bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly Specific Auto-Antibodies against Claudin-18 Isoform 2 Induced by a Chimeric HBcAg Virus-Like Particle Vaccine Kill Tumor Cells and Inhibit the Growth of Lung Metastases
Authors: Klamp Thorsten , Schumacher Jens , Huber Georg , Kühne Christoph , Meissner Ulrich , Selmi Abderraouf , Hiller Thomas , Kreiter Sebastian , Markl Jürgen , Türeci Özlem , Sahin Ugur 
Published: January 2011

AbstractStrategies for antibody-mediated cancer immunotherapy, such as active immunization with virus-like particle (VLP)-based vaccines, are gaining increasing attention. We developed chimeric hepatitis B virus core antigen (HBcAg)-VLPs that display a surface epitope of the highly selective tumor-associated cell lineage marker claudin-18 isoform 2 (CLDN18.2) flanked by a mobility-increasing linker. Auto-antibodies elicited by immunization with these chimeric HBcAg-VLPs in 2 relevant species (mouse and rabbit) bind with high precision to native CLDN18.2 at physiologic densities on the surface of living cells but not to the corresponding epitope of the CLDN18.1 splice variant that differs by merely one amino acid. The induced auto-antibodies are capable of efficiently killing CLDN18.2 expressing cells in vitro by complement-dependent and antibody-dependent cell-mediated cytotoxicity. Moreover, they provide partial protective immunity against the challenge of mice with syngeneic tumor cells stably expressing CLDN18.2. Our study provides a first proof-of-concept that immunization combining VLPs as antigen carriers with specific conformational epitopes of a highly selective differentiation antigen may elicit auto-antibodies with high cytocidal and tumoricidal potential. Cancer Res; 71(2); 516–27. ©2011 AACR.
Decreased Expression and Androgen Regulation of the Tumor Suppressor Gene INPP4B in Prostate Cancer
Authors: Hodgson Myles C. , Shao Long-jiang , Frolov Anna , Li Rile , Peterson Leif E. , Ayala Gustavo , Ittmann Michael M. , Weigel Nancy L. , Agoulnik Irina U. 
Published: January 2011

Abstract
Patients with metastatic prostate cancer who undergo androgen-ablation therapy invariably relapse and develop incurable castration-resistant disease. Activation of the prosurvival Akt pathway accompanies androgen ablation. We discovered that the androgen receptor induces the expression of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) but not PTEN in prostate cancer cells. Optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR. INPP4B dephosphorylates phosphatidylinositol-3, 4-bisphosphate, which leads to reduced phosphorylation and activity of Akt. In support of a key role for INPP4B in Akt control, INPP4B depletion activated Akt and increased cellular proliferation. The clinical significance of INPP4B in androgen-dependent prostate cancers was determined in normal or primary tumor prostate tissues derived from radical prostatectomy specimens. In primary tumors, the expression of both INPP4B and PTEN was substantially reduced compared with normal tissue. Further, the decreased expression of INPP4B reduced the time to biochemical recurrence. Thus, androgen ablation can activate the Akt pathway via INPP4B downregulation, thereby mitigating the antitumor effects of androgen ablation. Our findings reinforce the concept that patients undergoing androgen ablation may benefit from Akt-targeting therapies. Cancer Res; 71(2); 572–82. ©2011 AACR.
Minimal Engagement of CD103 on Cytotoxic T Lymphocytes with an E-Cadherin-Fc Molecule Triggers Lytic Granule Polarization via a Phospholipase Cγ–Dependent Pathway
Authors: Floc'h Audrey Le , Jalil Abdelali , Franciszkiewicz Katarzyna , Validire Pierre , Vergnon Isabelle , Mami-Chouaib Fathia 
Published: January 2011

