bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Epithelial-Mesenchymal Transition Mediator S100A4 Maintains Cancer-Initiating Cells in Head and Neck Cancers
Authors: Lo Jeng-Fan , Yu Cheng-Chia , Chiou Shih-Hwa , Huang Chih-Yang , Jan Chia-Ing , Lin Shu-Chun , Liu Chung-Ji , Hu Wen-Yuan , Yu Yau-Hua 
Published: December 2010

Abstract
Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemness-maintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs. Cancer Res; 71(5); 1912–23. ©2010 AACR.
A Mammaglobin-A Targeting Agent for Noninvasive Detection of Breast Cancer Metastasis in Lymph Nodes
Authors: Tafreshi Narges K. , Enkemann Steven A. , Bui Marilyn M. , Lloyd Mark C. , Abrahams Dominique , Huynh Amanda S. , Kim Jongphil , Grobmyer Stephen R. , Carter W. Bradford , Vagner Josef , Gillies Robert J. , Morse David L. 
Published: December 2010

Abstract
Pathologic axillary lymph node (ALN) status is an important prognostic factor for staging breast cancer. Currently, status is determined by histopathology following surgical excision of sentinel lymph node(s), which is an invasive, time consuming, and costly procedure with potential morbidity to the patient. Here, we describe an imaging platform for noninvasive assessment of ALN status, eliminating the need for surgical examination of patients to rule out nodal involvement. A targeted imaging probe (MamAb-680) was developed by conjugation of a mammaglobin-A–specific monoclonal antibody to a near-infrared fluorescent dye. Using DNA and tissue microarray, mammaglobin-A was validated as a cell-surface target that is expressed in ALN-positive patient samples but is not expressed in normal lymph nodes. In vivo selectivity was determined by i.v. injection of MamAb-680 into mice with mammaglobin-A–positive and -negative mammary fat pad (MFP) tumors; and by peritumoral MFP injection of the targeted imaging probe in mice with spontaneous ALN metastases. Fluorescence imaging showed that probe was only retained in positive tumors and metastases. As few as 1,000 cells that endogenously express mammaglobin-A were detected in ALN, indicating high sensitivity of this method. Translation of this approach offers considerable potential as a noninvasive clinical strategy to stage breast cancer. Cancer Res; 71(3); 1050–9. ©2010 AACR.
The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas
Authors: Jain Harsh Vardhan , Meyer-Hermann Michael 
Published: December 2010

AbstractResistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-xL, whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-xL that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-xL for survival. Numerical simulations predict the existence of a threshold of Bcl-xL below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 705–15. ©2010 AACR.
Explaining Marginal Benefits to Patients, When “Marginal” Means Additional but Not Necessarily Small
Authors: Smith Thomas J. , Hillner Bruce E. 
Published: December 2010

Abstract
Patients and their families want us to be realistic, honest, and caring about their prognosis and their options, even when the news is bad. Most oncologists will tell a patient if he is not curable, but not give specific survival information unless prompted. As an example, chemotherapy for pancreas cancer improves survival and does not worsen quality of life, but the impact on lifespan is small. Patients with advanced pancreas cancer have options that increase their average survival by about 16/100 at 1 year, and by about 9 weeks compared with best supportive care, but almost all patients are dead by 24 months. As an example of “marginal benefit” (“marginal” is defined here as more than that offered by the alternative care, not necessarily small or worthless), erlotinib added to gemcitabine compared with gemcitabine alone improves survival by six additional people at 1 year, and an average of 2 weeks, with no survival tail. In addition, the additional drug cost alone can be more than $12,000 a month. We use this clinical practice as a way to describe marginal benefit to patients. Telling patients that they have incurable disease and that treatment is ineffective is hard. Partly as a result, only about a third of cancer patients are told they are going to die, and those who are not told live no longer but have worse medical outcomes, such as dying on a ventilator and less time with hospice. These difficult conversations can be done if the oncologist has the right medical information, the right script, and some decision aids. Clin Cancer Res; 16(24); 5981–6. ©2010 AACR.
CYP24A1Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma
Authors: Chen Guoan , Kim So Hee , King Amanda N. , Zhao Lili , Simpson Robert U. , Christensen Paul J. , Wang Zhuwen , Thomas Dafydd G. , Giordano Thomas J. , Lin Lin , Brenner Dean E. , Beer David G. , Ramnath Nithya 
Published: December 2010

