bluuebunny/crossref_metadata_2025 huggingface dataset:
SPATIOTEMPORAL TRANSMISSION DYNAMICS OF RECENT EBOLA OUTBREAK IN SIERRA LEONE, WEST AFRICA: IMPACT OF CONTROL MEASURES
Authors: ROY PARIMITA , UPADHYAY RANJIT KUMAR
Published: July 2017

In this paper, we have formulated a compartmental epidemic model with exponentially decaying transmission rates to understand the Ebola transmission dynamics and study the impact of control measures to basic public health. The epidemic model exhibits two equilibria, namely, the disease-free and unique endemic equilibria. We have calculated the basic reproduction number through next generation matrix and investigated the spatial spread of the epidemic via reaction–diffusion modeling. Instead of fitting the model to the observed pattern of spread, we have used previously estimated parameter values and examined the efficacy of predictions of the designed model vis-à-vis the pattern of spread observed in Sierra Leone, West Africa. Further, we conducted a sensitivity analysis to determine the extent to which improvement in predictions is achievable through better parameterization.

We performed numerical simulations with and without control measure for the designed model system. A significant reduction in infection and death cases were observed when proper control measures are incorporated in the model system. Two-dimensional simulation experiments show that infectious population and the number of deaths will increase up to one and a half years without control, but it will decline after two years. We have reported the numerical results, and it closely matches with the real situation in Sierra Leone.
An Analytical Solution for Free Flexural Vibration of a Thin Cylindrical Shell Submerged in Acoustic Half-Space Bounded by a Free Surface
Authors: Wang Peng , Li Tian-Yun , Zhu Xiang , Guo Wen-Jie , Nie Rui
Published: July 2017

An analytical solution is proposed for the free flexural vibration of a finite cylindrical shell submerged in half-space bounded by a free surface in the low frequency range. The motion of the shell is described by the Flügge shell theory and the fluid surrounding the shell is assumed to be an acoustic media. The free surface effect is considered by satisfying the pressure release boundary condition. The accuracy of the present method is verified through comparison with the finite element solution. To throw light on the influence mechanism of free surface on the coupled modal frequencies, a modal added mass is introduced and calculated. Numerical results show that when the shell is close to the free surface, the presence of free surface will make a negative contribution to the modal added mass and finally result in the corresponding increase of the coupled modal frequencies. But the free surface effect will decrease when the immersion depth of the cylindrical shell increases. Finally, the free surface effect can be neglected if the immersion depth is higher than four times the shell radius. This conclusion is helpful to select proper test environment for an experiment on the dynamic characteristics of submerged cylindrical shells.
Making Machine-Learning Applications for Time-Series Sensor Data Graphical and Interactive
Authors: Kim Seungjun , Tasse Dan , Dey Anind K.
Published: July 2017

The recent profusion of sensors has given consumers and researchers the ability to collect significant amounts of data. However, understanding sensor data can be a challenge, because it is voluminous, multi-sourced, and unintelligible. Nonetheless, intelligent systems, such as activity recognition, require pattern analysis of sensor data streams to produce compelling results; machine learning (ML) applications enable this type of analysis. However, the number of ML experts able to proficiently classify sensor data is limited, and there remains a lack of interactive, usable tools to help intermediate users perform this type of analysis. To learn which features these tools must support, we conducted interviews with intermediate users of ML and conducted two probe-based studies with a prototype ML and visual analytics system, Gimlets. Our system implements ML applications for sensor-based time-series data as a novel domain-specific prototype that integrates interactive visual analytic features into the ML pipeline. We identify future directions for usable ML systems based on sensor data that will enable intermediate users to build systems that have been prohibitively difficult.
A Web-Based Infrastructure for the Assisted Annotation of Heritage Collections
Authors: Foley Jacob , Kwan Paul , Welch Mitchell
Published: July 2017

Annotations provide a valuable perspective on the semantic information present in digital heritage collections, and in recent years they've been employed in a number of innovative, user-centric techniques that can personalise a user's experience of heritage materials, such as by actively adapting exhibits as a user reveals their interests, or by guiding users to explore collections which are meaningfully linked to what they have previously encountered. Despite the captivating opportunities offered by these techniques, collecting annotations for a large heritage collection is no trivial task. A significant amount of work is required to manually annotate large quantities of heritage materials, and automated, computational approaches leave much to be desired regarding the level of insight and semantic richness that they can currently provide.

By analysing the emergent relationships between the initial annotations in a collection, we propose a metadata-driven algorithm for assisting and augmenting the annotation process. This algorithm, called SAGA (Semantically-Annotated Graph Analysis), allows for semi-automatic annotation, which balances the value of the contributions of human annotators with the time and effort-saving benefits of an automatic, suggestion-driven process. SAGA uses an entity relationship-driven approach to make annotation suggestions. It is used in the context of a web-based infrastructure called SAGE (Semantic Annotation by Group Exploration), a multiagent environment which assists groups of experts in creating comprehensive annotation sets for heritage collections. SAGA and SAGE are evaluated from the perspectives of suggestion accuracy, explicit user acceptance and implicit user acceptance, and demonstrate strong results in each evaluation.
Advances in Bolometer Technology for Fundamental Physics
Authors: Pirro S. , Mauskopf P.
Published: July 2017

