bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Suppression of Angiogenesis following Radiation Exposure Is Independent of Hematopoietic Reconstitution
Authors: Udagawa Taturo , Birsner Amy E. , Wood Mark , D'Amato Robert J. 
Published: March 2007

Abstract
Radiation can potentially suppress neovascularization by inhibiting the incorporation of hematopoietic precursors as well as damaging mature endothelial cells. The purpose of these studies was to quantify the effect of radiation on angiogenesis and to examine the relationship between bone marrow reconstitution and neovascularization. Immune competent, severe combined immunodeficient, RAG1-deficient, and green fluorescence protein transgenic mice in the C57 genetic background, as well as the highly angiogenic 129S1/SvlmJ strain of mice, underwent whole-body or localized exposure to radiation. The hematopoietic systems in the irradiated recipients were restored by bone marrow transfer. Hematopoietic reconstitution was assessed by doing complete blood counts. Angiogenesis was induced in the mouse cornea using 80 ng of purified basic fibroblast growth factor, and the neovascular response was quantified using a slit lamp biomicroscope. Following whole-body exposure and bone marrow transplantation, the hematopoietic system was successfully reconstituted over time, but the corneal angiogenic response was permanently and significantly blunted up to 66%. Localized exposure of the eyes to radiation suppressed corneal angiogenesis comparably to whole-body exposure. Whole-body irradiation with ocular shielding induced bone marrow suppression but did not inhibit corneal neovascularization. In mice exposed to radiation before tumor implantation, the reduced local angiogenic response correlated with significantly reduced growth of tumor cells in vivo. These results indicate that bone marrow suppression does not suppress neovascularization in the mouse cornea and that although hematopoietic stem cells can readily reconstitute peripheral blood, they do not restore a local radiation-induced deficit in neovascular response. [Cancer Res 2007;67(5):2040–5]
Serine-Arginine Protein Kinase 1 Overexpression Is Associated with Tumorigenic Imbalance in Mitogen-Activated Protein Kinase Pathways in Breast, Colonic, and Pancreatic Carcinomas
Authors: Hayes Gregory M. , Carrigan Patricia E. , Miller Laurence J. 
Published: March 2007

Abstract
Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serine-arginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. [Cancer Res 2007;67(5):2072–80]
Vincristine Induces Dramatic Lysosomal Changes and Sensitizes Cancer Cells to Lysosome-Destabilizing Siramesine
Authors: Groth-Pedersen Line , Ostenfeld Marie Stampe , Høyer-Hansen Maria , Nylandsted Jesper , Jäättelä Marja 
Published: March 2007

Abstract
Vincristine is a microtubule-destabilizing antimitotic drug that has been used in cancer therapy for over 40 years. However, the knowledge on vincristine-induced cell death pathways is still sparse. Here, we show that vincristine induces dramatic changes in the lysosomal compartment and sensitizes cells to lysosomal membrane permeabilization. In HeLa cervix carcinoma cells, vincristine induced mitotic arrest and massive cell death associated with an early increase in the lysosomal volume and lysosomal leakage followed by the activation of the intrinsic apoptosis program. In contrast, the majority of vincristine-treated MCF-7 breast carcinoma cells resisted apoptosis. Instead, they adapted to the spindle assembly checkpoint and escaped the mitotic arrest as micronucleated and senescent cells with an increase in the volume and the activity of their lysosomal compartment. Consistent with its substantial effects on the lysosomes, vincristine greatly sensitized cultured cancer cells as well as orthotopic breast cancer xenografts in mice to the cytotoxicity induced by siramesine, a sigma-2 receptor ligand that kills cancer cells by destabilizing their lysosomes. Importantly, the combination of nontoxic concentrations of vincristine and siramesine resulted in massive cell death even in MCF-7 cells that were capable of escaping vincristine-induced spindle assembly checkpoint and cell death. Similar synergism was observed when siramesine was combined with a semisynthetic vincristine analogue, vinorelbine, or with microtubule-stabilizing paclitaxel. These data strongly suggest that combination therapies consisting of microtubule-disturbing and lysosome-destabilizing drugs may prove useful in the treatment of otherwise therapy-resistant human cancers. [Cancer Res 2007;67(5):2217–25]
Overexpression of Dicer in Precursor Lesions of Lung Adenocarcinoma
Authors: Chiosea Simion , Jelezcova Elena , Chandran Uma , Luo Jianhua , Mantha Geeta , Sobol Robert W. , Dacic Sanja 
Published: March 2007