AbstractInteraction of the integrin αE(CD103)β7 expressed on tumor-infiltrating lymphocytes (TIL) with E-cadherin on epithelial tumor cells is required to trigger polarized exocytosis of cytotoxic granules in TIL that elicit tumor cell lysis. In this study, we investigated the functional and signaling properties of CD103 and its individual contribution to T-cell–mediated cancer-cell killing. Our results indicated that the binding of CD103 on tumor-specific CTL to immobilized recombinant E-cadherin-Fc is sufficient to induce the polarization of cytolytic granules, whereas the degranulation of cytolytic granules also requires the coengagement of the T-cell receptor. Moreover, minimal CD103 triggering promotes the phosphorylation of the ERK1/2 kinases and phospholipase Cγ1 (PLCγ1). Inhibiting PLCγ blocks granule relocalization, decreasing T-cell receptor–mediated cytotoxicity. Thus, our results emphasize a unique costimulatory role of CD103 in tumor-specific CTL activation by providing signals that promote T-cell effector functions needed to specifically target and lyse cancer cells. Cancer Res; 71(2); 328–38. ©2011 AACR.
MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
Authors: Ma Stephanie , Chan Yuen Piu , Kwan Pak Shing , Lee Terence K. , Yan Mingxia , Tang Kwan Ho , Ling Ming Tat , Vielkind Juergen R. , Guan Xin-Yuan , Chan Kwok Wah 
Published: January 2011

Abstract
Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
p190RhoGEF (Rgnef) Promotes Colon Carcinoma Tumor Progression via Interaction with Focal Adhesion Kinase
Authors: Yu Hong-Gang , Nam Ju-Ock , Miller Nichol L. G. , Tanjoni Isabelle , Walsh Colin , Shi Lei , Kim Linda , Chen Xiao Lei , Tomar Alok , Lim Ssang-Taek , Schlaepfer David D. 
Published: January 2011

Abstract
Focal adhesion kinase (FAK) functions downstream of integrins and growth factor receptors to promote tumor cell motility and invasion. In colorectal cancer, FAK is activated by amidated gastrin, a protumorigenic hormone. However, it is unclear how FAK receives signals from the gastrin receptor or other G-protein–coupled receptors that can promote cell motility and invasion. The Rho guanine-nucleotide exchange factor p190RhoGEF (Rgnef) binds FAK and facilitates fibroblast focal adhesion formation on fibronectin. Here we report that Rgnef mRNA and protein expression are significantly increased during colorectal tumor progression. In human colon carcinoma cells, Rgnef forms a complex with FAK and upon gastrin stimulation, FAK translocates to newly-forming focal adhesions where it facilitates tyrosine phosphorylation of paxillin. short hairpin (shRNA)-mediated knockdown of Rgnef or FAK, or pharmacological inhibition of FAK activity, is sufficient to block gastrin-stimulated paxillin phosphorylation, cell motility, and invadopodia formation in a manner dependent upon upstream cholecystokinin-2 receptor expression. Overexpression of the C-terminal region of Rgnef (Rgnef-C, amino acid 1,279–1,582) but not Rgnef-CΔFAK (amino acid 1,302–1,582 lacking the FAK binding site) disrupted endogenous Rgnef-FAK interaction and prevented paxillin phosphorylation and cell motility stimulated by gastrin. Rgnef-C–expressing cells formed smaller, less invasive tumors with reduced tyrosine phosphorylation of paxillin upon orthotopic implantation, compared with Rgnef-CΔFAK–expressing cells. Our studies identify Rgnef as a novel regulator of colon carcinoma motility and invasion, and they show that a Rgnef–FAK linkage promotes colon carcinoma progression in vivo. Cancer Res; 71(2); 360–70. ©2011 AACR.
The First Tianjin, China Forum on Tumor Microenvironment
Authors: Keller Evan T. , Li Lu-Yuan 
Published: January 2011

Abstract
Although it is well recognized that the tumor microenvironment plays a key role in regulating tumor progression, the mechanisms through which this occurs need to be defined. Current international research activities toward defining the role of the tumor microenvironment in cancer progression were the subject of the first Tianjin Forum on Tumor Microenvironment held at Nankai University in Tianjin, China, July 2 to 4, 2010. The importance of variety of processes, such as inflammation and angiogenesis, in the role of tumor progression was described for multiple tumor types including breast, prostate, and hepatic cancers, as well as the process of bone metastasis. Identification of novel signaling pathways that impact both angiogenesis and bone remodeling were presented. Several themes emerged from this meeting, such as: (i) tumor cells modify the microenvironment to enhance their own survival and progression; (ii) targeting host factors, in addition to targeting tumor cells, will have important therapeutic effects; and (iii) host cells distribution within the tumor has both prognostic and therapeutic significance. Several priorities for future research were defined including use of a systems biology approach to define the role of host factors in tumor progression, to define the importance of targeting both arms of the bone remodeling process for therapy of bone metastasis, and to determine how different cell subsets contribute to microenvironment-mediated regulation of tumor progression. Cancer Res; 71(2); 310–3. ©2011 AACR.
Combination Therapy with Vidaza and Entinostat Suppresses Tumor Growth and Reprograms the Epigenome in an Orthotopic Lung Cancer Model
Authors: Belinsky Steven A. , Grimes Marcie J. , Picchi Maria A. , Mitchell Hugh D. , Stidley Chris A. , Tesfaigzi Yohannes , Channell Meghan M. , Liu Yanbin , Casero Robert A. , Baylin Stephen B. , Reed Mathew D. , Tellez Carmen S. , March Thomas H. 
Published: January 2011

