bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cadherin-11 Increases Migration and Invasion of Prostate Cancer Cells and Enhances their Interaction with Osteoblasts
Authors: Huang Chih-Fen , Lira Cristina , Chu Khoi , Bilen Mehmet Asim , Lee Yu-Chen , Ye Xiangcang , Kim Soo Mi , Ortiz Angelica , Wu Fe-Lin Lin , Logothetis Christopher J. , Yu-Lee Li-Yuan , Lin Sue-Hwa 
Published: May 2010

Abstract
Cell adhesion molecules have been implicated in the colonization of cancer cells to distant organs. Prostate cancer (PCa) has a propensity to metastasize to bone, and cadherin-11, which is an osteoblast cadherin aberrantly expressed in PCa cells derived from bone metastases, has been shown to play a role in the metastasis of PCa cells to bone. However, the mechanism by which cadherin-11 is involved in this process is not known. Here, we show that expression of cadherin-11 in cadherin-11–negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer and also stimulates C4-2B4 cell migration and invasiveness. The downregulation of cadherin-11 in cadherin-11–expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane (JMD) and β-catenin binding domains (CBS) in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion, but not spreading. Gene array analyses showed that several invasion-related genes, including MMP-7 and MMP-15, are upregulated in cadherin-11–expressing, but not in cad11-ΔJMD–expressing or cad11-ΔCBS–expressing, C4-2B4 cells. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness that may facilitate the metastatic colonization of PCa cells in bone. Cancer Res; 70(11); 4580–9. ©2010 AACR.
Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs
Authors: Freeman Spencer A. , McLeod Sarah J. , Dukowski Janet , Austin Pamela , Lee Crystal C.Y. , Millen-Martin Brandie , Kubes Paul , McCafferty Donna-Marie , Gold Michael R. , Roskelley Calvin D. 
Published: May 2010

AbstractThe Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. This correlated with a decreased ability of the tumor cells to undergo transendothelial migration (TEM) in vitro and form dynamic, F-actin–rich pseudopodia that penetrate capillary endothelial walls in vivo. Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM. Cancer Res; 70(11); 4590–601. ©2010 AACR.
SuperiorIn vivoEfficacy of Afucosylated Trastuzumab in the Treatment of HER2-Amplified Breast Cancer
Authors: Junttila Teemu T. , Parsons Kathryn , Olsson Christine , Lu Yanmei , Xin Yan , Theriault Julie , Crocker Lisa , Pabonan Oliver , Baginski Tomasz , Meng Gloria , Totpal Klara , Kelley Robert F. , Sliwkowski Mark X. 
Published: May 2010

AbstractThe enhancement of immune effector functions has been proposed as a potential strategy for increasing the efficacy of therapeutic antibodies. Here, we show that removing fucose from trastuzumab (Herceptin) increased its binding to FcγRIIIa, enhanced antibody-dependent cell-mediated cytotoxicity, and more than doubled the median progression-free survival when compared with conventional trastuzumab in treating preclinical models of HER2-amplified breast cancer. Our results show that afucosylated trastuzumab has superior efficacy in treating in vivo models of HER2-amplified breast cancer and support the development of effector function–enhanced antibodies for solid tumor therapy. Cancer Res; 70(11); 4481–9. ©2010 AACR.
Immature Immunosuppressive CD14+HLA-DR−/low Cells in Melanoma Patients Are Stat3hi and Overexpress CD80, CD83, and DC-Sign
Authors: Poschke Isabel , Mougiakakos Dimitrios , Hansson Johan , Masucci Giuseppe V. , Kiessling Rolf 
Published: May 2010