Abstract
Differential microRNA (miR) expression is described in non–small cell lung carcinoma. miR biogenesis requires a set of proteins collectively referred to as the miR machinery. In the proposed multistep carcinogenesis model, peripheral adenocarcinoma of the lung develops from noninvasive precursor lesions known as atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC). The gene array analysis of BAC and adenocarcinoma showed a transient up-regulation of Dicer (a key effector protein for small interfering RNA and miR function) and PACT along with down-regulation of most genes encoding miR machinery proteins. Immunohistochemically, Dicer was up-regulated in AAH and BAC and down-regulated in areas of invasion and in advanced adenocarcinoma. A fraction of adenocarcinomas lose Dicer as a result of deletions at the Dicer locus. Expanded immunohistochemical and Western blot analysis showed higher Dicer level in squamous cell carcinoma (SCC) of the lung when compared with adenocarcinoma. Other proteins of the RNA-induced silencing complex (RISC; SND1, PACT, and FXR1) were also present at higher levels in a SCC cell line when compared with an adenocarcinoma cell line. In conclusion, the stoichiometry of miR machinery and RISC depends on histologic subtype of lung carcinoma, varies along the AAH-BAC-adenocarcinoma sequence, and might explain the observed abnormal miR profile in lung cancer. The status of the endogenous miR machinery in various histologic subtypes and stages of lung cancer may help to predict the toxicity of and susceptibility to future RNA interference–based therapy. [Cancer Res 2007;67(5):2345–50]
Breaking Chemoresistance and Radioresistance with [213Bi]anti-CD45 Antibodies in Leukemia Cells
Authors: Friesen Claudia , Glatting Gerhard , Koop Bernd , Schwarz Klaus , Morgenstern Alfred , Apostolidis Christos , Debatin Klaus-Michael , Reske Sven N. 
Published: March 2007

AbstractChemoresistance and radioresistance are considered one of the primary reasons for therapeutic failure in leukemias and solid tumors. Targeted radiotherapy using monoclonal antibodies radiolabeled with α-particles is a promising treatment approach for high-risk leukemia. We found that targeted radiotherapy using monoclonal CD45 antibodies radiolabeled with the α-emitter 213Bi ([213Bi]anti-CD45) induces apoptosis, activates apoptosis pathways, and breaks β-irradiation–, γ-irradiation–, doxorubicin-, and apoptosis-resistance in leukemia cells. In contrast to β-irradiation–, γ-irradiation–, and doxorubicin-mediated apoptosis and DNA damage, [213Bi]anti-CD45–induced DNA damage was not repaired, and apoptosis was not inhibited by the nonhomologous end-joining DNA repair mechanism. Depending on the activation of caspase-3, caspase-8, and caspase-9, [213Bi]anti-CD45 activated apoptosis pathways in leukemia cells through the mitochondrial pathway but independent of CD95 receptor/CD95 ligand interaction. Furthermore, [213Bi]anti-CD45 reversed deficient activation of caspase-3, caspase-8, and caspase-9, deficient cleavage of poly(ADP-ribose) polymerase, and deficient activation of mitochondria in chemoresistant and in radioresistant and apoptosis-resistant leukemia cells. These findings show that [213Bi]anti-CD45 is a promising therapeutic agent to break chemoresistance and radioresistance by overcoming DNA repair mechanisms in leukemia cells and provide the foundation for discovery of novel anticancer compounds. [Cancer Res 2007;67(5):1950–8]
Combined Treatment with Temozolomide and Methoxyamine: Blocking Apurininc/Pyrimidinic Site Repair Coupled with Targeting Topoisomerase IIα
Authors: Yan Ling , Bulgar Alina , Miao Yanling , Mahajan Varun , Donze Jon R. , Gerson Stanton L. , Liu Lili 
Published: March 2007

