bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncolytic Adenovirus ICOVIR-7 in Patients with Advanced and Refractory Solid Tumors
Authors: Nokisalmi Petri , Pesonen Sari , Escutenaire Sophie , Särkioja Merja , Raki Mari , Cerullo Vincenzo , Laasonen Leena , Alemany Ramon , Rojas Juan , Cascallo Manel , Guse Kilian , Rajecki Maria , Kangasniemi Lotta , Haavisto Elina , Karioja-Kallio Aila , Hannuksela Päivi , Oksanen Minna , Kanerva Anna , Joensuu Timo , Ahtiainen Laura , Hemminki Akseli 
Published: May 2010

Abstract
Purpose: Twenty-one patients with cancer were treated with a single round of oncolytic adenovirus ICOVIR-7.
Experimental Design: ICOVIR-7 features an RGD-4C modification of the fiber HI-loop of serotype 5 adenovirus for enhanced entry into tumor cells. Tumor selectivity is mediated by an insulator, a modified E2F promoter, and a Rb-binding site deletion of E1A, whereas replication is optimized with E2F binding hairpins and a Kozak sequence. ICOVIR-7 doses ranged from 2 × 1010 to 1 × 1012 viral particles. All patients had advanced and metastatic solid tumors refractory to standard therapies.
Results: ICOVIR-7 treatment was well tolerated with mild to moderate fever, fatigue, elevated liver transaminases, chills, and hyponatremia. One patient had grade 3 anemia but no other serious side effects were seen. At baseline, 9 of 21 of patients had neutralizing antibody titers against the ICOVIR-7 capsid. Treatment resulted in neutralizing antibody titer induction within 4 weeks in 16 of 18 patients. No elevations of serum proinflammatory cytokine levels were detected. Viral genomes were detected in the circulation in 18 of 21 of patients after injection and 7 of 15 of the samples were positive 2 to 4 weeks later suggesting viral replication.
Conclusions: Overall, objective evidence of antitumor activity was seen in 9 of 17 evaluable patients. In radiological analyses, 5 of 12 evaluable patients had stabilization or reduction in tumor size. These consisted of one partial response, two minor responses and two cases of stable disease, all occurring in patients who had progressive disease before treatment. In summary, ICOVIR-7 treatment is apparently safe, resulting in anticancer activity, and is therefore promising for further clinical testing. Clin Cancer Res; 16(11); 3035–43. ©2010 AACR.
Mature MicroRNA Sequence Polymorphism in MIR196A2 Is Associated with Risk and Prognosis of Head and Neck Cancer
Authors: Christensen Brock C. , Avissar-Whiting Michele , Ouellet Lauren G. , Butler Rondi A. , Nelson Heather H. , McClean Michael D. , Marsit Carmen J. , Kelsey Karl T. 
Published: May 2010

Abstract
Purpose: The central role of microRNAs as regulators of translation has been well established, whereas the relationships between genetic variation in microRNAs and disease risk is only beginning to be explored. A polymorphism in the MIR196A2 locus has shown associations with lung, breast, esophageal, and gastric tumors but has not been examined in head and neck cancers, which share similar pathology and etiology to these diseases.
Experimental Design: We studied a polymorphism in the mature sequence of MIR196A2 (rs11614913, C/T) in a population-based case-control study (n = 1,039) of head and neck squamous cell carcinoma (HNSCC) to determine if MIR196A2 genotype was associated with disease occurrence and patient survival.
Results: Presence of any variant allele was associated with a significantly reduced risk for HNSCC (odds ratio, 0.8; 95% confidence interval, 0.56-0.99). Homozygous variant allele carriers with pharyngeal tumors had significantly reduced survival compared with wild-type and heterozygous cases (hazard ratio, 7.4; 95% confidence interval, 1.9–28.2). Expression analysis in a subset of tumors (n = 83) revealed no significant difference in relative expression of either miR-196a or miR-196a* by MIR196A2 genotype.
Conclusion: These data demonstrate a role for MIR196A2 genotype in susceptibility and prognosis of HNSCC. Clin Cancer Res; 16(14); 3713–20. ©2010 AACR.
Reversible Epithelial to Mesenchymal Transition and Acquired Resistance to Sunitinib in Patients with Renal Cell Carcinoma: Evidence from a Xenograft Study
Authors: Hammers Hans J. , Verheul Henk M. , Salumbides Brenda , Sharma Rajni , Rudek Michelle , Jaspers Janneke , Shah Preeti , Ellis Leigh , Shen Li , Paesante Silvia , Dykema Karl , Furge Kyle , Teh Bin T. , Netto George , Pili Roberto 
Published: May 2010

