bluuebunny/crossref_metadata_2025 huggingface dataset:
Position–Yaw Tracking of Quadrotors
Authors: Sanchez-Orta Anand , Parra-Vega Vicente , Izaguirre-Espinosa Carlos , Garcia Octavio
Published: December 2014

A yaw angle, different from zero, introduces highly nonlinear couplings in the rotational and translational quadrotor dynamics, implying undesirable motions. This argument has motivated that the position control problem of quadrotors is studied generally regulating yaw at zero. However, zeroing yaw limits the maneuverability of underactuated quadrotors because yaw is one of the four actuated motions. In this paper, the simultaneous tracking of position and time-varying heading is proposed, based on an integral sliding mode control with a quaternion-based sliding surface. An exponential tracking with chattering-free is obtained without requiring any knowledge of the dynamic model or its parameters for implementation. Since a linear invariant orientation error manifold is enforced for all time, a time-varying gain is introduced for a well-posed finite time convergence, which is useful not only to realize the virtual position control scheme, due to underactuation, but also to guarantee a desired contact in a given point at a given desired contact time for the yaw motion. Illustrative applications are explored in a simulation study which shows the viability and versatility of position–yaw tracking in the surveillance of a field-of-view (FoV) target, aerial screw driver, and aerial grasping.
High-Fidelity Rendering of Contact With Virtual Objects
Authors: Mohtat Arash , Kövecses József
Published: December 2014

When interacting with a virtual object (VO) through a haptic device, it is crucial to feedback a contact force to the human operator (HO) that displays the VO physical properties with high fidelity. The core challenge, here, is to expand the renderable range of these properties, including larger stiffness and smaller inertia, at the available sampling rate. To address this challenge, a framework entitled high-fidelity contact rendering (HFCR) has been developed in this paper. The framework consists of three main strategies: an energy-based rendering of the contact force, smooth transition (ST) between contact modes, and remaining leak dissipation (LD). The essence of these strategies is to make the VO emulate its continuous-time counterpart. This is achieved via physically meaningful modifications in the constitutive relations to suppress artificial energy leaks. The strategies are first developed for the one-dimensional (1D) canonical VO; then, generalization to the multivariable case is discussed. Renderability has been analyzed exploring different stability criteria within a unified approach. This leads to stability charts and identification of renderable range of properties in the presence and absence of the HO. The framework has been validated through simulation and various experiments. Results verify its promising aspects for various scenarios including sustained contact and sudden collision events with or without the HO.
Optimal Control of a Formula One Car on a Three-Dimensional Track—Part 2: Optimal Control
Authors: Limebeer D. J. N. , Perantoni G.
Published: December 2014

The optimal control of a Formula One car on a three-dimensional (3D) track is studied. The track is described by its geodesic and normal curvatures, and its relative torsion. These curvature parameters are obtained from noisy measurement data using the optimal estimation technique described in Part 1. The optimal control calculations presented are based on the aforementioned track model and a vehicle model that is responsive to the geometric features of a 3D track. For vehicle modeling purposes, the track is treated as a plane tangent to a nearby point on the track's spine. This tangent plane moves under the car and is orthogonal to the principal normal vector m at the nearby spine point. Results are presented that compare two-dimensional (2D) and 3D minimum-lap-time results, with the two compared. The Barcelona Formula One track studied in Part 1 is used again as an illustrative example.
Boundary Backstepping Control of Flow-Induced Vibrations of a Membrane at High Mach Numbers
Authors: Sezgin Aziz , Krstic Miroslav
Published: December 2014

We design a controller for flow-induced vibrations of an infinite-band membrane, with flow running across the band and only above it, and with actuation only on the trailing edge of the membrane. Due to the infinite length of the membrane, the dynamics of the membrane in the spanwise direction are neglected, namely, we employ a one-dimensional (1D) model that focuses on streamwise vibrations. This framework is inspired by a flow along an airplane wing with actuation on the trailing edge. The model of the flow-induced vibration is given by a wave partial differential equation (PDE) with an antidamping term throughout the 1D domain. Such a model is based on linear aeroelastic theory for Mach numbers above 0.8. To design a controller, we introduce a three-stage backstepping transformation. The first stage gets the system to a critically antidamped wave equation, changing the stiffness coefficient's value but not its sign. The second stage changes the system from a critically antidamped to a critically damped equation with an arbitrary damping coefficient. The third stage adjusts stiffness arbitrarily. The controller and backstepping transformation map the original system into a target system given by a wave equation with arbitrary positive damping and stiffness.
Optimal Trajectory Planning of Motor Torque and Clutch Slip Speed for Gear Shift of a Two-Speed Electric Vehicle
Authors: Gao Bingzhao , Xiang Yu , Chen Hong , Liang Qiong , Guo Lulu
Published: December 2014

