bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Functional Monoclonal Antibody PF-04605412 Targets Integrin α5β1 and Elicits Potent Antibody-Dependent Cellular Cytotoxicity
Authors: Li Gang , Zhang Lianglin , Chen Enhong , Wang Jianying , Jiang Xin , Chen Jeffrey H. , Wickman Grant , Amundson Karin , Bergqvist Simon , Zobel James , Buckman Dana , Baxi Sangita M. , Bender Steven L. , Casperson Gerald F. , Hu-Lowe Dana D. 
Published: December 2010

Abstract
Integrin α5β1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies. Cancer Res; 70(24); 10243–54. ©2010 AACR.
Targeting the Mitotic Checkpoint for Cancer Therapy with NMS-P715, an Inhibitor of MPS1 Kinase
Authors: Colombo Riccardo , Caldarelli Marina , Mennecozzi Milena , Giorgini Maria Laura , Sola Francesco , Cappella Paolo , Perrera Claudia , Depaolini Stefania Re , Rusconi Luisa , Cucchi Ulisse , Avanzi Nilla , Bertrand Jay Aaron , Bossi Roberto Tiberio , Pesenti Enrico , Galvani Arturo , Isacchi Antonella , Colotta Francesco , Donati Daniele , Moll Jürgen 
Published: December 2010

Abstract
MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells. Cancer Res; 70(24); 10255–64. ©2010 AACR.
Prognostic Value and Function of KLF4 in Prostate Cancer: RNAa and Vector-Mediated Overexpression Identify KLF4 as an Inhibitor of Tumor Cell Growth and Migration
Authors: Wang Ji , Place Robert F. , Huang Vera , Wang Xiaoling , Noonan Emily J. , Magyar Clara E. , Huang Jiaoti , Li Long-Cheng 
Published: December 2010

Abstract
KLF4/GLKF4 is a transcription factor that can have divergent functions in different malignancies. The role of KLF4 in prostate cancer etiology remains unclear. We have recently reported that small double-stranded RNA can induce gene expression by targeting promoter sequence in a phenomenon referred to as RNA activation (RNAa). In this study, we examine KLF4 levels in prostate cancer tissue and utilize RNAa as a tool for gene overexpression to investigate its function. Expression analysis indicated that KLF4 is significantly downregulated in prostate cancer cell lines compared with nontumorigenic prostate cells. Meta-analysis of existing cDNA microarray data also revealed that KLF4 is frequently depleted in prostate cancer tissue with more pronounced reduction in metastases. In support, tissue microarray analysis of tumors and patient-matched controls indicated downregulation of KLF4 in metastatic tumor samples. Logistic regression analysis found that tumors with a KLF4 staining score less than 5 had a 15-fold higher risk for developing metastatic prostate cancer (P = 0.001; 95% confidence interval, 3.0–79.0). In vitro analysis indicated that RNAa-mediated overexpression of KLF4 inhibited prostate cancer cell proliferation and survival and altered the expression of several downstream cell-cycle–related genes. Ectopic expression of KLF4 via viral transduction recapitulated the RNAa results, validating its inhibitory effects on cancer growth. Reactivation of KLF4 also suppressed migration and invasion of prostate cancer cells. These results suggest that KLF4 functions as an inhibitor of tumor cell growth and migration in prostate cancer and decreased expression has prognostic value for predicting prostate cancer metastasis. Cancer Res; 70(24); 10182–91. ©2010 AACR.
Free Tubulin Modulates Mitochondrial Membrane Potential in Cancer Cells
Authors: Maldonado Eduardo N. , Patnaik Jyoti , Mullins Matthew R. , Lemasters John J. 
Published: December 2010