Abstract
Purpose: Methoxyamine has been shown to potentiate the cytotoxic effect of temozolomide both in vitro and in human tumor xenograft models. We postulate that the enhanced cytotoxicity is mediated by methoxyamine-bound apurininc/pyrimidinic (MX-AP) site, a key lesion formed by the combination of temozolomide and methoxyamine. When located within topoisomerase IIα (topo II) cleavage sites in DNA, MX-AP sites act as dual lethal targets, not only functionally disrupting the base excision repair (BER) pathway but also potentially poisoning topo II.
Experimental Design: Using oligonucleotide substrates, in which a position-specific MX-AP site is located within topo II cleavage sites, we examined the effect of MX-AP site on both AP endonuclease– and topo II–mediated DNA cleavage in vitro.
Results: MX-AP sites were refractory to the catalytic activity of AP endonuclease, indicating their ability to block BER. However, they were cleaved by either purified topo II or nuclear extracts from tumor cells expressing high levels of topo II, suggesting that MX-AP sites stimulate topo II–mediated DNA cleavages. In cells, treatment with temozolomide and methoxyamine increased the expression of topo II and enriched the formation of γH2AX foci, which were colocalized with up-regulated topo II, confirming that DNA double-strand breaks marked by γH2AX foci are associated with topo II in cells.
Conclusions: Our findings identify a molecular mechanism of cell death whereby MX-AP sites that cumulated in cells due to resistance to BER potentially convert topo II into biotoxins, resulting in enzyme-mediated DNA scission and cell death.
Tubedown Expression Correlates with the Differentiation Status and Aggressiveness of Neuroblastic Tumors
Authors: Martin Darryl T. , Gendron Robert L. , Jarzembowski Jason A. , Perry Arie , Collins Margaret H. , Pushpanathan Chitra , Miskiewicz Ewa , Castle Valerie P. , Paradis Hélène 
Published: March 2007

AbstractPurpose: The discovery and validation of new prognostic factors and further refinement of risk group stratification are needed to improve clinical interpretation of neuroblastoma. Our laboratory isolated and characterized a developmentally regulated gene named TUBEDOWN against which we have raised a monoclonal antibody (OE5). Tubedown becomes down-regulated postnatally yet remains strongly expressed in some neuroblastomas. The purpose of this study is to define the utility of Tubedown expression as a new measure of the differentiation status and aggressiveness of neuroblastic tumors.Experimental Design: Tubedown protein expression was quantitatively assessed in neuroblastic tumors (neuroblastomas, ganglioneuroblastomas, and ganglioneuromas) and normal adrenal tissues using Western blot and OE5 immunohistochemistry. Regulation of Tubedown expression during retinoic acid–induced neuronal differentiation in neuroblastoma cell lines was assessed by Western blotting.Results: High levels of Tubedown expression are observed in tumors with significant neuroblastic component, unfavorable histopathology, advanced stage, high-risk group, and poor outcome. In contrast, more differentiated subsets of neuroblastic tumors, ganglioneuroblastomas with favorable histopathology and ganglioneuromas, express low levels of Tubedown. In vitro, marked retinoic acid–induced neuronal differentiation responses of neuroblastoma cells are associated with a significant decrease in Tubedown expression, whereas limited neuronal differentiation responses to retinoic acid were associated with little or no decrease in Tubedown expression.Conclusions: Our results indicate that the levels of Tubedown expression are linked to the differentiation status and aggressiveness of neuroblastic tumors and represent an independent prognostic factor for neuroblastoma. Tubedown expression may be useful to more accurately define different neuroblastic tumor subsets and ultimately provide more adequate assessment and treatment for neuroblastoma patients.
Amplified in Breast Cancer 1 in Human Epidermal Growth Factor Receptor–Positive Tumors of Tamoxifen-Treated Breast Cancer Patients
Authors: Kirkegaard Tove , McGlynn Liane M. , Campbell Fiona M. , Müller Sven , Tovey Sian M. , Dunne Barbara , Nielsen Kirsten V. , Cooke Timothy G. , Bartlett John M.S. 
Published: March 2007