AbstractPurpose: The active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25-D3), exerts antiproliferative effects in cancers, including lung adenocarcinoma (AC). CYP24A1 is overexpressed in many cancers and encodes the enzyme that catabolizes 1,25-D3. The purpose of our study was to assess CYP24A1 as a prognostic marker and to study its relevance to antiproliferative activity of 1,25-D3 in lung AC cells.Experimental Design: Tumors and corresponding normal specimens from 86 patients with lung AC (stages I–III) were available. Affymetrix array data and subsequent confirmation by quantitative real time-PCR were used to determine CYP24A1 mRNA expression. A subsequent validation set of 101 lung AC was used to confirm CYP24A1 mRNA expression and its associations with clinical variables. The antiproliferative effects of 1,25-D3 were examined using lung cancer cell lines with high as well as low expression of CYP24A1 mRNA.Results: CYP24A1 mRNA was elevated 8- to 50-fold in lung AC (compared to normal nonneoplastic lung) and significantly higher in poorly differentiated cancers. At 5 years of follow-up, the probability of survival was 42% (high CYP24A1, n = 29) versus 81% (low CYP24A1, n = 57) (P = 0.007). The validation set of 101 tumors showed that CYP24A1 was independently prognostic of survival (multivariate Cox model adjusted for age, gender, and stage, P = 0.001). A549 cells (high CYP24A1) were more resistant to antiproliferative effects of 1,25-D3 compared with SKLU-1 cells (low CYP24A1).Conclusions: CYP24A1 overexpression is associated with poorer survival in lung AC. This may relate to abrogation of antiproliferative effects of 1,25-D3 in high CYP24A1 expressing lung AC. Clin Cancer Res; 17(4); 817–26. ©2010 AACR.
EfficientIn vivoPriming by Vaccination with Recombinant NY-ESO-1 Protein and CpG in Antigen Naïve Prostate Cancer Patients
Authors: Karbach Julia , Neumann Antje , Atmaca Akin , Wahle Claudia , Brand Kathrin , von Boehmer Lotta , Knuth Alexander , Bender Armin , Ritter Gerd , Old Lloyd J. , Jäger Elke 
Published: December 2010

AbstractPurpose: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated.Experimental Design: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 μg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor.Results: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91–110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4+ and/or CD8+ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8+ T-cell clones recognized and lyzed HLA-matched tumor cell lines in an antigen-specific manner.Conclusion: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8+ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo. Clin Cancer Res; 17(4); 1–10. ©2010 AACR.
Functional Genomics Reveals Diverse Cellular Processes That Modulate Tumor Cell Response to Oxaliplatin
Authors: Harradine Kelly A. , Kassner Michelle , Chow Donald , Aziz Meraj , Von Hoff Daniel D. , Baker Joffre B. , Yin Hongwei , Pelham Robert J. 
Published: December 2010

Abstract
Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects, including prolonged neurotoxicity, from oxaliplatin treatment creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, which when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to overexpress two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, overexpression conferred resistance to oxaliplatin. In summary, this study identified numerous putative predictive biomarkers of response to oxaliplatin that should be studied further in patient specimens for potential clinical application. Diverse gene networks seem to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin. Mol Cancer Res; 9(2); 173–82. ©2010 AACR.
High Glucose Enhances Thrombin Responses via Protease-Activated Receptor-4 in Human Vascular Smooth Muscle Cells
Authors: Dangwal Seema , Rauch Bernhard H. , Gensch Thomas , Dai Luru , Bretschneider Ellen , Vogelaar Christina Francisca , Schrör Karsten , Rosenkranz Anke C. 
Published: December 2010

Objective—
Diabetes is associated with vascular remodeling and increased thrombin generation. Thrombin promotes vascular smooth muscle cell (SMC) mitogenesis and migration via protease-activated receptors (PAR)-1, PAR-3, and PAR-4. We investigated the effect of high glucose on expression and function of vascular thrombin receptors.

