethinylestradiol/levonorgestrel, including 34 HIV positive women on Highly Active Antiretroviral Therapy (HAART) and 15 HAART naïve HIV infected women, purposively selected from Mulago Hospital, Uganda. A blood sample was collected once between days 20 and 22 of each woman’s menstrual cycle for measuring endogenous progesterone and efavirenz concentrations by electrochemiluminescence technology and High Performance Liquid Chromatography (HPLC), respectively. Descriptive statistical analysis and correlation and logistic regression analysis were done using SPSS v.21 and R3.1. Efavirenz showed a weak positive linear relationship with endogenous progesterone at efavirenz concentrations below 12 μg/ml. Based on serum endogenous progesterone, the observed hormonal contraceptives failure rate (24.5%) was higher than expected (maximum 8%). A higher proportion of HIV positive women on efavirenz based HAART (26.5%) was at risk of contraceptive failure than their HIV infected HAART naïve counterparts (20%) though it was not statistically significant (p=0.63). Efavirenz mid-dose plasma concentrations seem to have no significant effect on mid-luteal endogenous progesterone concentrations and contraceptive outcomes among HIV infected Ugandan women coadministering ethinylestradiol/levonorgestrel oral pills.
Option Price Decomposition in Spot-Dependent Volatility Models and Some Applications
Authors: Merino Raúl , Vives Josep
Published: July 2017

We obtain a Hull and White type option price decomposition for a general local volatility model. We apply the obtained formula to CEV model. As an application we give an approximated closed formula for the call option price under a CEV model and an approximated short term implied volatility surface. These approximated formulas are used to estimate model parameters. Numerical comparison is performed for our new method with exact and approximated formulas existing in the literature.
General Recurrent Neural Network for Solving Generalized Linear Matrix Equation
Authors: Li Zhan , Cheng Hong , Guo Hongliang
Published: July 2017

This brief proposes a general framework of the nonlinear recurrent neural network for solving online the generalized linear matrix equation (GLME) with global convergence property. If the linear activation function is utilized, the neural state matrix of the nonlinear recurrent neural network can globally and exponentially converge to the unique theoretical solution of GLME. Additionally, as compared with the case of using the linear activation function, two specific types of nonlinear activation functions are proposed for the general nonlinear recurrent neural network model to achieve superior convergence. Illustrative examples are shown to demonstrate the efficacy of the general nonlinear recurrent neural network model and its superior convergence when activated by the aforementioned nonlinear activation functions.
Estimating Sex of Modern Greeks Based on the Foramen Magnum Region
Authors: Chovalopoulou Maria-Eleni , Bertsatos Andreas
Published: July 2017

Sex determination is one of the principal aims when examining human skeletal remains. One method for sex determination is based on metric criteria using discriminant functions. However, discriminant function sexing formulas are population-specific. In the present study, we determined the use of the foramen magnum as well as the occipital condyles for sex determination on adults from a modern Greek population. Seven parameters were examined (4 obtained from the foramen magnum; 3 obtained from the occipital condyles) and the sample consisted of 154 adult crania (77 males and 77 females). The results indicate that the foramen magnum region exhibits sexual dimorphism and the mean values for all parameters were higher in males than females. In comparison, the occipital condyles provide a higher determination of the correct sex than the foramen magnum. The combination of the occipital condyle variables allowed for the development of discriminant functions that predicted the correct sex in 74% of all cases. Finally, although other anatomical regions can discriminate the sexes with higher accuracy, the functions developed in this study could be cautiously used in cases of fragmented crania.
The Advantage of Using International Multimodel Ensemble for Seasonal Precipitation Forecast over Israel
Authors: Givati Amir , Housh Mashor , Levi Yoav , Paz Dror , Carmona Itzhak , Becker Emily
Published: July 2017

