bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclophosphamide Augments Antitumor Immunity: Studies in an Autochthonous Prostate Cancer Model
Authors: Wada Satoshi , Yoshimura Kiyoshi , Hipkiss Edward L. , Harris Tim J. , Yen Hung-Rong , Goldberg Monica V. , Grosso Joseph F. , Getnet Derese , Demarzo Angelo M. , Netto George J. , Anders Robert , Pardoll Drew M. , Drake Charles G. 
Published: May 2009

AbstractTo study the immune response to prostate cancer, we developed an autochthonous animal model based on the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse in which spontaneously developing tumors express influenza hemagglutinin as a unique, tumor-associated antigen. Our prior studies in these animals showed immunologic tolerance to hemagglutinin, mirroring the clinical situation in patients with cancer who are generally nonresponsive to their disease. We used this physiologically relevant animal model to assess the immunomodulatory effects of cyclophosphamide when administered in combination with an allogeneic, cell-based granulocyte-macrophage colony-stimulating factor–secreting cancer immunotherapy. Through adoptive transfer of prostate/prostate cancer–specific CD8 T cells as well as through studies of the endogenous T-cell repertoire, we found that cyclophosphamide induced a marked augmentation of the antitumor immune response. This effect was strongly dependent on both the dose and the timing of cyclophosphamide administration. Mechanistic studies showed that immune augmentation by cyclophosphamide was associated with a transient depletion of regulatory T cells in the tumor draining lymph nodes but not in the peripheral circulation. Interestingly, we also noted effects on dendritic cell phenotype; low-dose cyclophosphamide was associated with increased expression of dendritic cell maturation markers. Taken together, these data clarify the dose, timing, and mechanism of action by which immunomodulatory cyclophosphamide can be translated to a clinical setting in a combinatorial cancer treatment strategy. [Cancer Res 2009;69(10):4309–18]
KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model
Authors: DiFeo Analisa , Huang Fei , Sangodkar Jaya , Terzo Esteban A. , Leake Devin , Narla Goutham , Martignetti John A. 
Published: May 2009

Abstract
Defects in apoptosis are not only a hallmark of cancer initiation and progression but can also underlie the development of chemoresistance. How the tightly regulated cascade of protein-protein interactions between members of three competing protein families regulating the apoptotic cascade is subverted in tumor cells is incompletely understood. Here, we show that KLF6-SV1, whose overexpression is associated with poor survival in several different cancers and is an alternatively spliced isoform of the Krüppel-like tumor suppressor KLF6, is a critical prosurvival/antiapoptotic protein. KLF6-SV1 binds the proapoptotic BH3-only protein NOXA, which results in their mutual HDM2-dependent degradation. In turn, this increases the intracellular concentration of the prosurvival binding partner of NOXA, Mcl-1, and effectively blocks apoptosis. In an ovarian cancer model, systemically delivered small interfering RNA against KLF6-SV1 induces spontaneous apoptosis of tumor cells, decreases tumor burden, and restores cisplatin sensitivity in vivo. Moreover, i.p. delivery of siKLF6-SV1 RNA halts ovarian tumor progression and improves median and overall survival (progression-free for &gt;15 months; P &lt; 0.0002) in mice in a dose-dependent manner. Thus, KLF6-SV1 represents a novel regulator of protein interactions in the apoptotic cascade and a therapeutically targetable control point. [Cancer Res 2009;69(11):4733–41]
Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death
Authors: Klemke Claus-Detlev , Brenner Dirk , Weiβ Eva-Maria , Schmidt Marc , Leverkus Martin , Gülow Karsten , Krammer Peter H. 
Published: May 2009

AbstractRestimulation of previously activated T cells via the T-cell receptor (TCR) leads to activation-induced cell death (AICD), which is, at least in part, dependent on the death receptor CD95 (APO-1, FAS) and its natural ligand (CD95L). Here, we characterize cutaneous T-cell lymphoma (CTCL) cells (CTCL tumor cell lines and primary CTCL tumor cells from CTCL patients) as AICD resistant. We show that CTCL cells have elevated levels of the CD95-inhibitory protein cFLIP. However, cFLIP is not responsible for CTCL AICD resistance. Instead, our data suggest that reduced TCR-proximal signaling in CTCL cells is responsible for the observed AICD resistance. CTCL cells exhibit no PLC-γ1 activity, resulting in an impaired Ca2+release and reduced generation of reactive oxygen species upon TCR stimulation. Ca2+ and ROS production are crucial for up-regulation of CD95L and reconstitution of both signals resulted in AICD sensitivity of CTCL cells. In accordance with these data, CTCL tumor cells from patients with Sézary syndrome do not up-regulate CD95L upon TCR-stimulation and are therefore resistant to AICD. These results show a novel mechanism of AICD resistance in CTCL that could have future therapeutic implications to overcome apoptosis resistance in CTCL patients. [Cancer Res 2009;69(10):4175–83]
Mesenchymal Stem Cell Delivery of TRAIL Can Eliminate Metastatic Cancer
Authors: Loebinger Michael R. , Eddaoudi Ayad , Davies Derek , Janes Sam M. 
Published: May 2009