In the last decade, cryogenic bolometers have provided increasingly improved resolution and sensitivity in particle and radiation detectors. Thermal particle detectors have proven their outstanding capabilities in different fields of fundamental physics, especially in rare event detection. Cryogenic incoherent detector arrays designed to detect millimeter-wave photons have helped enable precision measurements of anisotropies in the cosmic microwave background (CMB), providing a unique probe of early universe physics and helping to constrain parameters of particle physics such as the sum of the neutrino masses. We review the latest achievements of cryogenic particle detectors for direct detection searches for dark matter and double-[Formula: see text] decay, as well as for CMB measurements, and we discuss expected improvements aiming to increase the sensitivities of these experiments. An important challenge is the large-scale implementation of arrays of detectors such as transition edge sensors, especially in CMB polarization experiments. We describe the challenges of scaling up to these larger arrays, including fabrication throughput and development of new multiplexing electronics.
Reactor Neutrino Experiments: Present and Future
Authors: Wen L.J. , Cao J. , Wang Y.F.
Published: July 2017

Reactor neutrinos have been an important tool for both discovery and precision measurement in the history of neutrino studies. Since the first generation of reactor neutrino experiments in the 1950s, the detector technology has advanced greatly. New ideas, new knowledge, and modern software have also enhanced the power of the experiments. The current reactor neutrino experiments, Daya Bay, Double Chooz, and RENO, have led neutrino physics into the precision era. In this article, we review these developments and advances, address the key issues in designing a state-of-the-art reactor neutrino experiment, and explain how the challenging requirements of determining the neutrino mass hierarchy with the next-generation experiment JUNO could be realized in the near future.
Opioid Prescribing Practices and Training Needs of Québec Family Physicians for Chronic Noncancer Pain
Authors: Roy Élise , Côté Richard J. , Hamel Denis , Dubé Pierre-André , Langlois Éric , Labesse Maud Emmanuelle , Thibault Christiane , Boulanger Aline
Published: July 2017

Aim. To examine medical practices and training needs of Québec family physicians with respect to pain management and opioid prescription for chronic noncancer pain (CNCP). Methodology. An online survey was carried out in 2016. Results. Of 636 respondents (43.0% men; 54.3% ≥ 50 years old), 15.2% and 70.9% felt very or somewhat confident that they could properly prescribe opioids for CNCP. Concerns related to abuse (72.5% strongly/somewhat agree), dependence (73.2%), and lack of support (75.4%) were the main barriers reported. Only 19.7% always/often screened their patients for risks of abuse and dependence using a screening tool. About two-thirds of participants (65.7%) had recently (last five years) taken part in continuing education programs on opioid use for CNCP and 73.4% on CNCP management. Patient evaluation and differential diagnoses of chronic pain syndromes were rated as a top priority for further training. Conclusions. This study provides insights into Québec family physicians’ concerns, practices, and needs with respect to the management of CNCP. Physicians’ difficulties around the application of strategies to mitigate the problem of opioid abuse and addiction are worrying. The need to better train physicians in the field of pain and addiction cannot be emphasized enough.
Bilateral Ganglion Cysts of the Ligamentum Flavum in the Cervical Spine Causing a Progressive Cervical Radiculomyelopathy and Literature Review
Authors: Kim Juneki , Choi Jin-gyu , Son Byung-chul
Published: July 2017

Here we report a unique case of bilateral ganglion cysts originating from the ligamentum flavum in the cervical spine. Degenerative cysts of the ligamentum flavum are rare lesions, and most had been reported in the lumbar spine. Its occurrence in the cervical spine is extremely rare: only eight have been reported. A 66-year-old male patient presented with progressive paraparesis, pain, and paresthesia in his bilateral T1 dermatomes that had lasted for three weeks. Magnetic resonance imaging of the cervical spine demonstrated a well-demarcated cystic lesion in the bilateral dorsolateral aspects of the C7/T1 segment and significant compression of the cervical cord. All case reports of ganglion cysts of the cervical ligamentum flavum including the present one showed characteristic symptoms and signs of myelopathy such as paraparesis or quadriparesis associated with varying degrees of paresthesia or pain in the upper extremities. Ganglion cysts of the cervical ligamentum flavum are considered a cause of cervical radiculomyelopathy due to cervical intraspinal cystic lesions. Bilateral occurrence and associated subluxation of the involved cervical segments again support the degenerative pathogenesis of ganglion cysts of the ligamentum flavum in the cervical spine.
An Unexpected Case of Black Mamba (Dendroaspis polylepis) Bite in Switzerland
Authors: Quarch Verena , Brander Lukas , Cioccari Luca
Published: July 2017

Mambas (genusDendroaspis) are among the most feared venomous African snakes. Without medical treatment, mamba bites are frequently fatal. First-aid treatment includes lymphatic retardation with the pressure immobilization technique. Medical management comprises continuous monitoring, securing patency of the airway, ensuring adequate ventilation, symptomatic measures, and administration of specific antivenin. We report an unusual case of a snake breeder bitten by a black mamba in Switzerland, report the clinical course, and review the lifesaving emergency management of mamba bites. This case highlights the importance of early antivenin administration and suggests that emergency and critical care physicians as well as first responders all around the world should be familiar with clinical toxinology of exotic snake bites as well as with the logistics to most rapidly make the specific antivenin available.
Spiritual Struggle in Parents of Children with Cystic Fibrosis Increases Odds of Depression
Authors: Szczesniak Rhonda D. , Zou Yuanshu , Stamper Sophia M. , Grossoehme Daniel H.
Published: July 2017

