bluuebunny/crossref_metadata_2025 huggingface dataset:
SEMANTIC FIELD: A THEORETICAL PERSPECTIVE OF MODELING INFORMATION RETRIEVAL
Authors: YUE KUN , LIU WEI-YI
Published: January 2010

Information retrieval has been paid much attention and it is widely studied and applied in real world paradigms. For various aspects of information retrieval, various approaches have been proposed from various perspectives. It is necessary to provide a formally-unified and physically-interpretable model for classical problems in information retrieval (e.g., document classification, authority-page selection, and keyword extraction, etc.). In this paper we propose a theoretical model, called semantic field, inspired by the theories of lexical semantics and electrostatic field. Based on this physical model, information retrieval can be viewed from a theoretical perspective and interpreted by people's physical intuitions and natural heuristics. Centered on the concept of semantic field, we give some relevant properties, including semantic affinity, semantic coacervation degree and radiation of a semantic source. As the representative application of the proposed semantic field model, a novel method for automatic keyword extraction is discussed, and the feasibility is verified by corresponding experiments.
COMBINING FEATURE SELECTION WITH EXTRACTION: UNSUPERVISED FEATURE SELECTION BASED ON PRINCIPAL COMPONENT ANALYSIS
Authors: LI YUN , LU BAO-LIANG , ZHANG TENG-FEI
Published: January 2010

Principal components analysis (PCA) is a popular linear feature extractor, and widely used in signal processing, face recognition, etc. However, axes of the lower-dimensional space, i.e., principal components, are a set of new variables carrying no clear physical meanings. Thus we propose unsupervised feature selection algorithms based on eigenvectors analysis to identify critical original features for principal component. The presented algorithms are based on k-nearest neighbor rule to find the predominant row components and eight new measures are proposed to compute the correlation between row components in transformation matrix. Experiments are conducted on benchmark data sets and facial image data sets for gender classification to show their superiorities.
AN INTELLIGENT LEARNING APPROACH TO L-GRAMMAR EXTRACTION FROM IMAGE SEQUENCES OF REAL PLANTS
Authors: QU HONGCHUN , ZHU QINGSHENG , GUO MINGWEI , LU ZHONGHUA
Published: January 2010

In this paper, we propose an automatic analyzing and transforming approach to L-system grammar extraction from real plants. Instead of using manually designed rules and cumbersome parameters, our method establishes the relationship between L-system grammars and the iterative trend of botanical entities, which reflect the endogenous factors that caused the plant branching process. To realize this goal, we use a digital camera to take multiple images of unfoliaged (leafless) plants and capture the topological and geometrical data of plant entities using image processing methods. The data then stored into specific data structures. A Hidden Markov based statistical model is then employed to reveal the hidden relations of plant entities which have been classified into categories based on their statistical properties extracted by a classic EM algorithm, the hidden relations have been integrated into the target L-system as grammars. Results show that our method is capable of automatically generating L-grammars for a given unfoliaged plant no matter what branching type it is belongs to.
IDENTIFICATION AND CONTROL OF DISCRETE-TIME NONLINEAR SYSTEMS USING AFFINE SUPPORT VECTOR MACHINES
Authors: ZHANG LI , XI YU-GENG , ZHOU WEI-DA
Published: January 2010

Support vector machine (SVM) is a universal learning method. In this paper, an affine support vector machine (ASVM) for regression is presented for identification and control of input-affine nonlinear models. ASVM is a variant of SVM and so inherits its merits. The solution to ASVM is cast into a convex quadratic programming (QP). Hence ASVM has a unique global solution. In addition, the curse of dimensionality is avoided because ASVM is insensitive to the dimensionality of data. A commonly used model for a nonlinear system is a nonlinear autoregressive exogenous (NARX) model. ASVM could get good performance in both identification and control if a NARX model can be well represented by an input-affine nonlinear model. The experimental results validate the efficiency of ASVM in identification and control of discrete-time nonlinear systems.
A NEW PARAMETERIZED POTENTIAL FAMILY FOR PATH PLANNING ALGORITHMS
Authors: FERRARI FABRICIO
Published: January 2010

In this work, it is proposed a new family of potentials for path planning algorithms, one kind to the goal and other to the obstacles. With these new potentials it is possible to parameterize the potential scale length and strength easily, providing better control over the moving object path characteristics. In this way, the path problem can be treated analytically. For example, the minimum distance between the moving object and the obstacles can be calculated as a function of the potential parameters. Simulations are made to test its ability to guide a vehicle through an obstacle-free path towards the goal. The success rate of the moving object on reaching the goal is compared with the potential parameters and with obstacle configuration and distribution parameters.
Accidental Removal of a Carotid Endovascular Stent during Oropharyngeal Mass Biopsy
Authors: Rameh Charbel , Deveze Arnaud , Lavieille Jean-Pierre , Magnan Jacques , Sanjuan Melanie
Published: January 2010

