bluuebunny/crossref_metadata_2025_split huggingface dataset:
Approximating Fixed Points of Some Maps in Uniformly Convex Metric Spaces
Authors: Khan AbdulRahim , Fukhar-ud-din Hafiz , Domlo AbdulAziz 
Published: February 2010

AbstractWe study strong convergence of the Ishikawa iterates of qasi-nonexpansive (generalized nonexpansive) maps and some related results in uniformly convex metric spaces. Our work improves and generalizes the corresponding results existing in the literature for uniformly convex Banach spaces.
TRF1 Mediates Mitotic Abnormalities Induced by Aurora-A Overexpression
Authors: Ohishi Tomokazu , Hirota Toru , Tsuruo Takashi , Seimiya Hiroyuki 
Published: February 2010

Abstract
Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A–induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A–induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A–induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A–induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability. Cancer Res; 70(5); 2041–52
Thioredoxin Reductase-1 Mediates Curcumin-Induced Radiosensitization of Squamous Carcinoma Cells
Authors: Javvadi Prashanthi , Hertan Lauren , Kosoff Rachelle , Datta Tatini , Kolev Johann , Mick Rosemarie , Tuttle Stephen W. , Koumenis Constantinos 
Published: February 2010

Abstract
Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously showed that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the antioxidant enzyme thioredoxin reductase-1 (TxnRd1) is required for curcumin-mediated radiosensitization of squamous carcinoma cells. Stable knockdown of TxnRd1 in both HeLa and FaDu cells nearly abolished curcumin-mediated radiosensitization. TxnRd1 knockdown cells showed decreased radiation-induced reactive oxygen species and sustained extracellular signal-regulated kinase 1/2 activation, which we previously showed was required for curcumin-mediated radiosensitization. Conversely, overexpressing catalytically active TxnRd1 in HEK293 cells, with low basal levels of TxnRd1, increased their sensitivity to curcumin alone and to the combination of curcumin and ionizing radiation. These results show the critical role of TxnRd1 in curcumin-mediated radiosensitization and suggest that TxnRd1 levels in tumors could have clinical value as a predictor of response to curcumin and radiotherapy. Cancer Res; 70(5); 1941–50
An Oncogenic Role for ETV1 in Melanoma
Authors: Jané-Valbuena Judit , Widlund Hans R. , Perner Sven , Johnson Laura A. , Dibner Aurora C. , Lin William M. , Baker Alissa C. , Nazarian Rosalynn M. , Vijayendran Krishna G. , Sellers William R. , Hahn William C. , Duncan Lyn M. , Rubin Mark A. , Fisher David E. , Garraway Levi A. 
Published: February 2010

Abstract
Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of “driver” cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization analysis revealed copy gains spanning the ETV1 locus in &gt;40% of cases, with ETV1 amplification (&gt;6 copies/cell) present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage-independent growth. Moreover, overexpression of ETV1 in combination with oncogenic NRASG12D transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated microphthalmia-associated transcription factor expression in immortalized melanocytes, which was necessary for ETV1-dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy. Cancer Res; 70(5); 2075–84
HER Kinase Axis Receptor Dimer Partner Switching Occurs in Response to EGFR Tyrosine Kinase Inhibition despite Failure to Block Cellular Proliferation
Authors: Jain Anjali , Penuel Elicia , Mink Sheldon , Schmidt Joanna , Hodge Amanda , Favero Kristin , Tindell Charles , Agus David B. 
Published: February 2010