This study analyzes the results of monthly and seasonal precipitation forecasting from seven different global climate forecast models for major basins in Israel within October–April 1982–2010. The six National Multimodel Ensemble (NMME) models and the ECMWF seasonal model were used to calculate an International Multimodel Ensemble (IMME). The study presents the performance of both monthly and seasonal predictions of precipitation accumulated over three months, with respect to different lead times for the ensemble mean values, one per individual model. Additionally, we analyzed the performance of different combinations of models. We present verification of seasonal forecasting using real forecasts, focusing on a small domain characterized by complex terrain, high annual precipitation variability, and a sharp precipitation gradient from west to east as well as from south to north. The results in this study show that, in general, the monthly analysis does not provide very accurate results, even when using the IMME for one-month lead time. We found that the IMME outperformed any single model prediction. Our analysis indicates that the optimal combinations with the high correlation values contain at least three models. Moreover, prediction with larger number of models in the ensemble produces more robust predictions. The results obtained in this study highlight the advantages of using an ensemble of global models over single models for small domain.
Abstract 1114: Combining anti-androgen therapy and PARP inhibition results in synergistic cytotoxicity of metastatic castration-resistant prostate cancer (mCRPC) cells
Authors: Pamarthy Sahithi , Sagar Vinay , Vatapalli Rajita J. , Reinstein Zachary , Ansari Muhammad Zayd , Filho Benedito A. Carneiro , Giles Francis J. , Abdulkadir Sarki A.
Published: July 2017

Androgen deprivation therapy is an efficient first line therapy for advanced prostate cancer. However, in most cases resistance inevitably develops resulting in metastatic castration-resistant prostate cancer (mCRPC). Abiraterone and enzalutamide are approved to treat mCRPC and act by inhibiting androgen biosynthesis and androgen receptor (AR) signaling, respectively. Poly (ADP-ribose) polymerase 1 (PARP1) is a key enzyme in the DNA damage repair pathway and has also been implicated in AR signaling cascade. Recent reports suggest significant efficacy combining anti-androgens and inhibitors of Poly (ADP-ribose) polymerase (PARP) particularly against cells harboring mutations in the DNA repair pathway. Here, we provide evidence of synergistic cytotoxicity combining PARP inhibition and androgen signaling ablation in the AR positive human CRPC cell line 22RV1 harboring mutation in the DNA repair gene BRCA2. The PARP inhibitor talazoparib (IC50 - 0.05 μM) was upto 20 times more potent than olaparib (IC50 – 1.0 μM) in inducing cell death in 22RV1 as seen by cell viability and clonogenic assays. When combined with AR antagonist enzalutamide (IC50 – 0.25 μM) or androgen synthesis inhibitor abiraterone (IC50 – 1.25 μM) both PARP inhibitors showed significant synergy, although talazoparib was more prominent owing to its superior potency. Higher concentrations of enzalutamide and abiraterone (>10μM) induced PARP cleavage and increased expression of γ-H2AX, a marker for DNA damage. Our results suggest that AR signaling inhibition involves PARP mediated apoptosis and highlight the crosstalk between PARP and AR pathways. In summary, combining anti-androgen therapy and PARP inhibitors carry significant therapeutic potential for CRPC patients harboring mutations in DNA repair pathway.

Citation Format: Sahithi Pamarthy, Vinay Sagar, Rajita J. Vatapalli, Zachary Reinstein, Muhammad Zayd Ansari, Benedito A. Carneiro Filho, Francis J. Giles, Sarki A. Abdulkadir. Combining anti-androgen therapy and PARP inhibition results in synergistic cytotoxicity of metastatic castration-resistant prostate cancer (mCRPC) 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 1114. doi:10.1158/1538-7445.AM2017-1114
Abstract 1125: Eukaryotic Elongation Factor 2 Kinase (eEF-2K) is a novel therapeutic target in BRCA1+ mutated breast cancer
Authors: Asik Elif , Kahraman Nermin , Guray Tulin , Volkan Murvet , Lopez-Berestein Gabriel , Ozpolat Bulent
Published: July 2017