Abstract
Formation of the mitochondrial membrane potential (ΔΨ) depends on flux of respiratory substrates, ATP, ADP, and Pi through voltage-dependent anion channels (VDAC). As tubulin promotes single-channel closure of VDAC, we hypothesized that tubulin is a dynamic regulator of ΔΨ, which in cultured cancer cells was assessed by confocal microscopy of the potential-indicating fluorophore tetramethylrhodamine methylester (TMRM). Microtubule destabilizers, rotenone, colchicine, and nocodazole, and the microtubule stabilizer paclitaxel increased and decreased cellular free tubulin, respectively, and in parallel decreased and increased ΔΨ. Protein kinase A (PKA) activation by cAMP analogues and glycogen synthase kinase 3β (GSK-3β) inhibition decreased ΔΨ, whereas PKA inhibition hyperpolarized, consistent with reports that PKA and GSK-3β decrease and increase VDAC conductance, respectively. Plasma membrane potential assessed by DiBAC4(3) was not altered by any of the treatments. We propose that inhibition of VDAC by free tubulin limits mitochondrial metabolism in cancer cells. Cancer Res; 70(24); 10192–201. ©2010 AACR.
Imaging Cycling Tumor Hypoxia
Authors: Matsumoto Shingo , Yasui Hironobu , Mitchell James B. , Krishna Murali C. 
Published: December 2010

Abstract
Cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. Cycling hypoxia can exist more than 100-μm distances from a microvessel, and some of these regions have been shown to exist adjacent to normal tissue. Fluctuations in pO2 of approximately 20 mm Hg can occur with periodicities of minutes to hours and even days. These fluctuations have been attributed to changes in erythrocyte flux, perfusion, and also development of newer vascular networks. Cycling hypoxia has been shown to induce the expression of hypoxia-inducible transcription factor-1α (HIF-1α) and also confer tumor cells and tumor vascular endothelial cells with enhanced prosurvival pathways, making tumors less responsive to radiation and chemotherapy. Imaging of cycling hypoxia in tumors can provide capabilities to help plan appropriate treatment, by taking into account the magnitude and frequency of fluctuations and also their locations adjacent to normal tissue. Electron paramagnetic resonance imaging (EPRI) provides the ability to distinguish chronic and cycling hypoxic regions and has the required spatial and temporal resolutions to provide quantitative maps of tumor pO2. EPRI can serve as a valuable tool in examining tumor pO2 longitudinally in response to treatment and in an experimentally chosen time window to spatially map fluctuations in pO2 noninvasively in animal models of implanted or orthotopic tumors, with a potential for human applications. Cancer Res; 70(24); 10019–23. ©2010 AACR.
Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells
Authors: Ketola Kirsi , Vainio Paula , Fey Vidal , Kallioniemi Olli , Iljin Kristiina 
Published: December 2010

AbstractCurrent treatment options for advanced and hormone refractory prostate cancer are limited and responses to commonly used androgen pathway inhibitors are often unsatisfactory. Our recent results indicated that sodium ionophore monensin is one of the most potent and cancer-specific inhibitors in a systematic sensitivity testing of most known drugs and drug-like molecules in a panel of prostate cancer cell models. Because monensin has been extensively used in veterinary applications to build muscle mass in cattle, the link to prostate cancer and androgen signaling was particularly interesting. Here, we showed that monensin effects at nanomolar concentrations are linked to induction of apoptosis and potent reduction of androgen receptor mRNA and protein in prostate cancer cells. Monensin also elevated intracellular oxidative stress in prostate cancer cells as evidenced by increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response. Importantly, the antiproliferative effects of monensin were potentiated by combinatorial treatment with the antiandrogens and antagonized by antioxidant vitamin C. Taken together, our results suggest monensin as a potential well-tolerated, in vivo compatible drug with strong proapoptotic effects in prostate cancer cells, and synergistic effects with antiandrogens. Moreover, our data suggest a general strategy by which the effects of antiandrogens could be enhanced by combinatorial administration with agents that increase oxidative stress in prostate cancer cells. Mol Cancer Ther; 9(12); 3175–85. ©2010 AACR.
Combined Inhibition of Notch Signaling and Bcl-2/Bcl-xL Results in Synergistic Antimyeloma Effect
Authors: Li Ming , Chen Feng , Clifton Nicholas , Sullivan Daniel M. , Dalton William S. , Gabrilovich Dmitry I. , Nefedova Yulia 
Published: December 2010