AbstractThe human epidermal receptor (HER) axis consists of a dynamic, interconnected family of receptors that make critical contributions to a number of malignancies. Therapeutics targeting epidermal growth factor receptor (EGFR) are unable to effectively inhibit tumor growth in a majority of cases. These tumors are assumed to possess primary resistance to anti-EGFR therapies, but the consequence of inhibiting EGFR in these tumors is unclear. We established isogenic cell lines by prolonged gefitinib treatment at concentrations that are in excess of that which is required for complete EGFR kinase inhibition but only minimally affected growth. Subsequently, we monitored the ligand-dependent HER profiles based on receptor expression, phosphorylation, and dimerization in conjunction with measurements of cellular susceptibility to gefitinib. Chronic EGFR kinase inhibition rapidly switched the HER network from dependence on EGFR to HER2. However, both receptors activated the critical signaling proteins AKT and mitogen-activated protein kinase, and in both cases, HER3 was the common association partner. Remarkably, the switch in receptor dimers caused diminished susceptibility to EGFR-targeted inhibitors gefitinib and cetuximab but acquired susceptibility to the HER2-targeted inhibitor pertuzumab. Overall, our study indicates that the EGFR pathway is responsive to EGFR inhibiting therapies that are not dependent on EGFR for their growth and survival, thus challenging the current definition of primary therapeutic resistance. Furthermore, EGFR kinase inhibition induces HER kinase receptors to engage in alternative dimerization that can ultimately influence therapeutic selection and responsiveness. Cancer Res; 70(5); 1989–99
Evaluation of the ETS-Related Gene mRNA in Urine for the Detection of Prostate Cancer
Authors: Rice Kevin R. , Chen Yongmei , Ali Amina , Whitman Eric J. , Blase Amy , Ibrahim Mona , Elsamanoudi Sally , Brassell Stephen , Furusato Bungo , Stingle Norbert , Sesterhenn Isabell A. , Petrovics Gyorgy , Miick Siobhan , Rittenhouse Harry , Groskopf Jack , McLeod David G. , Srivastava Shiv 
Published: February 2010

Abstract
Purpose: Prevalent gene fusions in prostate cancer involve androgen-regulated promoters (primarily TMPRSS2) and ETS transcription factors (predominantly ETS-regulated gene (ERG)], which result in tumor selective overexpression of ERG in two thirds of patients. Because diverse genomic fusion events lead to ERG overexpression in prostate cancer, we reasoned that it may be more practical to capture such alterations using an assay targeting ERG sequences retained in such gene fusions. This study evaluates the potential of an assay quantitating ERG mRNA in post–digital rectal exam (DRE) urine for improving prostate cancer detection.
Experimental Design: Patients scheduled to undergo transrectal ultrasound-guided needle biopsy of the prostate were prospectively enrolled. On the day of biopsy, patients provided a urine sample immediately following a DRE. Urine ERG mRNA was measured and normalized to urine prostate-specific antigen (PSA) mRNA using the DTS 400 system. Demographic traits, clinical characteristics and biopsy results were analyzed for association with urine ERG score.
Results: The study was conducted on 237 patients. Prostate cancer was shown on biopsy in 40.9% of study subjects. A higher urine ERG score associated significantly with malignancy on biopsy (P = 0.0145), but not with clinical stage or Gleason score. Urine ERG score performed best in Caucasians and in men with a PSA of ≤4 ng/mL (area under the curve = 0.8).
Conclusions: A higher urine ERG score in post-DRE urine is associated with the diagnosis of prostate cancer on biopsy. Urine ERG score performed particularly well in men with a PSA of ≤4.0 ng/mL, a segment of the screening population in which further diagnostic markers are needed to determine in whom biopsy should be done. Clin Cancer Res; 16(5); 1572–6
Defucosylated Humanized Anti-CCR4 Monoclonal Antibody KW-0761 as a Novel Immunotherapeutic Agent for Adult T-cell Leukemia/Lymphoma
Authors: Ishii Toshihiko , Ishida Takashi , Utsunomiya Atae , Inagaki Atsushi , Yano Hiroki , Komatsu Hirokazu , Iida Shinsuke , Imada Kazunori , Uchiyama Takashi , Akinaga Shiro , Shitara Kenya , Ueda Ryuzo 
Published: February 2010

AbstractPurpose: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti–CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody.Experimental Design: The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods.Results: KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface.Conclusion: KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials. Clin Cancer Res; 16(5); 1520–31
Preclinical Investigation of PEGylated Tumor Necrosis Factor α in Dogs with Spontaneous Tumors: Phase I Evaluation
Authors: Thamm Douglas H. , Kurzman Ilene D. , Clark Mike A. , Ehrhart E.J. , Kraft Susan L. , Gustafson Daniel L. , Vail David M. 
Published: February 2010