AbstractTyrosine kinase inhibitors (TKI) targeting angiogenesis via inhibition of the vascular endothelial growth factor pathway have changed the medical management of metastatic renal cell carcinoma. Although treatment with TKIs has shown clinical benefit, these drugs will eventually fail patients. The potential mechanisms of resistance to TKIs are poorly understood. To address this question, we obtained an excisional biopsy of a skin metastasis from a patient with clear cell renal carcinoma who initially had a response to sunitinib and eventually progressed with therapy. Tumor pieces were grafted s.c. in athymic nude mice. Established xenografts were treated with sunitinib. Tumor size, microvascular density, and pericyte coverage were determined. Plasma as well as tissue levels for sunitinib were assessed. A tumor-derived cell line was established and assessed in vitro for potential direct antitumor effects of sunitinib. To our surprise, xenografts from the patient who progressed on sunitinib regained sensitivity to the drug. At a dose of 40 mg/kg, sunitinib caused regression of the subcutaneous tumors. Histology showed a marked reduction in microvascular density and pericyte dysfunction. More interestingly, histologic examination of the original skin metastasis revealed evidence of epithelial to mesenchymal transition, whereas the xenografts showed reversion to the clear cell phenotype. In vitro studies showed no inhibitory effect on tumor cell growth at pharmacologically relevant concentrations. In conclusion, the histologic examination in this xenograft study suggests that reversible epithelial to mesenchymal transition may be associated with acquired tumor resistance to TKIs in patients with clear cell renal carcinoma. Mol Cancer Ther; 9(6); 1525–35. ©2010 AACR.
Global Targeting of Subcellular Heat Shock Protein-90 Networks for Therapy of Glioblastoma
Authors: Siegelin Markus D. , Plescia Janet , Raskett Christopher M. , Gilbert Candace A. , Ross Alonzo H. , Altieri Dario C. 
Published: May 2010

Abstract
Drug discovery for complex and heterogeneous tumors now aims at dismantling global networks of disease maintenance, but the subcellular requirements of this approach are not understood. Here, we simultaneously targeted the multiple subcellular compartments of the molecular chaperone heat shock protein-90 (Hsp90) in a model of glioblastoma, a highly lethal human malignancy in urgent need of fresh therapeutic strategies. Treatment of cultured or patient-derived glioblastoma cells with Shepherdin, a dual peptidomimetic inhibitor of mitochondrial and cytosolic Hsp90, caused irreversible collapse of mitochondria, degradation of Hsp90 client proteins in the cytosol, and tumor cell killing by apoptosis and autophagy. Stereotactic or systemic delivery of Shepherdin was well tolerated and suppressed intracranial glioma growth via inhibition of cell proliferation, induction of apoptosis, and reduction of angiogenesis in vivo. These data show that disabling Hsp90 cancer networks in their multiple subcellular compartments improves strategies for drug discovery and may provide novel molecular therapy for highly recalcitrant human tumors. Mol Cancer Ther; 9(6); 1638–46. ©2010 AACR.
Decitabine Maintains Hematopoietic Precursor Self-Renewal by Preventing Repression of Stem Cell Genes by a Differentiation-Inducing Stimulus
Authors: Hu Zhenbo , Negrotto Soledad , Gu Xiaorong , Mahfouz Reda , Ng Kwok Peng , Ebrahem Quteba , Copelan Edward , Singh Harinder , Maciejewski Jaroslaw P. , Saunthararajah Yogen 
Published: May 2010