Abstract
Myeloid-derived suppressor cells (MDSC) have emerged as key immune modulators in various tumor models and human malignancies, but their characteristics in humans remain to be unequivocally defined. In this study, we have examined circulating CD14+HLA-DR−/low MDSC in 34 advanced malignant melanoma (MM) patients. Their frequency is significantly increased and associated with disease activity. Contrary to the common notion that MDSC are a heterogeneous population of exclusively immature cells, we find the coexpression of markers associated with mature phenotype. We show for the first time the overexpression of CD80, CD83, and DC-Sign in human MDSC. Further, increased levels of signal transducer and activator of transcription 3 (Stat3), an important regulator in MDSC development and function, were noted in MM-MDSC. Stat3 was altered toward an active, phosphorylated state in the HLA-DR− population of CD14+ cells and was more reactive to activating stimuli in patients. Importantly, inhibition of Stat3 abolished their suppressive activity almost completely. The described MM-MDSC use arginase in conjunction with other yet undefined mechanisms to suppress CD4+ and CD8+ T cells. Several observations suggest a redox imbalance in MDSC and indicate an important role of Stat3-dependent oxidative stress in MDSC-mediated T-cell suppression. These results emphasize the diversity of MDSC in human cancer and provide potential targets for therapeutic interventions. Cancer Res; 70(11); 4335–45. ©2010 AACR.
Estrogen Receptor β1 Expression Is Regulated by miR-92 in Breast Cancer
Authors: Al-Nakhle Hakeemah , Burns Philip A. , Cummings Michele , Hanby Andrew M. , Hughes Thomas A. , Satheesha Sampoorna , Shaaban Abeer M. , Smith Laura , Speirs Valerie 
Published: May 2010

Abstract
Estrogen receptor β1 (ERβ1) downregulation occurs in many breast cancers, but the responsible molecular mechanisms remain unclear. Here, we report that levels of ERβ1 expression are negatively regulated by the microRNA miR-92. Expression analysis in a cohort of primary breast tumors confirmed a significant negative correlation between miR-92 and both ERβ1 mRNA and protein. Inhibition of miR-92 in MCF-7 cells increased ERβ1 expression in a dose-dependent manner, whereas miR-92 overexpression led to ERβ1 downregulation. Reporter constructs containing candidate miR-92 binding sites in the 3′-untranslated region (UTR) of ERβ1 suggested by bioinformatics analysis confirmed that miR-92 downregulated ERβ1 via direct targeting of its 3′-UTR. Our results define a potentially important mechanism for downregulation of ERβ1 expression in breast cancer. Cancer Res; 70(11); 4778–84. ©2010 AACR.
Persistent Cyclooxygenase-2 Inhibition Downregulates NF-κB, Resulting in Chronic Intestinal Inflammation in the Min/+ Mouse Model of Colon Tumorigenesis
Authors: Carothers Adelaide M. , Davids Jennifer S. , Damas Beatrice C. , Bertagnolli Monica M. 
Published: May 2010

Abstract
Cyclooxygenase-2 (COX-2) inhibition prevents adenoma formation in humans and mouse models of colon cancer. The selective COX-2 inhibitor celecoxib reduces COX-2 and prostaglandin E2 (PGE2) expression and adenomas in the intestine of Min/+ mice after treatment for several weeks, but prolonged treatment increases PGE2 production, resulting in drug-resistant tumor formation and transforming growth factor β (TGFβ)–dependent intestinal fibrosis. In this study, we examined pathways that regulate COX-2 expression and suppress chronic intestinal inflammation. We show that NF-κB signaling was inhibited in the ileum of Min/+ mice receiving long-term treatment with celecoxib. This effect was associated with inhibition of TGFβ-associated kinase-1 and IκB kinase α/β activities and reduced expression of the Toll-like receptor (TLR) 2 and TLR4 that enhance colonic barrier function. Additionally, we observed reduced activities of protein kinases c-Jun NH2-terminal kinase 1 and protein kinase A and transcription factor cyclic AMP–responsive element binding protein, regulators of COX-2 expression, which cross-talk with NF-κB. In ileum subjected to long-term celecoxib treatment, we noted relatively higher expression of COX-2, vascular endothelial growth factor, and interleukin-1β in Paneth cells, whereas NF-κB and COX-2 were more strongly expressed by an expanded population of stromal myofibroblasts. Our findings argue that celecoxib resistance is an acquired adaptation to changes in the crypt microenvironment that is associated with chronic intestinal inflammation and impaired acute wound-healing responsiveness. Cancer Res; 70(11); 4433–42. ©2010 AACR.
Type III IFN Interleukin-28 Mediates the Antitumor Efficacy of Oncolytic Virus VSV in Immune-Competent Mouse Models of Cancer
Authors: Wongthida Phonphimon , Diaz Rosa Maria , Galivo Feorillo , Kottke Timothy , Thompson Jill , Pulido Jose , Pavelko Kevin , Pease Larry , Melcher Alan , Vile Richard 
Published: May 2010