BReast CAncer 1 and 2 (BRCA1/2) tumor suppressor genes are frequently mutated in familial breast and ovarian cancers. Recent clinical trials in breast cancers with BRCA1/2 mutations indicate that 50-75% of patients may not have response to poly (ADP-ribose) polymerase inhibitors (PARP) inhibitors. Thus, identification of novel molecular targets and therapeutic interventions are needed to improve poor clical outcome and patient survival. Here we report that Eukaryotic Elongation Factor-2 Kinase (EF2K), an atypical kinase, is highly upregulated in BRCA1+ mutated cell lines and involved in colony formation, migration/ invasion and enhances the effect of PARP inhibitors. Furthermore, in vivo therapeutic targeting of EF2K by once a week systemic injections with magnetic nanoparticles (MNPs) incorporating EF2K siRNA significantly inhibits growth of BRCA1+ tumors in orthotopic xenograft models in mice by inhibition of tumor cell proliferation, angiogenesis and induction of robust apoptosis, which were associated with in vivo inhibition of clinically relevant molecular pathways including, proliferation, survival/drug resistance (PI3K/Akt, c-Myc), cell cycle (Cyclin D1), motility/invasion (Src/FAK/Paxillin), translation (4E-BP1), angiogenesis (VEGF) and stem-cell markers. No toxicity was detected during the study and by postmortem analysis of major organs, indicating that targeting EF2K is safe. The combination of PARP inhibitor (AZD2281, Oleparib) with MNP-EF2K siRNA enhanced significantly growth inhibition in MDA-MB-436 cells indicting EF2K siRNA sensitize BRCA1 + mutation breast cancer cells to PARP inhibitors. Collectively, our results suggest, for the first time, that EF2K is involved in tumorigenesis and progression and may serve as a potential therapeutic target in BRCA1+ mutated breast cancers.

Citation Format: Elif Asik, Nermin Kahraman, Tulin Guray, Murvet Volkan, Gabriel Lopez-Berestein, Bulent Ozpolat. Eukaryotic Elongation Factor 2 Kinase (eEF-2K) is a novel therapeutic target in BRCA1+ mutated 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 1125. doi:10.1158/1538-7445.AM2017-1125
Abstract 1168: Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma
Authors: Booher Robert N. , Samson Maria Elena , Xu Guang-Xin , Cheng Hongsheng , Tuck David P.
Published: July 2017

IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of DLBCL cases. The MYD88 L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL.

We are developing an IRAK4 inhibitor, CA-4948, as a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 (previously AU-4948) is a selective and potent IRAK4 kinase inhibitor with in vivo activity in a TLR4-induced cytokine release model. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 was previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models using cell lines OCI-LY3 and OCI-LY10.

Here, we report the efficacy results from testing CA-4948 in a panel of well characterized, patient-derived DLBCL tumor xenograft (PDX) mouse models. CA-4948 exhibited the greatest efficacy in four of the five ABC-DLBCL PDX models tested as compared to GBC-DLBCL and ABC/GCB DLBCL PDX models. Furthermore, CA-4948 was efficacious in ABC-DLBCL PDX tumors containing activating mutations in both TLR/IL-1R and BCR signaling pathways (MYD88 and CD79B double mutants). Interestingly, the one ABC-DLBCL PDX model that failed to respond to CA-4948 treatment contained a MYD88 L265P mutation as well as a BCL6 translocation. While this particular PDX model was resistant to CA-4948, and showed a weak anti-tumor response to single-agent ibrutinib, the combination treatment of ibrutinib and CA-4948 exhibited a synergistic tumor growth inhibition effect. In summary, CA-4948 exhibited anti-tumor activity in ABC-type DLCBL PDX tumor models including those containing combinations of activating mutations in the TLR/IL-1R and BCR signaling pathways. These results underscore the therapeutic potential of IRAK4 kinase inhibition by CA-4948, as a single-agent or in combination with BCR inhibitors, for the treatment of DLBCL.

Citation Format: Robert N. Booher, Maria Elena Samson, Guang-Xin Xu, Hongsheng Cheng, David P. Tuck. Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma [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 1168. doi:10.1158/1538-7445.AM2017-1168
Abstract 1188: Sodium phenylbutyrate has an antineoplastic effect and enhances the cytotoxicity of 5-fluorouracil and irinotecan in colorectal cancer cell lines
Authors: Al-Keilani Maha , Darweesh Ruba
Published: July 2017

Colorectal cancer is the third most common cancer in the world and it is the second leading cause of cancer-related deaths in the United States. About 25% of colorectal cancer cases present with metastases at time of diagnosis and 50% of patients who undergo surgery will ultimately develop metastatic disease. Consequently, adjuvant chemotherapy is required in many cases and it aims to prevent tumor progression and metastasis.

Resistance to chemotherapy is the biggest obstacle in the treatment path of advanced colorectal cancer. Thus, highlighting the urgent need for the identification of new therapeutic agents that can enhance the cytotoxicity of the currently approved anticancer drugs.

Sodium phenylbutyrate (NaPB), a salt of a short chain fatty acid that is used for treatment of urea cycle disorders, is under investigation for its antineoplastic potential. NaPB acts as a histone deacetylase inhibitor and it has been shown to be associated with reduced ER stress and enhanced JNK signaling pathway. This indicates that NaPB may enhance the cytotoxicity of the currently approved agents for colorectal cancer including oxaliplatin, 5-fluorouracil, and irinotecan.

