bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of: iBioSeminars and iBioMagazineReview of: iBioSeminars (http://ibioseminars.org/) and iBio-Magazine (http://ibiomagazine.org/).
Authors: Marshall Pamela A.
Published: December 2013

Review of:
iBioSeminars (
http://ibioseminars.org/
) and iBio-Magazine (
http://ibiomagazine.org/
).
Unusual head metastasis of kidney cancer
Authors: Matias M , Casa-Nova M , Borges-Costa J , Ribeiro L
Published: December 2013

Renal cell carcinoma (RCC) metastasis can involve any organ. Head metastasis are rare, namely tongue, scalp and nose and only a few cases have been described. The authors describe three cases of unusual presentation of head metastasis of RCC. In case 1, a 50-year-old man with RCC underwent left nephrectomy, and presented 16 months later with nasal metastasis. In case 2, a 64-year-old woman with RCC operated 12 years ago, relapsed at multiple sites including scalp, which was treated surgically. In case 3, a 47-year-old man with RCC developed metastasis in multiple organs including a mass on the tongue that was operated and was compatible with primary tumour metastasis. These cases show the importance of correct diagnosis of rare presentations and local treatment of metastasis of RCC.
Poststroke psychosis in an 8-year-old child with moyamoya disease
Authors: Gnanavel Sundar
Published: December 2013

Psychiatric illnesses following cerebrovascular accidents has been a popular area of research in recent times. Though poststroke anxiety and mood disorders including depression have been reported often, reports of poststroke psychosis have been considerably rarer. This case report documents an even rarer occurrence of a psychotic disorder in an 8-year-old child with moyamoya disease following a cerebrovascular accident. The child was managed with low-dose atypical antipsychotic, risperidone and the psychotic symptoms eventually were under control around 3 weeks following the initiation of psychotropic medication.
Creating a safe, reliable hospital at night handover: a case study in implementation science
Authors: McQuillan Annette , Carthey Jane , Catchpole Ken , McCulloch Peter , Ridout Deborah A , Goldman Allan P
Published: December 2013

Background

We developed protocols to handover patients from day to hospital at night (H@N) teams.

Setting

NHS paediatric specialist hospital.

Method

We observed four handover protocols (baseline, Phases 1, 2 and 3) over 2 years. A mixed-method study (observation, interviews, task analysis, prospective risk assessment, document and case note review) explored the impact of different protocols on performance.

Intervention

In Phase 1, a handover protocol was introduced to resolve problems with the baseline H@N handover. Following this intervention, two further revisions to the handover occurred, driven by staff feedback (Phases 2 and 3).

Results

Variations in performance between handover protocols on three process measures, start time efficiency, total length of handover, and number of distractions and interruptions, were identified. Univariate regression analysis showed statistically significant differences between handover protocols on two surrogate outcome measures: number of flagging omissions and the number of out of hours deteriorations (p=0.04 for Phase 3 vs Phase 1 for both measures (CI 1.04 to 4.08; CI 1.03 to 4.33), and for Phase 3 vs Phase 2 (p=0.006 and p=0.001 (CI 1.22 to 5.15; CI 1.62 to 9.0)), respectively). The Phase 1 and 2 handover protocols were effective at identifying patients whose clinical condition warranted review overnight. Performance on both surrogate outcome measures, length of handover and distractions, deteriorated in Phase 3.

Conclusions

A carefully designed prioritisation process within the H@N handover can be effective at flagging acutely unwell patients. However, the protocol we introduced was unsustainable. In a complex healthcare system, sustainable implementation of new processes may be threatened by conflicting goals.
Connectivity-based and anchor-free localization in large-scale 2D/3D sensor networks
Authors: Tan Guang , Jiang Hongbo , Zhang Shengkai , Yin Zhimeng , Kermarrec Anne-Marie
Published: December 2013

A connectivity-based and anchor-free three-dimensional localization (CATL) scheme is presented for large-scale sensor networks with concave regions. It distinguishes itself from previous work with a combination of three features: (1) it works for networks in both 2D and 3D spaces, possibly containing holes or concave regions; (2) it is anchor-free and uses only connectivity information to faithfully recover the original network topology, up to scaling and rotation; (3) it does not depend on the knowledge of network boundaries, which suits it well to situations where boundaries are difficult to identify. The key idea of CATL is to discover the
notch nodes
, where shortest paths bend and hop-count-based distance starts to significantly deviate from the true Euclidean distance. An iterative protocol is developed that uses a
notch-avoiding
multilateration mechanism to localize the network. Simulations show that CATL achieves accurate localization results with a moderate per-node message cost.
Bringing java's wild native world under control
Authors: Sun Mengtao , Tan Gang , Siefers Joseph , Zeng Bin , Morrisett Greg
Published: December 2013