In order to improve the shift quality of a two-speed inverse automated manual transmission (I-AMT) of electric vehicle (EV), optimal control is used to generate the reference trajectories of the clutch slip speed and motor torque. The offline optimization results are fitted and used for online implementation. In order to compensate the disturbances and modeling errors, a proportional integral derivative (PID) controller is added to ensure the closed-loop control performance. The proposed controller is almost free of calibration effort, because the feedforward part of the proposed controller considered the simple but dominant system dynamics. Finally, the control algorithm is confirmed through large amounts of tests on a complete powertrain simulation model, and the designed controller can provide satisfactory performance even under large variation of vehicle mass and road grade.
The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields
Authors: Schmitz T. , Bassler N. , Blaickner M. , Ziegner M. , Hsiao M. C. , Liu Y. H. , Koivunoro H. , Auterinen I. , Serén T. , Kotiluoto P. , Palmans H. , Sharpe P. , Langguth P. , Hampel G.
Published: December 2014

Purpose:

The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed.

Methods:

Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a 60Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes fluka and mcnp. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen & Olsen alanine response model.

Results:

The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields.

Conclusions:

The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.
Interspinous process device versus standard conventional surgical decompression for lumbar spinal stenosis: randomised controlled trial
Authors: Moojen Wouter A , Arts Mark P , Jacobs Wilco C H , van Zwet Erik W , van den Akker-van Marle M Elske , Koes Bart W , Vleggeert-Lankamp Carmen L A M , Peul Wilco C
Published: December 2014

STUDY QUESTION

Is interspinous process device implantation more effective in the short term (eight weeks) than conventional surgical decompression for patients with intermittent neurogenic claudication due to lumbar spinal stenosis?

SUMMARY ANSWER

The use of interspinous implants did not result in a better outcome than conventional decompression, but the reoperation rate was significantly higher.

WHAT IS KNOWN AND WHAT THIS PAPER ADDS

Bony decompression and treatment with interspinous process devices are superior to conservative and non-surgical treatment for intermittent neurogenic claudication due to lumbar spinal stenosis. Interspinous implants surgery is not superior to bony decompression, and the reoperation rate is significantly higher.
Efficacy of Female Rat Models in Translational Cardiovascular Aging Research
Authors: Rice K. M. , Fannin J. C. , Gillette C. , Blough E. R.
Published: December 2014

Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. This review addresses the systemic pathophysiology of the cardiovascular system associated with aging and gender for aging research with regard to the applicability of rat derived data for translational application to human aging.
Cholangiocarcinoma Presenting as Uterine Metastasis
Authors: Dendas W. , Cappelle L. , Verguts J. , Orye G.
Published: December 2014

Metastases to the female genital tract are rare, with metastatic disease restricted to the uterus being even less frequent. The primary tumor is most often intragenital rather than extragenital. The diagnosis is usually made after occurrence of gynecological symptoms. We describe the case of a 26-year-old female, in whom a curettage for menorrhagia revealed a uterine malignancy, at first thought to be a carcinosarcoma. Biochemistry only showed iron deficiency anemia. Imaging showed discrepant results with liver lesions, suspect of neoplastic or inflammatory disease. She underwent an abdominal hysterectomy and, peroperatively, a frozen section of a mass in the liver hilus demonstrated a cholangiocarcinoma. The diagnosis of a uterine metastasized cholangiocarcinoma was made. We emphasize the fact that uterine metastases have to be excluded in every woman with abnormal uterine bleeding and a personal history of malignancy. However, our case also indicates that gynecological metastatic disease may be the first presentation of an extragenital primary neoplasm.
An Examination of Forest Certification Status among Logging Companies in Cameroon
Authors: Nukpezah Daniel , Alemagi Dieudonne , Duguma Lalisa , Minang Peter , Mbosso Charlie , Tchoundjeu Zac
Published: December 2014