The aims of this study were to identify the antineoplastic potential of NaPB in colorectal cell lines, and to identify its effect on the cytotoxicity of oxaliplatin, 5-fluorouracil, and irinotecan.

MTT proliferation assay showed that NaPB possessed a concentration dependent killing effect against HCT-116 and HT-29 colorectal cancer cell line (IC50 values were 5 and 10 mM respectively). Moreover, at clinically achievable and nontoxic concentration (2.5 mM), NaPB showed a synergistic effect in HCT-116 on 5-fluorouracil (R=14.176, p=0.006), on irinotecan (R=53.86, p=0.0117), and on oxaliplatin (R=20, p=0.004), but resulted in extensive cytotoxicity when used at 5 mM and 10 mM.

In HT-29 cells, NaPB at concentrations 5 mM and 10 mM, showed a synergistic effect on 5-fluorouracil (R=5.5, p<0.001; and R=125, p<0.001 respectively), on irinotecan (R=5.7, p=0.016; and R=21.3, p=0.018 respectively), and on oxaliplatin (R=2.4, p=0.003; and R=3, p=0.002 respectively). The addition of NaPB at concentration of 20 mM to the previous drugs resulted in profound cytotoxic effect toward HT-29 cells.

As a conclusion, NaPB is a promising new adjuvant antineoplastic agent that can be used to enhance the cytotoxicity of 5-fluorouracil, irinotecan, and oxaliplatin in colorectal cancer.

Citation Format: Maha Al-Keilani, Ruba Darweesh. Sodium phenylbutyrate has an antineoplastic effect and enhances the cytotoxicity of 5-fluorouracil and irinotecan in colorectal cancer cell lines [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 1188. doi:10.1158/1538-7445.AM2017-1188
Abstract 1366: Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS
Authors: Tran Timothy , Dharmaiah Sathiya , Chertov Oleg , Waybright Timothy , Gillette William , Esposito Dominic , Nissley Dwight , McCormick Frank , Stephen Andrew , Simanshu Dhirendra
Published: July 2017

RAS mutations are found in one-third of all human cancers. Among the three RAS isoforms - HRAS, KRAS and NRAS, KRAS is the most commonly mutated gene (in 86% of RAS-driven cancers) and the mutations are often detected in pancreatic, colorectal and lung cancers. RAS proteins function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. The active or inactive state of RAS proteins is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). In the GTP-bound state, RAS proteins interact with a variety of effector proteins, such as Raf, PI3K, and RalGDS, leading to activation of several signaling cascades within the cell. In 98% of the cases, oncogenic RAS mutations are found at amino acid positions G12, G13, and Q61 which impair intrinsic and GAP-mediated GTPase function resulting in accumulation of constitutively GTP-bound RAS in cells. To gain insights into the effect of oncogenic mutations on overall structure and GTP hydrolysis, we solved high-resolution crystal structures of wild type and six oncogenic mutants (G12C, G12D, G12V, G13D, Q61L and Q61R) of KRAS4b in complex with GMPPNP (a non-hydrolysable GTP analog) and magnesium. Comparison of GDP and GMPPNP bound structures of wild type (WT) KRAS4b suggests conformational changes that occur when KRAS4b transitions from inactive to active state. Comparison of mutant and wild-type KRAS structures has shown the appearance of new pockets in some cases that could be exploited for structure-based drug design. Structural superposition of mutants vs. wild type KRAS4b in complex with GMPPNP/Mg2+, and KRAS4b mutants vs. WT-HRAS bound to RASA1-GAP provides a rationale for impaired intrinsic and GAP-mediated GTP hydrolysis in the KRAS mutants.