Abstract
Cancer is a leading cause of mortality throughout the world and new treatments are urgently needed. Recent studies suggest that bone marrow–derived mesenchymal stem cells (MSC) home to and incorporate within tumor tissue. We hypothesized that MSCs engineered to produce and deliver tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a transmembrane protein that causes selective apoptosis of tumor cells, would home to and kill cancer cells in a lung metastatic cancer model. Human MSCs were transduced with TRAIL and the IRES-eGFP reporter gene under the control of a tetracycline promoter using a lentiviral vector. Transduced and activated MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death in coculture experiments. Subcutaneous xenograft experiments confirmed that directly delivered TRAIL-expressing MSCs were able to significantly reduce tumor growth [0.12 cm3 (0.04-0.21) versus 0.66 cm3 (0.21-1.11); P &lt; 0.001]. We then found, using a pulmonary metastasis model, systemically delivered MSCs localized to lung metastases and the controlled local delivery of TRAIL completely cleared the metastatic disease in 38% of mice compared with 0% of controls (P &lt; 0.05). This is the first study to show a significant reduction in metastatic tumor burden with frequent eradication of metastases using inducible TRAIL-expressing MSCs. This has a wide potential therapeutic role, which includes the treatment of both primary tumors and their metastases, possibly as an adjuvant therapy in clearing micrometastatic disease following primary tumor resection. [Cancer Res 2009;69(10):4134–42]
The Mechanical Rigidity of the Extracellular Matrix Regulates the Structure, Motility, and Proliferation of Glioma Cells
Authors: Ulrich Theresa A. , de Juan Pardo Elena M. , Kumar Sanjay 
Published: May 2009

Abstract
Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here, we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable with normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than on compliant ECMs. Pharmacologic inhibition of nonmuscle myosin II–based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells. [Cancer Res 2009;69(10):4167–74]
MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance
Authors: Moriyama Taiki , Ohuchida Kenoki , Mizumoto Kazuhiro , Yu Jun , Sato Norihiro , Nabae Toshinaga , Takahata Shunichi , Toma Hiroki , Nagai Eishi , Tanaka Masao 
Published: May 2009

Abstract
Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.[Mol Cancer Ther 2009;8(5):1067–74]
The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SKBR3 breast cancer cell and tumor growth by repressing erbB2 expression
Authors: Liu Xinyi , Abdelrahim Maen , Abudayyeh Ala , Lei Ping , Safe Stephen 
Published: May 2009

Abstract
Tolfenamic acid (TA) is a nonsteroidal anti-inflammatory drug that inhibits pancreatic cancer cell and tumor growth through decreasing expression of specificity protein (Sp) transcription factors. TA also inhibits growth of erbB2-overexpressing BT474 and SKBR3 breast cancer cells; however, in contrast to pancreatic cancer cells, TA induced down-regulation of erbB2 but not Sp proteins. TA-induced erbB2 down-regulation was accompanied by decreased erbB2-dependent kinase activities, induction of p27, and decreased expression of cyclin D1. TA also decreased erbB2 mRNA expression and promoter activity, and this was due to decreased mRNA stability in BT474 cells and, in both cell lines, TA decreased expression of the YY1 and AP-2 transcription factors required for basal erbB2 expression. In addition, TA also inhibited tumor growth in athymic nude mice in which BT474 cells were injected into the mammary fat pad. TA represents a novel and promising new anticancer drug that targets erbB2 by decreasing transcription of this oncogene. [Mol Cancer Ther 2009;8(5):OF1–11]
The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity
Authors: Mader Jamie S. , Mookherjee Neeloffer , Hancock Robert E.W. , Bleackley R. Chris 
Published: May 2009

