bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Constitutive Activation of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cells BearingEGFRGene Mutation and Amplification
Authors: Okabe Takafumi , Okamoto Isamu , Tamura Kenji , Terashima Masaaki , Yoshida Takeshi , Satoh Taroh , Takada Minoru , Fukuoka Masahiro , Nakagawa Kazuhiko 
Published: March 2007

AbstractThe identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition. [Cancer Res 2007;67(5):2046–53]
Metabotropic Glutamate Receptor 1 and Glutamate Signaling in Human Melanoma
Authors: Namkoong Jin , Shin Seung-Shick , Lee Hwa Jin , Marín Yarí E. , Wall Brian A. , Goydos James S. , Chen Suzie 
Published: March 2007

Abstract
Recently, several laboratories have started to investigate the involvement of glutamate signaling in cancer. In previous studies, we reported on a transgenic mouse model that develops melanoma spontaneously. Subsequent studies in these mice identified that the aberrant expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes played a critical role in the onset of melanoma. Confirmation of the etiologic role of GRM1 in melanoma development was shown in a second transgenic line with GRM1 expression under the regulation of a melanocyte-specific dopachrome tautomerase promoter. Ectopic expression of GRM1 was also detected in a subset of human melanoma cell lines and biopsies, suggesting that aberrant expression of GRM1 in melanocytes may contribute to the development of human melanoma. GRM1, a seven-transmembrane domain G protein–coupled receptor, is normally expressed and functional in neuronal cells, and its ligand, glutamate, is the major excitatory neurotransmitter. Human melanoma cells are shown here to release elevated levels of glutamate, implying a possible autocrine loop. Treatment of GRM1-expressing human melanoma cells with a GRM1 antagonist (LY367385 or BAY36-7620) or a glutamate release inhibitor (riluzole) leads to a suppression of cell proliferation as well as a decrease in levels of extracellular glutamate. Treatment of human melanoma cell xenografts with riluzole for 18 days via p.o. gavage or i.v. injection leads to inhibition of tumor growth by 50% in comparison with controls. These data suggest the importance of glutamate signaling in human melanoma and imply that the suppression of glutamate signaling may be a new target for melanoma therapy. [Cancer Res 2007;67(5):2298–305]
Twist and Epithelial-Mesenchymal Transition Are Induced by the EBV Oncoprotein Latent Membrane Protein 1 and Are Associated with Metastatic Nasopharyngeal Carcinoma
Authors: Horikawa Toshiyuki , Yang Jing , Kondo Satoru , Yoshizaki Tomokazu , Joab Irene , Furukawa Mitsuru , Pagano Joseph S. 
Published: March 2007

AbstractNasopharyngeal carcinoma (NPC), an EBV-associated malignancy, is highly metastatic compared with other head and neck tumors, perhaps because of its viral link. Here, we show that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), induces epithelial-mesenchymal transition (EMT) via Twist, a master transcriptional regulator in embryogenesis and newly implicated in metastasis, which, in turn, are likely to contribute to the highly metastatic character of NPC. LMP1 could induce EMT and its associated cell motility and invasiveness in a cell culture model, whereas expression of Twist small interfering RNA reversed LMP1-induced EMT. In diverse EBV-infected cell lines, expression of Twist correlates with expression of LMP1. Dominant-negative LMP1 could suppress Twist expression in EBV-positive cells, whereas LMP1 could induce Twist in EBV-negative nasopharyngeal cells. LMP1 signals through the nuclear factor-κB pathway, and an IκB superrepressor inhibited induction of Twist by LMP1. Finally, in human NPC tissues, expression of Twist and LMP1 is directly correlated and expression of Twist is associated with metastasis clinically. These results suggest that induction of Twist by a human viral oncoprotein LMP1 directly contributes to the metastatic nature of NPC. [Cancer Res 2007;67(5):1970–8]
CD4 T-Helper Responses to the Anaplastic Lymphoma Kinase (ALK) Protein in Patients with ALK-Positive Anaplastic Large-Cell Lymphoma
Authors: Ait-Tahar Kamel , Barnardo Martin C.N. , Pulford Karen 
Published: March 2007

AbstractWe have previously shown both humoral and CTL responses to anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large-cell lymphoma (ALCL). However, because CD4+ T-helper (Th) cells also play a vital role in developing and maintaining tumor immunity, we investigated the presence of a CD4+ Th response in ALK-positive ALCL. Using an IFN-γ ELISPOT assay, we identified two ALK-derived DRB1-restricted 24-mer promiscuous peptides, ALK1278–301 and ALK2233–256, as being immunogenic in six ALK-positive ALCL patients but not in two ALK-negative ALCL patients or five normal subjects. A significant interleukin-4 response to the ALK peptides was detected in only one ALK-positive patient. CD4+ Th cell lines lysed ALK-positive ALCL cell lines in a MHC class II–restricted manner. This first report of a CD4+ Th response to ALK provides valuable information for developing future immunotherapeutic options for ALK-positive ALCL patients who fail to respond well to conventional therapies. [Cancer Res 2007;67(5):1898–901]
Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b
Authors: Wang Wenjun , Edington Howard D. , Rao Uma N.M. , Jukic Drazen M. , Land Stephanie R. , Ferrone Soldano , Kirkwood John M. 
Published: March 2007