A 54-year-old male patient, with a history of a right mandibular adenocarcinoma, previously excised, and treated with post operative chemo- and radio-therapy, presented with a right oropharyngeal necrotic mass of several months duration. His history is pertinent for a right internal carotid endovascular stenting 2 years prior to presentation. During biopsy of his oropharyngeal lesion, a specimen of tissue was retrieved, with the carotid stent within. There was no bleeding. To the best of our knowledge, there is no such case reported in the literature. We present this case as a reminder on the importance and risks of radiation-induced necrosis and its distortion of the surrounding anatomy, especially in the presence of foreign bodies or protheses.
Highly Efficient Sigma Point Filter for Spacecraft Attitude and Rate Estimation
Authors: Fan Chunshi , You Zheng
Published: January 2010

Nonlinearities in spacecraft attitude determination problem has been studied intensively during the past decades. Traditionally, multiplicative extended Kalman filter_MEKF_algorithm has been a good solution for most nominal space missions. But in recent years, advances in space missions deserve a revisit of the issue. Though there exist a variety of advanced nonlinear filtering algorithms, most of them are prohibited for actual onboard implementation because of their overload computational complexity. In this paper, we address this difficulty by developing a new algorithm framework based on the marginal filtering principle, which requires only 4 sigma points to give a complete 6‐state attitude and angular rate estimation. Moreover, a new strategy for sigma point construction is also developed to further increase the efficiency and numerical accuracy. Incorporating the presented framework and novel sigma points, we proposed a new, nonlinear attitude and rate estimator, namely, the Marginal Geometric Sigma Point Filter. The new algorithm is of the same precision as traditional unscented Kalman filters, while keeping a significantly lower computational complexity, even when compared to the reduced sigma point algorithms. In fact, it has truly rivaled the efficiency of MEKF, even when simple closed‐form solutions are involved in the latter.
Severe Lactic Acidosis in a Patient with B-Cell Lymphoma: A Case Report and Review of the Literature
Authors: Chan Farn Huei , Carl Daniel , Lyckholm Laurel J.
Published: January 2010

Lactic acidosis is commonly observed in clinical situations such as shock and sepsis, as a result of tissue hypoperfusion and hypoxia. Lymphoma and leukemia are among other clinical situations where lactic acidosis has been reported. We present a case of a 59-year-old female with lactic acidosis who was found to have aggressive B-cell lymphoma. There have been 29 cases of lymphoma induced lactic acidosis reported thus far; however all reported cases have abnormal vital signs or concomitant medical conditions that may lead to lactic acidosis. The pathogenesis of malignancy-induced lactic acidosis is not well understood; however associated factors include increased glycolysis, increased lactate production by cancer cells, and decreased hepatic clearance of lactate. When it occurs, lactic acidosis is a poor prognostic sign in these patients. Prompt diagnosis and treatment of underlying lymphoma or leukemia remains the only way to achieve complete resolution of lactic acidosis in these patients.
YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death
Authors: Cao Ji , Zhang Lei , Ye Qing , Zhou Xinglu , Lou Jianshu , Zhu Difeng , Hu Yongzhou , He Qiaojun , Yang Bo
Published: January 2010

Overexpression of multidrug resistance proteins P‐glycoprotein (P‐gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3‐(1‐methyl‐1H‐indol‐3‐yl)‐1‐phenyl‐4‐(1‐(3‐(piperidin‐1‐yl)propyl)‐1H‐pyrazolo[3,4‐b]pyridine‐3‐yl)‐1H‐pyrrole‐2,5‐dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P‐gp, which contributed to its successfully escaping from the efflux mediated by P‐gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase‐3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.
Stochastic Passivity of Uncertain Neural Networks with Time‐Varying Delays
Authors: Zhou Jianting , Song Qiankun , Yang Jianxi
Published: January 2010