For performance and for incorporating legacy libraries, many Java applications contain native-code components written in unsafe languages such as C and C++. Native-code components interoperate with Java components through the Java Native Interface (JNI). As native code is not regulated by Java's security model, it poses serious security threats to the managed Java world. We introduce a security framework that extends Java's security model and brings native code under control. Leveraging software-based fault isolation, the framework puts native code in a separate sandbox and allows the interaction between the native world and the Java world only through a carefully designed pathway. Two different implementations were built. In one implementation, the security framework is integrated into a Java Virtual Machine (JVM). In the second implementation, the framework is built outside of the JVM and takes advantage of JVM-independent interfaces. The second implementation provides JVM portability, at the expense of some performance degradation. Evaluation of our framework demonstrates that it incurs modest runtime overhead while significantly enhancing the security of Java applications.
An experimental security analysis of two satphone standards
Authors: Driessen Benedikt , Hund Ralf , Willems Carsten , Paar Christof , Holz Thorsten
Published: December 2013

General-purpose communication systems such as GSM and UMTS have been in the focus of security researchers for over a decade now. Recently also technologies that are only used under more specific circumstances have come into the spotlight of academic research and the hacker scene alike. A striking example of this is recent work [Driessen et al. 2012] that analyzed the security of the over-the-air encryption in the two existing ETSI satphone standards GMR-1 and GMR-2. The firmware of handheld devices was reverse-engineered and the previously unknown stream ciphers A5-GMR-1 and A5-GMR-2 were recovered. In a second step, both ciphers were cryptanalized, resulting in a ciphertext-only attack on A5-GMR-1 and a known-plaintext attack on A5-GMR-2.

In this work, we extend the aforementioned results in the following ways: First, we improve the proposed attack on A5-GMR-1 and reduce its average-case complexity from 2
32
to 2
21
steps. Second, we implement a practical attack to successfully record communications in the Thuraya network and show that it can be done with moderate effort for approximately $5,000. We describe the implementation of our modified attack and the crucial aspects to make it practical. Using our eavesdropping setup, we recorded 30 seconds of our own satellite-to-satphone communication and show that we are able to recover Thuraya session keys in half an hour (on average). We supplement these results with experiments designed to highlight the feasibility of also eavesdropping on the satphone's emanations.

The purpose of this article is threefold: Develop and demonstrate more practical attacks on A5-GMR-1, summarize current research results in the field of GMR-1 and GMR-2 security, and shed light on the amount of work and expertise it takes from setting out to analyze a complex system to actually break it in the real world.
Learning schema mappings
Authors: Cate Balder Ten , Dalmau Víctor , Kolaitis Phokion G.
Published: December 2013

A schema mapping is a high-level specification of the relationship between a source schema and a target schema. Recently, a line of research has emerged that aims at deriving schema mappings automatically or semi-automatically with the help of data examples, that is, pairs consisting of a source instance and a target instance that depict, in some precise sense, the intended behavior of the schema mapping. Several different uses of data examples for deriving, refining, or illustrating a schema mapping have already been proposed and studied.

In this article, we use the lens of computational learning theory to systematically investigate the problem of obtaining algorithmically a schema mapping from data examples. Our aim is to leverage the rich body of work on learning theory in order to develop a framework for exploring the power and the limitations of the various algorithmic methods for obtaining schema mappings from data examples. We focus on GAV schema mappings, that is, schema mappings specified by GAV (Global-As-View) constraints. GAV constraints are the most basic and the most widely supported language for specifying schema mappings. We present an efficient algorithm for learning GAV schema mappings using Angluin's model of exact learning with membership and equivalence queries. This is optimal, since we show that neither membership queries nor equivalence queries suffice, unless the source schema consists of unary relations only. We also obtain results concerning the learnability of schema mappings in the context of Valiant's well-known PAC (Probably-Approximately-Correct) learning model, and concerning the learnability of restricted classes of GAV schema mappings. Finally, as a byproduct of our work, we show that there is no efficient algorithm for approximating the shortest GAV schema mapping fitting a given set of examples, unless the source schema consists of unary relations only.
Graph Isomorphism is Not AC0-Reducible to Group Isomorphism
Authors: Chattopadhyay Arkadev , Torán Jacobo , Wagner Fabian
Published: December 2013

We give a new upper bound for the Group and Quasigroup Isomorphism problems when the input structures are given explicitly by multiplication tables. We show that these problems can be computed by polynomial size nondeterministic circuits of unbounded fan-in with
O
(log log
n
) depth and
O
(log
2
n
) nondeterministic bits, where
n
is the number of group elements. This improves the existing upper bound for the problems. In the previous bound the circuits have bounded fan-in but depth
O
(log
2
n
) and also
O
(log
2
n
) nondeterministic bits. We then prove that the kind of circuits from our upper bound cannot compute the Parity function. Since Parity is AC
0
-reducible to Graph Isomorphism, this implies that Graph Isomorphism is strictly harder than Group or Quasigroup Isomorphism under the ordering defined by AC
0
reductions. We extend this result to the stronger ACC
0
[
p
] reduction and its randomized version.
Generating sound and effective memory debuggers
Authors: Wang Yan , Neamtiu Iulian , Gupta Rajiv
Published: December 2013