This paper assesses the level of interest, awareness, and adoption of ISO 14001 and Forest Stewardship Council (FSC) certification schemes among logging companies in Cameroon. Eleven logging companies located in Douala in the Littoral Region of Cameroon were assessed through a structured interview using an administered questionnaire which was mostly analyzed qualitatively thereafter. The findings indicated that none of the companies was certified for ISO 14001; however 63.64% of them were already FSC-certified. Four companies (36.36%) were neither FSC- nor ISO 14001 EMS-certified. Among the factors found to influence the adoption rate was the level of awareness about ISO 14001 and FSC certification schemes. The main drivers for pursuing FSC certification were easy penetration into international markets, tax holiday benefits, and enhancement of corporate image of the logging companies through corporate social responsibility fulfillments. Poor domestic market for certified products was found to be the major impediment to get certified. To make logging activities more environmentally friendly and socially acceptable, logging companies should be encouraged to get certified through the ISO 14001 EMS scheme which is almost nonexistent so far. This requires awareness creation about the scheme, encouraging domestic markets for certified products and creating policy incentives.
The Effect of Land Use Change on Transformation of Relief and Modification of Soils in Undulating Loess Area of East Poland
Authors: Rejman Jerzy , Rafalska-Przysucha Anna , Rodzik Jan
Published: December 2014

The change of primary forest areas into arable land involves the transformation of relief and modification of soils. In this study, we hypothesized that relatively flat loess area was largely transformed after the change of land use due to erosion. The modifications in soil pedons and distribution of soil properties were studied after 185 years of arable land use. Structure of pedons and solum depth were measured in 128 and soil texture and soil organic carbon in 39 points. Results showed that soils of noneroded and eroded profiles occupied 14 and 50%, respectively, and depositional soils 36% of the area. As a consequence, the clay, silt, and SOC concentration varied greatly in the plowed layer and subsoil. The reconstructed profiles of eroded soils and depositional soils without the accumulation were used to develop the map of past relief. The average inclination of slopes decreased from 4.3 to 2.2°, and slopes >5° vanished in the present topography. Total erosion was 23.8 Mg ha−1 year−1. From that amount, 88% was deposited within the study area, and 12% was removed outside. The study confirmed the hypothesis of the significant effect of the land use change on relief and soils in loess areas.
Thyroid-Induced Worsening of Parkinsonian Tremor Resistant to Drugs and Subthalamic Nucleus Deep Brain Stimulation
Authors: Minár Michal , Valkovič Peter
Published: December 2014

Introduction.Symptoms of both hypothyroidism and thyrotoxicosis can be easily overlooked in patients with Parkinson’s disease (PD). We report on a patient whose parkinsonian tremor worsened and proved refractory not only to common treatment, but also to deep brain stimulation (DBS).Case Presentation.A 61-year-old woman with advanced PD underwent bilateral subthalamic DBS, with an excellent outcome. Twenty-one months after the surgery, however, patient’s resting/postural tremor markedly worsened. There was a slight improvement for 1 month after repeated adjustments of DBS parameters, but then the tremor worsened again. Since even a minimal increase of the dose of dopaminergic drugs caused extremely severe dyskinesias, an anticholinergic drug biperiden and benzodiazepine clonazepam were introduced, what helped for another month. With the onset of severe diarrhoea, a laboratory workup was performed. Thyrotoxicosis was detected. During treatment with the antithyroid agent carbimazole, the parkinsonian tremor clearly improved within two weeks.Conclusion.A hyperthyroid state can markedly exaggerate all forms of tremor, as well as other types of movement disorders. This condition can be overlooked or masked by other symptoms. Therefore, if the tremor in a patient with PD gradually worsens and proves resistant to the usual treatment, examine the thyroid gland.
A Simple and Robust Gray Image Encryption Scheme Using Chaotic Logistic Map and Artificial Neural Network
Authors: Kengnou Telem Adelaïde Nicole , Meli Segning Colince , Kenne Godpromesse , Fotsin Hilaire Bertrand
Published: December 2014