The passivity problem is investigated for a class of stochastic uncertain neural networks with time‐varying
delay as well as generalized activation functions. By constructing appropriate Lyapunov‐Krasovskii functionals,
and employing Newton‐Leibniz formulation, the free‐weighting matrix method, and stochastic analysis technique, a
delay‐dependent criterion for checking the passivity of the addressed neural networks is established in terms of linear
matrix inequalities (LMIs), which can be checked numerically using the effective LMI toolbox in MATLAB. An example
with simulation is given to show the effectiveness and less conservatism of the proposed criterion. It is noteworthy that
the traditional assumptions on the differentiability of the time‐varying delays and the boundedness of its derivative are
removed.
Bayesian Classifier with Simplified Learning Phase for Detecting Microcalcifications in Digital Mammograms
Authors: Zyout Imad , Abdel-Qader Ikhlas , Jacobs Christina
Published: January 2010

Detection of clustered microcalcifications (MCs) in mammograms represents a significant step towards successful detection of breast cancer since their existence is one of the early signs of cancer. In this paper, a new framework that integrates Bayesian classifier and a pattern synthesizing scheme for detecting microcalcification clusters is proposed. This proposed work extracts textural, spectral, and statistical features of each input mammogram and generates models of real MCs to be used as training samples through a simplified learning phase of the Bayesian classifier. Followed by an estimation of the classifier′s decision function parameters, a mammogram is segmented into the identified targets (MCs) against background (healthy tissue). The proposed algorithm has been tested using 23 mammograms from the mini‐MIAS database. Experimental results achieved MCs detection with average true positive (sensitivity) and false positive (specificity) of 91.3% and 98.6%, respectively. Results also indicate that the modeling of the real MCs plays a significant role in the performance of the classifier and thus should be given further investigation.
Maintenance in Single‐Server Queues: A Game‐Theoretic Approach
Authors: Al-Matar Najeeb , Dshalalow Jewgeni H.
Published: January 2010

We use antagonistic stochastic games and fluctuation analysis to
examine a single‐server queue with bulk input and secondary work during server′s multiple vacations. When the buffer contents become exhausted the server leaves the system to perform some diagnostic service of a minimum of L jobs clustered in packets of random sizes (event A). The server is not supposed to stay longer than T units of time (event B). The server returns to the system when A or B occurs, whichever comes first. On the other hand, he may not break service of a packet in a middle even if A or B occurs. Furthermore, the server waits for batches of customers to arrive if upon his return the queue is still empty. We obtain a compact and explicit form functional for the queueing process in equilibrium.
Forepaw Sensorimotor Deprivation in Early Life Leads to the Impairments on Spatial Memory and Synaptic Plasticity in Rats
Authors: Zhang Yuanyuan , Li Fei , Cao Xiaohua , Jin Xingming , Yan Chonghuai , Tian Ying , Shen Xiaoming
Published: January 2010

To investigate the influence of forepaw sensorimotor deprivation on memory and synaptic plasticity, Sprague‐Dawley rats were divided into two groups: a sham‐operated group and a group deprived of forepaw sensorimotor function by microsurgical operation at postnatal day 13 (PN13). Behavioral and electrophysiological studies were performed at PN25, PN35, PN45, and PN60. Open field test was used to assess the spontaneous locomotor activity. Morris water maze was used to evaluate spatial reference learning and memory. The long‐term potentiation (LTP) in the medial perforant path—dentate gyrus (MPP‐DG) pathway was examined with hippocampal slices. We found that forepaw sensorimotor deprivation did not affect spontaneous activity of the rats. However, spatial reference learning and memory were significantly impaired in their early life (PN25, PN35, and PN45). In accordance with the behavior results, LTP in MPP‐DG pathway was significantly suppressed in their early life. These data demonstrated that forepaw sensorimotor deprivation led to the impairments on spatial memory via inducing pronounced deficits in the MPP‐DG pathway to exhibit LTP, one of the major cellular mechanisms underlying learning and memory.
Metastatic Carcinoma of Unknown Primary Presenting as Jugular Venous Thrombosis
Authors: Modayil Prince Cheriyan , Panthakalam Sathyan , Howlett David C.
Published: January 2010

Jugular venous thrombosis is unusual and is associated with central venous catheterisation, intravenous drug abuse and head and neck sepsis. It is rarely associated with malignancy. We report a case of metastatic carcinoma of unknown primary in a forty year old female which presented with jugular venous thrombosis. The discussion includes investigation and treatment options for this condition.
Trace-Inequalities and Matrix-Convex Functions
Authors: Ando Tsuyoshi
Published: January 2010

A real-valued continuous function "Equation missing" on an interval "Equation missing" gives rise to a map "Equation missing" via functional calculus from the convex set of "Equation missing" Hermitian matrices all of whose eigenvalues belong to the interval. Since the subpace of Hermitian matrices is provided with the order structure induced by the cone of positive semidefinite matrices, one can consider convexity of this map. We will characterize its convexity by the following trace-inequalities: "Equation missing" for "Equation missing". A related topic will be also discussed.
The Vacuolar-TypeH+-ATPase in Ovine Rumen Epithelium is Regulated by Metabolic Signals
Authors: Kuzinski Judith , Zitnan Rudolf , Warnke-Gurgel Christina , Schweigel Monika
Published: January 2010