AbstractPurpose: Tumor necrosis factor-α (TNF) is a cytokine with potent antitumor activity; however, toxicity and short half-life have limited its utility. Polyethylene glycol (PEG) conjugation of biotherapeutics can decrease immunogenicity while improving bioactivity and half-life. PEGylation of TNF (PEG-TNF) significantly improved half-life and toxicity in mice, resulting in enhanced antitumor activity. This study characterized toxicity, biological effect, and antitumor activity of PEG-TNF in pet dogs with spontaneous cancer.Experimental Design: A phase I clinical trial enrolled dogs with measurable tumors in which standard therapy had failed or been declined. Physiologic, hematologic, and biochemical parameters were evaluated and tumor biopsies obtained serially. A subset of patients underwent serial dynamic contrast-enhanced magnetic resonance imaging.Results: Fifteen dogs were enrolled at doses from 20.0 to 30.0 μg/kg. Dose-limiting toxicity at 30.0 μg/kg consisted of vascular leak in one and hypotension/coagulopathy in one, establishing 26.7 μg/kg as the maximum tolerated dose. Mean elimination half-life was 15.3 ± 4.9 hours. Biological activity (transient fever and leukopenia, increased tumor inflammation, and necrosis) was observed at all dosages. A significant increase in tumor blood flow was observed with dynamic contrast-enhanced magnetic resonance imaging. Minor/transient antitumor responses were observed in dogs with melanoma, squamous cell carcinoma, and mammary carcinoma, and a partial response was observed in a dog with angiosarcoma.Conclusions: Using a clinically relevant, spontaneous large animal model of neoplasia, we have shown that biologically effective doses of PEG-TNF can be administered safely, and that PEG-TNF administration is associated with encouraging biological activity. These results justify the clinical evaluation of PEG-TNF in human cancer. Clin Cancer Res; 16(5); 1498–508
IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group
Authors: van den Bent Martin J. , Dubbink Hendrikus J. , Marie Yannick , Brandes Alba A. , Taphoorn Martin J.B. , Wesseling Pieter , Frenay Marc , Tijssen Cees C. , Lacombe Denis , Idbaih Ahmed , van Marion Ronald , Kros Johan M. , Dinjens Winand N.M. , Gorlia Thierry , Sanson Marc 
Published: February 2010

Abstract
Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma.
Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation–dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization.
Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors.
Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/19q codeletion and MGMT promoter methylation. Clin Cancer Res; 16(5); 1597–604
Validation of Point Spread Functions of CERES Radiometers by the Use of Lunar Observations
Authors: Priestley Kory J. , Thomas Susan , Smith G. Louis 
Published: February 2010

Abstract
The Clouds and the Earth’s Radiant Energy System (CERES) scanning radiometers have been operating to make raster scans of the moon on a quarterly basis to validate the point response function for the three channels of flight models 1–4 aboard the Terra and Aqua spacecraft. Instrument pointing accuracy was verified by this method to 0.2° for the total channel of FM-3. The point response functions were computed from the lunar observations and were found to be nominal with the exception of the FM-2 window channel, which was found to have a region of high sensitivity. This anomaly is attributed to a delamination of the detector flake from the heat sink in that region. The influence of this anomaly is accounted for by the in-flight calibration and has no adverse effect on the application of the data.
Atmospheric Sensitivity to SST near the Kuroshio Extension during the Extratropical Transition of Typhoon Tokage*
Authors: Bond Nicholas A. , Cronin Meghan F. , Garvert Matthew 
Published: February 2010