A robust gray image encryption scheme using chaotic logistic map and artificial neural network (ANN) is introduced. In the proposed method, an external secret key is used to derive the initial conditions for the logistic chaotic maps which are employed to generate weights and biases matrices of the multilayer perceptron (MLP). During the learning process with the backpropagation algorithm, ANN determines the weight matrix of the connections. The plain image is divided into four subimages which are used for the first diffusion stage. The subimages obtained previously are divided into the square subimage blocks. In the next stage, different initial conditions are employed to generate a key stream which will be used for permutation and diffusion of the subimage blocks. Some security analyses such as entropy analysis, statistical analysis, and key sensitivity analysis are given to demonstrate the key space of the proposed algorithm which is large enough to make brute force attacks infeasible. Computing validation using experimental data with several gray images has been carried out with detailed numerical analysis, in order to validate the high security of the proposed encryption scheme.
NovelKIF6Polymorphism Increases Susceptibility to Type 2 Diabetes Mellitus and Coronary Heart Disease in Han Chinese Men
Authors: Wu Ge , Li Gui-Bin , Dai Bin , Zhang Dong-Qing
Published: December 2014

Objectives. The effect of theKIF6polymorphism Trp719Arg on the risk of T2DM and T2DM with CHD remains unclear.Methods. 946 unrelated subjects of Han Chinese origin were recruited, comprising 346 controls, 312 T2DM, and 288 T2DM + CHD patients. Genotyping was performed by high-resolution melting curve analysis using real-time qPCR. The impact of the variant on T2DM/T2DM + CHD and gene-sex interaction were evaluated by stepwise multiple regression analysis.Results. The frequencies of the Trp719 allele in T2DM and T2DM + CHD patients were similar to the control group, whereas significantly increased 719Arg allele frequencies were observed in male T2DM and T2DM + CHD patients compared with the corresponding control group. Further sex partition analysis revealed that only male 719Arg allele carriers had approximately 3-fold and 5-fold higher risk of T2DM and T2DM + CHD, respectively, than noncarriers. There was also a significant association between carriers and higher TG and lower HDL-C levels.Conclusion. The KIF6 719Arg allele may increase the risk of T2DM and T2DM + CHD only in Han Chinese men by modulating lipid metabolism, especially with regard to TG and HDL.
Accelerated Tumor Progression in Mice Lacking the ATP Receptor P2X7
Authors: Adinolfi Elena , Capece Marina , Franceschini Alessia , Falzoni Simonetta , Giuliani Anna L. , Rotondo Alessandra , Sarti Alba C. , Bonora Massimo , Syberg Susanne , Corigliano Domenica , Pinton Paolo , Jorgensen Niklas R. , Abelli Luigi , Emionite Laura , Raffaghello Lizzia , Pistoia Vito , Di Virgilio Francesco
Published: December 2014

The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. Cancer Res; 75(4); 635–44. ©2014 AACR.
HOXB7 Promotes Malignant Progression by Activating the TGFβ Signaling Pathway
Authors: Liu Shou , Jin Kideok , Hui Yvonne , Fu Jie , Jie Chunfa , Feng Sheng , Reisman David , Wang Qian , Fan Daping , Sukumar Saraswati , Chen Hexin
Published: December 2014

Overexpression of HOXB7 in breast cancer cells induces an epithelial–mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double-transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFβ/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFβ2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFβ2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFβ2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFβ2 or pharmacologic inhibition of TGFβ signaling. Furthermore, knockdown of TGFβ2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFβ2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFβ2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non–cell-autonomous manner through activation of the TGFβ signaling pathway. Cancer Res; 75(4); 709–19. ©2014 AACR.
Enterolignan-Producing Phenotypes Are Associated with Increased Gut Microbial Diversity and Altered Composition in Premenopausal Women in the United States
Authors: Hullar Meredith A.J. , Lancaster Samuel M. , Li Fei , Tseng Elizabeth , Beer Karlyn , Atkinson Charlotte , Wähälä Kristiina , Copeland Wade K. , Randolph Timothy W. , Newton Katherine M. , Lampe Johanna W.
Published: December 2014

Background: Lignans in plant foods are metabolized by gut bacteria to the enterolignans, enterodiol (END) and enterolactone (ENL). Enterolignans have biologic activities important to the prevention of cancer and chronic diseases. We examined the composition of the gut microbial community (GMC) as a contributor to human enterolignan exposure.