Abstract
Purpose: Amplified in breast cancer 1 (AIB1) is a member of the p160/steroid receptor coactivators family and is involved in estrogen-dependent gene transcription by reducing the antagonistic activity of tamoxifen-bound estrogen receptor-α (ER-α). The present study was carried out to test the hypothesis that AIB1 protein expression and/or gene amplification mediates tamoxifen resistance in breast cancer.
Experimental Design: Immunohistochemistry using AIB1 antibody and fluorescence in situ hybridization using probes specific for AIB1 and chromosome 20 was done on 402 ER-α–positive tamoxifen-treated breast cancers.
Results: AIB1 overexpression was not associated with relapse during treatment with tamoxifen. In contrast, high AIB1 expression in patients with human epidermal growth factor receptor (HER) 2– and HER3-overexpressing tumors or tumors expressing one or more of HER1, HER2, or HER3 (HER1-3 positive) was associated with an increased risk of relapse on tamoxifen [hazard ratio, 2.20; 95% confidence interval, 1.07-3.52 (P = 0.0416); hazard ratio, 2.42; 95% confidence interval, 1.32-4.43 (P = 0.0030), respectively]. AIB1 gene amplification was observed in 18 of 362 (5%) patients. High AIB1 gene copy number had no effect on overall or disease-free survival.
Conclusions: Data presented here support a role for AIB1 expression on relapse during tamoxifen treatment in hormone-responsive HER-expressing clinical breast cancers and support clinical evidence, suggesting a cross-talk between ER-α and growth factor receptor pathways through changes in expression of specific coactivator proteins, such as AIB1. This study highlights the potential that tumor profiling, using multiple markers of treatment response, may improve patient selection for endocrine treatment, such as tamoxifen or aromatase inhibitors.
Mesothelin Expression in Human Lung Cancer
Authors: Ho Mitchell , Bera Tapan K. , Willingham Mark C. , Onda Masanori , Hassan Raffit , FitzGerald David , Pastan Ira 
Published: March 2007

AbstractPurpose: To investigate mesothelin as a new target for immunotherapy in lung cancer.Experimental Design: Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific for mesothelin was assessed for its cytotoxic activity against lung cancer cells.Results: We found that mesothelin mRNA was expressed in 83% of lung adenocarcinomas (10 of 12 patients). The mesothelin precursor protein was detected in 82% of lung adenocarcinoma (9 of 11 patients), and its mature form was detected in 55% (6 of 11 patients). Immunohistochemistry showed strong and diffuse mesothelin staining in human lung adenocarcinomas and weak or modest staining in squamous cell carcinomas. We detected mesothelin mRNA in 78% of lung cancer cell lines (7 of 9) of the NCI-60 cell line panel. Mesothelin mRNA and proteins were expressed at a high level in non–small cell lung cancer lines EKVX, NCI-H460, NCI-H322M, and NCI-H522. Flow cytometric analysis showed high surface expression of mesothelin in NCI-H322M and EKVX cell lines. Immunotoxin SS1P showed high cytotoxic activity on NCI-H322M and EKVX cells with IC50 values ranging from 2 to 5 ng/mL.Conclusions: Mesothelin is expressed on the surface of most lung adenocarcinoma cells. Immunotoxin SS1P is cytotoxic against mesothelin-expressing lung cancer cell lines and merits evaluation as a new therapeutic agent in treating non–small cell lung cancer.
Absence of the Chemokine Receptor CCR2 Protects Against Cerebral Ischemia/Reperfusion Injury in Mice
Authors: Dimitrijevic Oliver B. , Stamatovic Svetlana M. , Keep Richard F. , Andjelkovic Anuska V. 
Published: March 2007

Background and Purpose—The chemokine, monocyte chemoattractant protein-1 (CCL2), is a major factor driving leukocyte infiltration into the brain parenchyma in a variety of neuropathologic conditions associated with inflammation, including stroke. In addition, recent studies indicate that CCL2 and its receptor (CCR2) could have an important role in regulating blood-brain barrier (BBB) permeability. This study evaluated the role of the CCL2/CCR2 axis in regulating postischemic inflammation, BBB breakdown, and vasogenic edema formation.Methods—CCR2−/−and CCR2+/+mice were subjected to focal transient cerebral ischemia. BBB permeability and brain edema formation were observed at days 1 and 5 of reperfusion by evaluating the product surface area for fluorescein isothiocyanate–albumin and measuring water and electrolyte contents. Immunohistochemistry was used to assess leukocyte infiltration. cDNA gene and protein arrays for inflammatory cytokines were used to assess inflammatory profiles in CCR2+/+and CCR2−/−mice.Results—CCR2−/−mice had reduced infarct sizes and significantly reduced BBB permeability and brain edema formation in the affected ischemic hemisphere compared with CCR2+/+mice. This reduction in injury was closely associated with reduced infiltration of not only monocytes but also neutrophils (7- and 4-fold decreases, respectively). In addition, CCR2−/−mice had reduced expression/production of inflammatory cytokines during reperfusion.Conclusions—These data suggest that inhibiting the CCL2/CCR2 axis affects brain reperfusion outcome by reducing brain edema, leukocyte infiltration, and inflammatory mediator expression.
Local Field Potentials and Spikes in the Human Medial Temporal Lobe are Selective to Image Category
Authors: Kraskov Alexander , Quiroga Rodrigo Quian , Reddy Leila , Fried Itzhak , Koch Christof 
Published: March 2007