Abstract
Signaling through the receptor/transcriptional regulator Notch plays an important role in tumor cell survival. Recent studies have demonstrated that pharmacological inhibition of the Notch pathway with γ-secretase inhibitor (GSI) induces apoptosis of multiple myeloma (MM) cells via upregulation of the proapoptotic protein Noxa. ABT-737, a novel BH3 mimetic, was shown to block Bcl-2 and Bcl-xL and induce MM cell apoptosis. Here, we investigated whether the inhibition of Notch signaling could enhance the proapoptotic effect of ABT-737. The antimyeloma effect of ABT-737 on MM cell lines or primary cells was substantially increased by the addition of Notch inhibitor. The synergistic effect of the GSI+ABT-737 combination was mediated by activation of Bak and Bax and release of cytochrome c. While toxic for MM cells, the combination of GSI and ABT-737 did not affect survival of peripheral blood mononuclear cells isolated from healthy donors. In vivo experiments using xenograft and SCID-hu models of MM demonstrated a significant antitumor effect of the GSI/ABT-737 combination as compared to the effect of Notch or Bcl-2/Bcl-xL inhibitors alone. Thus, this drug combination may be therapeutically beneficial for patients with MM. Mol Cancer Ther; 9(12); 3200–9. ©2010 AACR.
Combination of Vorinostat and Flavopiridol Is Selectively Cytotoxic to Multidrug-Resistant Neuroblastoma Cell Lines with Mutant TP53
Authors: Huang Jen-Ming , Sheard Michael A. , Ji Lingyun , Sposto Richard , Keshelava Nino 
Published: December 2010

Abstract
As p53 loss of function (LOF) confers high-level drug resistance in neuroblastoma, p53-independent therapies might have superior activity in recurrent neuroblastoma. We tested the activity of vorinostat, a histone deacetylase inhibitor, and flavopiridol, a pan-Cdk inhibitor, in a panel of multidrug-resistant neuroblastoma cell lines that included lines with wild-type (wt) and transcriptionally active TP53 (n = 3), mutated (mt), and LOF TP53 (n = 4) or p14ARF deletion (n = 1). The combination of vorinostat and flavopiridol was synergistic and significantly more cytotoxic (P &lt; 0.001) in cell lines with p53-LOF and in the clones stably transfected with dominant-negative p53 plasmids. Cell cycle analysis by flow cytometry showed prominent cell-cycle arrest in G2/M (37%) for a cell line with wt TP53 (SK-N-RA) at 16 to 20 hours, while cells with mt TP53 (CHLA-90) slipped into sub-G1 at 6 to 24 hours (25%–40% specific cell death). The morphological hallmarks of mitotic cell death, including defective spindle formation and abnormal cytokinesis, were detected by confocal microscopy after the treatment with vorinostat + flavopiridol combination in CHLA-90. The combination caused reduction in the expression of G2/M proteins (cyclin B1, Mad2, MPM2) in 2 cell lines with mt TP53 but not in those with wt TP53. Plk1 expression was reduced in all treated lines. Small interfering RNA knockdown of Mad2 and cyclin B1 or Plk1 synergistically reduced the clonogenicity of CHLA-90 cells. The combination of HDAC inhibitor and flavopiridol may be a unique approach to treating neuroblastomas with p53 LOF, one that evokes induction of mitotic failure. Mol Cancer Ther; 9(12); 3289–301. ©2010 AACR.
The Histone Deacetylase Inhibitor, Vorinostat, Reduces Tumor Growth at the Metastatic Bone Site and Associated Osteolysis, but Promotes Normal Bone Loss
Authors: Pratap Jitesh , Akech Jacqueline , Wixted John J. , Szabo Gabriela , Hussain Sadiq , McGee-Lawrence Meghan E. , Li Xiaodong , Bedard Krystin , Dhillon Robinder J. , van Wijnen Andre J. , Stein Janet L. , Stein Gary S. , Westendorf Jennifer J. , Lian Jane B. 
Published: December 2010