Methods: We evaluated the association between the GMC in stool, urinary enterolignan excretion, and diet from a 3-day food record in 115 premenopausal (ages 40–45 years) women in the United States. Urinary enterolignans were measured using gas chromatography–mass spectroscopy. The GMC was evaluated using 454 pyrosequencing of the 16S rRNA gene. Sequences were aligned in SILVA (www.arb-silva.de). Operational taxonomic units were identified at 97% sequence similarity. Taxonomic classification was performed and alpha and beta diversity in relationship to ENL production were assessed. Multivariate analysis and regression were used to model the association between enterolignan excretion and the GMC. Bacteria associated with ENL production were identified using univariate analysis and ridge regression.

Results: After adjusting for dietary fiber intake and adiposity, we found a significant positive association between ENL excretion and either the GMC (P = 0.0007), or the diversity of the GMC (P = 0.01). The GMC associated with high ENL production was distinct (UNIFRAC, P < 0.003, MRPP) and enriched in Moryella spp., Acetanaerobacterium spp., Fastidiosipila spp., and Streptobacillus spp.

Conclusion: Diversity and composition of the GMC are associated with increased human exposure to enterolignans.

Impact: Differences in gut microbial diversity and composition explain variation in gut metabolic processes that affect environmental exposures and influence human health. Cancer Epidemiol Biomarkers Prev; 24(3); 546–54. ©2014 AACR.
Baseline Serum β-carotene Concentration and Mortality among Long-Term Asbestos-Exposed Insulators
Authors: Hashim Dana , Gaughan Denise , Boffetta Paolo , Lucchini Roberto G.
Published: December 2014

Background: Although interventional trials demonstrated that moderate-dose β-carotene supplementation increases lung cancer mortality in smokers and asbestos-exposed workers, differences in serum concentrations in absence of supplementation have not been studied in asbestos-exposed workers.

Methods: A mortality analysis was performed to assess the relationship of nonsupplemented serum β-carotene to all-cause and cancer mortalities using 1981 to 1983 serum β-carotene concentration measurements from 2,646 U.S. white male insulators (mean age, 57.7 years). Multivariable-adjusted Cox proportional hazard models that included terms for age, duration of asbestos exposure, smoking, season, and region were fitted to estimate mortality HRs and 95% confidence intervals (CI) according to serum β-carotene concentrations.

Results: Median follow-up was 12.8 years and 984 (33.8%) subjects died during the follow-up period, including 415 deaths from overall cancer and 219 deaths from lung cancer. The overall mortality HR for a serum β-carotene increase of 10 μg/dL was 0.97 (95% CI, 0.96–0.99). Compared with the lowest quartile, HRs were 0.90 (95% CI, 0.76–1.07) for the second (38–65 μg/dL), 0.80 (95% CI, 0.67–0.96) for the third (66–104 μg/dL), and 0.63 (95% CI, 0.51–0.77) for the highest serum β-carotene quartile (≥105 μg/dL). There was no association between serum β-carotene and overall cancer mortality (HR, 1.00; 95% CI, 0.97–1.02) or lung cancer mortality (HR, 0.99; 95% CI, 0.96–1.02).

Conclusions: Higher nonsupplemented serum β-carotene concentrations were negatively associated with all-cause mortality among asbestos-exposed individuals.

Impact: Serum β-carotene can be a marker of one or more determinants of reduced mortality in asbestos-exposed workers. Cancer Epidemiol Biomarkers Prev; 24(3); 555–60. ©2014 AACR.
Variation in Levels of the Lung Carcinogen NNAL and Its Glucuronides in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer
Authors: Park Sungshim L. , Carmella Steven G. , Ming Xun , Vielguth Elizabeth , Stram Daniel O. , Le Marchand Loic , Hecht Stephen S.
Published: December 2014

Background: Results of the Multiethnic Cohort (MEC) study demonstrated that, for the same quantity of cigarettes smoked, African Americans and Native Hawaiians have a higher risk of lung cancer compared with whites, whereas Latinos and Japanese Americans have a lower risk. We hypothesize that the uptake and/or metabolism of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) could explain the differences in lung cancer risk.

Methods: We measured urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides and their sum (total NNAL), biomarkers of NNK uptake, in 2,252 smokers from the MEC. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, creatinine and total nicotine equivalents, a marker of total nicotine uptake.

