bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric oxide and reactive oxygen species in the nucleus revisitedThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.
Authors: Provost Chantale , Choufani Faten , Avedanian Levon , Bkaily Ghassan , Gobeil Fernand , Jacques Danielle 
Published: April 2010

Recent work from our group showed that the nuclear envelope membranes contain several G protein-coupled receptors, including prostaglandin E2 (EP3R) and endothelin-1 (ET-1) receptors. Activation of EP3R increased endothelial nitric oxide synthase (eNOS) RNA expression in nuclei. eNOS and inducible NOS (iNOS) are reported to also be present at the nuclear level. Furthermore, reactive oxygen species (ROS) were also localized at the nuclear level. In this review, we show that stimulation with NO donor sodium nitroprusside results in an increase of intranuclear calcium that was dependent on guanylate cyclase activation, but independent of MAPK. This increase in nuclear calcium correlated with an increase in nuclear transcription of iNOS. H2O2 and ET-1 increase both cytosolic and nuclear ROS in human endocardial endothelial cells and in human aortic vascular smooth muscle cells. This increase in ROS levels by H2O2 and ET-1 was reversed by the antioxidant glutathione. In addition, our results strongly suggest that cytosolic signalization is not only transmitted to the nucleus but is also generated by the nucleus. Furthermore, we demonstrate that oxidative stress can be sensed by the nucleus. These results highly suggest that ROS formation is also generated directly by the nucleus and that free radicals may contribute to ET-1 regulation of nuclear Ca2+ homeostasis.
Ischemia–reperfusion-induced changes in sarcolemmal Na+/K+-ATPase are due to the activation of calpain in the heartThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.
Authors: Singh Raja B. , Dhalla Naranjan S. 
Published: April 2010

Depression in cardiac performance due to ischemia–reperfusion (I/R) injury is associated with the development of oxidative stress and decreased sarcolemmal (SL) Na+/K+-ATPase activity. Since both I/R and oxidative stress have been reported to promote the occurrence of intracellular Ca2+ overload and activate proteases such as calpain, this study was undertaken to investigate whether the activation of calpain in I/R hearts is associated with alterations in the SL Na+/K+-ATPase activity and its isoform content. For this purpose, isolated rat hearts treated with and without 2 different calpain inhibitors (leupeptin and MDL28170) were subjected to 30 min ischemia followed by 60 min of reperfusion, and the cardiac function, SL Na+/K+-ATPase activity, Na+/K+-ATPase isoform protein content, and calpain activity were measured. The I/R-induced depressions in cardiac function, Na+/K+-ATPase activity, and protein content of Na+/K+-ATPase isoforms were associated with an increase in calpain activity , but were prevented by treatment of hearts with leupeptin. Incubation of SL membranes with calpain decreased the Na+/K+-ATPase activity and protein content of its isoforms; these changes were also attenuated by leupeptin. The I/R-induced alterations in cardiac function and the activity of SL Na+/K+-ATPase and calpain were Ca2+-dependent and were prevented by MDL28170, a specific inhibitor of calpain. The I/R-induced translocation of calpain isoforms (I and II) from the cytosol to SL and the changes in distribution of calpastatin were also attenuated by treatment with calpain inhibitors. These results suggest that the depression in cardiac function and SL Na+/K+-ATPase activity in I/R hearts may be due to changes in the activity and translocation of calpain.
Adventitial fibroblasts in vascular structure and function: the role of oxidative stress and beyondThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.
Authors: Wang Hui Di , Rätsep Matthew T. , Chapman Alexander , Boyd Ryan 
Published: April 2010

