bluuebunny/crossref_metadata_2025 huggingface dataset:
IP Geolocation with a Crowd-sourcing Broadband Performance Tool
Authors: Lee Yeonhee , Park Heasook , Lee Youngseok
Published: January 2016

In this paper, we propose an IP geolocation DB creation method based on a crowd-sourcing Internet broadband performance measurement tagged with locations and present an IP geolocation DB based on 7 years of Internet broadband performance data in Korea. Compared with other commercial IP geolocation DBs, our crowd-sourcing IP geolocation DB shows increased accuracy with fine-grained granularity. We confirm that the low accuracy of commercial IP geolocation DBs mainly results from selecting a single representative location for a large IP block from the Whois registry DB, parsing city names in a naive way, and resolving the wrong geolocation coordinates. We also found that the geographic location of IP blocks has continuously changed but has been stable. Although our IP geolocation DB is limited to Korea, the 32 million broadband performance test records over 7 years provide wide coverage as well as fine-grained accuracy.
A Comparative Look into Public IXP Datasets
Authors: Klöti Rowan , Ager Bernhard , Kotronis Vasileios , Nomikos George , Dimitropoulos Xenofontas
Published: January 2016

Internet eXchange Points (IXPs) are core components of the Internet infrastructure where Internet Service Providers (ISPs) meet and exchange traffic. During the last few years, the number and size of IXPs have increased rapidly, driving the flattening and shortening of Internet paths. However, understanding the present status of the IXP ecosystem and its potential role in shaping the future Internet requires rigorous data about IXPs, their presence, status, participants, etc. In this work, we do the first cross-comparison of three well-known publicly available IXP databases, namely of PeeringDB, Euro-IX, and PCH. A key challenge we address is linking IXP identifiers across databases maintained by different organizations. We find different AS-centric versus IXP-centric views provided by the databases as a result of their data collection approaches. In addition, we highlight differences and similarities w.r.t. IXP participants, geographical coverage, and co-location facilities. As a side-product of our linkage heuristics, we make publicly available the union of the three databases, which includes 40.2% more IXPs and 66.3% more IXP participants than the commonly-used PeeringDB. We also publish our analysis code to foster reproducibility of our experiments and shed preliminary insights into the accuracy of the union dataset.
It's a Match!
Authors: Lukovszki Tamás , Rost Matthias , Schmid Stefan
Published: January 2016

The virtualization and softwarization of modern computer networks offers new opportunities for the simplified management and exible placement of middleboxes as e.g. rewalls and proxies. This paper initiates the study of algorithmically exploiting the exibilities present in virtualized and software-defined networks. Particularly, we are interested in the initial as well as the incremental deployment of middleboxes. We present a deterministic
O
(log(min{
n,k
})) approximation algorithm for
n
-node computer networks, where
k
is the middlebox capacity. The algorithm is based on optimizing over a submodular function which can be computed efficiently using a fast augmenting path approach. The derived approximation bound is optimal: the underlying problem is computationally hard to approximate within sublogarithmic factors, unless
P
=
NP
holds. We additionally present an exact algorithm based on integer programming, and complement our formal analysis with simulations. In particular, we consider the number of used middleboxes and highlight the benefits of the approximation algorithm in incremental deployments. Our approach also finds interesting applications, e.g., in the context of incremental deployment of software-defined networks.
In-Band Synchronization for Distributed SDN Control Planes
Authors: Schiff Liron , Schmid Stefan , Kuznetsov Petr
Published: January 2016

Control planes of forthcoming Software-Defined Networks (SDNs) will be
distributed
: to ensure availability and fault-tolerance, to improve load-balancing, and to reduce overheads, modules of the control plane should be physically distributed. However, in order to guarantee
consistency
of network operation, actions performed on the data plane by different controllers may need to be
synchronized
, which is a nontrivial task. In this paper, we propose a synchronization framework for control planes based on atomic transactions, implemented
in-band
, on the data-plane switches. We argue that this in-band approach is attractive as it keeps the failure scope local and does not require additional out-of-band coordination mechanisms. It allows us to realize fundamental consensus primitives in the presence of controller failures, and we discuss their applications for consistent policy composition and fault-tolerant control-planes. Interestingly, by using part of the data plane configuration space as a shared memory and leveraging the match-action paradigm, we can implement our synchronization framework in today's standard OpenFlow protocol, and we report on our proof-of-concept implementation.
Perspectives on Net Neutrality and Internet Fast-Lanes
Authors: Habibi Gharakheili Hassan , Vishwanath Arun , Sivaraman Vijay
Published: January 2016