In this study, the effect of metabolic inhibition (MI) by glucose substitution with 2-deoxyglucose (2-DOG) and/or application of antimycin A on ovine rumen epithelial cells (REC) vacuolar-typeH+-ATPase (vH+-ATPase) activity was investigated. Using fluorescent spectroscopy, basalpHiof REC was measured to be7.3±0.1inHCO3−-free, glucose-containing NaCl medium. MI induced a strongpHireduction (−0.44±0.04pH units) with a more pronounced effect of 2-DOG compared to antimycin A (−0.30±0.03versus−0.21±0.03pH units). Treatment with foliomycin, a specific vH+-ATPase inhibitor, decreased RECpHiby0.21±0.05pH units. After MI induction, this effect was nearly abolished (−0.03±0.02pH units). In addition, membrane-associated localization of vH+-ATPase B subunit disappeared. Metabolic control of vH+-ATPase involving regulation of its assembly state by elements of the glycolytic pathway could provide a means to adapt REC ATP consumption according to energy availability.
Regularization and Iterative Methods for Monotone Variational Inequalities
Authors: Xu Xiubin , Xu Hong-Kun
Published: January 2010

We provide a general regularization method for monotone variational inequalities, where the regularizer is a Lipschitz continuous and strongly monotone operator. We also introduce an iterative method as discretization of the regularization method. We prove that both regularization and iterative methods converge in norm.
Taenia crassicepsInfection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes
Authors: Espinoza-Jiménez Arlett , Rivera-Montoya Irma , Cárdenas-Arreola Roberto , Morán Liborio , Terrazas Luis I.
Published: January 2010

Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronicT. crassicepsinfection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS). Healthy or previouslyT. crassiceps-infected mice received MLDS and type 1 diabetes (T1D) symptoms were evaluated for 6 weeks following the induction of MLDS.T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage ofT. crassiceps-infected mice (40%) developed T1D compared to the uninfected group (100%). Insulitis was remarkably absent inT. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection withT. crassicepscauses an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.
The STELLA Robotic Observatory on Tenerife
Authors: Strassmeier Klaus G. , Granzer Thomas , Weber Michael , Woche Manfred , Popow Emil , Järvinen Arto , Bartus Janos , Bauer Svend-Marian , Dionies Frank , Fechner Thomas , Bittner Wilbert , Paschke Jens
Published: January 2010

The Astrophysical Institute Potsdam (AIP) and the Instituto de Astrofísica de Canarias (IAC) inaugurated the robotic telescopes STELLA‐I and STELLA‐II (STELLar Activity) on Tenerife on May 18, 2006. The observatory is located on the Izaña ridge at an elevation of 2400 m near the German Vacuum Tower Telescope. STELLA consists of two 1.2 m alt‐az telescopes. One telescope fiber feeds a bench‐mounted high‐resolution echelle spectrograph while the other telescope feeds a wide‐field imaging photometer. Both scopes work autonomously by means of artificial intelligence. Not only that the telescopes are automated, but the entire observatory operates like a robot, and does not require any human presence on site.
Sodium Orthovanadate Inhibits p53-Mediated Apoptosis
Authors: Morita Akinori , Yamamoto Shinichi , Wang Bing , Tanaka Kaoru , Suzuki Norio , Aoki Shin , Ito Azusa , Nanao Tomohisa , Ohya Soichiro , Yoshino Minako , Zhu Jin , Enomoto Atsushi , Matsumoto Yoshihisa , Funatsu Osamu , Hosoi Yoshio , Ikekita Masahiko
Published: January 2010

Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) α. We compared the effects of vanadate to PFTα and PFTμ, an inhibitor of transcription-independent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcription-independent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis. Cancer Res; 70(1); 257–65
Nucleolar Targeting of RelA(p65) Is Regulated by COMMD1-Dependent Ubiquitination
Authors: Thoms Hazel C. , Loveridge Carolyn J. , Simpson James , Clipson Alexandra , Reinhardt Karina , Dunlop Malcolm G. , Stark Lesley A.
Published: January 2010