AbstractPurpose: The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFNα2b (HDI) in relation to the balance of pSTAT1 and pSTAT3.Experimental Design: We evaluated STAT1 and STAT3 jointly as mediators of IFNα effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies.Results: HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).Conclusion: IFNα2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.
NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 Activity and Expression in Bladder and Ovarian Cancer and Lower NRH:Quinone Oxidoreductase 2 Activity Associated with an NQO2 Exon 3 Single-Nucleotide Polymorphism
Authors: Jamieson David , Wilson Kerrie , Pridgeon Simon , Margetts Jane P. , Edmondson Richard J. , Leung Hing Y. , Knox Richard , Boddy Alan V. 
Published: March 2007

Abstract
Purpose: NRH:quinone oxidoreductase 2 (NQO2) is a homologue of NAD(P)H:quinone oxidoreductase 1 (NQO1). Despite 54% homology with human NQO1, NQO2 has little endogenous enzymatic activity. However, NQO2 has potential as a therapeutic target because the addition of the nonbiogenic electron donor dihydronicotinamide riboside (NRH) selectively potentiates the bioactivation of the alkylating agent tretazicar (CB 1954). The NQO activity of ovarian and bladder tumors was determined and the effect of NQO polymorphisms on NQO activity was investigated.
Experimental Design: Intraperitoneal ovarian metastases and bladder tumor clinical samples were analyzed for NQO1 and NQO2 activity, mRNA expression by semiquantitative reverse transcription-PCR, and genotype by RFLP analysis.
Results: NQO1 activity was higher in the bladder cohort than in the ovarian cohort (0-283 and 0-30 nmol/min/mg, respectively; P &lt; 0.0001). In contrast, NQO2 activity was higher in the ovarian tissue than in the bladder samples (0.15-2.27 and 0-1.14 nmol/min/mg, respectively; P = 0.0004). In both cohorts, the NQO1 C609T single-nucleotide polymorphism (SNP) was associated with ∼7-fold lower NQO1 activity. The NQO2 exon 3 T14055C SNP was associated with lower NQO2 activity relative to wild-type [median values of 0.18 and 0.37 nmol/min/mg in the bladder samples (P = 0.007) and 0.82 and 1.16 nmol/min/mg in the ovarian cohort (P = 0.034)].
Conclusion: This is the first observation reporting an apparent association between an NQO2 exon 3 SNP and lower enzymatic activity. The high NQO2 activity of intraperitoneal ovarian metastases relative to other tissues indicates a potential for tretazicar therapy in the treatment of this disease. In contrast, the low level of NQO1 activity and expression relative to other tissues suggests that NQO1-directed therapies would not be appropriate.
Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51
Authors: Yao Qing , Weigel Brenda , Kersey John 
Published: March 2007

Abstract
Purpose: DNA-damaging agents, such as etoposide, while clinically useful in leukemia therapy, are limited by DNA repair pathways that are not well understood. 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90 (Hsp90), inhibits growth and induces apoptosis in FLT3+ leukemia cells. In this study, we evaluated the effects of etoposide and 17-AAG in leukemia cells and the roles of Hsp90, FMS-like tyrosine kinase 3 (FLT3), checkpoint kinase 1 (Chk1), Rad51, and topoisomerase II in this inhibition.
Experimental Design: The single and combined effects of 17-AAG and etoposide and the mechanism of these effects were evaluated. FLT3 and the DNA repair-related proteins, Chk1 and Rad51, were studied in small interfering RNA (siRNA)–induced cell growth inhibition experiments in human leukemia cells with wild-type or mutated FLT3.
Results: We found that etoposide and the Hsp90/FLT3 inhibitor 17-AAG, had synergistic inhibitory effects on FLT3+ MLL-fusion gene leukemia cells. Cells with an internal tandem duplication (ITD) FLT3 (Molm13 and MV4;11) were more sensitive to etoposide/17-AAG than leukemias with wild-type FLT3 (HPB-Null and RS4;11). A critical role for FLT3 was shown in experiments with FLT3 ligand and siRNA targeted to FLT3. An important role for topoisomerase II and the DNA repair-related proteins, Chk1 and Rad51, in the synergistic effects was suggested from the results.
Conclusions: The repair of potentially lethal DNA damage by etoposide in leukemia cells is dependent on intact and functioning FLT3 especially leukemias with ITD-FLT3. These data suggest a rational therapeutic strategy for FLT3+ leukemias that combines etoposide or other DNA-damaging agents with Hsp90/FLT3 inhibitors such as 17-AAG.
Selective Visual Dimension Weighting Deficit after Left Lateral Frontopolar Lesions
Authors: Pollmann S. , Mahn K. , Reimann B. , Weidner R. , Tittgemeyer M. , Preul C. , Müller H. J. , von Cramon D. Y. 
Published: March 2007