"Net neutrality" and Internet "fast-lanes" have been the subject of raging debates for several years now, with various viewpoints put forth by stakeholders (Internet Service Providers, Content Service Providers, and consumers) seeking to influence how the Internet is regulated. In this paper we summarize the perspectives on this debate from multiple angles, and propose a fresh direction to address the current stalemate. Our first contribution is to highlight the contentions in the net neutrality debate from the viewpoints of technology (what mechanisms do or do not violate net neutrality?), economics (how does net neutrality help or hurt investment and growth?), and society (do fast-lanes disempower consumers?). Our second contribution is to survey the state-of-play of net neutrality in various regions of the world, highlighting the influence of factors such as consumer choice and public investment on the regulatory approach taken by governments. Our final contribution is to propose a new model that engages consumers in fast-lane negotiations, allowing them to customize fast-lane usage on their broadband link. We believe that our approach can provide a compromise solution that can break the current stalemate and be acceptable to all parties.
How events unfold
Authors: Hua Ting , Zhao Liang , Chen Feng , Lu Chang-Tien , Ramakrishnan Naren
Published: January 2016

There has been significant recent interest in the application of social media analytics for spatiotemporal event mining. However, no structured survey exists to capture developments in this space. This paper seeks to fill this void by reviewing recent research trends. Three branches of research are summarized here---corresponding (resp.) to modeling the past, present, and future---information tracking and backward analysis, spatiotemporal event detection, and spatiotemporal event forecasting. Each branch is illustrated with examples, challenges, and accomplishments.
GeoPrivacy 2015 workshop report
Authors: McKenzie Grant , Janowicz Krzysztof , Kossinets Gueorgi
Published: January 2016

Developments in mobile and surveying technologies over the past decade have enabled the collection of individual-level and aggregated geographic information at unprecedented scale. These data are valuable sources for answering scientific questions about human behavior and improving related services, from public transportation to location-aware recommendations. However, privacy intrusion is an imminent risk when individual trajectories (and in some cases aggregated travel patterns) are used for commercial purposes such as customer profiling, or even for political persecution. Similarly, there is a trade-off between location privacy and quality of spatial search and recommender systems. The GeoPrivacy workshop will hence focus on discussing methods to protect individuals' privacy while enabling collection, analysis, and sharing of useful geographic information.
EM-GIS 2015 workshop report
Authors: Zhang Hui , Huang Yan , Thill Jean-Claude
Published: January 2016

Emergency management aims to develop strategies and establish operations to decrease the potential impact of unexpected events (i.e., human or natural disasters). By quick response and rescue, it saves human lives from the secondary disasters and enhances the stability of communities after disasters. Emergency management requires lots of new geospatial technologies to support the quick response and recovery and the integrating of location-based wireless information streams. With the advances of GIS technologies, the improvement of the emergency management research becomes possible.
MELT 2015 workshop report
Authors: Zhang Ying , Priyantha Bodhi
Published: January 2016

After a decade of research and development for GPS-less localization and tracking, there has been significant progress in location-awareness and location-based services around the world. Almost all cell phone platforms, Android, iPhone and Windows phones, have localization and tracking facilities. In addition, special hardware and infrastructure (e.g., RFID, UWB and BLE or sensor tags) have been developed and deployed for tracking people and merchandise. The advances in cameras and computer vision make it possible for cheap simultaneous localization and mapping (SLAM). However, there are still many challenging problems to be solved, such as accuracy, power management, effective sensor fusion with increasingly powerful embedded computation and resourceful parallel computing backend, learning, transmitting and storing individual trajectories and spatial environment representation, labor-less environmental survey or infrastructure establishment for location-awareness, crowd computing or collective intelligence for map creations, and big data analytics of real-time and historical semantic locations that helps improving efficiency for both consumers and businesses.
Nexus between Artisanal and Small-Scale Gold Mining and Livelihood in Prestea Mining Region, Ghana
Authors: Arthur Francis , Agyemang-Duah Williams , Gyasi Razak Mohammed , Yeboah Joseph Yaw , Otieku Evans
Published: January 2016