Objective. Spiritual struggle (SS) is associated with poorer health outcomes including depression. The study’s main objectives were to characterize change in depression over time, examine longitudinal associations between SS and depression, and determine the extent to which experiencing SS at baseline was predictive of developing depression at follow-up. Methods. A two-site study collected questionnaire responses of parents (N=112; 72% female) of children with cystic fibrosis followed longitudinally. Generalized linear mixed effects modeling examined the association between depression and SS over time and assessed potential mediators, moderators, and confounders. Results. Prevalence of depression increased from baseline to follow-up (OR: 3.6, P<0.0001), regardless of degree of SS. Parents with Moderate/Severe SS were more likely to have depressive symptoms, compared to parents without SS (OR: 15.2, P=0.0003) and parents who had Mild SS (OR: 10.2, P=0.0001). Being female and feeling less “at peace” also significantly predicted increased depression (OR: 2.5, P=0.0397, and OR: 1.15, P=0.0419, resp.). Experiencing SS at baseline was not predictive of having depression subsequently at follow-up. Conclusions. Parents experiencing SS were significantly more likely to report depressive symptoms. Interventions to reduce SS have shown efficacy and may be considered.
Comparison of Machine Learning Methods for the Arterial Hypertension Diagnostics
Authors: Kublanov Vladimir S. , Dolganov Anton Yu. , Belo David , Gamboa Hugo
Published: July 2017

The paper presents results of machine learning approach accuracy applied analysis of cardiac activity. The study evaluates the diagnostics possibilities of the arterial hypertension by means of the short-term heart rate variability signals. Two groups were studied: 30 relatively healthy volunteers and 40 patients suffering from the arterial hypertension of II-III degree. The following machine learning approaches were studied: linear and quadratic discriminant analysis, k-nearest neighbors, support vector machine with radial basis, decision trees, and naive Bayes classifier. Moreover, in the study, different methods of feature extraction are analyzed: statistical, spectral, wavelet, and multifractal. All in all, 53 features were investigated. Investigation results show that discriminant analysis achieves the highest classification accuracy. The suggested approach of noncorrelated feature set search achieved higher results than data set based on the principal components.
Topology Detection for Output‐Coupling Weighted Complex Dynamical Networks with Coupling and Transmission Delays
Authors: Wang Xinwei , Jiang Guo-Ping , Fan Chunxia , Wu Xu
Published: July 2017

Topology detection for output‐coupling weighted complex dynamical networks with two types of time delays is investigated in this paper. Different from existing literatures, coupling delay and transmission delay are simultaneously taken into account in the output‐coupling network. Based on the idea of the state observer, we build the drive‐response system and apply LaSalle’s invariance principle to the error dynamical system of the drive‐response system. Several convergent criteria are deduced in the form of algebraic inequalities. Some numerical simulations for the complex dynamical network, with node dynamics being chaotic, are given to verify the effectiveness of the proposed scheme.
Effect of Isopropyl Alcohol Concentration and Etching Time on Wet Chemical Anisotropic Etching of Low-Resistivity Crystalline Silicon Wafer
Authors: Abdur-Rahman Eyad , Alghoraibi Ibrahim , Alkurdi Hassan
Published: July 2017

A micropyramid structure was formed on the surface of a monocrystalline silicon wafer (100) using a wet chemical anisotropic etching technique. The main objective was to evaluate the performance of the etchant based on the silicon surface reflectance. Different isopropyl alcohol (IPA) volume concentrations (2, 4, 6, 8, and 10%) and different etching times (10, 20, 30, 40, and 50 min) were selected to study the total reflectance of silicon wafers. The other parameters such as NaOH concentration (12% wt.), the temperature of the solution (81.5°C), and range of stirrer speeds (400 rpm) were kept constant for all processes. The surface morphology of the wafer was analyzed by optical microscopy and atomic force microscopy (AFM). The AFM images confirmed a well-uniform pyramidal structure with various average pyramid sizes ranging from 1 to 1.6 μm. A UV-Vis spectrophotometer with integrating sphere was used to obtain the total reflectivity. The textured silicon wafers show high absorbance in the visible region. The optimum texture-etching parameters were found to be 4–6% vol. IPA and 40 min at which the average total reflectance of the silicon wafer was reduced to 11.22%.
Antagonist Muscle Prefatigue Increases the Intracortical Communication between Contralateral Motor Cortices during Elbow Extension Contraction
Authors: Wang Lejun , Ma Aidi , Wang Yuting , You Songhui , Lu Aiyun
Published: July 2017

To investigate the cortico-cortical coupling changes related to antagonist muscle prefatigue, we recorded EEG at FC3, C3, FC4, and C4 electrodes of twelve young male volunteers during a 30-second-long, nonfatiguing isometric elbow extension contraction with a target force level of 20% MVC before and after a sustained fatiguing elbow flexion contraction until task failure. EEG-EEG phase synchronization indices in alpha and beta frequency bands were calculated for the pre- and postfatigue elbow extension contractions. The phase synchronization index in the beta frequency band was found significantly increased between EEG of FC3-C3. The increased phase synchronization index may reflect an enhanced intracortical communication or integration of the signals between contralateral motor cortices with antagonist muscle prefatigue, which may be related to the central modulation so as to compensate for the antagonist muscle prefatigue-induced joint instability.
Temperature Sensor Using a Multiwavelength Erbium-Doped Fiber Ring Laser
Authors: Diaz Silvia , Fabian Noe San , Socorro-Leranoz Abian B. , Matias Ignacio R.
Published: July 2017