Abstract
The cytosine analogue decitabine alters hematopoietic differentiation. For example, decitabine treatment increases self-renewal of normal hematopoietic stem cells. The mechanisms underlying decitabine-induced shifts in differentiation are poorly understood, but likely relate to the ability of decitabine to deplete the chromatin-modifying enzyme DNA methyltransferase 1 (DNMT1), which plays a central role in transcription repression. HOXB4 is a transcription factor that promotes hematopoietic stem cell self-renewal. In hematopoietic precursors induced to differentiate by the lineage-specifying transcription factor Pu.1 or by the cytokine granulocyte-colony stimulating factor, there is rapid repression of HOXB4 and other stem cell genes. Depletion of DNMT1 using shRNA or decitabine prevents HOXB4 repression by Pu.1 or granulocyte-colony stimulating factor and maintains hematopoietic precursor self-renewal. In contrast, depletion of DNMT1 by decitabine 6 hours after the differentiation stimulus, that is, after repression of HOXB4 has occurred, augments differentiation. Therefore, DNMT1 is required for the early repression of stem cell genes, which occurs in response to a differentiation stimulus, providing a mechanistic explanation for the observation that decitabine can maintain or increase hematopoietic stem cell self-renewal in the presence of a differentiation stimulus. Using decitabine to deplete DNMT1 after this early repression phase does not impair progressive differentiation. Mol Cancer Ther; 9(6); 1536–43. ©2010 AACR.
Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer
Authors: Nazarenko Irina , Jenny Marcel , Keil Jana , Gieseler Cornelia , Weisshaupt Karen , Sehouli Jalid , Legewie Stefan , Herbst Lena , Weichert Wilko , Darb-Esfahani Silvia , Dietel Manfred , Schäfer Reinhold , Ueberall Florian , Sers Christine 
Published: May 2010

Abstract
Intracellular signaling governed by serine/threonine kinases comprises the molecular interface between cell surface receptors and the nuclear transcriptional machinery. The protein kinase C (PKC) family members are involved in the control of many signaling processes directing cell proliferation, motility, and survival. Here, we examined a role of different PKC isoenzymes in protein phosphatase 2A (PP2A) and HRSL3 tumor suppressor–dependent cell death induction in the ovarian carcinoma cell line OVCAR-3. Phosphorylation and activity of PKC isoenzymes were measured in response to PP2A or phosphoinositide 3-kinase inhibition or HRSL3 overexpression. These experiments indicated a regulation of PKCθ, ϵ, ζ, and ι through PP2A and/or HRSL3, but not of PKCα and β. Using isoform-specific peptide inhibitors and overexpression approaches, we verified a contribution to PP2A- and HRLS3-dependent apoptosis only for PKCζ, suggesting a proapoptotic function of this kinase. We observed a significant proportion of human ovarian carcinomas expressing high levels of PKCζ, which correlated with poor prognosis. Primary ovarian carcinoma cells isolated from patients also responded to okadaic acid treatment with increased phosphorylation of PKCζ and apoptosis induction. Thus, our data indicate a contribution of PKCζ in survival control in ovarian carcinoma cells and suggest that upregulation or activation of tyrosine kinase receptors in this tumor might impinge onto apoptosis control through the negative regulation of the atypical PKCζ. Mol Cancer Res; 8(6); 919–34. ©2010 AACR.
Rictor Phosphorylation on the Thr-1135 Site Does Not Require Mammalian Target of Rapamycin Complex 2
Authors: Boulbes Delphine , Chen Chien-Hung , Shaikenov Tattym , Agarwal Nitin K. , Peterson Timothy R. , Addona Terri A. , Keshishian Hasmik , Carr Steven A. , Magnuson Mark A. , Sabatini David M. , Sarbassov Dos D. 
Published: May 2010