We present a new approach for constructing debuggers based on declarative specification of bug conditions and root causes, and automatic generation of debugger code. We illustrate our approach on several classes of bugs, memory or otherwise. For each bug class, bug conditions and their root cause are specified declaratively, in First-order logic, using 1 to 4 predicates. We employ a low-level operational semantics and abstract traces to permit concise bug specification and prove soundness. To facilitate locating bugs, we introduce a new concept of value propagation chains that reduce programmer burden by narrowing the fault to a handful of executed instructions (1 to 16 in our experiments). We employ automatic translation to generate the debugger implementation, which runs on top of the Pin infrastructure. Experiments with using our system on 7 versions of 4 real-world programs show that our approach is expressive, effective at finding bugs and their causes, and efficient. We believe that, using our approach, other kinds of declaratively-specified, provably-correct, auto-generated debuggers can be constructed with little effort.
Rigorous benchmarking in reasonable time
Authors: Kalibera Tomas , Jones Richard
Published: December 2013

Experimental evaluation is key to systems research. Because modern systems are complex and non-deterministic, good experimental methodology demands that researchers account for uncertainty. To obtain valid results, they are expected to run many iterations of benchmarks, invoke virtual machines (VMs) several times, or even rebuild VM or benchmark binaries more than once. All this repetition costs time to complete experiments. Currently, many evaluations give up on sufficient repetition or rigorous statistical methods, or even run benchmarks only in training sizes. The results reported often lack proper variation estimates and, when a small difference between two systems is reported, some are simply unreliable.

In contrast, we provide a statistically rigorous methodology for repetition and summarising results that makes efficient use of experimentation time. Time efficiency comes from two key observations. First, a given benchmark on a given platform is typically prone to much less non-determinism than the common worst-case of published corner-case studies. Second, repetition is most needed where most uncertainty arises (whether between builds, between executions or between iterations). We capture experimentation cost with a novel mathematical model, which we use to identify the number of repetitions at each level of an experiment necessary and sufficient to obtain a given level of precision.

We present our methodology as a cookbook that guides researchers on the number of repetitions they should run to obtain reliable results. We also show how to present results with an effect size confidence interval. As an example, we show how to use our methodology to conduct throughput experiments with the DaCapo and SPEC CPU benchmarks on three recent platforms.
ACDC
Authors: Aigner Martin , Kirsch Christoph M.
Published: December 2013

We present ACDC, an open-source benchmark that may be configured to emulate explicit single- and multi-threaded memory allocation, sharing, access, and deallocation behavior to expose virtually any relevant allocator performance differences. ACDC mimics periodic memory allocation and deallocation (AC) as well as persistent memory (DC). Memory may be allocated thread-locally and shared among multiple threads to study multicore scalability and even false sharing. Memory may be deallocated by threads other than the allocating threads to study blowup memory fragmentation. Memory may be accessed and deallocated sequentially in allocation order or in tree-like traversals to expose allocator deficiencies in exploiting spatial locality. We demonstrate ACDC's capabilities with seven state-of-the-art allocators for C/C++ in an empirical study which also reveals interesting performance differences between the allocators.
Adaptive scanning reduces sweep time for the Lisp2 mark-compact garbage collector
Authors: Morikawa Kazuya , Ugawa Tomoharu , Iwasaki Hideya
Published: December 2013

Mark-compact garbage collection helps long-running programs avoid fragmentation. The Lisp2 mark-compact collector is a classic but still widely-used compaction algorithm. It sequentially scans the entire heap to compact all live objects at one end of the heap while preserving their order of addresses. Since the heap is generally large, this scanning takes a long time. Although some collectors adopt a separate bitmap into which mark bits of objects are stored to reduce the scanning time, we observed that scanning the bitmap can take longer than scanning the heap if objects are densely located. We propose a new scanning method from this observation, which adaptively alternates methods of scanning depending on heap usage; it scans those parts of the heap where live objects are densely located whereas it scans the bitmap for the remaining parts. We implemented this scanning method in the Lisp2 collector of Jikes RVM.

The experimental results revealed that the adaptive scanner scanned faster than the method that only scanned the heap and the method that only scanned the bitmap.
Precise and scalable context-sensitive pointer analysis via value flow graph
Authors: Li Lian , Cifuentes Cristina , Keynes Nathan
Published: December 2013

In this paper, we propose a novel method for context-sensitive pointer analysis using the value flow graph (VFG) formulation. We achieve context-sensitivity by simultaneously applying function cloning and computing context-free language reachability (CFL-reachability) in a novel way. In contrast to existing clone-based and CFL-based approaches, flow-sensitivity is easily integrated in our approach by using a flow-sensitive VFG where each value flow edge is computed in a flow-sensitive manner. We apply context-sensitivity to both local variables and heap objects and propose a new approximation for heap cloning.