The vascular adventitia, defined as the area between the external elastic lamina and the outermost edge of the blood vessel, is composed primarily of fibroblasts and for years was thought to be merely a passive structural support for the blood vessel. Consequently, studies pertaining to the role of the adventitia in regulating vascular function have been far outnumbered by those regarding the vascular endothelium. However, recent work has begun to reveal the dynamic properties of the adventitia. It was therefore the aim of this review to provide an overview of the existing knowledge demonstrating the role of the adventitia in regulating vessel structure and function. The main topics covered in this review include the cellular composition of the adventitia and the role of the adventitia in vascular oxidative stress, vasomotor responses, extracellular matrix protein expression, growth factor expression, and endothelin-1 (ET-1) expression. Recent evidence suggests that the adventitia is a major producer of vascular reactive oxygen species. It displays a distinct response to injury, hypoxia, and pulmonary hypertension, mediating vascular remodelling, repair, and extracellular matrix deposition. It may also play a role in regulating vascular tone. More recently, it has been reported that adventitial fibroblasts can produce ET-1 after Ang II treatment. Additionally, emerging evidence suggests that the adventitia may be a potent source of vasoactive hormones such as growth factors and ET-1, which may regulate vascular structure and function via autocrine or paracrine signalling mechanisms. Despite these findings, many important questions regarding the role of the vascular adventitia remain unanswered, suggesting the need for further research to determine its exact function in health and disease.
Phospholipase C as a potential target for cardioprotection during oxidative stressThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.
Authors: Tappia Paramjit S. , Asemu Girma , Rodriguez-Leyva Delfin 
Published: April 2010

Cardiac dysfunction due to ischemia–reperfusion (I/R) is associated with marked changes in membrane function and subsequent Ca2+-handling abnormalities in cardiomyocytes. The membrane abnormalities in hearts subjected to I/R arise primarily from oxidative stress as a consequence of increased formation of reactive oxygen species and other oxidants, as well as reduced antioxidant defenses. Little is known, however, about the nature and mechanisms of the sarcolemmal membrane changes with respect to phospholipase C (PLC)-related signaling events. In addition, the mechanisms involved in protection of the postischemic myocardium and in ischemic preconditioning with respect to PLC function need to be established. Accordingly, this article reviews the historical and current information on PLC-mediated signal transduction mechanisms in I/R, as well as outlining future directions that should be addressed. Such information will extend our knowledge of ischemic heart disease and help improve its therapy.
Common Fixed Point Theorem for Non-Self Mappings Satisfying Generalized Ćirić Type Contraction Condition in Cone Metric Space
Authors: Sumitra R , Rhymend Uthariaraj V , Hemavathy R , Vijayaraju P 
Published: April 2010

AbstractWe prove common fixed point theorem for coincidentally commuting nonself mappings satisfying generalized contraction condition of Ćirić type in cone metric space. Our results generalize and extend all the recent results related to non-self mappings in the setting of cone metric space.
5-Fluorouracil Selectively Kills Tumor-Associated Myeloid-Derived Suppressor Cells Resulting in Enhanced T Cell–Dependent Antitumor Immunity
Authors: Vincent Julie , Mignot Grégoire , Chalmin Fanny , Ladoire Sylvain , Bruchard Mélanie , Chevriaux Angélique , Martin François , Apetoh Lionel , Rébé Cédric , Ghiringhelli François 
Published: April 2010

AbstractMyeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumor bed during tumor growth. They contribute to the immune tolerance of cancer notably by inhibiting the function of CD8(+) T cells. Thus, their elimination may hamper tumor growth by enhancing antitumor T-cell functions. We have previously reported that some anticancer agents relied on T cell–dependent anticancer responses to achieve maximal efficacy. However, the effect of anticancer agents on MDSC has remained largely unexplored. In this study, we observed that gemcitabine and 5-fluorouracil (5FU) were selectively cytotoxic on MDSC. In vivo, the treatment of tumor-bearing mice with 5FU led to a major decrease in the number of MDSC in the spleens and tumor beds of animals whereas no significant effect on T cells, natural killer cells, dendritic cells, or B cells was noted. Interestingly, 5FU showed a stronger efficacy over gemcitabine to deplete MDSC and selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5FU increased IFN-γ production by tumor-specific CD8(+) T cells infiltrating the tumor and promoted T cell–dependent antitumor responses in vivo. Altogether, these findings suggest that the antitumor effect of 5FU is mediated, at least in part, by its selective cytotoxic action on MDSC. Cancer Res; 70(8); 3052–61. ©2010 AACR.
Integrin α4β1 Signaling Is Required for Lymphangiogenesis and Tumor Metastasis
Authors: Garmy-Susini Barbara , Avraamides Christie J. , Schmid Michael C. , Foubert Philippe , Ellies Lesley G. , Barnes Leo , Feral Chloe , Papayannopoulou Thalia , Lowy Andrew , Blair Sarah L. , Cheresh David , Ginsberg Mark , Varner Judith A. 
Published: April 2010