Drawing on the DFID’s sustainable livelihood framework, this paper explores the nexus between artisanal and small-scale mining (ASM) and livelihood in Prestea mining region, Ghana. A cross-sectional mixed method survey involving simple random and purposively sampled participants (N=151) was carried out. The results suggest both positive and negative relationships between ASM and livelihoods of the people. The study found various livelihood assets associated with ASM and how critical assets are adversely affected by ASM activities. Limited employment opportunities in rural areas (82%), economic hardships/poverty situations of people (59%), and “quick” income earnings from ASM (90%) were the major factors that influenced people to combine and use their personal assets to enable them to engage in ASM. ASM contributes to the livelihood enhancement through income generation, increased well-being and asset acquisition (50.7%), reduced vulnerabilities (31.1%), and empowerment of people (19.2%) to establish other economic activities. However, the small-scale miners and farmers as well as farmlands, forest, and water resources are most vulnerable to adverse effects of ASM activities. Accidents of various degrees, diseases, and death were the shocks in ASM. Regarding the massive impact of ASM on employment creation and poverty reduction in rural communities, it is recommended that stakeholders recast Ghana’s mineral policy to ensure concurrent environmental sustainability and socioeconomic development.
An Improved Cuckoo Search Optimization Algorithm for the Problem of Chaotic Systems Parameter Estimation
Authors: Wang Jun , Zhou Bihua , Zhou Shudao
Published: January 2016

This paper proposes an improved cuckoo search (ICS) algorithm to establish the parameters of chaotic systems. In order to improve the optimization capability of the basic cuckoo search (CS) algorithm, the orthogonal design and simulated annealing operation are incorporated in the CS algorithm to enhance the exploitation search ability. Then the proposed algorithm is used to establish parameters of the Lorenz chaotic system and Chen chaotic system under the noiseless and noise condition, respectively. The numerical results demonstrate that the algorithm can estimate parameters with high accuracy and reliability. Finally, the results are compared with the CS algorithm, genetic algorithm, and particle swarm optimization algorithm, and the compared results demonstrate the method is energy-efficient and superior.
Lifor Solution: An Alternative Preservation Solution in Small Bowel Transplantation
Authors: Guo Mingxiao , Lu Chunlei , Gao Ying , Zhang Haifeng , Chen Dongfeng , Li Yousheng
Published: January 2016

Background and Objectives. The intestinal mucosa is extremely sensitive to ischemia. Better intestinal preservation is the first step to improve the results of intestinal transplantation. The aim of the study is to investigate the effect of cold Lifor solution on preservation of swine small bowel.Methods. Swine ileum segments (200 cm) were allotransplanted heterotopically after 9-hour cold storage with UW solution (group 1,n=6), with Lifor solution (group 2,n=6), or without storage (group 3,n=6), respectively. After cold storage, mucosal adenosine triphosphate (ATP) concentrations and histopathologic analysis after preservation were performed. At day 7 after the transplantation, intestinal absorptive function was also observed.Results. After 9 h cold preservation, pathological changes, the content of ATP in the intestinal mucosa, and the intestinal absorptive function after transplantation in group 2 were similar to those of group 1.Conclusion. The effect of cold storage of swine small bowel with Lifor solution is similar to that of UW solution. It may provide additional rationale for further exploration of Lifor as an alternative preservation solution in small bowel transplantation.
Septic Lateral Sinus Thrombosis: Sinus Exploration Is Unnecessary
Authors: Singh Gautam Bir , Arora Rubeena , Garg Sunil , Kumar Deepak , Ranjan Shruti
Published: January 2016

The algorithm of treatment of septic lateral sinus thrombosis (SLST) has undergone a paradigm shift with the understanding of the natural history of sigmoid sinus thrombosis. Thus, the recent medical literature promulgates the management of these cases with no sinus exploration. However, in view of marked paucity of literature on the cited subject, not much is known about this form of treatment. We present our experience of treating two paediatric cases of SLST with mastoid surgery and no sinus exploration: both cases had excellent recovery. Finally, conclusions are drawn in light of contemporary literature on this subject.
Two-Layer Hidden Markov Model for Human Activity Recognition in Home Environments
Authors: Kabir M. Humayun , Hoque M. Robiul , Thapa Keshav , Yang Sung-Hyun
Published: January 2016