We prove that our approach can achieve context-sensitivity without loss of precision, i.e., it is as precise as inlining all function calls. We develop an efficient algorithm and implement a context-, flow-, and field-sensitive pointer analysis with heap cloning support in LLVM. We evaluate the efficiency and precision of our implementation using standard SPEC CPU2006 benchmarks. Our experimental results show that the analysis is much faster than existing approaches, it scales well to large real-world applications, and it enables more effective compiler optimizations.
Flow Patterns Transition Law of Oil-Water Two-Phase Flow under a Wide Range of Oil Phase Viscosity Condition
Authors: Wang Wei , Cheng Wei , Li Kai , Lou Chen , Gong Jing
Published: December 2013

A systematic work on the prediction of flow patterns transition of the oil-water two-phase flows is carried out under a wide range of oil phase viscosities, where four main flow regimes are considered including stratified, dispersed, core-annular, and intermittent flow. For oil with a relatively low viscosity, VKH criterion is considered for the stability of stratified flow, and critical drop size model is distinguished for the transition of o/w and w/o dispersed flow. For oil with a high viscousity, boundaries of core-annular flow are based on criteria proposed by Bannwart and Strazza et al. and neutral stability law ignoring that the velocity of the viscous phase is introduced for stratified flow. Comparisons between predictions and quantities of available data in both low and high viscosity oil-water flow from literatures show a good agreement. The framework provides extensive information about flow patterns transition of oil-water two-phase flow for industrial application.
Upper and Lower Solution Method for Fractional Boundary Value Problems on the Half-Line
Authors: Yang Dandan , Bai Chuanzhi
Published: December 2013

We establish the existence of unbounded solutions for nonlinear fractional boundary value problems on the half-line. By the upper and lower solution method technique, sufficient conditions for the existence of solutions for the fractional boundary value problems are established. An example is presented to illustrate our main result.
Complex System Optimization Using Biogeography-Based Optimization
Authors: Du Dawei , Simon Dan
Published: December 2013

Complex systems are frequently found in modern industry. But with their multisubsystems, multiobjectives, and multiconstraints, the optimization of complex systems is extremely hard. In this paper, a new algorithm adapted from biogeography-based optimization (BBO) is introduced for complex system optimization. BBO/Complex is the combination of BBO with a multiobjective ranking system, an innovative migration approach, and effective diversity control. Based on comparisons with three complex system optimization algorithms (multidisciplinary feasible (MDF), individual discipline feasible (IDF), and collaborative optimization (CO)) on four real-world benchmark problems, BBO/Complex demonstrates competitive performance. BBO/Complex provides the best performance in three of the benchmark problems and the second best in the fourth problem.
Intelligent Motion Control for Four-Wheeled Holonomic Mobile Robots Using FPGA-Based Artificial Immune System Algorithm
Authors: Huang Hsu-Chih
Published: December 2013

This paper presents an intelligent motion controller for four-wheeled holonomic mobile robots with four driving omnidirectional wheels equally spaced at 90 degrees from one another by using field-programmable gate array (FPGA)-based artificial immune system (AIS) algorithm. Both the nature-inspired AIS computational approach and motion controller are implemented in one FPGA chip to address the optimal control problem of real-world mobile robotics application. The proposed FPGA-based AIS method takes the advantages of artificial intelligence and FPGA technology by using system-on-a-programmable chip (SoPC) methodology. Experimental results are conducted to show the effectiveness and merit of the proposed FPGA-based AIS intelligent motion controller for four-wheeled omnidirectional mobile robots. This FPGA-based AIS autotuning intelligent controller outperforms the conventional nonoptimal controllers, the genetic algorithm (GA) controller, and the particle swarm optimization (PSO) controller.
Retroperitoneal Malignant Peripheral Nerve Sheath Tumor Replacing an Absent Kidney in a Child
Authors: Alavi Samin , Arzanian M. T. , Nilipour Yalda
Published: December 2013

Malignant peripheral nerve sheath tumors (MPNSTs) are nonrhabdomyosarcoma soft tissue sarcomas with rare occurrence in children specially in the retroperitoneum. We describe a young child who presented with an abdominal mass. Both ultrasound and computed tomography revealed a large right-sided abdominal mass in the anatomic place of right kidney, while no kidney or ureter was observed at that side. He underwent surgical resection of the tumor with a primary impression of Wilms tumor. To the authors’ knowledge, this is the first case of retroperitoneal malignant peripheral nerve sheath tumor and absent kidney. This case suggests the very rare probability of association of MPNSTs in children with genitourinary tract anomalies such as renal agenesis.
Venous Thromboembolism in Critically Ill Cirrhotic Patients: Practices of Prophylaxis and Incidence
Authors: Al-Dorzi Hasan M. , Tamim Hani M. , Aldawood Abdulaziz S. , Arabi Yaseen M.
Published: December 2013

Objectives. We compared venous thromboembolism (VTE) prophylaxis practices and incidence in critically ill cirrhotic versus noncirrhotic patients and evaluated cirrhosis as a VTE risk factor. Methods. A cohort of 798 critically ill patients followed for the development of clinically detected VTE were categorized according to the diagnosis of cirrhosis. VTE prophylaxis practices and incidence were compared. Results. Seventy-five (9.4%) patients had cirrhosis with significantly higher INR (2.2 ± 0.9 versus 1.3 ± 0.6, P<0.0001), lower platelet counts (115,000 ± 90,000 versus 258,000 ± 155,000/μL, P<0.0001), and higher creatinine compared to noncirrhotic patients. Among cirrhotics, 31 patients received only mechanical prophylaxis, 24 received pharmacologic prophylaxis, and 20 did not have any prophylaxis. Cirrhotic patients were less likely to receive pharmacologic prophylaxis (odds ratio, 0.08; 95% confidence interval (CI), 0.04–0.14). VTE occurred in only two (2.7%) cirrhotic patients compared to 7.6% in noncirrhotic patients (P=0.11). The incidence rate was 2.2 events per 1000 patient-ICU days for cirrhotic patients and 3.6 events per 1000 patient-ICU days for noncirrhotics (incidence rate ratio, 0.61; 95% CI, 0.15–2.52). On multivariate Cox regression analysis, cirrhosis was not associated with VTE risk (hazard ratio, 0.40; 95% CI, 0.10–1.67). Conclusions. In critically ill cirrhotic patients, VTE incidence did not statistically differ from that in noncirrhotic patients.
Long Channel Carbon Nanotube as an Alternative to Nanoscale Silicon Channels in Scaled MOSFETs
Authors: Tan Michael Loong Peng
Published: December 2013