Abstract
Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of proapoptotic genes and the cyclin-dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the reexpression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings show the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs. Cancer Res; 71(2); 454–62. ©2011 AACR.
A 4-Gene Signature Associated with Clinical Outcome in High-Grade Gliomas
Authors: de Tayrac Marie , Aubry Marc , Saïkali Stephan , Etcheverry Amandine , Surbled Cyrille , Guénot Frédérique , Galibert Marie-Dominique , Hamlat Abderrahmane , Lesimple Thierry , Quillien Véronique , Menei Philippe , Mosser Jean 
Published: January 2011

Abstract
Purpose: Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors.
Experimental Design: We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status.
Results: This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P &lt; 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26–0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P &lt; 0.001).
Conclusion: The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas. Clin Cancer Res; 17(2); 317–27. ©2011 AACR.
Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Sorafenib
Authors: Kelly Ronan J. , Rajan Arun , Force Jeremy , Lopez-Chavez Ariel , Keen Corrine , Cao Liang , Yu Yunkai , Choyke Peter , Turkbey Baris , Raffeld Mark , Xi Liqiang , Steinberg Seth M. , Wright John J. , Kummar Shivaani , Gutierrez Martin , Giaccone Giuseppe 
Published: January 2011

AbstractPurpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non–small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity.Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (&lt;6 vs. &gt;6 pg/mL; P = 0.042), whereas a PFS benefit was seen with bFGF at day 28 (&lt;6 vs. &gt;6; P = 0.028).Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition. Clin Cancer Res; 17(5); 1190–9. ©2011 AACR.
Biology, Models, and the Analysis of Tumor Xenograft Experiments
Authors: Heitjan Daniel F. 
Published: January 2011

Abstract
Advances in statistical modeling and analysis technology have improved our ability to derive valid inferences from tumor xenograft experiments. Further challenges in this area include the modeling of intertumor heterogeneity and the development of robust statistical models that describe key parameters in the underlying tumor biology. Clin Cancer Res; 17(5); 949–52. ©2011 AACR.
ORAI1-Mediated Calcium Influx in Lactation and in Breast Cancer
Authors: McAndrew Damara , Grice Desma M. , Peters Amelia A. , Davis Felicity M. , Stewart Teneale , Rice Michelle , Smart Chanel E. , Brown Melissa A. , Kenny Paraic A. , Roberts-Thomson Sarah J. , Monteith Gregory R. 
Published: January 2011

Abstract
The entry of calcium into the mammary epithelial cell from the maternal plasma (i.e., calcium influx mechanisms) during lactation is poorly understood. As alterations in calcium channels and pumps are a key feature of some cancers, including breast cancer, understanding these calcium influx pathways may have significance beyond mammary biology. We show that the store-operated calcium influx protein, Orai1, is increased during lactation whereas the Orai1 activator Stim1, but not Stim2, is downregulated. Stim2 siRNA reduced basal calcium levels in a lactation model. Our results suggest that calcium influx is remodeled in mammary epithelial cells during lactation, with calcium influx increased through Orai1, activated by Stim2. Breast cancer cell lines had increased levels of ORAI1. ORAI1 siRNA in breast cancer cells reduced store-operated calcium entry and remodeled the calcium influx associated with invasive stimuli. Analysis of microarray data from 295 breast cancers showed that the transcriptional breast cancer subtype with the poorest prognosis (basal) was associated with an altered relationship between the ORAI1 regulators STIM1 and STIM2, and that women with breast cancers with STIM1high/STIM2low tumors had a significantly poorer prognosis. Our studies show that during lactation there is a remodeling in the nature of calcium influx and that alteration in the ORAI1 influx pathway may be a feature of some breast cancers, particularly those with the poorest prognosis. Our studies suggest that this pathway may be a novel therapeutic target for breast cancer treatment in these women. Mol Cancer Ther; 10(3); 448–60. ©2011 AACR.
A highly sensitive thrombin generation assay for assessment of recombinant activated factor VII therapy in haemophilia patients with an inhibitor
Authors: Zivelin Ariella , Rima Dardik , Livnat Tami , Martinowitz Uri , Kenet Gili 
Published: January 2011