AbstractVorinostat, an oral histone deacetylase inhibitor with antitumor activity, is in clinical trials for hematologic and solid tumors that metastasize and compromise bone structure. Consequently, there is a requirement to establish the effects of vorinostat on tumor growth within bone. Breast (MDA-231) and prostate (PC3) cancer cells were injected into tibias of SCID/NCr mice and the effects of vorinostat on tumor growth and osteolytic disease were assessed by radiography, micro-computed tomography, and histologic and molecular analyses. Vorinostat-treated and control mice without tumors were also examined. Tumor growth in bone was reduced ∼33% by vorinostat with inhibited osteolysis in the first few weeks of the experiment. However, osteolysis became more severe in both the vehicle and vorinostat-treated groups. Vorinostat increased the expression of tumor-derived factors promoting bone resorption, including PTHrP, IL-8, and osteopontin. After 4 weeks of vorinostat therapy, the non–tumor-bearing contralateral femurs and limbs from vorinostat-treated tumor-free SCID mice showed significant bone loss (50% volume density of controls). Thus, our studies indicate that vorinostat effectively inhibits tumor growth in bone, but has a negative systemic effect reducing normal trabecular bone mass. Vorinostat treatment reduces tumor growth in bone and accompanying osteolytic disease as a result of decreased tumor burden in bone. However, vorinostat can promote osteopenia throughout the skeleton independent of tumor cell activity. Mol Cancer Ther; 9(12); 3210–20. ©2010 AACR.
GT-094, a NO-NSAID, Inhibits Colon Cancer Cell Growth by Activation of a Reactive Oxygen Species-MicroRNA-27a: ZBTB10-Specificity Protein Pathway
Authors: Pathi Satya S. , Jutooru Indira , Chadalapaka Gayathri , Sreevalsan Sandeep , Anand S , Thatcher Gregory RJ , Safe Stephen 
Published: December 2010

Abstract
Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094) is a novel nitric oxide (NO) chimera containing an nonsteroidal anti-inflammatory drug (NSAID) and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity. In this study, the effects and mechanism of action of GT-094 were investigated in RKO and SW480 colon cancer cells. GT-094 inhibited cell proliferation and induced apoptosis in both cell lines and this was accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and these responses were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated genes associated with cell growth [cyclin D1, hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR)], survival (bcl-2, survivin), and angiogenesis [VEGF and its receptors (VEGFR1 and VEGFR2)]. Results of previous RNA interference studies in this laboratory has shown that these genes are regulated, in part, by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in colon and other cancer cell lines and not surprisingly, GT-094 also decreased Sp1, Sp3, and Sp4 in colon cancer cells. GT-094–mediated repression of Sp and Sp-regulated gene products was due to downregulation of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a, and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to activation of an ROS-miR-27a:ZBTB10-Sp transcription factor pathway. Mol Cancer Res; 9(2); 195–205. ©2010 AACR.
Effects of a Highly Selective Acetylcholine-Activated K+Channel Blocker on Experimental Atrial Fibrillation
Authors: Machida Taiichi , Hashimoto Norio , Kuwahara Ippei , Ogino Yasuhiro , Matsuura Junji , Yamamoto Wataru , Itano Yasuhiro , Zamma Akira , Matsumoto Ryo , Kamon Junji , Kobayashi Tsunefumi , Ishiwata Norihisa , Yamashita Toru , Ogura Takehiko , Nakaya Haruaki 
Published: December 2010