Long channel carbon nanotube transistor (CNT) can be used to overcome the high electric field effects in nanoscale length silicon channel. When maximum electric field is reduced, the gate of a field‐effect transistor (FET) is able to gain control of the channel at varying drain bias. The device performance of a zigzag CNTFET with the same unit area as a nanoscale silicon metal‐oxide semiconductor field‐effect transistor (MOSFET) channel is assessed qualitatively. The drain characteristic of CNTFET and MOSFET device models as well as fabricated CNTFET device are explored over a wide range of drain and gate biases. The results obtained show that long channel nanotubes can significantly reduce the drain‐induced barrier lowering (DIBL) effects in silicon MOSFET while sustaining the same unit area at higher current density.
Anti-Inflammatory Effects and Mechanisms ofFatsia polycarpaHayata and Its Constituents
Authors: Cheng Hsueh-Ling , Nurkholis  , Cheng Shi-Yie , Huang Shen-Da , Lu Yan-Ting , Wang Xiao-Wen , Liu Yu-Liang , Chou Chang-Hung
Published: December 2013

Fatsia polycarpa, a plant endemic to Taiwan, is an herbal medicine known for treating several inflammation-related diseases, but its biological function needs scientific support. Thus, the anti-inflammatory effects and mechanisms of the methanolic crude extract (MCE) ofF. polycarpaand its feature constituents, that is, brassicasterol (a phytosterol), triterpenoids 3α-hydroxyolean-11,13(18)-dien-28-oic acid (HODA), 3α-hydroxyolean-11-en-28,13β-olide (HOEO), fatsicarpain D, and fatsicarpain F, were investigated. MCE and HOEO, but not brassicasterol, dose-dependently inhibited lipopolysaccharide- (LPS-)induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophage line, whereas HODA, fatsicarpain D and fatsicarpain F were toxic to RAW cells. Additionally, MCE and HOEO suppressed LPS-induced production of nitric oxide, prostaglandin E2, and interleukin-1βand interfered with LPS-promoted activation of the inhibitor kappa B kinase (IKK)/nuclear factor-κB (NF-κB) pathway, and that of the mitogen-activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. In animal tests, MCE and HOEO effectively ameliorated 12-O-tetradecanoylphorobol-13 acetate- (TPA-)induced ear edema of mice. Thus, MCE ofF. polycarpaexhibited an obvious anti-inflammatory activityin vivoandin vitrothat likely involved the inhibition of the IKK/NF-κB pathway and the MAPKs, which may be attributed by triterpenoids such as HOEO.
Uterine Rupture with Massive Late Postpartum Hemorrhage due to Placenta Percreta Left Partially In Situ
Authors: Salman Mehmet Coskun , Calis Pinar , Deren Ozgur
Published: December 2013

Placental adhesive disorders involve the growth of placental tissue into or through the uterine wall. Among these disorders, placenta percreta is the rarest one. However, it may cause significant complications. This report aimed to report a neglected patient with placenta percreta who developed uterine rupture with life-threatening late postpartum intra-abdominal hemorrhage. On admission, the patient had acute abdomen with moderate abdominal distention and was subjected to emergency laparotomy. A full-thickness defect of the anterior uterine wall involving the hysterotomy site was seen. Placental tissues occupied both sides of the incision and posterior bladder wall was also invaded by placenta. Total abdominal hysterectomy with partial resection of the posterior bladder wall was performed.
Hybrid Model Based on Genetic Algorithms and SVM Applied to Variable Selection within Fruit Juice Classification
Authors: Fernandez-Lozano C. , Canto C. , Gestal M. , Andrade-Garda J. M. , Rabuñal J. R. , Dorado J. , Pazos A.
Published: December 2013

Given the background of the use of Neural Networks in problems of apple juice classification, this paper aim at implementing a newly developed method in the field of machine learning: the Support Vector Machines (SVM). Therefore, a hybrid model that combines genetic algorithms and support vector machines is suggested in such a way that, when using SVM as a fitness function of the Genetic Algorithm (GA), the most representative variables for a specific classification problem can be selected.
Metastatic Growth Progression Caused by PSGL-1–Mediated Recruitment of Monocytes to Metastatic Sites
Authors: Hoos Alexandra , Protsyuk Darya , Borsig Lubor
Published: December 2013