Activities of Daily Livings (ADLs) refer to the activities that are carried out by an individual for everyday living. Recognition of ADLs is key element for building intelligent and pervasive environments. We propose a two-layer HMM to build a ADLs recognition model that can represent the mapping between low-level sensor data and high-level activity based on the binary sensor data. We used embedded sensor with appliances or object to get object used sequence data as well as object name, type, interaction time, and location. In the first layer, we use location data of object used sensor to predict the activity class and in the second layer object used sequence data to determine the exact activity. We perform comparison with other activity recognition models using three real datasets to validate the proposed model. The results show that the proposed model achieves significantly better recognition performance than other models.
Simple One-Pot Synthesis of Hexagonal ZnO Nanoplates as Anode Material for Lithium-Ion Batteries
Authors: Li Haipeng , Wei Yaqiong , Zhao Yan , Zhang Yongguang , Yin Fuxing , Zhang Chengwei , Bakenov Zhumabay
Published: January 2016

Hexagonal ZnO nanoplates were synthesizedviasimple one-pot hydrothermal reaction of Zn(CH3COO)2and CO(NH2)2. XRD, SEM, and HRTEM were used to investigate the composition and microstructure of the material. Together with the facile strain relaxation during structure and volume change upon cycling, this plate-like structure of ZnO is favorable for physical and chemical interactions with lithium ions because of its large contact area with the electrolyte, providing more active sites and short diffusion distances. The resulting hexagonal ZnO nanoplates electrode exhibited good cyclability and delivered a reversible discharge capacity of 368 mAh g−1after 100 cycles at 0.1 C.
A Simple Tool to Identify Representative Wind Sites for Air Pollution Modelling Applications
Authors: Elangasinghe M. A. , Dirks K. N. , Singhal N. , Salmond J. A. , Longley I. , Dirks V. I.
Published: January 2016

This paper investigates the use of the Site-Optimized Semiempirical (SOSE) air pollution model to identify the surface wind measurement site characteristics that yield the best air pollution predictions for urban locations. It compares the modelling results from twelve meteorological sites with varying anemometer heights, located at different distances from the air pollution measurements and exhibiting different land use characteristics. The results show that the index of agreement (IA) between observed and predicted concentrations can be improved from 0.4 to 0.8 by using the most compared to the least representative wind data as input to the air pollution model. Although improvements can be achieved using wind data from a site closer to the air quality monitoring site, choosing the closest wind site does not necessarily yield the best results, especially if the meteorological station is located in a region of complex land use. In addition, both the height of the anemometer and the openness of the terrain surrounding the anemometer were found to be equally important in obtaining good model predictions. The simple SOSE model can therefore be used to complement regulatory meteorological guidelines by providing a quantitative assessment of wind site representativeness for air quality applications in complex urban environments.
MR Imaging in Diagnosis of Pelvic Floor Descent: Supine versus Sitting Position
Authors: Iacobellis Francesca , Brillantino Antonio , Renzi Adolfo , Monaco Luigi , Serra Nicola , Feragalli Beatrice , Iacomino Aniello , Brunese Luca , Cappabianca Salvatore
Published: January 2016

Introduction. Functional disorders of the pelvic floor represent have a significant impact on the quality of life. The advent of open-configuration systems allowed for the evaluation of defecation with MR imaging in sitting position. The purpose of the present study is to compare the results of static and dynamic pelvic MR performed in supine position versus sitting position, using a new MR prototype machine, in the diagnosis of pelvic floor descent.Materials and Methods. Thirty-one patients with pelvic floor disorders were enrolled, and underwent MR Defecography in supine position with 1.5 T closed magnet (MAGNETOM Symphony, Siemens, Germany) and in sitting position with a 0.25-Tesla open magnet system (G-Scan ESAOTE, Italy).Results. In rest and squeezing phases, positions of bladder, vagina, and ARJ were significantly different when the patient was imaged in supine versus sitting position. In the defecation phase, a significant difference for the bladder and vagina position was detected between the two exams whereas a significant difference for the ARJ was not found. A statistically significant difference exists when the pelvic floor descent is evaluated in sitting versus supine position.Conclusion. Our results show that MR Defecography in sitting position may represent a useful tool to correctly diagnose and grade the pelvic organ descent.
Compensation of Vestibular Function and Plasticity of Vestibular Nucleus after Unilateral Cochleostomy
Authors: Suh Myung-Whan , Hyun Jaihwan , Lyu Ah-Ra , Kim Dong Woon , Park Sung Jae , Choi Jin Woong , Hur Gang Min , Park Yong-Ho
Published: January 2016