Citation Format: Timothy Tran, Sathiya Dharmaiah, Oleg Chertov, Timothy Waybright, William Gillette, Dominic Esposito, Dwight Nissley, Frank McCormick, Andrew Stephen, Dhirendra Simanshu. Structural basis of impaired GTP hydrolysis in oncogenic mutants of KRAS [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 1366. doi:10.1158/1538-7445.AM2017-1366
Abstract 1382: A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers
Authors: Wang Nenghui , Yin Mingzhu , Yan Qin
Published: July 2017

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins have emerged as a promising option for cancer therapy. NHWD-870 is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. NHWD-870 exhibited robust single agent activity in cell viability assay across cancer cell lines derived from solid tumors, leukemia and lymphomas. Further characterization of cancer cell responses to NHWD-870 indicated that NHWD-870 manifested diverse mechanisms of action in different cancer settings. These include: 1) inhibition of tumor cell growth by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC signaling in tumor cells; 2) inhibition of tumor angiogenesis by decreasing PDGF production in tumor cells and the PDGFRβ and MEK1/2 signaling in endothelial cells. Consistent with its broad spectrum of activities in vitro, NHWD-870 has potent tumor suppressive efficacies in xenograft mouse models of small cell lung cancer, triple negative breast cancer and ovarian cancer. These results support its further development for diverse solid tumor indications in the clinic.

Citation Format: Nenghui Wang, Mingzhu Yin, Qin Yan. A novel BET family bromodomain inhibitor NHWD-870 represents a promising therapeutic agent for a broad spectrum of cancers [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 1382. doi:10.1158/1538-7445.AM2017-1382
Abstract 1475: miRNA-450a suppresses adhesion but promotes invasion through targeting of TMEM182 in oral squamous cell carcinoma
Authors: Hsing En-Wei , Shiah Shine-Gwo , Kuo Ching-Chuan , Chang Jang-Yang
Published: July 2017

Our microRNA (miRNA) expression signatures of oral squamous cell carcinoma (OSCC) revealed that miR-450a was significantly increased in cancer tissues compared with normal epithelium. In this study, we focused on the functional significance of miR-450a in cancer cells and identification of miR-450a-regulated novel targets in OSCC. Overexpression of miR-450a in DOK and SAS cells showed significant inhibition of cell adhesion and induction of cell invasiveness, suggesting that miR-450a functions as an onco-miRNA. We performed genome-wide gene expression analysis to search for miR-450a-regulated molecular targets. Gene expression data and luciferase reporter assays revealed that TMEM182 was directly targeted by miR-450a. The miR-450a-reduced cellular adhesion was blocked by TMEM182 restoration, suggesting that miR-450a exhibits its oncogenic activity through negatively regulating TMEM182 level. Furthermore, miR-450a expression could be induced by the cytokine TNF-α primarily through activating extracellular signal-regulated kinase (ERK) signaling pathway. ERK inhibitor prevented the TNF-α-induced miR-450a expression and enhanced adhesion ability. Taken together, these data indicate that TNF-α/ERK-dependent expression of miR-450a plays an important role in mediating cellular adhesion and invasiveness, and scavenging miR-450a function using antagomir may have therapeutic potential for the treatment of OSCC. (The study was supported by the following grants: MOST 103-2320-B-006-036-MY3 and MOST 105-2325-B-400-001 from the Ministry of Science and Technology of Taiwan, ROC)

Citation Format: En-Wei Hsing, Shine-Gwo Shiah, Ching-Chuan Kuo, Jang-Yang Chang. miRNA-450a suppresses adhesion but promotes invasion through targeting of TMEM182 in oral squamous cell carcinoma [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 1475. doi:10.1158/1538-7445.AM2017-1475
Abstract 1518: Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC)
Authors: Schafer Johanna , Lehmann Brian , Liu Phillip , Stubbs Matthew , Scherle Peggy , Pietenpol Jennifer
Published: July 2017

Triple-negative breast cancers (TNBCs) lack expression of estrogen receptor (ER), progesterone receptor (PR), and amplifications in the human epidermal growth factor receptor 2 (HER2). With currently no FDA-approved targeted therapies for TNBC, patients with TNBC have a higher risk of local and distant recurrence, and an overall increased rate of mortality. Recent studies have demonstrated increased sensitivity of TNBC to the anti-proliferative effects of BETi compared to the other breast cancer subtypes. To determine mechanisms of sensitivity to BET inhibition, we analyzed the effect of two BET inhibitors, INCB054329 and OTX-015, across a panel of TNBC cell line models and identified cell lines that were both sensitive and insensitive to BETi. With the intent of identifying biomarkers of sensitivity, we performed RNA-seq and precision nuclear run-on and sequencing (PRO-seq) on both sensitive and resistant cell line models and data generated identified significant differences in key growth regulatory and apoptotic signaling pathways, including notable differences in Myc-dependent signaling. Our data suggest potential biomarkers of BETi sensitivity that may be of value in further pre-clinical studies. Further, our results provide mechanistic rationale for combinations of BETi with select, targeted therapies in a disease that is in need of new therapeutic intervention.