Methods and Results—
In human vascular SMCs, high glucose (25 versus 5.5 mmol/L) induced a rapid and sustained increase in PAR-4 mRNA, protein, and cell surface expression. PAR-1 and PAR-3 expression were not changed. High glucose pretreatment (48 hours) enhanced thrombin or PAR-4–activating peptide but not PAR-1–activating peptide evoked intracellular calcium mobilization, migration, and tumor necrosis factor α gene expression. This enhancement of thrombin-stimulated migration and gene expression by high glucose was abolished by endogenous PAR-4 knockdown.
PAR-4 regulation was prevented by inhibition of protein kinase (PK)C-β and -δ isoforms or nuclear factor (NF)κB. Nuclear translocation of NFκB in high glucose–stimulated SMCs led to PKC-dependent NFκB binding to the PAR-4 promoter in a chromatin immunoprecipitation assay. Furthermore, in situ hybridization and immunohistochemistry confirmed high abundance of PAR-4 in human diabetic vessels as compared with nondiabetic vessels.

Conclusion—
High glucose enhances SMC responsiveness to thrombin through transcriptional upregulation of PAR-4, mediated via PKC-β, -δ, and NFκB. This may play an important role in the vascular complications of diabetes.
Familial Thoracic Aortic Aneurysms and Dissections
Authors: Guo Dong-Chuan , Regalado Ellen S. , Minn Charles , Tran-Fadulu Van , Coney Joshua , Cao Jiumei , Wang Min , Yu Robert K. , Estrera Anthony L. , Safi Hazim J. , Shete Sanjay S. , Milewicz Dianna M. 
Published: December 2010

Background—
Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease.

Methods and Results—
A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene.

Conclusions—
Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.
Tissue Kallikrein Is Essential for Invasive Capacity of Circulating Proangiogenic Cells
Authors: Spinetti Gaia , Fortunato Orazio , Cordella Daniela , Portararo Paola , Kränkel Nicolle , Katare Rajesh , Sala-Newby Graciela B. , Richer Christine , Vincent Marie-Pascale , Alhenc-Gelas Francois , Tonolo Giancarlo , Cherchi Sara , Emanueli Costanza , Madeddu Paolo 
Published: December 2010

Rationale:Homing of proangiogenic cells (PACs) is guided by chemoattractants and requires proteases to disrupt the extracellular matrix. The possibility that PAC recruitment involves an interaction between proteases and chemotactic factor receptors remains largely unexplored.Objective:To determine the role of human tissue kallikrein (hK1) in PAC invasion and its dependency on kinin receptor signaling.Methods and Results:Human mononuclear cells (MNCs) and culture-selected PACs express and release mature hK1 protein. HK1 gene (KLK1) silencing reduced PACs migratory, invasive, and proangiogenic activities.KLK1-knockout mouse bone marrow–derived MNCs showed similar impairments and were unable to support reparative angiogenesis in a mouse model of peripheral ischemia. Conversely, adenovirus-mediatedKLK1(Ad.KLK1) gene transfer enhanced PAC-associated functions, whereas the catalytically inactive variantR53H-KLK1was ineffective. HK1-induced effects are mediated by a kinin B2receptor (B2R)-dependent mechanism involving inducible nitric oxide synthase and metalloproteinase-2 (MMP2). Lower hK1 protein levels were observed in PACs from type 2 diabetic (T2D) patients, whereasKLK1mRNA levels were similar to those of healthy subjects, suggesting a post-transcriptional defect. Furthermore, B2R is normally expressed on T2D-PACs but remains uncoupled from downstream signaling. Importantly, whereasAd.KLK1alone could not restore T2D-PAC invasion capacity, combinedKLK1andB2Rexpression rescued the diabetic phenotype.Conclusions:This study reveals new interactive components of the PACs invasive machinery, acting via protease- and kinin receptor–dependent mechanisms.
Targeting the Ischemic Penumbra
Authors: Ramos-Cabrer Pedro , Campos Francisco , Sobrino Tomás , Castillo José 
Published: December 2010

Background—
In the last 3 decades, and from a therapeutic point of view, the classical concept of ischemic penumbra based on hemodynamic and electrophysiological parameters has loosened up the rigidity of therapeutic windows in acute stroke management. Thirty years later, the ischemic penumbra is an evolved concept that presents more applications. Thus, the ischemic penumbra is a diagnostic target, allowing the extension of therapeutic windows; it is also a biochemical target, in which an intermittent bioenergetic compromise takes place, and it is a target for brain plasticity, neuroprotection, and neurorepair.