Dizziness and vertigo frequently occur after cochlear implantation (CI) surgery, particularly during the early stages. It could recover over time but some of the patients suffered from delayed or sustained vestibular symptoms after CI. This study used rat animal models to investigate the effect of unilateral cochleostomy on the vestibular organs over time. Twenty-seven Sprague Dawley rats underwent cochleostomy to evaluate the postoperative changes in hearing threshold, gain and symmetry of the vestibular ocular response, overall balance function, number of hair cells in the crista, and the c-Fos activity in the brainstem vestibular nucleus. Loss of vestibular function was observed during the early stages, but function recovered partially over time. Histopathological findings demonstrated a mild decrease in vestibular hair cells numbers. Increased c-Fos immunoreactivity in the vestibular nucleus, observed in the early stages after cochleostomy, decreased over time. Cochleostomy is a risk factor for peripheral vestibular organ damage that can cause functional impairment in the peripheral vestibular organs. Altered vestibular nucleus activity may be associated with vestibular compensation and plasticity after unilateral cochleostomy.
Structural Performance Assessment Based on Statistical and Wavelet Analysis of Acceleration Measurements of a Building during an Earthquake
Authors: Kaloop Mosbeh R. , Hu Jong Wan , Sayed Mohamed A. , Seong Jiyoung
Published: January 2016

This study introduces the analysis of structural health monitoring (SHM) system based on acceleration measurements during an earthquake. The SHM system is applied to assess the performance investigation of the administration building in Seoul National University of Education, South Korea. The statistical and wavelet analysis methods are applied to investigate and assess the performance of the building during an earthquake shaking which took place on March 31, 2014. The results indicate that (1) the acceleration, displacement, and torsional responses of the roof recording point on the top floor of the building are more dominant in theXdirection; (2) the rotation of the building has occurred at the base recording point; (3) 95% of the energy content of the building response is shown in the dominant frequency range (6.25–25 Hz); (4) the wavelet spectrum illustrates that the roof vibration is more obvious and dominant during the shaking; and (5) the wavelet spectrum reveals the elasticity responses of the structure during the earthquake shaking.
Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer
Authors: Raynal Noël J.-M. , Lee Justin T. , Wang Youjun , Beaudry Annie , Madireddi Priyanka , Garriga Judith , Malouf Gabriel G. , Dumont Sarah , Dettman Elisha J. , Gharibyan Vazganush , Ahmed Saira , Chung Woonbok , Childers Wayne E. , Abou-Gharbia Magid , Henry Ryan A. , Andrews Andrew J. , Jelinek Jaroslav , Cui Ying , Baylin Stephen B. , Gill Donald L. , Issa Jean-Pierre J.
Published: January 2016

Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer. Cancer Res; 76(6); 1494–505. ©2015 AACR.
VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth
Authors: O'Donnell Rebekah K. , Falcon Beverly , Hanson Jeff , Goldstein Whitney E. , Perruzzi Carole , Rafii Shahin , Aird William C. , Benjamin Laura E.
Published: January 2016