A novel temperature sensor is presented based on a multiwavelength erbium-doped fiber ring laser. The laser is comprised of fiber Bragg grating reflectors as the oscillation wavelength selecting filters. The performance of the temperature sensor in terms of both wavelength and laser output power was investigated, as well as the application of this system for remote temperature measurements.
Use of Diagnostic Laparoscopy for Identification of Bilateral Noncommunicating Hydroceles in an Infant with Right-Sided Abdominoscrotal Mass and Left-Sided Scrotal Mass
Authors: Asanad Kian , Banapour Pooya , Metzdorf Monica
Published: July 2017

Infantile abdominoscrotal hydrocele (ASH) is a rare condition characterized by a dumbbell-shaped cystic mass extending from the scrotum to the abdomen. We present the case of a 4-month-old infant who presented with progressively enlarging bilateral scrotal swelling and a tense, ballotable right-sided abdominal mass with extension into the scrotum. Scrotal ultrasound revealed bilateral hydroceles but exam and ultrasound could not rule out communication. At the time of planned hydrocelectomy, initial diagnostic laparoscopy was used to identify a massive right-sided ASH extending from the internal ring to the umbilicus and a large noncommunicating left-sided hydrocele that was visible with application of pressure to the left side of the scrotum. Following confirmation of anatomy with diagnostic laparoscopy, a scrotal approach to hydrocelectomy was performed as well as bilateral orchidopexy.
Use of TBzTD as Noncarcinogenic Accelerator for ENR/SiO2 Nanocomposites: Cured Characteristics, Mechanical Properties, Thermal Behaviors, and Oil Resistance
Authors: Raksaksri Laksamon , Chuayjuljit Saowaroj , Chaiwutthinan Phasawat , Boonmahitthisud Anyaporn
Published: July 2017

This study reported the use of tetrabenzylthiuram disulphide (TBzTD) as a noncarcinogenic accelerator in a traditional sulfur curing system of epoxidized natural rubber (ENR)/nanosilica (nSiO2) composites. ENR used in this work was synthesized via in situ epoxidation of natural rubber (NR) in the presence of performic acid generated from the reaction of formic acid and hydrogen peroxide at 50°C for 8 h to acquire the epoxide content of about 40 mol%. Accordingly, the resulting ENR was referred to as ENR 40. The curing characteristics, mechanical properties, thermal behaviors, dynamic mechanical properties, and oil resistance of ENR 40/nSiO2 nanocomposites filled with three loadings of nSiO2 (1, 2, and 3 parts per hundred parts of rubber) were investigated and compared with NR and neat ENR 40. The results revealed that the scorch and cure times of ENR 40/nSiO2 nanocomposites were slightly longer than those of NR but slightly shorter than those of ENR 40. The tensile properties and tear strength for both before and after aging of all ENR 40/nSiO2 nanocomposites were higher than those of ENR 40, while the glass transition temperature, storage modulus at −65°C, thermal stability, and oil resistance of ENR 40/nSiO2 nanocomposites were higher than those of NR and ENR 40.
Abstract 1003: Extranuclear ERα-mTOR signaling rewires cancer cell metabolism during obesity-associated breast cancer
Authors: Erdogan Zeynep Madak , Zhao Yiru C. , Rossi Gianluigi , Wrobel Kinga , Kulkoyluoglu Eylem , Kim Sung Hoon , Katzenellenbogen John A. , Flaws Jodi , Smith Rebecca
Published: July 2017

Obesity is a preventable risk factor for post-menopausal ERα-(+) breast cancer. We hypothesized that serum from obese post-menopausal women contain factors that would increase tumorigenicity of breast cancer cells and increase risk of ERα-(+) breast cancer. Using whole metabolite profiling and OLINK biomarker panel of about 400 proteins associated with cancer, inflammation and cardiovascular disease, we identified biomarkers that were differentially present in serum from 50 obese v.s. 50 non-obese postmenopausal women. Next, using in vitro cell based assays as proxy we identified certain free fatty acids (FFAs) as factors from serum that correlate with increased cell proliferation, motility and mTOR activation in ERα(+) breast cancer cells. We performed RNA-Seq, ERα ChIP-Seq and metabolomics analysis in breast cancer cells that are exposed to conditions that mimic serum from obese postmenopausal women. This integrative -omics approach enabled us to uncover ERα and mTOR pathway-dependent metabolic rewiring in breast cancer cells under these conditions. Pathway preferential estrogens (PaPEs), which target ERα and mTOR signaling, were able to block free fatty acid-dependent proliferation of breast cancer cells. In fact, efficient cancer cell killing by PaPEs was achieved only in the presence of FFAs, suggesting a role for obesity-associated metabolic rewiring in providing new vulnerabilities for the breast cancer cells. In summary, we uncovered a novel role for extranuclear-initiated ERα signaling in rewiring breast cancer cell metabolism in response to obesity-associated factors in the serum. Our findings provide a basis for preventing or inhibiting obesity-associated breast cancer by using PaPEs that would exploit new metabolic vulnerabilities of breast tumors in obese postmenopausal women.