Abstract
Innate immune effector mechanisms triggered by oncolytic viruses may contribute to the clearance of both infected and uninfected tumor cells in immunocompetent murine hosts. Here, we developed an in vitro tumor cell/bone marrow coculture assay and used it to dissect innate immune sensor and effector responses to intratumoral vesicular stomatitis virus (VSV). We found that the type III IFN interleukin-28 (IL-28) was induced by viral activation of innate immune-sensing cells, acting as a key mediator of VSV-mediated virotherapy of B16ova melanomas. Using tumor variants which differentially express the IL-28 receptor, we showed that IL-28 induced by VSV within the tumor microenvironment sensitizes tumor cells to natural killer cell recognition and activation. These results revealed new insights into the immunovirological mechanisms associated with oncolytic virotherapy in immune-competent hosts. Moreover, they defined a new class of tumor-associated mutation, such as acquired loss of responsiveness to IL-28 signaling, which confers insensitivity to oncolytic virotherapy through a mechanism independent of viral replication in vitro. Lastly, the findings suggested new strategies to manipulate immune signals that may enhance viral replication, along with antitumor immune activation, and improve the efficacy of oncolytic virotherapies. Cancer Res; 70(11); 4539–49. ©2010 AACR.
The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation
Authors: Zhao Dong , Zheng Han-Qiu , Zhou Zhongmei , Chen Ceshi 
Published: May 2010

Abstract
Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes breast cell proliferation and tumorigenesis through upregulating FGF-BP. The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCFFbw7) targets KLF5 for ubiquitin-mediated degradation in a GSK3β-mediated KLF5 phosphorylation–dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif (303SPPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and breast cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers. Cancer Res; 70(11); 4728–38. ©2010 AACR.
Targeted Nanoparticles That Deliver a Sustained, Specific Release of Paclitaxel to Irradiated Tumors
Authors: Passarella Ralph J. , Spratt Daniel E. , van der Ende Alice E. , Phillips John G. , Wu Hongmei , Sathiyakumar Vasanth , Zhou Li , Hallahan Dennis E. , Harth Eva , Diaz Roberto 
Published: May 2010

Abstract
To capitalize on the response of tumor cells to XRT, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to XRT. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to 3 weeks. Compared with controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P = 0.0001) in MDA-MB-231 and 12 days in GL261 (P &lt; 0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel-encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches. Cancer Res; 70(11); 4550–9. ©2010 AACR.
CXCL12 (SDF-1)/CXCR4 Pathway in Cancer
Authors: Teicher Beverly A. , Fricker Simon P. 
Published: May 2010

Abstract
Chemokines, small proinflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 [stromal cell-derived factor-1 (SDF-1)] binds primarily to CXC receptor 4 (CXCR4; CD184). The binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription. CXCR4 is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells, and cancer cells. The CXCL12/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is a target for therapeutics that can block the CXCL12/CXCR4 interaction or inhibit downstream intracellular signaling. Clin Cancer Res; 16(11); 2927–31. ©2010 AACR.
Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers
Authors: Harrington Kevin J. , Karapanagiotou Eleni M. , Roulstone Victoria , Twigger Katie R. , White Christine L. , Vidal Laura , Beirne Debbie , Prestwich Robin , Newbold Kate , Ahmed Merina , Thway Khin , Nutting Christopher M. , Coffey Matt , Harris Dean , Vile Richard G. , Pandha Hardev S. , DeBono Johann S. , Melcher Alan A. 
Published: May 2010