Results: African Americans had the highest median total NNAL levels (1.80 pmol/mL urine) and Japanese Americans had the lowest (0.914 pmol/mL urine), with intermediate values in the other three groups. Geometric mean of total NNAL in African Americans was also highest, and in Japanese Americans it was lowest; Japanese American geometric mean was statistically different from whites (P = 0.004).

Conclusions: African Americans had higher levels of total NNAL per mL urine than whites, while Japanese Americans had lower levels, consistent with lung cancer risk among smokers in these groups. However, our data were not consistent with the high and low lung cancer risks of Native Hawaiian and Latino smokers, respectively.

Impact: The higher lung cancer susceptibility of African-American smokers and the lower susceptibility of Japanese-American smokers compared with whites can be explained in part by exposure to the potent lung carcinogen NNK. Cancer Epidemiol Biomarkers Prev; 24(3); 561–9. ©2014 AACR.
Plasma Isoflavones and Risk of Primary Liver Cancer in Japanese Women and Men with Hepatitis Virus Infection: A Nested Case–Control Study
Authors: Michikawa Takehiro , Inoue Manami , Sawada Norie , Tanaka Yasuhito , Yamaji Taiki , Iwasaki Motoki , Shimazu Taichi , Sasazuki Shizuka , Mizokami Masashi , Tsugane Shoichiro
Published: December 2014

Background: Evidence suggests that estrogen plays a preventive role in primary liver cancer development, and it might be thought that isoflavones, which are structurally similar to estrogens and bind to estrogen receptors, are associated with the risk of liver cancer. We investigated this suspected association by measuring plasma concentrations of isoflavones in a nested case–control study of a population-based prospective cohort in Japan.

Methods: From 18,628 target participants ages 40 to 69 years who returned the baseline questionnaire and provided blood samples, we selected those with either hepatitis B or hepatitis C virus infection at baseline (n = 1,544). Among these, 90 (28 women and 62 men) were newly diagnosed with primary liver cancer from 1993 through 2006; they were matched with 175 controls (54 women and 121 men). Plasma concentrations of isoflavones (genistein, daidzein, glycitein, and equol) were measured using triple quadrupole tandem liquid chromatography-mass spectrometry. The ORs of liver cancer development based on plasma concentrations were estimated with a conditional logistic regression model.

Results: Basically, distributions of plasma isoflavone concentrations did not differ between the cases and controls. No statistically significant associations of genistein, daidzein, glycitein, and equol with primary liver cancer risk were found in either women or men.

Conclusions: In middle-aged Japanese women and men with hepatitis virus infection, plasma isoflavones were unassociated with the occurrence of primary liver cancer.

Impact: The role of isoflavones in liver carcinogenesis merits further study using both biomarkers and data on dietary intake of isoflavones. Cancer Epidemiol Biomarkers Prev; 24(3); 532–7. ©2014 AACR.
Vitamin D–Associated Genetic Variation and Risk of Breast Cancer in the Breast and Prostate Cancer Cohort Consortium (BPC3)
Authors: Mondul Alison M. , Shui Irene M. , Yu Kai , Weinstein Stephanie J. , Tsilidis Konstantinos K. , Joshi Amit D. , Agudo Antonio , Berg Christine D. , Black Amanda , Buring Julie E. , Chasman Daniel I. , Gaudet Mia M. , Haiman Christopher , Hankinson Susan E. , Henderson Brian E. , Hoover Robert N. , Hunter David J. , Khaw Kay-Tee , Kühn Tilman , Kvaskoff Marina , Le Marchand Loic , Lindström Sara , McCullough Marjorie L. , Overvad Kim , Peeters Petra H. , Riboli Elio , Ridker Paul M. , Stram Daniel O. , Sund Malin , Trichopoulos Dimitrios , Tumino Rosario , Weiderpass Elisabete , Willett Walter , Kraft Peter , Ziegler Regina G. , Albanes Demetrius
Published: December 2014

Background: Two recent genome-wide association studies (GWAS) identified SNPs in or near four genes related to circulating 25-hydroxyvitamin D [25(OH)D] concentration. To examine the hypothesized inverse relationship between vitamin D status and breast cancer, we studied the associations between SNPs in these genes and breast cancer risk in a large pooled study of 9,456 cases and 10,816 controls from six cohorts.

Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped and examined both individually and as a 4-SNP polygenic score. Logistic regression was used to estimate the associations between the genetic variants and risk of breast cancer.