Summary of Review—
In this work, we review how the concept of ischemic penumbra has been evolving from its purely electrophysiological/ hemodynamic based definition to the wider metabolic–cellular–therapeutic concept that is managed today by neuroscientists.
The Ecclesial Body's Grace: Obedience and Faithfulness in Rowan Williams' Ecclesiology
Authors: Higton Mike 
Published: December 2010

AbstractIn his 1989 lecture, 'The Body's Grace', Rowan Williams describes sexual relationships as capable of playing a role in the communication and learning of the gospel. I argue that the lecture gives the church a threefold task in relation to such relationships: to call them to loving mutuality, to faithfulness, and to faith. The same pattern characterises Williams' ecclesiology, and helps make sense of many of his public statements about recent Anglican controversies: as Archbishop of Canterbury he sees himself as tasked with issuing the same threefold call to the participants in ecclesial arguments about obedience.
An Ecclesiological Journey: The Way of the Methodist – Roman Catholic International Dialogue
Authors: Wainwright Geoffrey 
Published: December 2010

AbstractEcclesiology eventually imposed itself as the main theme of the international Methodist / Catholic dialogue by virtue of what have been from the beginning the differences in the respective self-understanding and ecclesial claims of the partners. Confessing that no ecclesiology shaped in a time of division is likely to be entirely satisfactory, the Joint Commission in its Nairobi Report of 1986 ('Towards a Statement on the Church') began exploring 'ways of being one Church' that might obtain in the case of reunion, and the goal of the Methodist / Catholic dialogue was formulated as 'full communion in faith, mission and sacramental life'; and so it has remained, although 'governance' should probably be added as a fourth element in communion. By the time of the Seoul Report of 2006 ('The Grace Given You in Christ: Catholics and Methodists Reflect Further on the Church'), the Commission decided to face head-on the need for 'a mutual reassessment' in the 'new context' set by the ecumenical movement: each partner would look at the other with the eye of faith for what could be discerned there as 'truly of Christ and of the Gospel and thereby of the Church'. The way was thus opened for an 'exchange of gifts' on the road to 'full communion'. The dialogue continues to confront long-standing questions on what may be called 'the instrumentality of grace' as the Joint Commission prepares a Report for Durban 2011 on 'Encountering Christ the Saviour: Church and Sacraments'. The classic Faith and Order themes of baptism, eucharist and ministry remain in need of full settlement, and an ecumenical confession of 'the faith of the Church' would be welcome. Meanwhile, the Joint Commission has produced – under the title 'Together to Holiness'- a thematic synthesis of the first eight rounds of dialogue (1967-2006).
ПЕРЕПИСКА А. С. ЛАППО-ДАНИЛЕВСКОГО И П. Н. МИЛЮКОВА
Authors:   Трибунский
Published: December 2010

AbstractПереписка двух известных русских историков рубежа XIX–XX вв. А.С. ЛаппоДанилевского (1863–1919) и П.Н. Милюкова (1859–1943) охватывает 1889–1914 гг., с преимущественным вниманием к периоду 1889–1891 гг. Переписка велась в период становления их как историков, вхождения в ученую корпорацию, времени появления их первых серьезных трудов. Основные темы переписки: диссертация ЛаппоДанилевского о финансовой истории Московской Руси и возражения на нее Милюкова, продвижение коллег по службе, новости и сплетни об историках. Переписка позволяет восстановить существенные детали развития исторической науки в России, университетской жизни конца XIX в., биографии ряда историков. Публикация сопровождается достаточно полным комментарием по содержанию и вводит в научный оборот ценный исторический источник из трех архивных хранилищ России и США.