Citation Format: Johanna Schafer, Brian Lehmann, Phillip Liu, Matthew Stubbs, Peggy Scherle, Jennifer Pietenpol. Mechanisms of bromodomain and extra-terminal motif inhibitor (BETi) sensitivity in triple-negative breast cancer (TNBC) [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 1518. doi:10.1158/1538-7445.AM2017-1518
Abstract 1539: Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer model
Authors: Yan Mingfei , Many Alexander , Guan Hong , Or Penelope M. , Chan Andrew M.
Published: July 2017

PTEN (Phosphatase and tensin homolog) functions as a key negative regulator of PI3K-Akt pathway through its lipid phosphatase activity. Mutations or loss of PTEN is frequently observed in brain, breast, prostate and endometrial cancer. PTEN possesses a PDZ-binding domain (PDZ-BD) at the end of its carboxyl terminus. Functionally, PDZ-BD mediates PTEN’s interactions with other PDZ domain-containing proteins, including ZO-1, PSD-95, DLG, etc, which are involved in the formation of cell junctions, post-synaptic densities, and serves as scaffolding proteins for multiple signaling complexes. However, whether the PTEN PDZ-binding domain is required to suppress tumorigenesis still remains obscure.

To study the role of PTEN PDZ-BD in breast epithelial tumorigenesis, a PTEN-ΔPDZ mice lacking this domain was generated. PTEN expression level and activity of PI3K-Akt pathway are not changed in the mammary epithelial cells, indicating that PDZ-BD is dispensable for PTEN stability and negative regulation of the PI3K-Akt pathway. Further, we crossed the PTEN-ΔPDZ mice with the MMTV-PyMT breast cancer model and observed increased total tumor burden as well as higher tendency of lung metastasis in PTEN-ΔPDZ mice. This data indicates that PTEN PDZ-BD is indeed important for tumor suppression during breast cancer progression.

Previously, PTEN has been reported to govern the integrity of tight junctions and apical-basal polarity of epithelial cells, which requires PTEN’s interactions with other proteins through the PDZ-BD. However, through in vitro three-dimensional culture of primary mouse mammary epithelial cells, we failed to observe any disruption of either apical-basal polarity or tight junction. Meanwhile, we investigated the alteration of the transcriptome of breast cancer tissue in PTEN-ΔPDZ mice by performing RNA-sequencing. Several enriched signaling pathways were identified by Ingenuity Pathway Analysis (IPA), which seems to be mainly associated with cell skeleton signaling as well as signaling interaction between extracellular matrix and the cancer cell. A list of genes were validated by RT-PCR, and functional validation of these genes during the tumorigenesis in our animal model is to be carried out in the near future.

This work was supported by a General Research Fund grant (#460713) from the Hong Kong University Grants Committee to AC. YM was supported by a Hong Kong PhD Fellowship (PF12-13584), and a Lo Kwee-Seong Biomedical Research Seed Fund to AC.

Citation Format: Mingfei Yan, Alexander Many, Hong Guan, Penelope M. Or, Andrew M. Chan. Investigating the mechanisms of tumor suppression mediated by PTEN PDZ-binding domain in a murine breast cancer model [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 1539. doi:10.1158/1538-7445.AM2017-1539
Abstract 1599: Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models
Authors: Bellovin David I. , Wondyfraw Nebiyu , Sennino Barbara , Walker Quinn , Johnson Susan , Levin Anita , Masteller Emma , Barbee Susannah D. , Sikorski Robert , Brennan Tom
Published: July 2017