Background—The acetylcholine-activated K+current (IK,ACh) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement ofIK,AChin atrial fibrillation (AF) using NTC-801, a novel potent and selectiveIK,AChblocker.Methods and Results—The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-2H-benzopyran-3-ol, onIK,AChand other cardiac ionic currents (INa,ICaL,Ito,IKur,IKr,IKs,IKl,IKATP, andIf) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-inducedIK,AChin guinea pig atrial cells and the GIRK1/4 current inXenopusoocytes with IC50values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibitedIK,ACh>1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD90) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD90at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in 3 AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period without affecting ventricular effective refractory period under vagal nerve stimulation. NTC-801 dose-dependently converted AF to normal sinus rhythm in both vagal nerve stimulation–induced (0.3 to 3 μg · kg−1· min−1IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg−1· min−1IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent.Conclusions—A selectiveIK,AChblockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest thatIK,AChmay be important in the development and maintenance of AF.
Willingness To Pay To Eliminate the Risk of Restenosis Following Percutaneous Coronary Intervention
Authors: Guertin Jason R. , Liu Aihua , Abrahamowicz Michal , Cohen David J. , Ismail Salma , LeLorier Jacques , Brophy James M. , Rinfret Stéphane 
Published: December 2010

Background—
Percutaneous coronary intervention (PCI) remains limited by the risk of restenosis. Patients' perceptions of the health benefits and value of avoiding restenosis are incompletely known.

Methods and Results—
We used a contingent valuation approach to assess the willingness to pay (WTP) for a hypothetical treatment that eliminates the risk of restenosis among 270 PCI patients. Patients were provided with a scenario describing a baseline 10% or 20% probability of restenosis in the year following the procedure, which could lead to repeat PCI or, more rarely, bypass surgery, without any increase in mortality. Six different “take it or leave it” bids ($500, $1000, $1500, $2000, $2500, and $3000) and both risk levels were randomly assigned. Multiple logistic regression was used to identify independent predictors of a positive response to the WTP question. Using nonparametric methods, the median WTP to eliminate the risk of restenosis was estimated at $2802. As expected, higher income was independently associated with a higher probability of a positive response to the WTP question (odds ratio, 2.81; 95% CI, 1.32 to 5.97). Bids also were independently associated with the probability of being willing to pay, and this association followed a quadratic effect. Below $1500, bid had little impact on patient answers. However, as prices increased, the probability of being willing to pay started to decrease sharply.

Conclusion—
The potential to eliminate the risk of restenosis, a benign complication, would have substantial value for patients undergoing PCI.
An Analysis of Near-Surface Winds, Air Temperature, and Cyclone Activity in Terra Nova Bay, Antarctica, from 1993 to 2009
Authors: Knuth Shelley L. , Cassano John J. 
Published: December 2010

Abstract
In September 2009, the first unmanned aerial vehicles were flown over Terra Nova Bay, Antarctica, to collect information regarding air–sea interactions. Prior to the field season, wind and temperature data from a local automatic weather station (AWS) were collected from 1993 to 2007 and compared with an August–October 2006–08 satellite cyclone analysis to place the September 2009 observations into a broader context. AWS wind data revealed a strong tendency toward downslope flow in the region regardless of season, as the majority (55%) of winds were from the west to northwesterly directions. Most winds observed at the site were less than 20 m s−1, but 83% of the stronger winds were associated with downslope flow. Of 15 strong wind events (greater than 20 m s−1 for more than 10 h) evaluated during the cyclone analysis period, 100% occurred in the presence of a cyclone in the adjacent Ross Sea. Winter experienced the greatest number of strong wind events (68%), and summer had the least (4%). Most temperatures were between −15° and −25°C, with temperatures influenced by wind fluctuations. The cyclone analysis revealed that 64% of systems were comma shaped, and most cyclones (84%) within the Ross Sea were mesocyclones. A comparison of AWS data for Septembers 1993–2007 and September 2009 showed more strong wind events during 2009, while the cyclone analysis revealed a shift in cyclonic activity eastward. Reanalysis data comparing September 1993–2007 and September 2009 show an eastward shift in a deeper upper-level trough, indicating that September 2009 was an anomalous year.