Citation Format: Zeynep Madak Erdogan, Yiru C. Zhao, Gianluigi Rossi, Kinga Wrobel, Eylem Kulkoyluoglu, Sung Hoon Kim, John A. Katzenellenbogen, Jodi Flaws, Rebecca Smith. Extranuclear ERα-mTOR signaling rewires cancer cell metabolism during obesity-associated 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 1003. doi:10.1158/1538-7445.AM2017-1003
Abstract 1012: Patient-derived tumor microenvironment models uncover nonautonomous TKI resistance mechanisms in NSCLC
Authors: Hu Haichuan , Mulvey Hillary , Noeen Sundus , David Kodack , Hata Aaron , Niederst Matthew , Benes Cyril , Engelman Jeffrey
Published: July 2017

Background: Tyrosine kinase inhibitors (TKI) have yielded great responses in non-small-cell lung cancer (NSCLC) with EGFR mutations and ALK translocations, however these and other targeted therapies are limited by intrinsic and acquired drug resistance. Previous study from our group was looking into tumor autonomous resistance mechanisms by developing patient-derived cancer models (PDCs). In this study, we aimed to decipher the non-autonomous resistance mechanisms via tumor microenvironment by developing patient-derived fibroblast (PDF) cell lines.

Method: Cancer-associated fibroblast cells are isolated directly from EGFR mutant and ALK translocated NSCLC biopsies. Over 30 PDFs models have been established, which represent different clinical features and response profiles.

Result: By co-culturing the PDCs with PDFs, we found that there is considerable variability in both models for their magnitude and mechanism by which the TKI treatment is desensitized. Both HGF dependent and HGF independent resistance mechanisms can be overcome by specific therapeutic combinations.

Conclusion: Together, our results indicate that PDFs are clinically relevant models for deciphering non-autonomous resistance mechanisms, that they are heterogeneous in protecting cancer cells from TKI treatment, and that the resistance mediated by PDFs can be overcome by specific therapeutic combinations.

Citation Format: Haichuan Hu, Hillary Mulvey, Sundus Noeen, Kodack David, Aaron Hata, Matthew Niederst, Cyril Benes, Jeffrey Engelman. Patient-derived tumor microenvironment models uncover nonautonomous TKI resistance mechanisms in NSCLC [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 1012. doi:10.1158/1538-7445.AM2017-1012
Abstract 1019: In vivo CRISPR screening identifies Ptpn2 as a target for cancer immunotherapy
Authors: Manguso Robert T. , Pope Hans W. , Zimmer Margaret D. , Brown Flavian D. , Yates Kathleen B. , Miller Brian C. , Collins Natalie B. , Bi Kevin , Lafleur Martin W. , Juneja Vikram R. , Weiss Sarah A. , Fisher David E. , Root David E. , Sharpe Arlene H. , Doench John G. , Haining W Nicholas
Published: July 2017

Despite the dramatic clinical success of cancer immunotherapy with PD-1 checkpoint blockade, most patients don’t experience sustained clinical benefit, suggesting that additional therapeutic strategies are needed. Functional genomic screens in cancer cells to discover new therapeutic targets are usually carried out in vitro where interaction with the immune system is absent. Here we report a pooled, loss-of-function genetic screening approach using CRISPR/Cas9 genome editing that is conducted in vivo in mouse transplantable tumors treated with vaccination and PD-1 checkpoint blockade. We tested 2,400 genes expressed by melanoma cells for those that synergize with or cause resistance to checkpoint blockade, and recovered the known immune evasion molecules, PD-L1 and CD47. Loss of function of multiple genes required to sense interferon-y caused resistance to immunotherapy. Deletion of Ptpn2, a pleotropic protein tyrosine phosphatase improved response to immunotherapy. In vivo, Ptpn2 deficient tumors showed increased infiltration of activated CD8+T cells. In vitro, Ptpn2 loss by tumor cells increased antigen presentation to T cells. Biochemical, transcriptional and genetic epistasis experiments demonstrated that loss of function of Ptpn2 sensitizes tumors to immunotherapy by enhancing interferon-y-mediated effects on the tumor cell. Thus, augmenting interferon-y signaling in tumor cells could increase the efficacy of immunotherapy. More generally, in vivo genetic screens in tumor models can identify new immunotherapy targets and rationally prioritize combination therapies.

Citation Format: Robert T. Manguso, Hans W. Pope, Margaret D. Zimmer, Flavian D. Brown, Kathleen B. Yates, Brian C. Miller, Natalie B. Collins, Kevin Bi, Martin W. Lafleur, Vikram R. Juneja, Sarah A. Weiss, David E. Fisher, David E. Root, Arlene H. Sharpe, John G. Doench, W Nicholas Haining. In vivo CRISPR screening identifies Ptpn2 as a target for cancer immunotherapy [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 1019. doi:10.1158/1538-7445.AM2017-1019
Abstract 1030: Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal cancer
Authors: Davis Ryan J. , Gonen Mehmet , Hockenbery David , Margolin Adam , Clurman Bruce E.
Published: July 2017