Stimulation of the NF-κB pathway can have proapoptotic or antiapoptotic consequences, and one mechanism that determines the outcome is the nuclear distribution of RelA. Certain stress stimuli induce nucleolar accumulation of RelA thereby mediating apoptosis, whereas others induce nucleoplasmic accumulation and inhibition of apoptosis. Here we investigated the mechanisms that regulate the nuclear distribution of RelA, specifically, the role of the ubiquitin/proteasome system. We found that stress-induced nucleolar translocation of RelA is preceded by ubiquitination of the protein. We also found that chemical proteasome inhibitors induce the ubiquitination and nucleolar translocation of RelA and that this is required for the apoptotic response to these agents. We show that the RelA nucleolar localization signal (amino acids 27–30) is a critical domain for ubiquitination of the protein but that the lysine residue within this motif is not a direct target. We show that RelA binds COMMD1, the rate-limiting component of the RelA ubiquitin ligase complex, in response to stress. Furthermore, we show that overexpression of COMMD1 promotes stress-mediated nucleolar targeting of RelA, whereas knockdown of COMMD1 blocks this effect, causing RelA to remain in the nucleoplasm. These data identify a new role for COMMD1 in regulating the nuclear/nucleolar distribution of RelA and suggest that ubiquitination acts as a signal for transport of RelA to the nucleolus. These findings have relevance to the design of chemopreventative/anticancer agents that act by targeting RelA to the nucleolar compartment. Cancer Res; 70(1); 139–49
Recurrent Focal Copy-Number Changes and Loss of Heterozygosity Implicate Two Noncoding RNAs and One Tumor Suppressor Gene at Chromosome 3q13.31 in Osteosarcoma
Authors: Pasic Ivan , Shlien Adam , Durbin Adam D. , Stavropoulos Dimitrios J. , Baskin Berivan , Ray Peter N. , Novokmet Ana , Malkin David
Published: January 2010

Osteosarcomas are copy number alteration (CNA)–rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes. Cancer Res; 70(1); 160–71
Combining Human and Rat Sequences in Her-2 DNA Vaccines Blunts Immune Tolerance and Drives Antitumor Immunity
Authors: Jacob Jennifer B. , Quaglino Elena , Radkevich-Brown Olga , Jones Richard F. , Piechocki Marie P. , Reyes Joyce D. , Weise Amy , Amici Augusto , Wei Wei-Zen
Published: January 2010

Immune tolerance to tumor-associated self-antigens poses a major challenge in the ability to mount an effective cancer vaccine response. To overcome immune tolerance to HER-2, we formulated DNA vaccines that express both human HER-2 and heterologous rat Neu sequences in separate plasmids or as single hybrid constructs that encode HER-2/Neu fusion proteins. Candidate vaccines were tested in Her-2 transgenic (Tg) mice of BALB/c (BALB), BALB/c × C57BL/6 F1 (F1), or C57BL/6 (B6) background, which exhibit decreasing immune responsiveness to HER-2. Analysis of various cocktails or hybrid vaccines defined a requirement for particular combination of HER/2/Neu sequences to effectively prime immune effector cells in HER-2 Tg mice. In B6 HER-2 Tg mice, rejection of HER-2–positive tumors protected mice from HER-2–negative tumors, providing evidence of epitope spreading. Our findings show that a strategy of combining heterologous antigen with self-antigens could produce a potent DNA vaccine that may be applicable to other tumor-associated antigens. Cancer Res; 70(1); 119–28
A Novel Mouse Model for De novo Melanoma
Authors: Kumasaka Mayuko Y. , Yajima Ichiro , Hossain Khaled , Iida Machiko , Tsuzuki Toyonori , Ohno Tamio , Takahashi Masahide , Yanagisawa Masashi , Kato Masashi
Published: January 2010

Nevus-associated melanomas arise from pre-existing benign lesions, but de novo melanomas can also develop in the absence of such lesions. Few studies have addressed the latter phenomenon because no animal models have been described in which melanomas clearly develop in a de novo manner. In this study, we have address this need in defining RFP-RET-transgenic mice (RET mice) as a mouse model for multi-step melanomagenesis that proceeds via tumor-free, benign, premalignant, and malignant stages. Melanomas from RET mice exhibited decreased expression levels of endothelin receptor B (Ednrb) compared with benign tumors. In RET mice that were heterozygous for Ednrb (Ednrb+/−;RET mice), >80% of the arising primary tumors were malignant. Life span after tumor development in the mice was significantly shorter than in RET mice. Lung metastasis after tumor development was significantly higher than in RET mice. The observed process of melanomagenesis in Ednrb+/−;RET mice, which proceeded without a pre-existing benign lesion, along with the emergent characteristics in the model after tumor development corresponded well with the formation of de novo melanoma in humans. Our findings define a novel transgenic mouse model for de novo melanoma and suggest that reduced expression of Ednrb might facilitate the development of de novo melanoma in humans. Cancer Res; 70(1); 24–9
Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity
Authors: Sottoriva Andrea , Verhoeff Joost J.C. , Borovski Tijana , McWeeney Shannon K. , Naumov Lev , Medema Jan Paul , Sloot Peter M.A. , Vermeulen Louis
Published: January 2010