Tumor cell–derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non–tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII−/−)–deficient mice. Experimental metastasis of MC-38GFP and Lewis lung (3LL) carcinoma cells was attenuated in Fuc-TVII−/− mice, which express minimal amount of selectin ligands. We show that metastasis is dependent on selectin ligands carried on hematopoietic cells. P-selectin glycoprotein ligand-1 (PSGL-1) was identified as the major ligand facilitating monocyte accumulation at metastatic sites. Reduced recruitment of monocytes to metastasizing tumor cells in Fuc-TVII−/− mice correlated with attenuated metastasis. Adoptive transfer of Fuc-T7+ monocytes rescued metastasis in Fuc-TVII−/− mice, indicating that selectin ligand–dependent recruitment of monocytes is required for cancer progression. Cytokine analysis in metastatic lungs revealed high expression of CCL2 in C57BL/6 mice that was significantly lower in Fuc-TVII−/− mice. The absence of monocyte recruitment in Fuc-TVII−/− mice correlated with increased apoptosis of tumor cells. Thus, the recruitment of monocytes to metastasizing tumor cells is facilitated by endogenous selectin ligands on monocytes that enable efficient tumor cell survival, extravasation, and metastasis. Cancer Res; 74(3); 695–704. ©2013 AACR.
Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
Authors: Hast Bridgid E. , Cloer Erica W. , Goldfarb Dennis , Li Heng , Siesser Priscila F. , Yan Feng , Walter Vonn , Zheng Ning , Hayes D. Neil , Major Michael B.
Published: December 2013

NRF2 is a transcription factor that mediates stress responses. Oncogenic mutations in NRF2 localize to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-dependent degradation of NRF2. Somatic mutations in KEAP1 occur commonly in human cancer, where KEAP1 may function as a tumor suppressor. These mutations distribute throughout the KEAP1 protein but little is known about their functional impact. In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinoma tumor set. Four mutations behaved as wild-type KEAP1, thus are likely passenger events. R554Q, W544C, N469fs, P318fs, and G333C mutations attenuated binding and suppression of NRF2 activity. The remaining mutations exhibited hypomorphic suppression of NRF2, binding both NRF2 and CUL3. Proteomic analysis revealed that the R320Q, R470C, G423V, D422N, G186R, S243C, and V155F mutations augmented the binding of KEAP1 and NRF2. Intriguingly, these “super-binder” mutants exhibited reduced degradation of NRF2. Cell-based and in vitro biochemical analyses demonstrated that despite its inability to suppress NRF2 activity, the R320Q “superbinder” mutant maintained the ability to ubiquitinate NRF2. These data strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KEAP1 mechanics. Cancer Res; 74(3); 808–17. ©2013 AACR.
Adaptive Prediction Model in Prospective Molecular Signature–Based Clinical Studies
Authors: Xiao Guanghua , Ma Shuangge , Minna John , Xie Yang
Published: December 2013

Use of molecular profiles and clinical information can help predict which treatment would give the best outcome and survival for each individual patient, and thus guide optimal therapy, which offers great promise for the future of clinical trials and practice. High prediction accuracy is essential for selecting the best treatment plan. The gold standard for evaluating the prediction models is prospective clinical studies, in which patients are enrolled sequentially. However, there is no statistical method using this sequential feature to adapt the prediction model to the current patient cohort. In this article, we propose a reweighted random forest (RWRF) model, which updates the weight of each decision tree whenever additional patient information is available, to account for the potential heterogeneity between training and testing data. A simulation study and a lung cancer example are used to show that the proposed method can adapt the prediction model to current patients' characteristics, and, therefore, can improve prediction accuracy significantly. We also show that the proposed method can identify important and consistent predictive variables. Compared with rebuilding the prediction model, the RWRF updates a well-tested model gradually, and all of the adaptive procedure/parameters used in the RWRF model are prespecified before patient recruitment, which are important practical advantages for prospective clinical studies. Clin Cancer Res; 20(3); 531–9. ©2013 AACR.
Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer
Authors: Wick Darin A. , Webb John R. , Nielsen Julie S. , Martin Spencer D. , Kroeger David R. , Milne Katy , Castellarin Mauro , Twumasi-Boateng Kwame , Watson Peter H. , Holt Rob A. , Nelson Brad H.
Published: December 2013

Purpose: Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.

Experimental Design: Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence.

Results: The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8+ T-cell response to the mutation hydroxysteroid dehydrogenase–like protein 1 (HSDL1)L25V was detected in one patient. In the primary tumor, the HSDL1L25V mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1L25V-specific CD8+ T-cell response. At second recurrence, the HSDL1L25V mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.

Conclusion: The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy. Clin Cancer Res; 20(5); 1125–34. ©2013 AACR.
Dynamic Interplay of Oncogenes and T Cells Induces PD-L1 in the Tumor Microenvironment
Authors: Rech Andrew J. , Vonderheide Robert H.
Published: December 2013

Summary: Tumor-infiltrating T cells have recently been found to upregulate immunosuppressive pathways, such as programmed cell death protein 1 ligand 1 (PD-L1), in a paracrine fashion on tumor cells, but tumor cell–intrinsic regulation of PD-L1 is another potential mechanism. In this issue of Cancer Discovery, Akbay and colleagues show that signaling via mutant EGF receptor (EGFR) in murine lung tumor cells directly upregulates tumor PD-L1 and that therapeutic blockade of this pathway improves survival in EGFR-driven preclinical models—highlighting the dynamic interplay and therapeutic opportunities of cancer cell biology and immune biology. Cancer Discov; 3(12); 1330–2. ©2013 AACR.