Antiangiogenesis–based cancer therapies, specifically those targeting the VEGF-A/VEGFR2 pathway, have been approved for subsets of solid tumors. However, these therapies result in an increase in hematologic adverse events. We surmised that both the bone marrow vasculature and VEGF receptor–positive hematopoietic cells could be impacted by VEGF pathway–targeted therapies. We used a mouse model of spontaneous breast cancer to decipher the mechanism by which VEGF pathway inhibition alters hematopoiesis. Tumor-bearing animals, while exhibiting increased angiogenesis at the primary tumor site, showed signs of shrinkage in the sinusoidal bone marrow vasculature accompanied by an increase in the hematopoietic stem cell–containing Lin-cKit+Sca1+ (LKS) progenitor population. Therapeutic intervention by targeting VEGF-A, VEGFR2, and VEGFR3 inhibited tumor growth, consistent with observed alterations in the primary tumor vascular bed. These treatments also displayed systemic effects, including reversal of the tumor-induced shrinkage of sinusoidal vessels and altered population balance of hematopoietic stem cells in the bone marrow, manifested by the restoration of sinusoidal vessel morphology and hematopoietic homeostasis. These data indicate that tumor cells exert an aberrant systemic effect on the bone marrow microenvironment and VEGF-A/VEGFR targeting restores bone marrow function. Cancer Res; 76(3); 517–24. ©2015 AACR.
HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc
Authors: Li Yinghui , Wang Zhen , Shi Hui , Li Hang , Li Leilei , Fang Runping , Cai Xiaoli , Liu Bowen , Zhang Xiaodong , Ye Lihong
Published: January 2016

c-Myc is regarded as a transcription factor, but the basis for its function remains unclear. Here, we define a long noncoding RNA (lncRNA)/protein complex that mediates the transcriptional activation by c-Myc in breast cancer cells. Among 388 c-Myc target genes in human MCF-7 breast cancer cells, we found that their promoters could be occupied by the oncoprotein HBXIP. We confirmed that the HBXIP expression correlated with expression of the c-Myc target genes cyclin A, eIF4E, and LDHA. RNAi-mediated silencing of HBXIP abolished c-Myc–mediated upregulation of these target genes. Mechanistically, HBXIP interacted directly with c-Myc through the leucine zippers and recruited the lncRNA Hotair along with the histone demethylase LSD1, for which Hotair serves as a scaffold. Silencing of HBXIP, Hotair, or LSD1 was sufficient to block c-Myc–enhanced cancer cell growth in vitro and in vivo. Taken together, our results support a model in which the HBXIP/Hotair/LSD1 complex serves as a critical effector of c-Myc in activating transcription of its target genes, illuminating long-standing questions on how c-Myc drives carcinogenesis. Cancer Res; 76(2); 293–304. ©2015 AACR.
Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer
Authors: Ohar Jill A. , Cheung Mitchell , Talarchek Jacqueline , Howard Suzanne E. , Howard Timothy D. , Hesdorffer Mary , Peng Hongzhuang , Rauscher Frank J. , Testa Joseph R.
Published: January 2016

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention. Cancer Res; 76(2); 206–15. ©2015 AACR.
Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer
Authors: Huang Huang-Chiao , Mallidi Srivalleesha , Liu Joyce , Chiang Chun-Te , Mai Zhiming , Goldschmidt Ruth , Ebrahim-Zadeh Neema , Rizvi Imran , Hasan Tayyaba
Published: January 2016

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment. Cancer Res; 76(5); 1066–77. ©2015 AACR.
Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell–Mediated Antitumor Immunity
Authors: Brentville Victoria A. , Metheringham Rachael L. , Gunn Barbara , Symonds Peter , Daniels Ian , Gijon Mohamed , Cook Katherine , Xue Wei , Durrant Lindy G.
Published: January 2016

Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4+ T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8+ T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy. Cancer Res; 76(3); 548–60. ©2015 AACR.
Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells
Authors: Mittal Deepak , Caramia Franco , Michiels Stefan , Joensuu Heikki , Kellokumpu-Lehtinen Pirkko-Liisa , Sotiriou Christos , Loi Sherene , Smyth Mark J.
Published: January 2016

The HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is combined with chemotherapy as a standard-of-care for newly diagnosed HER2+ breast cancer patients, but some patients treated with this combination therapy experience early relapse. Our analysis of data from a clinical trial evaluating the efficacy of chemotherapy plus/minus trastuzumab suggested that the magnitude of trastuzumab benefit on distant disease-free survival was higher for increasing expression of the IL21 receptor (IL21R). Therefore, we investigated a possible role for IL21 signaling in promoting HER2 mAb therapeutic efficacy. We found that IL21R-deficient mice and wild-type mice treated with a neutralizing anti-IL21 mAb were less susceptible to trastuzumab-like anti-ErbB2 therapy. Furthermore, IL21R expression on CD8+ T cells, but not on natural killer cells, was required for optimal anti-ErbB2 mAb efficacy, and IL21 expression was enhanced in tumor-infiltrating CD4+ T lymphocytes after anti-ErbB2 therapy. Finally, we found that administering recombinant IL21 in combination with anti-ErbB2 therapy was therapeutic against primary tumors and experimental metastases in mice. Collectively, our findings suggest that elevating IL21 signaling may enhance trastuzumab efficacy, thus constituting a novel candidate strategy to overcome trastuzumab resistance and improve patient survival. Cancer Res; 76(2); 264–74. ©2016 AACR.
Redirecting Transport of Nanoparticle Albumin-Bound Paclitaxel to Macrophages Enhances Therapeutic Efficacy against Liver Metastases
Authors: Tanei Tomonori , Leonard Fransisca , Liu Xuewu , Alexander Jenolyn F. , Saito Yuki , Ferrari Mauro , Godin Biana , Yokoi Kenji
Published: January 2016

Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of paclitaxel and MSV in the liver, specifically in macrophages, whereas paclitaxel levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of paclitaxel compared with treatment with nAb-PTX. The cytotoxic potency of the released paclitaxel was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side effects. Cancer Res; 76(2); 429–39. ©2016 AACR.
Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
Authors: Qi Jing , Dong Zizheng , Liu Jianguo , Peery Robert C. , Zhang Shaobo , Liu Jing-Yuan , Zhang Jian-Ting
Published: January 2016

Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule–based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453–62. ©2016 AACR.
Cancer Cell Dissemination and Homing to the Bone Marrow in a Zebrafish Model
Authors: Sacco Antonio , Roccaro Aldo M. , Ma Dongdong , Shi Jiantao , Mishima Yuji , Moschetta Michele , Chiarini Marco , Munshi Nikhil , Handin Robert I. , Ghobrial Irene M.
Published: January 2016

Advancement of many solid tumors and hematologic malignancies is frequently characterized by dissemination and homing of cancer cells to the bone marrow (BM). Methods to quantitatively characterize these key steps of the metastatic cascade in mammalian models are currently limited and do not offer opportunities to perform rapid, large-scale genomic, or drug screening. Because of their optical clarity, we used zebrafish to develop an in vivo model of cancer cell dissemination and homing to the BM. We performed intracardiac injection of multiple myeloma (MM) cells derived from human BM or cell lines and monitored their migration to the caudal hematopoietic tissue (CHT), the region where hematopoiesis occurs in the zebrafish embryo, which recapitulates a BM-like niche. Transcriptomic analyses confirmed that MM cells homing to the CHT displayed gene-expression differences compared with MM cells outside of the CHT, including significant enrichment for genes known to regulate interleukin-6 (IL6) signaling, cell adhesion, and angiogenesis. Collectively, our findings point to the zebrafish as a valuable model in which to study cancer cell homing to the hematopoietic niche and to establish a screening platform for the identification of factors and mechanisms contributing to the early steps of bone metastasis. Cancer Res; 76(2); 463–71. ©2016 AACR.
Meeting Report Europhosphatase 2015: Phosphatases as Drug Targets in Cancer
Authors: Hoekstra Elmer , Peppelenbosch Maikel P. , Fuhler Gwenny M.
Published: January 2016

Phosphatases are key regulators of cellular signaling and as such play an important role in nearly all cellular processes governing diseases, including cancer. However, due to their highly conserved structure and highly charged and reactive catalytic site, they have been regarded as “undruggable.” Fortunately, during the recent Europhosphatase meeting (Turku, Finland), it became clear that phosphatases can no longer be ignored as potential targets in cancer therapy. As reactivation of tumor-suppressor phosphatases or direct inhibition of phosphatases acting as oncogenes is becoming available, this class of enzymes can now be considered as feasible drug targets. Cancer Res; 76(2); 193–6. ©2016 AACR.
Accumulated Metabolites of Hydroxybutyric Acid Serve as Diagnostic and Prognostic Biomarkers of Ovarian High-Grade Serous Carcinomas
Authors: Hilvo Mika , de Santiago Ines , Gopalacharyulu Peddinti , Schmitt Wolfgang D. , Budczies Jan , Kuhberg Marc , Dietel Manfred , Aittokallio Tero , Markowetz Florian , Denkert Carsten , Sehouli Jalid , Frezza Christian , Darb-Esfahani Silvia , Braicu Elena Ioana
Published: January 2016

Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but it is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. Cancer Res; 76(4); 796–804. ©2015 AACR.
Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis
Authors: Cox Thomas R. , Gartland Alison , Erler Janine T.
Published: January 2016

Secondary metastatic cancer remains the single biggest cause of mortality and morbidity across most solid tumors. In breast cancer, 100% of deaths are attributed to metastasis. At present, there are no “cures” for secondary metastatic cancer of any form and there is an urgent unmet clinical need to improve the tools available in our arsenal against this disease, both in terms of treatment, but also prevention. Recently, we showed that hypoxic induction of the extracellular matrix modifying enzyme lysyl oxidase (LOX) correlates with metastatic dissemination to the bone in estrogen receptor negative breast cancer and is essential for the formation of premetastatic osteolytic lesions. We showed that in models of breast cancer metastasis, targeting LOX, or its downstream effects, significantly inhibited premetastatic niche formation and the resulting metastatic burden, offering preclinical validation of this enzyme as a therapeutic target for metastatic breast cancer. Our work is the latest in an emerging body of work supporting the targeting of LOX and calls for greater efforts in developing therapeutics against this extracellular secreted factor in the prevention of cancer progression across multiple solid tumor types. Cancer Res; 76(2); 188–92. ©2016 AACR.
STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis
Authors: Jones Laura M. , Broz Miranda L. , Ranger Jill J. , Ozcelik John , Ahn Ryuhjin , Zuo Dongmei , Ursini-Siegel Josie , Hallett Michael T. , Krummel Matthew , Muller William J.
Published: January 2016

Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by antitumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor STAT3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathologic analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, nonmetastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3-inhibitory strategies that may reactivate the immunosurveillance program. Cancer Res; 76(6); 1416–28. ©2015 AACR.
Factors Associated with Multiple Biomarkers of Systemic Inflammation
Authors: Navarro Sandi L. , Kantor Elizabeth D. , Song Xiaoling , Milne Ginger L. , Lampe Johanna W. , Kratz Mario , White Emily
Published: January 2016

Background: While much is known about correlates of C-reactive protein (CRP), little is known about correlates of other inflammation biomarkers. As these measures are increasingly being used in epidemiologic studies, it is important to determine what factors affect inflammation biomarker concentrations.

Methods: Using age, sex, and body mass index (BMI) adjusted linear regression, we examined 38 exposures (demographic and anthropometric measures, chronic disease history, NSAIDs, dietary factors, and supplement use) of 8 inflammation biomarkers [CRP, IL1β, IL6, IL8, TNFα, and soluble TNF receptors (sTNFR) in plasma; and prostaglandin E2 metabolite (PGE-M) in urine] in 217 adults, ages 50 to 76 years.

Results: Increasing age was associated with higher concentrations of all biomarkers except IL1β. BMI was positively associated with CRP and sTNFR I and II. Saturated fat intake was associated with increased CRP, sTNFRII, TNFα, and IL1β, whereas eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) intake (diet or total) was associated with decreased CRP, TNFα, and IL1β. Results for sex were varied: CRP and IL6 were lower among men, whereas PGE-M and sTNFRI were higher. Higher CRP was also associated with smoking, hormone replacement therapy use, and γ-tocopherol intake; lower CRP with physical activity, and intakes of dietary vitamin C and total fiber.

Conclusions: Although the associations varied by biomarker, the factors having the greatest number of significant associations (P ≤ 0.05) with the inflammation biomarkers were age, BMI, dietary saturated fat, and EPA+DHA omega-3 fatty acids.

Impact: Our results suggest that potential confounders in epidemiologic studies assessing associations with inflammation biomarkers vary across specific biomarkers. Cancer Epidemiol Biomarkers Prev; 25(3); 521–31. ©2016 AACR.