The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46–56
K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate
Authors: Smith B. Douglas , Kasamon Yvette L. , Kowalski Jeanne , Gocke Christopher , Murphy Kathleen , Miller Carole B. , Garrett-Mayer Elizabeth , Tsai Hua-Ling , Qin Lu , Chia Christina , Biedrzycki Barbara , Harding Thomas C. , Tu Guang Haun , Jones Richard , Hege Kristen , Levitsky Hyam I.
Published: January 2010

Purpose: Chronic myeloid leukemia (CML) can be responsive to T-cell–mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a GM-CSF producing vaccine derived from a CML cell line that expresses several CML-associated antigens. A pilot study was developed to determine if K562/GM-CSF immunotherapy could improve clinical responses to imatinib mesylate (IM) in patients with chronic myeloid leukemia.

Experimental Design: Patients with chronic phase CML who achieved at least a major cytogeneic response but remained with persistent, measurable disease despite one or more years on imatinib mesylate were eligible. Each was given a series of four vaccines administered in three-week intervals, with or without topical imiquimod, while remaining on a stable dose of imatinib mesylate. CML disease burden was measured serially before and after vaccination.

Results: Nineteen patients were vaccinated, with a median duration of previous imatinib mesylate therapy of 37 (13–53) months. Mean PCR measurements of BCR-ABL for the group declined significantly following the vaccines (P = 0.03). Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable.

Conclusions: K562/GM-CSF vaccine appears to improve molecular responses in patients on imatinib mesylate, including achieving complete molecular remissions, despite long durations of previous imatinib mesylate therapy. Clin Cancer Res; 16(1); 338–47
The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth
Authors: Marian Calin O. , Cho Steve K. , Mcellin Brian M. , Maher Elizabeth A. , Hatanpaa Kimmo J. , Madden Christopher J. , Mickey Bruce E. , Wright Woodring E. , Shay Jerry W. , Bachoo Robert M.
Published: January 2010

Purpose: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo.

Experimental Design: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat.

Results: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45 μmol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed ∼70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth.

Conclusion: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. Clin Cancer Res; 16(1); 154–63
ERP Correlates of Word Production before and after Stroke in an Aphasic Patient
Authors: Laganaro Marina , Morand Stéphanie , Michel Christoph M. , Spinelli Laurent , Schnider Armin
Published: January 2010

Changes in brain activity characterizing impaired speech production after brain damage have usually been investigated by comparing aphasic speakers with healthy subjects because prestroke data are normally not available. However, when interpreting the results of studies of stroke patients versus healthy controls, there is an inherent difficulty in disentangling the contribution of neuropathology from other sources of between-subject variability. In the present work, we had an unusual opportunity to study an aphasic patient with severe anomia who had incidentally performed a picture naming task in an ERP study as a control subject one year before suffering a left hemisphere stroke. The fortuitous recording of this patient's brain activity before his stroke allows direct comparison of his pre- and poststroke brain activity in the same language production task. The subject did not differ from other healthy subjects before his stroke, but presented major electrophysiological differences after stroke, both in comparison to himself before stroke and to the control group. ERP changes consistently appeared after stroke in a specific time window starting about 250 msec after picture onset, characterized by a single divergent but stable topographic configuration of the scalp electric field associated with a cortical generator abnormally limited to left temporal posterior perilesional areas. The patient's pattern of anomia revealed a severe lexical–phonological impairment and his ERP responses diverged from those of healthy controls in the time window that has previously been associated with lexical–phonological processes during picture naming. Given that his prestroke ERPs were indistinguishable from those of healthy controls, it seems highly likely that the change in his poststroke ERPs is due to changes in language production processes as a consequence of stroke. The patient's neurolinguistic deficits, combined with the ERPs results, provide unique evidence for the role of left temporal cortex in lexical–phonological processing from about 250 to 450 msec during word production.
Musicians and the Metric Structure of Words
Authors: Marie Céline , Magne Cyrille , Besson Mireille
Published: January 2010