See related article by Akbay et al., p. 1355
Metastatic Plasmacytoid Urothelial Carcinoma: A Case Report and Review of the Literature
Authors: Olsen Daniel L. , Anderson Scott R.
Published: December 2013

Plasmacytoid urothelial carcinoma is a rare form of invasive urothelial carcinoma first described in 1991 by Sahin et al. [Acta Cytol 1991;35:277-280]. Since this original publication, over 70 cases of plasmacytoid urothelial carcinoma have been described. A small number of cytologic descriptions have been published, including cases involving cerebrospinal fluid cytology, bladder washings and urine cytology. To our knowledge, we describe the first fine needle aspiration of metastatic plasmacytoid urothelial carcinoma in a 75-year-old man who presented with a pathologic fracture of the L4 vertebral body. One of the diagnostic pitfalls in the cytologic evaluation of this rare malignancy is the positive staining with CD138. While CD138 is a marker for plasma cell differentiation, it is also positive in plasmacytoid urothelial carcinoma. In addition to recognizing the cytomorphologic details, a full immunohistochemical panel is helpful in properly characterizing this entity. A brief discussion of long-term prognosis and treatment benefit is provided.
Fine Needle Aspiration of Oncocytic Variants of Pancreatic Neuroendocrine Tumor: A Report of Three Misdiagnosed Cases
Authors: Chen Shaoxiong , Wang Xiaoyan , Lin Jingmei
Published: December 2013

Objectives: An oncocytic variant of pancreatic neuroendocrine tumors (PanNET) is exceedingly rare. Here we report cytomorphological features of the oncocytic variant of PanNET and discuss how to avoid diagnostic pitfalls. Study Design: A computerized search of our laboratory information system was performed over an 18-year period to identify all cytology and surgical pathology cases where a diagnosis of PanNET was made or considered in the differential diagnosis. Three cases of the oncocytic variant of PanNET were identified. Results: Endoscopic ultrasound-guided fine needle aspiration (FNA) smears showed cohesive clusters of large atypical cells with abundant eosinophilic granular cytoplasm, anisonucleosis, nuclear enlargement and overlapping, prominent nucleoli, and a relatively smooth nuclear membrane. Nuclei were round to oval with finely granular chromatin. Additional features included rare isolated cells and glandular formation. Some of these morphological features, such as anisonucleosis, nuclear enlargement, and overlapping, prominent nucleoli, are also commonly seen in the pancreatic adenocarcinoma. All these cases were misclassified by FNA as adenocarcinoma (2 cases) or suspicious for carcinoma (1 case) and were histologically confirmed to be oncocytic variants of PanNET. Conclusions: Useful salient features of the oncocytic variant of PanNET include abundant eosinophilic granular cytoplasm, finely granular chromatin, and relatively smooth nuclear membrane. The awareness of this variant will help to avoid misdiagnosis.
Cardiovascular Events Associated With Smoking Cessation Pharmacotherapies
Authors: Mills Edward J. , Thorlund Kristian , Eapen Shawn , Wu Ping , Prochaska Judith J.
Published: December 2013

Background—

Stopping smoking is associated with many important improvements in health and quality of life. The use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease events associated within the quitting period. We aimed to examine whether the 3 licensed smoking cessation therapies—nicotine replacement therapy, bupropion, and varenicline—were associated with an increased risk of cardiovascular disease events using a network meta-analysis.

Methods and Results—

We searched 10 electronic databases, were in communication with authors of published randomized, clinical trials (RCTs), and accessed internal US Food and Drug Administration reports. We included any RCT of the 3 treatments that reported cardiovascular disease outcomes. Among 63 eligible RCTs involving 21 nicotine replacement therapy RCTs, 28 bupropion RCTs, and 18 varenicline RCTs, we found no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54–1.73) or varenicline (RR, 1.30; 95% CI, 0.79–2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39–3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21–0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66–2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26–4.30).

Conclusion—

Smoking cessation therapies do not appear to raise the risk of serious cardiovascular disease events.
Refractory Hypertension
Authors: Calhoun David A. , Booth John N. , Oparil Suzanne , Irvin Marguerite R. , Shimbo Daichi , Lackland Daniel T. , Howard George , Safford Monika M. , Muntner Paul
Published: December 2013