Abstract
LL-37 is a human cationic host defense peptide (antimicrobial peptide) belonging to the cathelicidin family of peptides. In this study, LL-37 was shown to kill Jurkat T leukemia cells via apoptosis. A loss of mitochondrial membrane potential, DNA fragmentation, and phosphatidylserine externalization were detected following LL-37 exposure, whereas apoptosis was independent of caspase family members. The specific apoptotic pathway induced by LL-37 was defined through the utilization of Jurkat cells modified to express antiapoptotic proteins, as well as cells deficient in various proteins associated with apoptosis. Of interest, both Bcl-2–overexpressing cells and cells deficient in Bax and Bak proteins displayed a significant reduction in LL-37–induced apoptosis. In addition, Jurkat cells modified in the Fas receptor–associated pathway showed no reduction in apoptosis when exposed to LL-37. Analysis of the involvement of apoptosis-inducing factor (AIF) in LL-37–mediated apoptosis revealed that AIF transferred from the mitochondria to the nucleus of cells exposed to LL-37, where it may lead to large-scale DNA fragmentation and chromatin condensation. AIF knockdown analysis resulted in LL-37–resistant cells. This suggests that AIF is mandatory in LL-37–mediated killing. Lastly, chelation or inhibition of Ca2+ or calpains inhibited LL-37–mediated killing. Further analysis revealed that calpains were required for LL-37–mediated Bax translocation to mitochondria. Together, these data show that LL-37–induced apoptosis is mediated via the mitochondria-associated pathway in a caspase-independent and calpain- and AIF-dependent manner that involves Bax activation and translocation to mitochondria. (Mol Cancer Res 2009;7(5):689–702)
Host Deficiency in Vav2/3 Guanine Nucleotide Exchange Factors Impairs Tumor Growth, Survival, and Angiogenesis In vivo
Authors: Brantley-Sieders Dana M. , Zhuang Guanglei , Vaught David , Freeman Tanner , Hwang Yoonha , Hicks Donna , Chen Jin 
Published: May 2009

Abstract
Vav guanine nucleotide exchange factors modulate changes in cytoskeletal organization through activation of Rho, Rac, and Cdc42 small GTPases. Although Vav1 expression is restricted to the immune system, Vav2 and Vav3 are expressed in several tissues, including highly vascularized organs. Here, we provide the first evidence that Vav2 and Vav3 function within the tumor microenvironment to promote tumor growth, survival, and neovascularization. Host Vav2/3 deficiency reduced microvascular density, as well as tumor growth and/or survival, in transplanted B16 melanoma and Lewis lung carcinoma models in vivo. These defects were due in part to Vav2/3 deficiency in endothelial cells. Vav2/3-deficient endothelial cells displayed reduced migration in response to tumor cells in coculture migration assays, and failed to incorporate into tumor vessels and enhance tumor volume in tumor-endothelial cotransplantation experiments. These data suggest that Vav2/3 guanine nucleotide exchange factors play a critical role in host-mediated tumor progression and angiogenesis, particularly in tumor endothelium.(Mol Cancer Res 2009;7(5):615–23)
A Key Role for Early Growth Response-1 and Nuclear Factor-κB in Mediating and Maintaining GRO/CXCR2 Proliferative Signaling in Esophageal Cancer
Authors: Wang Bo , Khachigian Levon M. , Esau Luke , Birrer Michael J. , Zhao Xiaohang , Parker M. Iqbal , Hendricks Denver T. 
Published: May 2009

Abstract
Although early growth response-1 (EGR-1) has been shown as a key transcription factor in controlling cell growth, proliferation, differentiation, and angiogenesis, its role in the development of esophageal cancer is poorly understood despite the high frequency of this disease in many parts of the world. Here, immunohistochemistry showed that EGR-1 is overexpressed in 80% of esophageal tumor tissues examined. Furthermore, EGR-1 is constitutively expressed in all esophageal cancer cell lines analyzed. Esophageal squamous carcinoma WHCO1 cells stably transfected with EGR-1 short hairpin RNA displayed a 55% reduction in EGR-1 protein levels, 50% reduction in cell proliferation, a 50% reduction in cyclin-dependent kinase 4 levels, and a 2-fold induction in p27Kip1 levels associated with a G2-M cell cycle arrest. EGR-1 knockdown also caused a marked induction in IκBα expression, an effect also observed in GROβ RNA interference-expressing WHCO1 cells, because EGR-1 lies downstream of GRO/CXCR2 signaling. Furthermore, p65 mRNA levels were also reduced in cells treated with either short hairpin RNA EGR-1 or small interfering RNA EGR-1. Immunohistochemical analysis indicated that p65 is elevated in 78% (n = 61) of esophageal tumor sections analyzed. Moreover, nuclear factor-κB inhibition with either sodium salicylate or p65 RNA interference led to a significant reduction in GROα and GROβ expression. These results indicate that EGR-1 and nuclear factor-κB mediate GRO/CXCR2 proliferative signaling in esophageal cancer and may represent potential target molecules for therapeutic intervention.(Mol Cancer Res 2009;7(5):755–64)
Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration
Authors: Li Chao-Chin , Chu Hui-Yi , Yang Chu-Wen , Chou Chen-Kung , Tsai Ting-Fen 
Published: May 2009