Abstract
In animal cells, growth factors coordinate cell proliferation and survival by regulating the phosphoinositide 3-kinase/Akt signaling pathway. Deregulation of this signaling pathway is common in a variety of human cancers. The PI3K-dependent signaling kinase complex defined as mammalian target of rapamycin complex 2 (mTORC2) functions as a regulatory Ser-473 kinase of Akt. We find that activation of mTORC2 by growth factor signaling is linked to the specific phosphorylation of its component rictor on Thr-1135. The phosphorylation of this site is induced by the growth factor stimulation and expression of the oncogenic forms of ras or PI3K. Rictor phosphorylation is sensitive to the inhibition of PI3K, mTOR, or expression of integrin-linked kinase. The substitution of wild-type rictor with its specific phospho-mutants in rictor null mouse embryonic fibroblasts did not alter the growth factor–dependent phosphorylation of Akt, indicating that the rictor Thr-1135 phosphorylation is not critical in the regulation of the mTORC2 kinase activity. We found that this rictor phosphorylation takes place in the mTORC2-deficient cells, suggesting that this modification might play a role in the regulation of not only mTORC2 but also the mTORC2-independent function of rictor. Mol Cancer Res; 8(6); 896–906. ©2010 AACR.
Resveratrol Suppresses Oxidative Stress and Inflammatory Response in Diethylnitrosamine-Initiated Rat Hepatocarcinogenesis
Authors: Bishayee Anupam , Barnes Kendra F. , Bhatia Deepak , Darvesh Altaf S. , Carroll Richard T. 
Published: May 2010

Abstract
Hepatocellular carcinoma (HCC), one of the most frequent and deadliest cancers, has been increasing considerably in the United States. In the absence of a proven effective therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC. Recently, we have reported that resveratrol, a compound present in grapes and red wine, significantly prevents diethylnitrosamine (DENA)–induced liver tumorigenesis in rats, although the mechanism of action is not completely understood. In the present study, we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis. There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study (20 weeks). Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals. Dietary resveratrol (50-300 mg/kg) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA. Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2–related factor 2 (Nrf2). Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated, at least in part, in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats. The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC. Cancer Prev Res; 3(6); 753–63. ©2010 AACR.
Nonpreferred Stimuli Modify the Representation of Faces in the Fusiform Face Area
Authors: Axelrod Vadim , Yovel Galit 
Published: May 2010

Abstract
The ventral visual cortex has a modular organization in which discrete and well-defined regions show a much stronger response to certain object categories (e.g., faces, bodies) than to other categories. The majority of previous studies have examined the response of these category-selective regions to isolated images of preferred or nonpreferred categories. Thus, little is known about the way these category-selective regions represent more complex visual stimuli, which include both preferred and nonpreferred stimuli. Here we examined whether glasses (nonpreferred) modify the representation of simultaneously presented faces (preferred) in the fusiform face area. We used an event-related fMR-adaptation paradigm in which faces were presented with glasses either on or above the face while subjects performed a face or a glasses discrimination task. Our findings show that the sensitivity of the fusiform face area to glasses was maximal when glasses were presented on the face than above the face during a face discrimination task rather than during a glasses discrimination task. These findings suggest that nonpreferred stimuli may significantly modify the representation of preferred stimuli, even when they are task irrelevant. Future studies will determine whether this interaction is specific to faces or may be found for other object categories in category-selective areas.
The Shelter of the Savage: “From Valladolid to the New World”
Authors: Pereda Felipe 
Published: May 2010

AbstractVegetal architecture, also known as Astwerk (literally “branch-work”) spread since the middle of the 15th century until the first two decades of the following century all over Europe. Efforts to interpret this phenomenon, however, have remained focused on the North European examples. The analysis of the extraordinary building of the Colegio of San Gregorio (Valladolid, Spain) shows how Astwerk in Castile was shaped both by the concrete ideas that related architecture and nature in the writings of Seneca, but also as a reflection of the first impressions of Europe’s encounter with the New World, where, as first reported by Columbus, the forces of nature and technology were viewed through startling and new lens.
Simulating Global and North American Climate Using the Global Environmental Multiscale Model with a Variable-Resolution Modeling Approach
Authors: Markovic Marko , Lin Hai , Winger Katja 
Published: May 2010