Abstract
Recent studies have shown that lymphangiogenesis or the growth of lymphatic vessels at the periphery of tumors promotes tumor metastasis to lymph nodes. We show here that the fibronectin-binding integrin α4β1 and its ligand fibronectin are novel functional markers of proliferative lymphatic endothelium. Tumors and lymphangiogenic growth factors, such as vascular endothelial growth factor-C (VEGF-C) and VEGF-A, induce lymphatic vessel expression of integrin α4β1. Integrin α4β1 then promotes growth factor and tumor-induced lymphangiogenesis, as genetic loss of integrin α4β1 expression in Tie2Cre+ α4loxp/loxp mice or genetic loss of α4 signaling in α4Y991A knock-in mice blocks growth factor and tumor-induced lymphangiogenesis, as well as tumor metastasis to lymph nodes. In addition, antagonists of integrin α4β1 suppress lymphangiogenesis and tumor metastasis. Our studies show that integrin α4β1 and the signals it transduces regulate the adhesion, migration, invasion, and survival of proliferating lymphatic endothelial cells. As suppression of α4β1 expression, signal transduction, or function in tumor lymphatic endothelium not only inhibits tumor lymphangiogenesis but also prevents metastatic disease, these results show that integrin α4β1–mediated tumor lymphangiogenesis promotes metastasis and is a useful target for the suppression of metastatic disease. Cancer Res; 70(8); 3042–51. ©2010 AACR.
Astrocyte Elevated Gene-1 Upregulates Matrix Metalloproteinase-9 and Induces Human Glioma Invasion
Authors: Liu Liping , Wu Jueheng , Ying Zhe , Chen Baixue , Han Anjia , Liang Yingjie , Song Libing , Yuan Jie , Li Jun , Li Mengfeng 
Published: April 2010

Abstract
The poor prognosis of malignant gliomas is largely attributed to their highly invasive nature. The molecular mechanism underlying the invasiveness of glioma cells, however, remains to be elucidated. The present study found that astrocyte elevated gene-1 (AEG-1) was upregulated in human glioma cell lines and glioma tissues compared with normal astrocytes and brain tissues. AEG-1 was found to be upregulated in 265 of 296 (89.5%) glioma sections, and the AEG-1 expression level significantly correlated with clinicopathologic stages of gliomas. Ectopic expression or short hairpin RNA silencing of AEG-1 significantly enhanced or inhibited, respectively, the invasive ability of glioma cells. At the molecular level, we showed that upregulated AEG-1 in glioma cells interacted with matrix metalloproteinase-9 (MMP-9) promoter and transactivated MMP-9 expression, whereas knockdown of AEG-1 expression reduced the level of MMP-9. Two regions in MMP-9 promoter were found to be involved in the interaction with AEG-1. Suppression of endogenous MMP-9 abrogated the effects of AEG-1 on invasiveness. Consistent with these observations, immunostaining analysis revealed a significant correlation between the expressions of AEG-1 and MMP-9 in a cohort of clinical glioma samples. Moreover, intracranial xenografts of glioma cells engineered to express AEG-1 were highly invasive compared with the parental cells and expressed high level of MMP-9. Collectively, these findings provide evidence that AEG-1 contributes to glioma progression by enhancing MMP-9 transcription and, hence, tumor cell invasiveness, and underscore the importance of AEG-1 in glioma development and progression. Cancer Res; 70(9); 3750–9. ©2010 AACR.
Pseudopodial Actin Dynamics Control Epithelial-Mesenchymal Transition in Metastatic Cancer Cells
Authors: Shankar Jay , Messenberg Anat , Chan Jackie , Underhill T. Michael , Foster Leonard J. , Nabi Ivan R. 
Published: April 2010