Fbw7 is an evolutionary conserved F box protein that functions as a substrate adapter for the Skp1-Cullin 1-F box (SCF) E3 ubiquitin ligase complex. Fbw7 is also a tumor suppressor gene that is mutated in diverse human cancers. Many Fbw7 substrates are oncogenic transcription factors, including c-Myc, Notch, and Jun. Cancer-associated Fbw7 mutations diminish its ability to interact with substrates, which results in inappropriate oncoprotein accumulation. One of the significant challenges for understanding the consequences of Fbw7 mutations in tumors is that Fbw7 coordinately regulates approximately two dozen broadly-acting transcription factors. To address this problem, we used novel computational methods to analyze TCGA gene expression datasets to derive transcriptional signatures that could predict a tumor’s Fbw7 mutational status; these signatures were then analyzed for enrichment of genes involved in specific biological processes. We found that genes associated with mitochondrial function were highly predictive of Fbw7 mutations across several tumor types, suggesting that metabolic reprogramming is a crucial oncogenic consequence of Fbw7 mutations. We validated this prediction by creating isogenic colorectal cancer cells with normal or mutant Fbw7 alleles. We found that mitochondrial signature genes are elevated in Fbw7 mutant cells, which also exhibit increased oxidative metabolism. Moreover, metabolomic studies revealed deregulation of other metabolic pathways in Fbw7-mutant cells, including amino acid and nucleotide biosynthesis. These data suggest that metabolic vulnerabilities may represent novel therapeutic targets in Fbw7-associated cancers.

Citation Format: Ryan J. Davis, Mehmet Gonen, David Hockenbery, Adam Margolin, Bruce E. Clurman. Metabolic reprogramming caused by mutations of the Fbw7 ubiquitin ligase in colorectal 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 1030. doi:10.1158/1538-7445.AM2017-1030
Abstract 1032: Identification of Ran binding protein 6 as a novel negative regulator of EGFR and candidate tumor suppressor in glioblastoma
Authors: Hsieh Wan-Ying , Oldrini Barbara , Erdjument-Bromage Hediye , Codega Paolo , Carro Maria S. , Vivanco Igor , Rohle Dan , Campos Carl , Bielski Craig , Taylor Barry , Tempst Paul , Squatrito Massimo , Mellinghoff Ingo K.
Published: July 2017

Amplification and overexpression of the epidermal growth factor receptor (EGFR) are common in glioblastoma (GBM) and frequently associated with silencing of the phosphatase and tensin homologue (PTEN) tumor suppressor. PTEN silencing has been associated with clinical resistance to EGFR tyrosine kinase inhibitors, in part by raising EGFR levels. Here, we investigated the effect of PTEN on the EGFR signaling complex by EGFR affinity immunopurification and mass spectrometry with and without PTEN knockdown. We identified Ran binding protein 6 (RanBP6), a 125-kDa protein of previously unknown functions, as EGFR interacting protein in PTEN expressing, but not PTEN knockdown cells. Further studies of the effect of RanBP6 on EGFR revealed that RanBP6 depletion by shRNA or CRISPR/Cas9-mediated gene silencing resulted in increased EGFR mRNA levels and upregulation of EGFR promoter activity. Consistent with a model of a negative EGFR regulation by RanBP6, we observed an inverse correlation between RanBP6 and EGFR mRNA levels in PTEN wildtype but not PTEN altered cancer cells in a large panel of human cancer cell lines (Cancer Cell Line Encyclopedia). To further understand the mechanism of how RanBP6 negatively regulates EGFR mRNA level, we found that RanBP6 interacted with nuclear Ran-GTPase and repressed EGFR transcription by promoting nuclear import of Signal transducer and activator of transcription 3 (STAT3). Lastly, RanBP6 appeared to be frequently deleted on chromosome 9p in GBM. We showed that RanBP6 silencing raised EGFR levels and signal output and accelerated in-vivo glioma growth. Our results establish a novel function of RanBP6 as a link between EGFR signaling and the Ran-mediated nuclear import pathway, and identify RanBP6 as candidate tumor suppressor on chromosome 9p.

Citation Format: Wan-Ying Hsieh, Barbara Oldrini, Hediye Erdjument-Bromage, Paolo Codega, Maria S. Carro, Igor Vivanco, Dan Rohle, Carl Campos, Craig Bielski, Barry Taylor, Paul Tempst, Massimo Squatrito, Ingo K. Mellinghoff. Identification of Ran binding protein 6 as a novel negative regulator of EGFR and candidate tumor suppressor in glioblastoma [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 1032. doi:10.1158/1538-7445.AM2017-1032
Abstract 1034: Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance
Authors: Jeong Youngtae , Hoang Ngoc , Stehr Henning , Lovejoy Alexander , Gentles Andrew , Chaudhuri Aadel , Loo Billy , Alizadeh Ash , Diehn Maximilian
Published: July 2017

Although lung squamous cell carcinomas (LSCC) comprise a large fraction of non-small cell lung cancers (NSCLCs), their pathogenesis and cell of origin remain incompletely understood and biomarkers that predict therapeutic responses are lacking. Here we describe novel, clinically relevant murine LSCC models driven by inactivation of Trp53 with or without Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal both in vitro and in in vivo, suggesting that Trp53 or Keap1 mutations lead to expansion of mutant stem cell clones. Deletion of Trp53 with or without Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs. However, deletion of Trp53 with or without Keap1 in type II pneumocytes (ATIIs) or bronchioalveolar stem cells (BASCs) produced tumors with the features of adenocarcinoma, indicating that ABSCs represent the likely cell of origin for LSCC in this model. Deletion of Keap1 promoted tumor growth, metastasis and resistance to oxidative stress. N-acetylcysteine (NAC) treatment enhanced tumorsphere formation and metastasis in Keap1WT LSCCs, but not in Keap1-/- LSCCs, suggesting that NRF2-ROS pathway activation is the main mediator of Keap1 loss. Finally, Keap1 deletion induced radioresistance in vitro and in vivo in both LSCCs and lung adenocarcinomas (LUADs). Congruous with these findings, KEAP1/NRF2 mutation status strongly predicted risk of local recurrence in NSCLC patients treated with RT and these mutations could be non-invasively identified in circulating tumor DNA. These data suggest that Trp53 and Keap1 mutations in ABSCs play important roles in LSCC initiation and progression and identify KEAP1/NRF2 mutations as predictive biomarkers that could be used for personalization of therapeutic strategies for NSCLCs, and likely other cancers in which they are recurrently mutated.