AbstractThe left lateral frontopolar (LFP) cortex showed dimension change-related activation in previous event-related functional magnetic resonance imaging studies of visual singleton feature search with non-brain-lesioned participants. Here, we tested the hypothesis that LFP actively supports changes of attention from the old to the new target-defining dimension in singleton feature search. Singleton detection was selectively slowed in this task when the target-defining dimension changed in patients with left LFP lesions, compared with patients with frontomedian lesions as well as with matched controls without brain lesions. We discuss a potential role of LFP in change detection when the optimal allocation of dimension-based attention is not clearly defined by the task.
Auditory Brainstem Correlates of Perceptual Timing Deficits
Authors: Johnson Krista L. , Nicol Trent G. , Zecker Steven G. , Kraus Nina 
Published: March 2007

Abstract
Children with language-based learning problems often exhibit pronounced speech perception difficulties. Specifically, these children have increased difficulty separating brief sounds occurring in rapid succession (temporal resolution). The purpose of this study was to better understand the consequences of auditory temporal resolution deficits from the perspective of the neural encoding of speech. The findings provide evidence that sensory processes relevant to cognition take place at much earlier levels than traditionally believed. Thresholds from a psychophysical backward masking task were used to divide children into groups with good and poor temporal resolution. Speech-evoked brainstem responses were analyzed across groups to measure the neural integrity of stimulus-time mechanisms. Results suggest that children with poor temporal resolution do not have an overall neural processing deficit, but rather a deficit specific to the encoding of certain acoustic cues in speech. Speech understanding relies on the ability to attach meaning to rapidly fluctuating changes of both the temporal and spectral information found in consonants and vowels. For this to happen properly, the auditory system must first accurately encode these time-varying acoustic cues. Speech perception difficulties that often co-occur in children with poor temporal resolution may originate as a neural encoding deficit in structures as early as the auditory brainstem. Thus, speech-evoked brainstem responses are a biological marker for auditory temporal processing ability.
Setting the Stage for Automatic Syntax Processing: The Mismatch Negativity as an Indicator of Syntactic Priming
Authors: Hasting Anna S. , Kotz Sonja A. , Friederici Angela D. 
Published: March 2007

Abstract
The present study investigated the automaticity of morphosyntactic processes and processes of syntactic structure building using event-related brain potentials. Two experiments were conducted, which contrasted the impact of local subject-verb agreement violations (Experiment 1) and word category violations (Experiment 2) on the mismatch negativity, an early event-related brain potential component reflecting automatic auditory change detection. The two violation types were realized in two-word utterances comparable with regard to acoustic parameters and structural complexity. The grammaticality of the utterances modulated the mismatch negativity response in both experiments, suggesting that both types of syntactic violations were detected automatically within 200 msec after the violation point. However, the topographical distribution of the grammaticality effect varied as a function of violation type, which indicates that the brain mechanisms underlying the processing of subject-verb agreement and word category information may be functionally distinct even at this earliest stage of syntactic analysis. The findings are discussed against the background of studies investigating syntax processing beyond the level of two-word utterances.
Spatio-temporal Brain Dynamics Underlying Saccade Execution, Suppression, and Error-related Feedback
Authors: Herdman Anthony T. , Ryan Jennifer D. 
Published: March 2007

Abstract
Human and nonhuman animal research has outlined the neural regions that support saccadic eye movements. The aim of the current work was to outline the sequence by which distinct neural regions come on-line to support goal-directed saccade execution and error-related feedback. To achieve this, we obtained behavioral responses via eye movement recordings and neural responses via magnetoencephalography (MEG), concurrently, while participants performed an antisaccade task. Neural responses were examined with respect to the onset of the saccadic eye movements. Frontal eye field and visual cortex activity distinguished subsequently successful goal-directed saccades from (correct and erroneous) reflexive saccades prior to the deployment of the eye movement. Activity in the same neural regions following the saccadic movement distinguished correct from incorrect saccadic responses. Error-related activity in the frontal eye fields preceded that from visual regions, suggesting a potential feedback network that may drive corrective eye movements. This work provides the first empirical demonstration of simultaneous remote eyetracking and MEG recording. The coupling of behavioral and neuroimaging technologies, used here to characterize dynamic brain networks underlying saccade execution and error-related feedback, demonstrates a novel within-paradigm converging evidence approach by which to outline the neural underpinnings of cognition.
Immersive Video Teleconferencing with User-Steerable Views
Authors: Yang Ruigang , Kurashima Celso Setsuo , Towles Herman , Nashel Andrew , Zuffo Marcelo Knörich 
Published: March 2007