SummaryBypass agents are the common treatment for haemophilia patients who develop inhibitory antibodies. Laboratory assessment of the efficacy of bypassing agent therapy is a challenge. In the present work we modified the conditions triggering thrombin generation (TG) assay in order to find the most sensitive assay for detection of rFVIIa and its analogue NN1731 in haemophilic plasma. TG was measured in samples of normal plasma, plasma of haemophilia patient with inhibitors, as well as haemophilia induced plasma. Recalcification-induced TG was compared to tissue factor (TF) -induced TG in the presence and absence of rFVIIa and NN1731. Recalcification-induced TG (without TF) in haemophilic plasma yielded baseline flat curves, with increased TG as a consequence of spiking the plasma rFVIIa. Using our system, we observed both dose-dependence and time-dependence of rFVIIa effect on TG. Elevated concentrations of TF mask the difference between rFVIIa-treated and non-treated haemophilic plasma. NN1731 yielded normal-isation of recalcification-induced TG curves (without TF) which may reflect high potency. In conclusion, we suggest that triggering TG by recalcification-only may be the most sensitive assay for determining the impact of bypassing agents in haemophilic plasma, and may serve as a caution surrogate safety marker in future studies.
Clinical Referral Patterns for Carotid Artery Stenting Versus Carotid Endarterectomy
Authors: Longmore Ryan B. , Yeh Robert W. , Kennedy Kevin F. , Anderson H. Vernon , White Christopher J. , Longmore Lance S. , Rosenfield Kenneth , Ho Kalon K. L. , Spertus John A. 
Published: January 2011

Background—
Carotid artery stenting (CAS) and carotid endarterectomy (CEA) are alternative strategies for stroke prevention in patients with atherosclerotic carotid disease. Although randomized clinical trials are the gold standard for assessing the relative benefits of different treatments, observational research is necessary for determining “real-world” effectiveness. Current recommendations limit the application of CAS to high-risk patients, undermining the ability to “balance” the characteristics of patients treated with either approach. We compared the clinical profiles of patients referred for CAS versus CEA in a large national database.

Methods and Results—
Clinical characteristics of 12 701 patients referred for CAS or CEA in the National Cardiovascular Data Registry–Carotid Artery Revascularization and Endarterectomy were compared for 44 clinical and demographic variables. To investigate the comparability of CAS and CEA patients, we stratified the cohort into quintiles of the propensity score for referral for CAS. Among 8069 patients referred for CAS and 4632 referred for CEA, the CAS patients had significantly more comorbidities. Whereas the propensity model balanced most covariates, the pooled standardized differences (≥10%) suggested persistent imbalance for ischemic heart disease, recent myocardial infarction, and restenosis of prior CAS/CEA, all of which were more common in the CAS group. After stratification of propensity scores by quintile, CEA patients comprised only 14% of the upper 2 quintiles.

Conclusions—
Characteristics of patients referred for CAS differ markedly from those referred for CEA. Because of extreme clinical disparities between these patients, generalizable comparative effectiveness analyses of observational data will be difficult.
Temporal Frames of Reference: Conceptual Analysis and Empirical Evidence from German, English, Mandarin Chinese and Tongan
Authors: Bender Andrea , Beller Sieghard , Bennardo Giovanni 
Published: January 2011

Abstract
Despite a close correspondence between spatial and temporal cognition, empirical approaches to the two domains have used distinct theoretical conceptions: frames of reference for the former, and moving perspectives and reference-point metaphors for the latter. Our analysis reveals that these conceptions can ‐ and should ‐ be related more closely to each other. Mapping spatial frames of reference (FoRs) onto temporal relations, we obtain a taxonomy that allows us to distinguish more types of referencing than existing conceptions do and that is applicable to linguistic cases not accounted for so far. A cross-cultural experiment with speakers of German, English, Chinese and Tongan provides evidence for the psychological reality of the newly proposed FoRs and establishes culture-specific preferences. We conclude that spatial referencing systems indeed help to organize temporal representations.