The colony stimulating factor 1 receptor (CSF-1R) signaling pathway promotes tumor progression via the recruitment, differentiation, and survival of immuno-suppressive tumor-associated macrophages (TAMs). FivePrime has developed cabiralizumab (FPA008), an IgG4 antibody against CSF-1R that blocks the ability of both CSF-1 and IL-34 to bind and activate this receptor, thereby modulating the immune response to tumorigenesis. In order to investigate the impact of CSF-1R signaling inhibition in preclinical models, we generated a surrogate antibody, cmFPA008, which targets mouse CSF-1R and demonstrates equivalent affinity and ligand-blocking ability as FPA008. Utilizing a combination of flow cytometry and immunofluorescence analyses, we have identified alterations in the tumor microenvironment that occur upon CSF-1R inhibition, including significant reduction of immunosuppressive TAMs and an increase in tumor PD-L1 expression. Interestingly, we observe a transient increase in CD8+ T cell number and activation upon TAM depletion, followed by a subsequent increase in MDSC populations that corresponds with reduction of the CD8+ T cell numbers. Moreover, we have used murine syngeneic tumor models to examine the anti-tumor impact of CSF-1R inhibition in combination with other immuno-oncology agents. Our results show that, when added to PD-1/PD-L1 blockade, cmFPA008 can significantly enhance anti-tumor efficacy. We are currently exploring the effects of combining cmFPA008-induced TAM depletion with additional immuno-oncology agents, including T cell agonists. Our preclinical results demonstrate that inhibition of the CSF-1R pathway can combine with various immuno-oncology agents with distinct mechanisms of action. FivePrime has initiated a clinical trial in collaboration with Bristol-Myers Squibb (BMS) to investigate the use of cabiralizumab in combination with nivolumab (anti-PD-1, OPDIVO®) in six different tumor types.

Citation Format: David I. Bellovin, Nebiyu Wondyfraw, Barbara Sennino, Quinn Walker, Susan Johnson, Anita Levin, Emma Masteller, Susannah D. Barbee, Robert Sikorski, Tom Brennan. Antibody-based inhibition of CSF-1R as a component of combination immunotherapy in preclinical models [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 1599. doi:10.1158/1538-7445.AM2017-1599
Abstract 1605: Combined oral cytokine therapy effectively treats colon cancer in a murine model
Authors: Bhutiani Neal , Li Qingsheng , Anderson Charles D. , Gu Tao , Egilmez Nejat K.
Published: July 2017

Background: Regardless of its etiology, colorectal cancer development is intimately associated with dysregulation of the intestinal immune system. Sustained release, orally delivered IL-10 not only inhibits colon tumor growth but restores T cell homeostasis both locoregionally and systemically. However, it does not induce tumor regression. We aimed to combine orally delivered IL-12, a potent immunostimulatory molecule with robust anti-tumor effect, with oral IL-10 therapy to induce tumor regression.

Methods: 6 week old APCmin mice were inoculated with enterotoxic Bacteroides fragilis (serotype 086) after five days of intestinal flora depletion with antibiotics dissolved in drinking water. 7-10 days after bacterial inoculation, mice were treated three times weekly with either 1) blank polylactic acid microspheres for 3 weeks, 2) IL-10 containing microspheres (0.5 microgram/dose) for 3 weeks, 3) IL-12 containing microspheres (0.25 micrograms/dose) for 3 weeks, or 4) IL-10 containing microspheres for 1 week followed by a combination of IL-10 and IL-12 containing microspheres for 2 weeks. After euthanasia, colons were assessed for polyp counts and select polyps were isolated for confocal microscopy analysis. Mesenteric lymph node lymphocytes were isolated and analyzed using flow cytometry.

Results: Mice treated with oral IL-10 and IL-12 demonstrated a reduction in polyp number compared to those mice treated with IL-10 alone, and both groups had fewer polyps than mice treated with either IL-12 or blank microspheres. Addition of IL-12 resulted in increased CD8+ T cell numbers and IFN-γ production compared to treatment with IL-10 alone. IL-10 retained its effect on CD4+ T cells when combining it with IL-12, resulting in a decrease in conventional regulatory T cells (FoxP3+ RORγT -) as well as pathogenic regulatory T cells (FoxP3+ RORγT+) and IL-17 producing CD4+ T cells.

Conclusions: The addition of IL-12 to IL-10 therapy augments the therapeutic effect of oral cytokine treatment on colon adenocarcinoma in the APCmin B. fragilis model. The effect appears additive and mediated by both IL-10’s effect on regulatory T cell populations and IL-12’s effect on CD8+ T cells. Further studies in the setting of more advanced disease, including liver metastases, will elucidate the therapeutic potential of combination oral cytokine therapy with IL-10 and IL-12 for treatment of colorectal cancer.

Citation Format: Neal Bhutiani, Qingsheng Li, Charles D. Anderson, Tao Gu, Nejat K. Egilmez. Combined oral cytokine therapy effectively treats colon cancer in a murine model [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 1605. doi:10.1158/1538-7445.AM2017-1605