Abstract
Purpose: To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses.
Experimental Design: Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 × 108 and 1 × 1010 TCID50. In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 × 1010 TCID50. End points were safety, viral replication, immunogenicity, and antitumoral activity.
Results: Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease.
Conclusions: The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent. Clin Cancer Res; 16(11); 3067–77. ©2010 AACR.
Structural Basis on the Dityrosyl-Diiron Radical Cluster and the Functional Differences of Human Ribonucleotide Reductase Small Subunits hp53R2 and hRRM2
Authors: Zhou Bingsen , Su Leila , Yuan Yate-Ching , Un Frank , Wang Norby , Patel Madhukar , Xi Bixin , Hu Shuya , Yen Yun 
Published: May 2010

Abstract
Ribonucleotide reductase (RNR) is an enzyme for the de novo conversion of ribonucleotides to deoxyribonucleotides. The two human RNR small subunits hRRM2 and hp53R2 share 83% sequence homology but show distinct expression patterns and function. Structural analyses of the oxidized form of hRRM2 and hp53R2 indicate that both proteins contain a conserved Gln127-hp53R2/Gln165-hRRM2 close to the dinuclear iron center and the essential tyrosine residue Tyr124-hp53R2/Tyr162-hRRM2 forms hydrogen bonds with the tyrosine and iron ligands, implying a critical role for the glutamine residue in assembling the dityrosyl-diiron radical cofactor. The present work also showed that Tyr221 in hRRM2, which is replaced by Phe183 in hp53R2, forms a hydrogen bond with Tyr162 to extend the hydrogen bond network from Gln165-hRRM2. Mutagenesis and spectroscopic experiments suggested that the tyrosine-to-phenylalanine switch at Phe183-hp53R2/Tyr221-hRRM2 could lead to differences in radical generation or enzymatic activity for hp53R2 and hRRM2. This study correlates the distinct catalytic mechanisms of the small subunits hp53R2 and hRRM2 with a hydrogen-bonding network and provides novel directions for designing and developing subunit-specific therapeutic agents for human RNR enzymes. Mol Cancer Ther; 9(6); 1669–79. ©2010 AACR.
p53-Independent Apoptosis by Benzyl Isothiocyanate in Human Breast Cancer Cells Is Mediated by Suppression of XIAP Expression
Authors: Kim Su-Hyeong , Singh Shivendra V. 
Published: May 2010

Abstract
We have shown previously that cruciferous vegetable constituent benzyl isothiocyanate (BITC) suppresses viability of cultured MCF-7 and MDA-MB-231 human breast cancer cells and retards mammary cancer development in MMTV-neu mice by causing apoptosis, but the mechanism of cell death is not fully understood. We now show that whereas p53 is dispensable for BITC-induced cell death, proapoptotic response to this promising chemopreventive agent is mediated by suppression of X-linked inhibitor of apoptosis (XIAP) protein expression. The BITC treatment increased levels of total and Ser15-phosphorylated p53 protein in MCF-7 cells, but the proapoptotic response to this agent was maintained even after knockdown of the p53 protein level. Exposure of MCF-7 and MDA-MB-231 cells to BITC resulted in a marked decrease in protein level of XIAP as early as 8 hours after treatment. Ectopic expression of XIAP conferred statistically significant protection against BITC-mediated cytoplasmic histone-associated apoptotic DNA fragmentation in both cell lines. Moreover, inhibition of MDA-MB-231 cell growth in vivo in female athymic mice by BITC administration correlated with a modest but statistically significant decrease in XIAP protein level in the tumor xenograft. The BITC treatment also resulted in induction as well as nuclear translocation of survivin only in the MCF-7 cells. The BITC-induced apoptosis was modestly but statistically significantly augmented by RNA interference of survivin in MCF-7 cells. In conclusion, the present study provides novel insight into the molecular circuitry of BITC-induced apoptosis to indicate suppression of XIAP expression as a critical mediator of this process. Cancer Prev Res; 3(6); 718–26. ©2010 AACR.
Immediate Percutaneous Coronary Intervention Is Associated With Better Survival After Out-of-Hospital Cardiac Arrest
Authors: Dumas Florence , Cariou Alain , Manzo-Silberman Stéphane , Grimaldi David , Vivien Benoît , Rosencher Julien , Empana Jean-Philippe , Carli Pierre , Mira Jean-Paul , Jouven Xavier , Spaulding Christian 
Published: May 2010