Citation Format: Youngtae Jeong, Ngoc Hoang, Henning Stehr, Alexander Lovejoy, Andrew Gentles, Aadel Chaudhuri, Billy Loo, Ash Alizadeh, Maximilian Diehn. Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance [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 1034. doi:10.1158/1538-7445.AM2017-1034
Abstract 1042: CLIC4 is incorporated into extracellular vesicles of murine breast cancer cells and may influence metastatic burden
Authors: Craig-Lucas Alayna B. , Sanchez Vanesa C. , Read Abigail , Lou Ji , Shukla Anjali , Yuspa Stuart H.
Published: July 2017

Chloride intracellular channel 4 (CLIC4) is an evolutionarily conserved, 29kD, dimorphic protein that contributes to TGF-β signaling by preventing the de-phosphorylation of phospho-SMAD2/3 upon nuclear translocation. In several cancer types, CLIC4 is excluded from the nucleus and downregulated in the cytoplasm of the tumor cells as the tumor progresses, suggesting that CLIC4 acts as tumor suppressor. In a parallel sequence, CLIC4 becomes upregulated in the stromal compartment, where it enhances tumor growth and invasion. Recent reports have suggested that CLIC4 is detectable in the serum of cancer patients and incorporated into extracellular vesicles, and has potential as a biomarker. We hope to gain a better understanding of the role that CLIC4 plays in the tumor stromal and epithelial compartments as well as their respective release of extracellular vesicles. Using in-vitro and in-vivo assays, we have conducted experiments using the FVB mouse MMTV-c-MYC 6DT1 breast cancer model. By CRISPR/ Cas9 system, CLIC4 was deleted from wild type 6DT1 cells. Following clonal selection, the loss of the CLIC4 protein at both the cellular and released vesicle level was validated. Both functional assays on CLIC4 deleted clones and evaluation of their extra-cellular vesicles were undertaken in order to further understand their tumorigenic and metastatic capabilities. In-vitro, CLIC4 was not necessary for vesicle biogenesis and its deletion did not have a significant effect on cellular proliferation. In vivo, selected clones were orthotopically injected into the 4th mammary fat pad of wild type FVB mice. Compared to wild type 6DT1 clones, CLIC4 deleted clones formed primary tumors that had greater mass but a fewer number of lung metastasis. Future studies are designed to isolate vesicles circulating in tumor bearing hosts to determine their stromal or epithelial origin and to provide a better understanding of the role that CLIC4 may play in tumor growth, creating a metastatic niche and as a potential serological biomarker.

Citation Format: Alayna B. Craig-Lucas, Vanesa C. Sanchez, Abigail Read, Ji Lou, Anjali Shukla, Stuart H. Yuspa. CLIC4 is incorporated into extracellular vesicles of murine breast cancer cells and may influence metastatic burden [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 1042. doi:10.1158/1538-7445.AM2017-1042
Abstract 1046: Conditional knockout of N-Myc and STAT Interactor disrupts normal mammary development and enhances metastatic ability of mammary tumors
Authors: Pruitt Hawley Christine , Metge Brandon J. , Weeks Shannon E. , Chen Dongquan , Wei Shi , Shevde Lalita A. , Samant Rajeev S.
Published: July 2017

The process of development requires a delicate balance between plasticity and differentiation. This balance is disrupted in cancer initiation and progression, ultimately ending in metastasis and plummeting rates of patient survival. Recent findings from our lab have revealed that protein expression of evolutionarily conserved, N-Myc and STAT Interactor (NMI) is decreased in 70% of primary patient specimens with metastatic breast cancer. To study how Nmi loss facilitates metastatic behavior and gain insight into its role in normal mammary biology, we created a novel mammary specific Nmi knock out mouse model, which we then challenged with carcinogen and oncogene induced tumorigenesis. Our studies show that Nmi is induced at the onset of pregnancy and its expression remains throughout lactation. Furthermore, prolactin stimulation and differentiation of HC11 murine mammary epithelial cells is accompanied by up-regulation of Nmi. STAT5 is the downstream effector of prolactin and is essential for differentiation of secretory alveolar epithelium. NMI interacts with STAT5 and this interaction appears to be critical to normal differentiation of mammary epithelium. Indeed, loss of Nmi in vivo caused a decrease in STAT5 activity and a subsequent transcriptomic shift in mammary epithelial and breast cancer cells. Moreover, knockdown of Nmi in HC11 cells impedes the expression of beta-casein upon differentiation with prolactin. Concurrently, Nmi knock out alveoli exhibit an extensive presence of nuclear beta-catenin, a mediator of stem cell maintenance in the mammary gland. As a result, mice exhibit an increased number of alveoli and more proliferating mammary epithelial cells (MECs). The Nmi knock out pubertal ductal tree extends into the mammary fat pad at an accelerated rate and exhibits enhanced terminal end bud numbers, a phenotype that mirrors mice altered for Wnt signaling. Tumors derived from Nmi null mammary epithelium contain significantly more cells with stem and progenitor markers, indicating that these tumors are less differentiated than their littermate counterparts. In addition, Nmi null mammary tumors exhibit invasive morphology as well as enhanced distant metastasis. We observe that conditional Nmi loss disrupts differentiation in the mammary gland and promotes the progression of tumors with aggressive metastatic characteristics.