Results: We found no association between any of the four SNPs or their polygenic score and breast cancer risk.

Conclusions: Our findings do not support an association between vitamin D status, as reflected by 25(OH)D–related genotypes, and breast cancer risk.

Impact: These findings may contribute to future meta-analyses and scientific review articles, and provide new data about the association between vitamin D–related genes and breast cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 627–30. ©2014 AACR.
Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein
Authors: Janakiram Murali , Chinai Jordan M. , Fineberg Susan , Fiser Andras , Montagna Cristina , Medavarapu Ramadevi , Castano Ekaterina , Jeon Hyungjun , Ohaegbulam Kim C. , Zhao Ruihua , Zhao Aimin , Almo Steven C. , Sparano Joseph A. , Zang Xingxing
Published: December 2014

Purpose: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.

Experimental Design: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.

Results: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I–III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.

Conclusions: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy. Clin Cancer Res; 21(10); 2359–66. ©2014 AACR.

See related commentary by Xiao and Freeman, p. 2201
Neuregulin 1 Expression Is a Predictive Biomarker for Response to AV-203, an ERBB3 Inhibitory Antibody, in Human Tumor Models
Authors: Meetze Kristan , Vincent Sylvie , Tyler Steven , Mazsa Elizabeth K. , Delpero Andrea R. , Bottega Steve , McIntosh Donna , Nicoletti Richard , Winston William M. , Weiler Solly , Feng Bin , Gyuris Jeno , Weng Zhigang
Published: December 2014

Purpose: ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic.

Experimental Design: We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models.

Results: A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models.

Conclusions: NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203. Clin Cancer Res; 21(5); 1106–14. ©2014 AACR.
Ligand-Independent EPHA2 Signaling Drives the Adoption of a Targeted Therapy–Mediated Metastatic Melanoma Phenotype
Authors: Paraiso Kim H.T. , Thakur Meghna Das , Fang Bin , Koomen John M. , Fedorenko Inna V. , John Jobin K. , Tsao Hensin , Flaherty Keith T. , Sondak Vernon K. , Messina Jane L. , Pasquale Elena B. , Villagra Alejandro , Rao Uma N. , Kirkwood John M. , Meier Friedegund , Sloot Sarah , Gibney Geoffrey T. , Stuart Darrin , Tawbi Hussein , Smalley Keiran S.M.
Published: December 2014

Many patients with BRAF inhibitor resistance can develop disease at new sites, suggesting that drug-induced selection pressure drives metastasis. Here, we used mass spectrometry–based phosphoproteomic screening to uncover ligand-independent EPHA2 signaling as an adaptation to BRAF inhibitor therapy that led to the adoption of a metastatic phenotype. The EPHA2-mediated invasion was AKT-dependent and readily reversible upon removal of the drug as well as through PI3K and AKT inhibition. In xenograft models, BRAF inhibition led to the development of EPHA2-positive metastases. A retrospective analysis of patients with melanoma on BRAF inhibitor therapy showed that 68% of those failing therapy develop metastases at new disease sites, compared with 35% of patients on dacarbazine. Further IHC staining of melanoma specimens taken from patients on BRAF inhibitor therapy as well as metastatic samples taken from patients failing therapy showed increased EPHA2 staining. We suggest that inhibition of ligand-independent EPHA2 signaling may limit metastases associated with BRAF inhibitor therapy.

Significance: This study provides evidence that BRAF inhibition promotes the adoption of a reversible, therapy-driven metastatic phenotype in melanoma. The cotargeting of ligand-independent EPHA2 signaling and BRAF may be one strategy to prevent the development of therapy-mediated disease at new sites. Cancer Discov; 5(3); 264–73. ©2014 AACR.

See related article by Miao et al., p. 274

This article is highlighted in the In This Issue feature, p. 213
EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma
Authors: Miao Benchun , Ji Zhenyu , Tan Li , Taylor Michael , Zhang Jianming , Choi Hwan Geun , Frederick Dennie T. , Kumar Raj , Wargo Jennifer A. , Flaherty Keith T. , Gray Nathanael S. , Tsao Hensin
Published: December 2014

BRAFV600E is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in-class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.

Significance: In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance. Cancer Discov; 5(3); 274–87. ©2014 AACR.