Abstract
A key cellular process associated with the invasive or metastatic program in many cancers is the transformation of epithelial cells toward a mesenchymal state, a process called epithelial to mesenchymal transition or EMT. Actin-dependent protrusion of cell pseudopodia is a critical element of mesenchymal cell migration and therefore of cancer metastasis. However, whether EMT occurs in human cancers and, in particular, whether it is a prerequisite for tumor cell invasion and metastasis, remains a subject of debate. Microarray and proteomic analysis of actin-rich pseudopodia from six metastatic human tumor cell lines identified 384 mRNAs and 64 proteins common to the pseudopodia of six metastatic human tumor cell lines of various cancer origins leading to the characterization of 19 common pseudopod-specific proteins. Four of these (AHNAK, septin-9, eIF4E, and S100A11) are shown to be essential for pseudopod protrusion and tumor cell migration and invasion. Knockdown of each of these proteins in metastatic cells resulted in reduced actin cytoskeleton dynamics and induction of mesenchymal-epithelial transition (MET) that could be prevented by the stabilization of the actin cytoskeleton. Actin-dependent pseudopodial protrusion and tumor cell migration are therefore determinants of EMT. Protein regulators of pseudopodial actin dynamics may represent unique molecular targets to induce MET and thereby inhibit the metastatic potential of tumor cells. Cancer Res; 70(9); 3780–90. ©2010 AACR.
Oncogenic Role of miR-483-3p at the IGF2/483 Locus
Authors: Veronese Angelo , Lupini Laura , Consiglio Jessica , Visone Rosa , Ferracin Manuela , Fornari Francesca , Zanesi Nicola , Alder Hansjuerg , D'Elia Gemma , Gramantieri Laura , Bolondi Luigi , Lanza Giovanni , Querzoli Patrizia , Angioni Adriano , Croce Carlo M. , Negrini Massimo 
Published: April 2010

Abstract
hsa-mir-483 is located within intron 2 of the IGF2 locus. We found that the mature microRNA (miRNA) miR-483-3p is overexpressed in 100% of Wilms' tumors. In addition, colon, breast, and liver cancers exhibit high or even extremely high levels of miR-483-3p in ∼30% of the cases. A coregulation with IGF2 mRNA was detected, although some tumors exhibited high expression of miR-483-3p without a concomitant increase of IGF2. These findings suggested that miR-483-3p could cooperate with IGF2 or act as an autonomous oncogene. Indeed, here we prove that an anti-miRNA oligonucleotide against miR-483-3p could inhibit the miRNAs without affecting IGF2 mRNA and it could suppress tumorigenicity of HepG2 cells, a cell line that overexpresses miR-483-3p and IGF2. Conversely, no antitumor effect was elicited by inhibition of IGF2. The oncogenic mechanism of miR-483-3p was at least partially clarified by the finding that it could modulate the proapoptotic protein BBC3/PUMA and miR-483-3p enforced expression could protect cells from apoptosis. Our results indicate that miR-483-3p could function as an antiapoptotic oncogene in various human cancers and reveal a new, potentially important target for anticancer therapy. Cancer Res; 70(8); 3140–9. ©2010 AACR.
Melanocyte-Stimulating Hormone Directly Enhances UV-Induced DNA Repair in Keratinocytes by a Xeroderma Pigmentosum Group A–Dependent Mechanism
Authors: Dong Liang , Wen Ji , Pier Eric , Zhang Xiao , Zhang Bo , Dong Fangzheng , Ziegler Nick , Mysz Margaret , Armenta Rafael , Cui Rutao 
Published: April 2010