Refractory hypertension is an extreme phenotype of antihypertensive treatment failure. Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a large (n=30 239), population-based cohort were evaluated to determine the prevalence of refractory hypertension and associated cardiovascular risk factors and comorbidities. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic, ≥140/90 mm Hg) on ≥5 antihypertensive drug classes. Participants with resistant hypertension (systolic/diastolic, ≥140/90 mm Hg on ≥3 or <140/90 mm Hg on ≥4 antihypertensive classes) and all participants treated for hypertension served as comparator groups. Of 14 809 REGARDS participants receiving antihypertensive treatment, 78 (0.5%) had refractory hypertension. The prevalence of refractory hypertension was 3.6% among participants with resistant hypertension (n=2144) and 41.7% among participants on ≥5 antihypertensive drug classes. Among all participants with hypertension, black race, male sex, living in the stroke belt or buckle, higher body mass index, lower heart rate, reduced estimated glomerular filtration rate, albuminuria, diabetes mellitus, and history of stroke and coronary heart disease were associated with refractory hypertension. Compared with resistant hypertension, prevalence ratios for refractory hypertension were increased for blacks (3.00; 95% confidence interval, 1.68–5.37) and those with albuminuria (2.22; 95% confidence interval, 1.40–3.52) and diabetes mellitus (2.09; 95% confidence interval, 1.32–3.31). The median 10-year Framingham risk for coronary heart disease and stroke was higher among participants with refractory hypertension when compared with those with either comparator group. These data indicate that although resistant hypertension is relatively common among treated patients with hypertension, true antihypertensive treatment failure is rare.
The Value of N-Terminal Pro–B-Type Natriuretic Peptide in Determining Antihypertensive Benefit
Authors: Welsh Paul , Poulter Neil R. , Chang Choon L. , Sever Peter S. , Sattar Naveed
Published: December 2013

We investigated 3 hypotheses: (1) N-terminal pro–B-type natriuretic peptide (NT-proBNP) predicts cardiovascular disease events in patients with hypertension, (2) NT-proBNP is associated with blood pressure variability, and (3) NT-proBNP predicts benefit from antihypertensive regimens. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized a subset of 6549 patients at risk with no history of coronary heart disease to either atenolol-based or amlodipine-based blood pressure–lowering treatment. During 5.5 years of follow-up, 485 cardiovascular disease cases accrued and were matched with 1367 controls. Baseline and 6-month in-trial NT-proBNP were measured. The results show that NT-proBNP improves cardiovascular disease risk prediction beyond established predictors, continuous net reclassification improvement of 22.3% (
P
<0.0001). Furthermore, a 1-mm Hg increase in the SD of systolic blood pressure was associated with 2% higher baseline NT-proBNP in a multivariable regression analysis (
P
<0.0001). However, NT-proBNP predicted cardiovascular disease risk independently of blood pressure variation (odds ratio per SD increase in log NT-proBNP 1.24; 95% confidence interval, 1.06–1.45;
P
=0.007). Atenolol-based treatment led to a 69.6% increase in NT-proBNP at 6 months (
P
<0.0001). In contrast, amlodipine-based treatment reduced NT-proBNP by 36.5% (
P
<0.0001). Amlodipine recipients who achieved a 6-month NT-proBNP below the median (61 pg/mL) were at lower risk of cardiovascular disease when compared with those who did not (odds ratio, 0.58; 95% confidence interval, 0.37–0.91) after adjustment for confounders inclusive of baseline NT-proBNP and achieved blood pressure. If confirmed, these novel results suggest that NT-proBNP, as well as aiding cardiovascular disease risk assessment, may also help assess the efficacy of specific antihypertensive regimens. Further relevant studies seem warranted.
Excess LIGHT Contributes to Placental Impairment, Increased Secretion of Vasoactive Factors, Hypertension, and Proteinuria in Preeclampsia
Authors: Wang Wei , Parchim Nicholas F. , Iriyama Takayuki , Luo Renna , Zhao Cheng , Liu Chen , Irani Roxanna A. , Zhang Weiru , Ning Chen , Zhang Yujin , Blackwell Sean C. , Chen Lieping , Tao Lijian , Hicks M. John , Kellems Rodney E. , Xia Yang
Published: December 2013

Preeclampsia, a prevalent hypertensive disorder of pregnancy, is believed to be secondary to uteroplacental ischemia. Accumulating evidence indicates that hypoxia-independent mediators, including inflammatory cytokines and growth factors, are associated with preeclampsia, but it is unclear whether these signals directly contribute to placental damage and disease development in vivo. We report that LIGHT, a novel tumor necrosis factor superfamily member, is significantly elevated in the circulation and placentas of preeclamptic women compared with normotensive pregnant women. Injection of LIGHT into pregnant mice induced placental apoptosis, small fetuses, and key features of preeclampsia, hypertension and proteinuria. Mechanistically, using neutralizing antibodies specific for LIGHT receptors, we found that LIGHT receptors herpes virus entry mediator and lymphotoxin β receptor are required for LIGHT-induced placental impairment, small fetuses, and preeclampsia features in pregnant mice. Accordingly, we further revealed that LIGHT functions through these 2 receptors to induce secretion of soluble fms-like tyrosine kinase-1 and endothelin-1, 2 well-accepted pathogenic factors in preeclampsia, and thereby plays an important role in hypertension and proteinuria in pregnant mice. Lastly, we extended our animal findings to human studies and demonstrated that activation of LIGHT receptors resulted in increased apoptosis and elevation of soluble fms-like tyrosine kinase-1 secretion in human placental villous explants. Overall, our human and mouse studies show that LIGHT signaling is a previously unrecognized pathway responsible for placental apoptosis, elevated secretion of vasoactive factors, and subsequent maternal features of preeclampsia, and reveal new therapeutic opportunities for the management of the disease.