Abstract
Results from two simulations using the Global Environmental Multiscale (GEM) model in a variable-resolution modeling approach are evaluated. Simulations with a highly resolved domain positioned over North America and over the tropical Pacific–eastern Indian Ocean are assessed against the GEM uniform grid control run, 40-yr ECMWF Re-Analysis (ERA-40), and available observations in terms of regional and global climate and interannual variability.
It is found that the variable-resolution configurations realistically simulate global and regional climate over North America with seasonal means and variability generally closer to ERA-40 or observations than the control run. Systematic errors of the control run are still present within the variable-resolution simulations but alleviated to some extent over their respective highly resolved domains. Additionally, there is some evidence of performance deterioration due to the increased resolution.
There is little evidence that an increased resolution over the tropical Pacific–eastern Indian Ocean, with better-resolved local processes (e.g., convection and equatorial waves), has a significant impact on the extratropical time mean fields. However, in terms of simulating the Northern Hemisphere atmospheric flow anomaly associated with the dominant mode of sea surface temperature interannual variability in the equatorial eastern Pacific (i.e., El Niño), both stretched configurations have more realistic teleconnection patterns than the control run.
Defining priorities in prognostication research: results of a consensus workshop
Authors: Stevinson C. , Preston N. , Todd C. ,   Cancer Experiences Collaborative (CECo)
Published: May 2010

Purpose: To establish consensus among palliative care researchers on the priorities for prognostication research. Methods: A nominal group technique was employed involving palliative care researchers attending a workshop within a scientific meeting on prognostication. Participants worked in small facilitated groups to generate future research questions which were amalgamated and rated according to importance. Results: Twenty-five meeting delegates took part in the workshop including 10 palliative care physicians and four nurses, one dietician, and 10 academic researchers, all of whom had experience and/or interest in prognosis research. A total of 40 research questions were generated and after prioritization ratings, the top five questions were: (1) How valid are prognostic tools? (=2) Can we use prognostic criteria as entry criteria for research? (=2) How do we judge the impact of a prognostic score in clinical practice? (4) What is the best way of presenting survival data to patients? (5) What is the most user-friendly validated tool? Conclusions: Although a wide range of research questions relating to prognostication were identified, the strongest priority to emerge from the consensus data concerned the validity of prognostic tools. Further research to validate existing tools is essential to ensure their clinical value.
Barriers to the development of palliative care in Western Europe
Authors: Lynch T. , Clark D. , Centeno C. , Rocafort J. , de Lima L. , Filbet M. , Hegedus K. , Belle O. , Giordano A. , Guillén F. , Wright M. 
Published: May 2010

The Eurobarometer Survey of the EAPC Task Force on the Development of Palliative Care in Europe is part of a programme of work to produce comprehensive information on the provision of palliative care across Europe. Aim: To identify barriers to the development of palliative care in Western Europe. Method: A qualitative survey was undertaken amongst boards of national associations, eliciting opinions on opportunities for, and barriers to, palliative care development. By July 2006, 44/52 (85%) European countries had responded to the survey; we report here on the results from 22/25 (88%) countries in Western Europe. Analysis: Data from the Eurobarometer Survey were analysed thematically by geographical region and by the degree of development of palliative care in each country. Results: From the data contained within the Eurobarometer, we identified six significant barriers to the development of palliative care in Western Europe: (i) lack of palliative care education and training programmes; (ii) lack of awareness and recognition of palliative care; (iii) limited availability of/knowledge about opioid analgesics; (iv) limited funding; (v) lack of coordination amongst services; and (vi) uneven palliative care coverage. Conclusion: Findings from the EAPC Eurobarometer Survey suggest that barriers to the development of palliative care in Western Europe may differ substantially from each other in both their scope and context and that some may be considered to be of greater significance than others. A number of common barriers to the development of the discipline do exist and much work still remains to be done in the identified areas. This paper provides a road map of which barriers need to be addressed.