Abstract
It is hypothesized that the tropical-to-extratropical transition of a cyclone in the western North Pacific can be sensitive to the underlying sea surface temperature (SST) distribution. This hypothesis was tested through a case study of Typhoon Tokage using a series of high-resolution simulations by the Weather Research Forecast (WRF) numerical weather prediction model. Simulations were carried out for a control SST distribution and for SST distributions with imposed warm and cold perturbations of 1.5°C maximum amplitude in the vicinity of the Kuroshio Extension. The simulations with the warm SST perturbation yielded a cyclone slightly weaker than in the control SST case about 2 days after transition. In contrast, the cold SST perturbation case yielded a cyclone with a central pressure 10 hPa lower than in the control case at the same point in the storm’s life cycle, apparently due to its more northward track and hence closer proximity to an approaching upper-level trough and perhaps in association with a stronger warm front. The effects of the regional SST on the simulated storms are manifested not just locally, but also cause substantial impacts on 500-hPa geopotential heights over much of the North Pacific basin. Retrospective analysis of meridional heat fluxes associated with these events using the NCEP–NCAR reanalysis was carried out for early fall (September–November) seasons with relatively warm and cool SST in the region of the imposed SST perturbations. Differences in the patterns of these fluxes between the warm and cool years are broadly consistent with the results from the warm versus cool SST simulations for Typhoon Tokage.
Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells
Authors: Will Britta , Siddiqi Tanya , Jordà Meritxell Alberich , Shimamura Takeshi , Luptakova Katarina , Staber Philipp B. , Costa Daniel B. , Steidl Ulrich , Tenen Daniel G. , Kobayashi Susumu 
Published: February 2010

AbstractThe activating mutation JAK2 V617F plays a central role in the pathogenesis of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Inhibition of JAK2 activity leads to growth inhibition and apoptosis in cells with mutated JAK2. However, the proapoptotic proteins involved in JAK2 inhibition-induced apoptosis remain unclear. In this study, we show that JAK2 inhibition-induced apoptosis correlated with up-regulation of the nonphosphorylated form of the BH3-only protein Bim in hematopoietic cell lines bearing JAK2 mutations. Knockdown of Bim dramatically inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic agent ABT-737. In addition, ABT-737 enhanced the apoptosis induced by JAK2 inhibition in JAK2 V617F+ HEL and SET-2 cells. The combination of JAK inhibitor I and ABT-737 reduced the number of erythroid colonies derived from CD34+ cells isolated from JAK2 V617F+ polycythemia vera patients more efficiently than either drug alone. These data suggest that Bim is a key effector molecule in JAK2 inhibition-induced apoptosis and that targeting this apoptotic pathway could be a novel therapeutic strategy for patients with activating JAK2 mutations.
Allo-HLA reactivity of virus-specific memory T cells is common
Authors: Amir Avital L. , D'Orsogna Lloyd J. A. , Roelen Dave L. , van Loenen Marleen M. , Hagedoorn Renate S. , de Boer Renate , van der Hoorn Menno A. W. G. , Kester Michel G. D. , Doxiadis Ilias I. N. , Falkenburg J. H. Frederik , Claas Frans H. J. , Heemskerk Mirjam H. M. 
Published: February 2010

AbstractGraft-versus-host disease and graft rejection are major complications of allogeneic HLA-mismatched stem cell transplantation or organ transplantation that are caused by alloreactive T cells. Because a range of acute viral infections have been linked to initiating these complications, we hypothesized that the cross-reactive potential of virus-specific memory T cells to allogeneic (allo) HLA molecules may be able to mediate these complications. To analyze the allo-HLA reactivity, T cells specific for Epstein-Barr virus, cytomegalovirus, varicella zoster virus, and influenza virus were tested against a panel of HLA-typed target cells, and target cells transduced with single HLA molecules. Eighty percent of T-cell lines and 45% of virus-specific T-cell clones were shown to cross-react against allo-HLA molecules. The cross-reactivity of the CD8 and CD4 T-cell clones was directed primarily against HLA class I and II, respectively. However, a restricted number of CD8 T cells exhibited cross-reactivity to HLA class II. T-cell receptor (TCR) gene transfer confirmed that allo-HLA reactivity and virus specificity were mediated via the same TCR. These results demonstrate that a substantial proportion of virus-specific T cells exert allo-HLA reactivity, which may have important clinical implications in transplantation settings as well as adoptive transfer of third-party virus-specific T cells.