Abstract
Aurora-A, a serine-threonine kinase, is frequently overexpressed in human cancers, including hepatocellular carcinoma. To study the phenotypic effects of Aurora-A overexpression on liver regeneration and tumorigenesis, we generated transgenic mice overexpressing human Aurora-A in the liver. The overexpression of Aurora-A after hepatectomy caused an earlier entry into S phase, a sustaining of DNA synthesis, and premitotic arrest in the regenerating liver. These regenerating transgenic livers show a relative increase in binuclear hepatocytes compared with regenerating wild-type livers; in addition, multipolar segregation and trinucleation could be observed only in the transgenic hepatocytes after hepatectomy. These results together suggest that defects accumulated after first round of the hepatocyte cell cycle and that there was a failure to some degree of cytokinesis. Interestingly, the p53-dependent checkpoint was activated by these abnormalities, indicating that p53 plays a crucial role during liver regeneration. Indeed, the premitotic arrest and abnormal cell death, mainly necrosis, caused by Aurora-A overexpression were genetically rescued by p53 knockout. However, trinucleation of hepatocytes remained in the regenerating livers of the transgenic mice with a p53 knockout background, indicating that the abnormal mitotic segregation and cytokinesis failure were p53 independent. Moreover, overexpression of Aurora-A in transgenic liver led to a low incidence (3.8%) of hepatic tumor formation after a long latency period. This transgenic mouse model provides a useful system that allows the study of the physiologic effects of Aurora-A on liver regeneration and the genetic pathways of Aurora-A–mediated tumorigenesis in liver.
Virtual Religion and Duality of Religious Spaces
Authors: Ameli Saied Reza 
Published: May 2009

AbstractTo present a relatively apparent communication picture from the virtual religion and its features in “the current virtualized world” or in the ground of “dual-globalized” processes requires the discussion of four basic questions in relation to the virtual religion. Although it is not possible to provide detailed and analytical answers to these questions, aspects of the questions and facets of the answers will be analyzed. As Martin Heidegger (AP 1373:1)* has suggested, a question itself possesses leading features and opens ways of thought: 1) What is the virtual religion? 2) Which ontology can offer a presence of religion in virtual-real space — vireal space? 3) Is there any fundamental difference between a virtual and the real religion? And eventually, it is important to answer the question: 4) What are the outcomes of duality space and what is the place of religion's existence? To answer these questions we will look at ongoing literature on “the virtual religion” and on religious typology in virtual space from an “ontological” view and we will analyze structural differences between these two spaces. And finally we will address the representation of religion in two spaces through a “dual globalization paradigm” and “communication paradigm of dual spacization”.
Restorative Justice: Opportunities for Christian Engagement
Authors: Broughton Geoff 
Published: May 2009

AbstractThe restorative justice movement incorporates a growing body of academic theory and diversity of practice. 'Basic Principles' on the use of restorative justice were endorsed by the Eleventh Session of the United Nations Economic and Social Council (ECOSOC) in 2002. This article begins with a preliminary critique of contemporary restorative justice, arguing that a preoccupation with technique and process has subverted the theological vision of some foundational theorists. The discussion continues with a brief overview of key Christian contributions to restorative justice theory, focusing on the work of Howard Zehr, Christopher D. Marshall and Daniel W. Van Ness, and concludes by asserting that a more holistic Christology is required from future theological contributions to restorative justice practices.
Satisfying Justice
Authors: Thomson Heather 
Published: May 2009

AbstractThis article addresses justice as an issue in public theology. Since Christian theology and practice has engaged in violence in the name of justice (human and divine), the notion of justice is examined here so that it may better serve peace and reconciliation. In particular, the relation of justice to punishment, vengeance and morality are key issues, if justice is to serve peace. In my discussion I gain insights from South Africa's experience of the transition from apartheid to democracy, where justice became a central public issue. I bring advocates of punitive and restorative justice into conversation in order to establish what satisfies justice (punishment or healing), and I draw implications from this to how we are to understand divine justice. Finally, the atonement is reconsidered as a form of transitional justice.
Justice and Divine Judgement: Scriptural Perspectives for Public Theology
Authors: Neville David 
Published: May 2009

AbstractFrom Jewish and Christian Scripture this article retrieves conceptions of justice and divine judgement with the potential to contribute to the public good. Although justice is not a homogenous concept in Scripture, there is a justice-trajectory that is more restorative than retributive and, as such, has profound public import. Through the discussion of scriptural justice this article raises the question of the role of Scripture in public theology. While affirming that justice is a central scriptural concern and therefore indispensable to Christian faith and practice, in this article I also explore the nexus between justice and divine judgement, with a view to indicating by means of inner-biblical critique that divine judgement, no less than justice in the biblical tradition, leans towards restoration rather than (solely) retribution. Special attention is paid to the work of Karen Lebacqz and Dan Via, and Mt. 11:2–6 is also discussed.