The present study aimed to examine the influence of musical expertise on the metric and semantic aspects of speech processing. In two attentional conditions (metric and semantic tasks), musicians listened to short sentences ending in trisyllabic words that were semantically and/or metrically congruous or incongruous. Both ERPs and behavioral data were analyzed and the results were compared to previous nonmusicians' data. Regarding the processing of meter, results showed that musical expertise influenced the automatic detection of the syllable temporal structure (P200 effect), the integration of metric structure and its influence on word comprehension (N400 effect), as well as the reanalysis of metric violations (P600 and late positivities effects). By contrast, results showed that musical expertise did not influence the semantic level of processing. These results are discussed in terms of transfer of training effects from music to speech processing.
Inhibitory Control and the Frontal Eye Fields
Authors: Muggleton Neil G. , Chen Chiao-Yun , Tzeng Ovid J. L. , Hung Daisy L. , Juan Chi-Hung
Published: January 2010

Inhibitory control mechanisms are important in a range of behaviors to prevent execution of motor acts which, having been planned, are no longer necessary. Ready examples of this can be seen in a range of sports, such as cricket and baseball, where the choice between execution or inhibition of a bat swing must be made in a brief time interval. The role of the FEFs, an area typically described in relation to eye movement functions but also involved in visual processes, was investigated in an inhibitory control task using transcranial magnetic stimulation (TMS). A stop signal task with manual responses was used, providing measures of impulsivity and inhibitory control. TMS over FEF had no effect on response generation (impulsivity, indexed by go signal RT) but disrupted inhibitory control (indexed by stop signal RT). This is the first demonstration of a role for FEF in this type of task in normal subjects in a task which did not require eye movements and complements previous TMS findings of roles for pre-SMA and inferior frontal gyrus (IFG) in inhibitory control.
The Emergence of Perceived Position in the Visual System
Authors: Fischer Jason , Spotswood Nicole , Whitney David
Published: January 2010

Representing object position is one of the most critical functions of the visual system, but this task is not as simple as reading off an object's retinal coordinates. A rich body of literature has demonstrated that the position in which we perceive an object depends not only on retinotopy but also on factors such as attention, eye movements, object and scene motion, and frames of reference, to name a few. Despite the distinction between perceived and retinal position, strikingly little is known about how or where perceived position is represented in the brain. In the present study, we dissociated retinal and perceived object position to test the relative precision of retina-centered versus percept-centered position coding in a number of independently defined visual areas. In an fMRI experiment, subjects performed a five-alternative forced-choice position discrimination task; our analysis focused on the trials in which subjects misperceived the positions of the stimuli. Using a multivariate pattern analysis to track the coupling of the BOLD response with incremental changes in physical and perceived position, we found that activity in higher level areas—middle temporal complex, fusiform face area, parahippocampal place area, lateral occipital cortex, and posterior fusiform gyrus—more precisely reflected the reported positions than the physical positions of the stimuli. In early visual areas, this preferential coding of perceived position was absent or reversed. Our results demonstrate a new kind of spatial topography present in higher level visual areas in which an object's position is encoded according to its perceived rather than retinal location. We term such percept-centered encoding “perceptotopy”.
Knowing Your Lines but Missing Your Cue: Rostral Prefrontal Lesions Impair Prospective Memory Cue Detection, but Not Action-intention Superiority
Authors: Uretzky Sharon , Gilboa Asaf
Published: January 2010

Prospective memory (PM) deficits are a common consequence of lesions to PFC, but their underlying neurocognitive mechanisms and processes are poorly understood. Here, we report on a patient, Z. P., who suffers from a chronic focal PM deficit, while other cognitive functions including memory are intact. His lesion involves right polar PFC (Brodmann's areas 10 and 9). Z. P. was very impaired on tasks that require detection of PM cues during an ongoing task. He was impaired regardless of whether the PM cues involved effortful or nearly effortless detection on the part of controls. By contrast, on tasks that tap the underlying (implicit) representations of intentions to perform an action, Z. P. showed normal patterns of intention superiority effects (ISEs) for to-be-performed actions and an inhibition effect for prospective actions after they had been performed. Thus, this is the first report of a neuropsychological dissociation between preserved privileged representation of prospective intentions and impaired detection of cues that support the opportune recovery of PM. Our data are compatible with the “gateway hypothesis” of rostral PFC, but also suggest there are components that are unique to PM and that remain intact after lesions to this region.
Multisensory Facilitation of Behavior in Monkeys: Effects of Stimulus Intensity
Authors: Cappe Céline , Murray Micah M. , Barone Pascal , Rouiller Eric M.
Published: January 2010