Existing video teleconferencing techniques suffer from limited field of view, low resolution, and fixed viewpoint. We present a set of novel techniques to overcome these limitations. Based on the light field rendering concept, we utilize an array of cameras to capture the participant(s) from multiple view angles. Based on either assumed or estimated scene geometry, these images are assembled to create a high-resolution seamless image from a user-controllable viewpoint. Two different camera configurations, one dense and one sparse, are presented; the dense format is optimized for high-fidelity view synthesis while the sparse configuration is for expanded viewing volume. For the dense configuration, we provide a detailed analysis on the number of camera images required. For the sparse configuration, we present a robust technique to estimate an approximation of the scene geometry to provide smooth transition when the viewpoint is changed.The novelty of our approach is that it allows the users to electronically steer the viewpoint in real time for a live scene. Therefore it can be used in 3D teleconferencing systems to generate stereoscopic views, or in group teleconferencing to provide virtual camera views that minimize the overall perspective distortions. We demonstrate the effectiveness of our approach with a point-to-point teleconferencing system distributed in several locations across the continental United States.
Physiological-social score (PMEWS) vs. CURB-65 to triage pandemic influenza: a comparative validation study using community-acquired pneumonia as a proxy
Authors: Challen Kirsty , Bright John , Bentley Andrew , Walter Darren 
Published: March 2007

Abstract
Background
An influenza pandemic may increase Emergency Department attendance 7-fold. In the absence of a validated "flu score" to assess severity and assist triage decisions from primary into secondary care, current UK draft management recommendations have suggested the use of CURB-65 and chest X-ray as a proxy. We developed the Pandemic Medical Early Warning Score (PMEWS) to track and triage flu patients, taking into account physiological and social factors and without requiring laboratory or radiology services.

Methods
Validation of the PMEWS score against an unselected group of patients presenting and admitted to an urban UK teaching hospital with community acquired pneumonia. Comparison of PMEWS performance against CURB-65 for three outcome measures: need for admission, admission to high dependency or intensive care, and inpatient mortality using area under ROC curve (AUROC) and the Hanley-McNeil method of comparison.

Results
PMEWS was a better predictor of need for admission (AUROC 0.944) and need of higher level of care (AUROC 0.83) compared with CURB-65 (AUROCs 0.881 and 0.640 respectively) but was not as good a predictor of subsequent inpatient mortality (AUROC 0.663).

Conclusion
Although further validation against other disease datasets as a proxy for pandemic flu is required, we show that PMEWS is rapidly applicable for triage of large numbers of flu patients to self-care, hospital admission or HDU/ICU care. It is scalable to reflect changing admission thresholds that will occur during a pandemic.
High serum levels of soluble CD40-L in patients with undifferentiated nasopharyngeal carcinoma: pathogenic and clinical relevance
Authors: Caggiari Laura , Guidoboni Massimo , Vaccher Emanuela , Barzan Luigi , Franchin Giovanni , Gloghini Annunziata , Martorelli Debora , Zancai Paola , Bortolin Maria Teresa , Mazzucato Mario , Serraino Diego , Carbone Antonino , De Paoli Paolo , Dolcetti Riccardo 
Published: March 2007

AbstractBackgroundEngagement of CD40 promotes survival of undifferentiated nasopharyngeal carcinoma (UNPC) cells and similar effects are induced by the EBV oncoprotein LMP-1 that is expressed in a fraction of cases. Considering that CD40 may be activated also by the soluble isoform of CD40L (sCD40L), we investigated the serum levels of sCD40L in a series of 61 UNPC patients from Italy, a non-endemic area for this disease.ResultsAt diagnosis, serum samples of UNPC patients contained significantly higher levels of sCD40L than age-matched healthy controls (p < 0.001). High levels of sCD40L (i.e., >18 ng/ml) were more frequently found in patients <40 years of age (p = 0.03) and with distant metastases at presentation (p = 0.03). Serum levels of sCD40L were inversely associated with the expression of the EBV oncoprotein LMP-1 (p = 0.03), which mimics a constitutively activated CD40. The amount of sCD40L decreased in a fraction of patients treated with local radiotherapy alone. Moreover, CD40L+lymphoid cells admixed to neoplastic UNPC cells were detected in cases with high serum levels of sCD40L, suggesting that sCD40L is probably produced within the tumor mass.ConclusionsCD40L may contribute to CD40 activation in UNPC cells, particularly of LMP-1-negative cases, further supporting the crucial role of CD40 signalling in the pathogenesis of UNPC. sCD40L levels may be useful to identify UNPC patients with occult distant metastases at presentation.