Abstract
Local field potentials (LFPs) reflect the averaged dendrosomatic activity of synaptic signals of large neuronal populations. In this study, we investigate the selectivity of LFPs and single neuron activity to semantic categories of visual stimuli in the medial temporal lobe of nine neurosurgical patients implanted with intracranial depth electrodes for clinical reasons. Strong selectivity to the category of presented images was found for the amplitude of LFPs in 8% of implanted microelectrodes and for the firing rates of single and multiunits in 14% of microelectrodes. There was little overlap between the LFP- and spike-selective microelectrodes. Separate analysis of the power and phase of LFPs revealed that the mean phase was category-selective around the θ frequency range and that the power of the LFPs was category-selective for high frequencies around the γ rhythm. Of the 36 microelectrodes with amplitude-selective LFPs, 30 were found in the hippocampus. Finally, it was possible to readout information about the category of stimuli presented to the patients with both spikes and LFPs. Combining spiking and LFP activity enhanced the decoding accuracy in comparison with the accuracy obtained with each signal alone, especially for short time intervals.
Human-Nonhuman Animal Relationships in Australia: An Overview of Results from the First National Survey and Follow-up Case Studies 2000-2004
Authors: Franklin Adrian 
Published: March 2007

AbstractThis paper provides an overview of results from an Australian Research Council-funded project "Sentiments and Risks: The Changing Nature of Human-Animal Relations in Australia." The data discussed come from a survey of 2000 representative Australians at the capital city, state, and rural regional level. It provides both a snapshot of the state of involvement of Australians with nonhuman animals and their views on critical issues: ethics, rights, animals as food, risk from animals, native versus introduced animals, hunting, fishing, and companionate relations with animals. Its data point to key trends and change. The changing position of animals in Australian society is critical to understand, given its historic export markets in meat and livestock, emerging tourism industry with its strong wildlife focus, native animals' place in discourses of nation, and the centrality of animal foods in the national diet. New anxieties about risk from animal-sourced foods and the endangerment of native animals from development and introduced species, together with tensions between animals' rights and the privileging of native species, contribute to the growth of a strongly contested animal politics in Australia.
More Than a Furry Companion: The Ripple Effect of Companion Animals on Neighborhood Interactions and Sense of Community
Authors: Bulsara Max , Wood Lisa , Giles-Corti Billie , Bosch Darcy 
Published: March 2007

AbstractCompanion animals (pets) exemplify the affinities possible between humans and nonhuman animals. Evidence documenting a diversity of emotional, physical, and therapeutic benefits of pet guardianship (ownership) substantiates sentimental anecdotes from pet owners. Although the literature focuses primarily on the "one to one" benefits accruing from interactions with pets, this paper explores the potential role of pets as facilitators of social interactions and sense of community. The paper uses triangulation to synthesize findings from qualitative and quantitative research undertaken in three Western Australian suburbs. The qualitative data derive from 12 focus groups and quantitative data, from a survey of 339 residents. In both qualitative and quantitative research, pet ownership positively associated with social interactions, favor exchanges, civic engagement, perceptions of neighborhood friendliness, and sense of community. Pets appeared to ameliorate some determinants of mental health such as loneliness. Findings suggest pets have a ripple effect extending beyond their guardians (owners) to non-pet owners and the broader community. Given the high rates of pet residency in neighborhoods, there is merit in further considering the nexus between pets and community health and well being.