Background—
Acute coronary occlusion is the leading cause of cardiac arrest. Because of limited data, the indications and timing of coronary angiography and angioplasty in patients with out-of-hospital cardiac arrest are controversial. Using data from the Parisian Region Out of hospital Cardiac ArresT prospective registry, we performed an analysis to assess the effect of an invasive strategy on hospital survival.

Methods and Results—
Between January 2003 and December 2008, 714 patients with out-of-hospital cardiac arrest were referred to a tertiary center in Paris, France. In 435 patients with no obvious extracardiac cause of arrest, an immediate coronary angiogram was performed at admission followed, if indicated, by coronary angioplasty. At least 1 significant coronary artery lesion was found in 304 (70%) patients, in 128 (96%) of 134 patients with ST-segment elevation on the ECG performed after the return of spontaneous circulation, and in 176 (58%) of 301 patients without ST-segment elevation. The hospital survival rate was 40%. Multivariable analysis showed successful coronary angioplasty to be an independent predictive factor of survival, regardless of the postresuscitation ECG pattern (odds ratio, 2.06; 95% CI, 1.16 to 3.66).

Conclusions—
Successful immediate coronary angioplasty is associated with improved hospital survival in patients with or without ST-segment elevation. Therefore, our findings support the use of immediate coronary angiography in patients with out-of-hospital cardiac arrest with no obvious noncardiac cause of arrest regardless of the ECG pattern.
Catheter-Based Left Atrial Appendage (LAA) Ligation for the Prevention of Embolic Events Arising From the LAA
Authors: Lee Randall J. , Bartus Krzysztof , Yakubov Steven J. 
Published: May 2010

Background—
Surgical ligation of the left atrial appendage (LAA) has been shown to be an effective alternative to warfarin therapy in patients with atrial fibrillation. A novel catheter-based approach for LAA ligation was evaluated for safety and effectiveness in a canine model.

Methods and Results—
A total of 26 healthy mongrel dogs underwent ligation of the LAA through a catheter-based approach. Intracardiac echocardiography and contrast fluoroscopy were used to position a marker balloon at the origin of the LAA. An over-the-wire approach was used to guide the LARIAT snare device over the LAA to enable ligation of the LAA. Sixteen dogs were euthanized acutely. The LAA was examined to assess the placement and completeness of the ligation. The remaining 10 dogs were used for long-term follow-up. The snare delivery device was able to completely capture, advance, and close the anatomic base of the LAA in all cases. In all animals, complete LAA exclusion through this closed-chest approach was achieved without complications. Chronic follow-up revealed healthy active dogs. Examination of the LAA at 7 days, 1 month, and 3 months demonstrated completely endothelialized orifice of the LAA.

Conclusions—
Using a closed-chest approach in the canine model, the catheter-based snare delivery device achieved safe and reliable ligation of the entire LAA. The clinical application of this novel approach may provide an alternative to warfarin or to permanent device implants in patients with nonvalvular atrial fibrillation for the prevention of embolic events originating from the LAA.