Citation Format: Hawley Christine Pruitt, Brandon J. Metge, Shannon E. Weeks, Dongquan Chen, Shi Wei, Lalita A. Shevde, Rajeev S. Samant. Conditional knockout of N-Myc and STAT Interactor disrupts normal mammary development and enhances metastatic ability of mammary tumors [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 1046. doi:10.1158/1538-7445.AM2017-1046
Abstract 1049: Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia
Authors: Gali-Muhtasib Hala , Fakhoury Isabelle , Fatfat Maamoun , Mismar Rasha , Schneider-Stock Regine
Published: July 2017

Doxorubicin (Dox) is a clinically approved drug which suffers from drug resistance and cardiotoxicity. Recent studies have shown that thymoquinone (TQ) in combination with Dox can reduce Dox toxic side effects in vitro as well as in vivo. Both TQ and Dox have shown promising anticancer effects against aggressive adult T-cell leukemia (ATL), however, the anticancer potential of TQ and Dox combination treatment has never been tested against ATL. We hypothesized that co-treatment with TQ could enable the use of lower doses of Dox to achieve similar or enhanced anticancer activity. The effects of TQ and Dox combination on cell death and cell cycle were evaluated by trypan blue and propidium iodide. TUNEL assay was used to investigate the mode of cell death. The levels of reactive species (ROS) were determined using DCFH assay, and mitochondrial membrane potential was measured by rhodamine assay. The regulation of key proteins involved in cell cycle regulation and cell death was determined by Western blot. The results reveal that the human T-lymphotropic virus (HTLV-1) positive HuT-102 cells are more resistant to treatment with Dox alone, than the HTLV-1 negative Jurkat cells. However, treatment with high doses of TQ and low doses of Dox simultaneously, enhances cell death in both cancer cell lines as compared to treatment with Dox alone. TUNEL assay on Jurkat and HuT-102 cells further indicated that the combination of TQ and Dox caused cell death by apoptosis. An increase in ROS production was noted in response to treatment with TQ alone and

with TQ and Dox combination in both Jurkat and HuT-102 cells. The oxidative stress; however, was only shown to play a role in the disruption of the mitochondria of Jurkat cells. Similarly, caspase activation was involved in the disruption of the mitochondria of Jurkat cells. The expression levels of key regulatory proteins were modulated in response to treatment with the combination. In conclusion, the combination of TQ and Dox effectively inhibits ATL leukemic cancer cell growth at lower doses of Dox which can potentially lower the side effects of the drug. In vivo studies are still warranted to assess the adjuvant chemotherapeutic potential of TQ in combination with Dox.

Citation Format: Hala Gali-Muhtasib, Isabelle Fakhoury, Maamoun Fatfat, Rasha Mismar, Regine Schneider-Stock. Combinatorial effects of thymoquinone on the anticancer activity of doxorubicin in adult T-cell leukemia [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 1049. doi:10.1158/1538-7445.AM2017-1049
Abstract 1053: Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast cancer cells
Authors: Algayadh Ibrahim G. , Sylvester Paul William
Published: July 2017

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. Rho GTPases play a crucial role in regulating different cellular functions, including cell proliferation, gene expression, cell morphology, actin polymerization, cell motility, metastasis and apoptosis. Wiskott-Aldrich syndrome protein family verprolin-homologous protein2 (WAVE2) is a member within the Wiskott-Aldrich syndrome protein (WASP) family displays a significant role in actin polymerization and cytoskeletal organization which, are essential for cellular migration and invasion. γ-Tocotrienol is a natural isoform within the vitamin E family that displays anticancer activity against a variety of cancer cell types. Pterostilbene is a natural dimethyl ether analog of resveratrol that has several beneficial effects such as anticancer activity. Studies were conducted to examine the effects of combined γ-tocotrienol and pterostilbene on Rac1/WAVE 2 signaling in mouse +SA and human MDA-MB231 breast cancer cells and cellular migration. Results show that combined treatment of γ-tocotrienol and pterostilbene caused a synergistic inhibition of both mouse +SA and human MDA-MB231 breast cancer cells growth, and corresponding reduction in Rac1/WAVE2 signaling as characterized by a significant inhibition in the levels of phospho-Rac1/cdc42, WAVE2, Arp2, and Arp3 expression. Additional studies indicated that this combination resulted in a significant inhibition in mammary cancer cell migration. In summary, these findings strongly suggest that combined treatment of γ-tocotrienol with pterostilbene may provide great benefit as a therapeutic approach in the treatment of metastatic breast cancer. Supported by a grant from the Louisiana Cancer Foundation.

Citation Format: Ibrahim G. Algayadh, Paul William Sylvester. Synergistic anticancer effects of combined γ-tocotrienol and pterostilbene is associated with a suppression in Rac1/WAVE 2 signaling in highly malignant breast 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 1053. doi:10.1158/1538-7445.AM2017-1053