See related article by Paraiso et al., p. 264

This article is highlighted in the In This Issue feature, p. 213
Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody
Authors: Xu Hong , Cheng Ming , Guo Hongfen , Chen Yuedan , Huse Morgan , Cheung Nai-Kong V.
Published: December 2014

Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >105-fold selectivity over normal tissues, releasing Th1 cytokines (TNFα, IFNγ, and IL2) when GD2(+) tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells. Cancer Immunol Res; 3(3); 266–77. ©2014 AACR.
Syndecan-1 Modulates the Motility and Resolution Responses of Macrophages
Authors: Angsana Julianty , Chen Jiaxuan , Smith Sumona , Xiao Jiantao , Wen Jing , Liu Liying , Haller Carolyn A. , Chaikof Elliot L.
Published: December 2014

Objective—

Syndecan-1 (Sdc-1) is a member of a family of cell surface proteoglycans, which has been reported to participate in the regulation of events relevant to tissue repair and chronic injury responses, including cell–substrate interactions, matrix remodeling, and cell migration. In this study, we report the functional significance of Sdc-1 in polarized macrophage populations and its role in adhesion and motility events relevant to resolution of the inflammatory program.

Approach and Results—

Macrophage Sdc-1 expression is associated with differentiated M2 macrophages with high intrinsic motility, and Sdc-1 deficiency is characterized by impaired migration and enhanced adhesion. Leukocyte infiltration and emigration were examined in a thioglycollate-induced model of peritonitis in Sdc-1
+/+
and Sdc-1
−/−
mice. Although the infiltration of inflammatory cells was similar in both cohorts, a significant delay in the lymphatic clearance of Sdc-1
−/−
macrophages was observed. Moreover, we observed enhanced inflammation and greater burden of atherosclerotic plaques in ApoE
−/−
Sdc-1
−/−
mice maintained on a Western diet.

Conclusions—

These results demonstrate that defective motility in Sdc-1
−/−
macrophages promotes a persistent inflammatory state with relevance to the pathogenesis of atherosclerosis.
Limited Reliability of Computed Tomographic Perfusion Acute Infarct Volume Measurements Compared With Diffusion-Weighted Imaging in Anterior Circulation Stroke
Authors: Schaefer Pamela W. , Souza Leticia , Kamalian Shervin , Hirsch Joshua A. , Yoo Albert J. , Kamalian Shahmir , Gonzalez R. Gilberto , Lev Michael H.
Published: December 2014

Background and Purpose—

Diffusion-weighted imaging (DWI) can reliably identify critically ischemic tissue shortly after stroke onset. We tested whether thresholded computed tomographic cerebral blood flow (CT-CBF) and CT-cerebral blood volume (CT-CBV) maps are sufficiently accurate to substitute for DWI for estimating the critically ischemic tissue volume.

Methods—

Ischemic volumes of 55 patients with acute anterior circulation stroke were assessed on DWI by visual segmentation and on CT-CBF and CT-CBV with segmentation using 15% and 30% thresholds, respectively. The contrast:noise ratios of ischemic regions on the DWI and CT perfusion (CTP) images were measured. Correlation and Bland–Altman analyses were used to assess the reliability of CTP.

Results—

Mean contrast:noise ratios for DWI, CT-CBF, and CT-CBV were 4.3, 0.9, and 0.4, respectively. CTP and DWI lesion volumes were highly correlated (
R
2
=0.87 for CT-CBF;
R
2
=0.83 for CT-CBV;
P
<0.001). Bland–Altman analyses revealed little systemic bias (−2.6 mL) but high measurement variability (95% confidence interval, ±56.7 mL) between mean CT-CBF and DWI lesion volumes, and systemic bias (−26 mL) and high measurement variability (95% confidence interval, ±64.0 mL) between mean CT-CBV and DWI lesion volumes. A simulated treatment study demonstrated that using CTP-CBF instead of DWI for detecting a statistically significant effect would require at least twice as many patients.

Conclusions—

The poor contrast:noise ratios of CT-CBV and CT-CBF compared with those of DWI result in large measurement error, making it problematic to substitute CTP for DWI in selecting individual acute stroke patients for treatment. CTP could be used for treatment studies of patient groups, but the number of patients needed to identify a significant effect is much higher than the number needed if DWI is used.