Multisensory stimuli can improve performance, facilitating RTs on sensorimotor tasks. This benefit is referred to as the redundant signals effect (RSE) and can exceed predictions on the basis of probability summation, indicative of integrative processes. Although an RSE exceeding probability summation has been repeatedly observed in humans and nonprimate animals, there are scant and inconsistent data from nonhuman primates performing similar protocols. Rather, existing paradigms have instead focused on saccadic eye movements. Moreover, the extant results in monkeys leave unresolved how stimulus synchronicity and intensity impact performance. Two trained monkeys performed a simple detection task involving arm movements to auditory, visual, or synchronous auditory–visual multisensory pairs. RSEs in excess of predictions on the basis of probability summation were observed and thus forcibly follow from neural response interactions. Parametric variation of auditory stimulus intensity revealed that in both animals, RT facilitation was limited to situations where the auditory stimulus intensity was below or up to 20 dB above perceptual threshold, despite the visual stimulus always being suprathreshold. No RT facilitation or even behavioral costs were obtained with auditory intensities 30–40 dB above threshold. The present study demonstrates the feasibility and the suitability of behaving monkeys for investigating links between psychophysical and neurophysiologic instantiations of multisensory interactions.
Neural Correlates of Foreign-language Learning in Childhood: A 3-Year Longitudinal ERP Study
Authors: Ojima Shiro , Nakamura Naoko , Matsuba-Kurita Hiroko , Hoshino Takahiro , Hagiwara Hiroko
Published: January 2010

A foreign language (a language not spoken in one's community) is difficult to master completely. Early introduction of foreign-language (FL) education during childhood is becoming a standard in many countries. However, the neural process of child FL learning still remains largely unknown. We longitudinally followed 322 school-age children with diverse FL proficiency for three consecutive years, and acquired children's ERP responses to FL words that were semantically congruous or incongruous with the preceding picture context. As FL proficiency increased, various ERP components previously reported in mother-tongue (L1) acquisition (such as a broad negativity, an N400, and a late positive component) appeared sequentially, critically in an identical order to L1 acquisition. This finding was supported not only by cross-sectional analyses of children at different proficiency levels but also by longitudinal analyses of the same children over time. Our data are consistent with the hypothesis that FL learning in childhood reproduces identical developmental stages in an identical order to L1 acquisition, suggesting that the nature of the child's brain itself may determine the normal course of FL learning. Future research should test the generalizability of the results in other aspects of language such as syntax.
Differential Contributions of the Intraparietal Sulcus and the Inferior Parietal Lobe to Attentional Blink: Evidence from Transcranial Magnetic Stimulation
Authors: Kihara Ken , Ikeda Takashi , Matsuyoshi Daisuke , Hirose Nobuyuki , Mima Tatsuya , Fukuyama Hidenao , Osaka Naoyuki
Published: January 2010

When two targets (T1 and T2) are to be identified in rapid serial visual presentation, the response to T1 induces impairment of T2 report if T2 appears within 500 msec after T1 (attentional blink: AB). AB is thought to reflect temporal limitations of attention which affect target perception. Recent research suggests that the intraparietal sulcus (IPS) contributes to an attentional set associated with task goals, whereas the inferior parietal lobe (IPL) is associated with the disengagement and reorienting of attention to a relevant stimulus presented outside the current focus of attention. We investigated respective involvement of the IPS and the IPL in AB using transcranial magnetic stimulation (TMS). The results of Experiment 1 showed that the magnitude of AB deficit decreased TMS disrupted activity of the IPS after T1 onset. In addition, an increased AB deficit occurred when TMS was delivered over the IPS or IPL after T2 onset. In Experiment 2, where participants were instructed to ignore T1, they showed an AB-like T2 deficit only when TMS was delivered to the IPS after a T2 onset. Findings are discussed in terms of hypotheses about the respective roles of the IPS, in realizing an attentional set, and the IPL, in contributing to a disengagement of attention (from T1 to T2) during an AB period.
Verbal Labels Modulate Perceptual Object Processing in 1-Year-Old Children
Authors: Gliga Teodora , Volein Agnes , Csibra Gergely
Published: January 2010

Whether verbal labels help infants visually process and categorize objects is a contentious issue. Using electroencephalography, we investigated whether possessing familiar or novel labels for objects directly enhances 1-year-old children's neural processes underlying the perception of those objects. We found enhanced gamma-band (20–60 Hz) oscillatory activity over the visual cortex in response to seeing objects with labels familiar to the infant (Experiment 1) and those with novel labels just taught to the infant (Experiment 2). No such effect was observed for objects that infants were familiar with but had no label for. These results demonstrate that learning verbal labels modulates how the visual system processes the images of the associated objects and suggest a possible top–down influence of semantic knowledge on object perception.