Abstract
Melanocyte-stimulating hormone (MSH) reduces UV-induced DNA damage through the induction of pigmentation. In this study, we provide evidence that MSH also enhances DNA repair in skin keratinocytes by modulating the function of DNA repair molecules. Intracutaneous injection of MSH prevented UV-induced DNA damage in human and mouse skin independent of its effects on melanogenesis. In keratinocytes, MSH bound to the melanocyte melanocortin receptor type 1 and activated adenylate cyclase activity, which in turn activated Xeroderma pigmentosum group A (XPA)–binding protein 1 and induced nuclear translocation of XPA, a critical factor controlling nucleotide excision repair signaling pathways. Together, our findings reveal a novel pigmentation-independent mechanism that underlies MSH–mediated DNA repair following UVB irradiation. Cancer Res; 70(9); 3547–56. ©2010 AACR.
Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer
Authors: Hamstra Daniel A. , Eisbruch Avraham , Naidu Maddireddy U.R. , Ramana Gogula V. , Sunkara Prasad , Campbell Kathleen C.M. , Ross Brian D. , Rehemtulla Alnawaz 
Published: April 2010

Abstract
Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.
Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.
Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.
Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.
EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma
Authors: Lee Jeong-Won , Stone Rebecca L. , Lee Sun Joo , Nam Eun Ji , Roh Ju-Won , Nick Alpa M. , Han Hee-Dong , Shahzad Mian M.K. , Kim Hye-Sun , Mangala Lingegowda S. , Jennings Nicholas B. , Mao Shenlan , Gooya John , Jackson Dowdy , Coleman Robert L. , Sood Anil K. 
Published: April 2010

Abstract
Purpose: EphA2 overexpression is frequently observed in endometrial cancers and is predictive of poor clinical outcome. Here, we use an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor monomethylauristatin F.
Experimental Design: EphA2 expression was examined in endometrial cancer cell lines by Western blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models.
Results: EphA2 was expressed in the Hec-1A and Ishikawa cells but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2-positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays showed that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86% to 88% growth inhibition (P &lt; 0.001) in the orthotopic Hec-1A and Ishikawa models compared with controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The antitumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells.
Conclusions: The preclinical data for endometrial cancer treatment using MEDI-547 show substantial antitumor activity. Clin Cancer Res; 16(9); 2562–70. ©2010 AACR.
Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis
Authors: Wang Yajun , Chan David W. , Liu Vincent W.S. , Chiu PM , Ngan Hextan Y.S. 
Published: April 2010

Abstract
Purpose: Aberrant overexpression of growth factor receptor–bound protein 7 (GRB7) and its variant GRB7v has been found in numerous human cancers. The goal of this study was to characterize the functions of GRB7 and GRB7v in the ovarian carcinogenesis and to investigate the differential roles of GRB7 and GRB7v in the modulation of signaling pathways.
Experimental Design: Quantitative reverse transcription–PCR, Western blot, and immunohistochemical analyses were used to evaluate the levels of GRB7 and GRB7v. The cellular localization, functions, and signaling pathways regulated by GRB7 and GRB7v were investigated by enforced expression of GRB7 and GRB7v.
Results: Quantitative reverse transcription–PCR and Western blot analyses showed that GRB7 and GRB7v were frequently upregulated in ovarian cancer samples. The overexpressed GRB7 (P = 0.009) and GRB7v (P = 0.017) were significantly correlated with high-grade ovarian cancer. Immunohistochemical analysis on ovarian cancer tissue array confirmed that the upregulated GRB7 was significantly correlated with high-grade ovarian cancer (P = 0.001). Confocal microscopy analysis showed that GRB7 and GRB7v predominately localized in cytoplasm of ovarian cancer cells, consistent with their roles as signaling adaptors. Enforced expression of GRB7 promoted cell proliferation, migration, and invasion, whereas GRB7v only increased cell proliferation and anchorage-independent growth ability. With the treatment of specific kinase inhibitors, we showed that both GRB7 and GRB7v promoted cell proliferation through activating extracellular signal-regulated kinase signaling, whereas GRB7 enhanced cell migration/invasion by activating c-Jun NH2 terminal kinase signaling.
Conclusions: Our studies implicate that the overexpressed GRB7 and GRB7v are associated with high-grade tumors and exert distinct tumorigenic functions through regulating different signaling pathways in ovarian cancer cells. Clin Cancer Res; 16(9); 2529–39. ©2010 AACR.