bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role for Stroma-Derived Annexin A1 as Mediator in the Control of Genetic Susceptibility to T-Cell Lymphoblastic Malignancies through Prostaglandin E2 Secretion
Authors: Santos Javier , González-Sánchez Laura , Matabuena-deYzaguirre María , Villa-Morales María , Cozar Patricia , López-Nieva Pilar , Fernández-Navarro Pablo , Fresno Manuel , Díaz-Muñoz Manuel D. , Guenet Jean-Louis , Montagutelli Xavier , Fernández-Piqueras José 
Published: February 2009

AbstractCancer susceptibility is essentially attributable to multiple low-penetrance genes. Using interspecific consomic and congenic mice between the tumor-resistant SEG/Pas and the tumor-sensitive C57BL/6J strains, a region on chromosome 19 involved in the genetic resistance to γ-irradiation–induced T-cell lymphomas (Tlyr1) has been identified. Through the development of nonoverlapping subcongenic strains, it has been further shown that Anxa1 may be a candidate resistance gene on the basis of its differential expression in thymus stroma cells after γ-radiation exposure. In addition, thymus stroma cells of thymic lymphomas exhibited a significant reduction in the expression levels of Anxa1. Interestingly, the activity of Anxa1 relies on prostaglandin E2 (PGE2) induction that brings about apoptosis in thymocytes. In fact, in vitro transfection experiments revealed that PGE2 production was enhanced when HEK 293 cells were transfected with full-length cDNAs of Anxa1, with PGE2 production in the cells transfected with the allele of the resistant strain (Anxa1Tyr) being higher than that in cells transfected with the allele of the susceptible strain (Anxa1Phe). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4+CD8+CD3low cells in a dose-dependent manner. These results improve our knowledge of the molecular mechanisms triggering T-cell lymphoblastic lymphoma development while highlighting the relevance of the stroma in controlling genetic susceptibility and the use of PGE2 as a new therapeutic approach in T-cell hematologic malignancies. [Cancer Res 2009;69(6):2577–87]
Design and Activity of a Murine and Humanized Anti-CEACAM6 Single-Chain Variable Fragment in the Treatment of Pancreatic Cancer
Authors: Riley Christopher J. , Engelhardt Kevin P. , Saldanha Jose W. , Qi Wenqing , Cooke Laurence S. , Zhu Yingting , Narayan Satya T. , Shakalya Kishore , Croce Kimiko Della , Georgiev Ivan G. , Nagle Raymond B. , Garewal Harinder , Von Hoff Daniel D. , Mahadevan Daruka 
Published: February 2009

AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal disease, with surgery being the only curative modality for localized disease, and gemcitabine with or without erlotinib remains the standard of therapy for unresectable or metastatic disease. CEACAM6 is overexpressed in human PDA independent of stage or grade and causes anoikis resistance when dysregulated. Because murine monoclonal antibody 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed a humanized anti-CEACAM6 single-chain variable fragment (scFv) based on monoclonal antibody 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFvs bound CEACAM6 with high affinity, exhibited cytotoxic activity, and induced dose-dependent poly(ADP-ribose) polymerase cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition, which was enhanced in combination with gemcitabine. Immunohistochemistry showed significant apoptosis, with inhibition of angiogenesis and proliferation, and preservation of the target. Collectively, our results have important implications for the development of novel antibody-based therapies against CEACAM6 in PDA. [Cancer Res 2009;69(5):1933–40]
miR-205 Exerts Tumor-Suppressive Functions in Human Prostate through Down-regulation of Protein Kinase Cε
Authors: Gandellini Paolo , Folini Marco , Longoni Nicole , Pennati Marzia , Binda Mara , Colecchia Maurizio , Salvioni Roberto , Supino Rosanna , Moretti Roberta , Limonta Patrizia , Valdagni Riccardo , Daidone Maria Grazia , Zaffaroni Nadia 
Published: February 2009

Abstract
Limited information is available concerning the expression and role of microRNAs in prostate cancer. In this study, we investigated the involvement of miR-205 in prostate carcinogenesis. Significantly lower miR-205 expression levels were found in cancer than in normal prostate cell lines as well as in tumor compared with matched normal prostate tissues, with a particularly pronounced reduction in carcinomas from patients with local-regionally disseminated disease. Restoring the expression of miR-205 in prostate cancer cells resulted in cell rearrangements consistent with a mesenchymal-to-epithelial transition, such as up-regulation of E-cadherin and reduction of cell locomotion and invasion, and in the down-regulation of several oncogenes known to be involved in disease progression (i.e., interleukin 6, caveolin-1, EZH2). Our evidence suggests that these events are driven by the concurrent repression of specific predicted miR-205 targets, namely N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase Cε. Strikingly, the latter seemed to play a direct role in regulating epithelial-to-mesenchymal transition. In fact, its down-regulation led to a cell phenotype largely reminiscent of that of cells ectopically expressing miR-205. Overall, we showed for the first time that miR-205 exerts a tumor-suppressive effect in human prostate by counteracting epithelial-to-mesenchymal transition and reducing cell migration/invasion, at least in part through the down-regulation of protein kinase Cε. [Cancer Res 2009;69(6):2287–95]
IFNγ Promotes Papilloma Development by Up-regulating Th17-Associated Inflammation
Authors: Xiao Mingjie , Wang Chunhui , Zhang Jinhua , Li Zhiguang , Zhao Xueqiang , Qin Zhihai 
Published: February 2009

AbstractIFNγ plays a crucial role in immunity against a variety of transplanted tumors and methylcholanthrene-mediated tumorigenesis in mice. However, it is not clear whether and how endogenous IFNγ influences 7,12-dimethylbenz(a)anthracene (DMBA)–induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced papilloma development. We found here that IFNγ expression was markedly up-regulated shortly after DMBA/TPA application to the skin. Surprisingly, neutralizing IFNγ activity in vivo did not increase but rather decreased tumor development. Furthermore, IFNγ receptor–deficient mice were also more resistant to papilloma development than their counterparts were. IFNγ acted mainly in the promotion stage of papilloma development by enhancing TPA-induced leukocyte infiltration and epidermal hyperproliferation. The up-regulation of tumor necrosis factor α, interleukin (IL)-6, and transforming growth factor β was largely dependent on host IFNγ responsiveness. Remarkably, up-regulation of both IL-17 expression in the skin and T helper 17 (Th17) cell number in draining lymph nodes after DMBA/TPA treatment was dependent on IFNγ signaling. Depletion of IL-17 not only decreased the DMBA/TPA–induced inflammation and keratinocyte proliferation but also delayed papilloma development. These results show that IFNγ, under certain conditions, may promote tumor development by enhancing a Th17-associated inflammatory reaction. [Cancer Res 2009;69(5):2010–7]
Control of HIF-1α Expression by eIF2α Phosphorylation–Mediated Translational Repression
Authors: Zhu Keyi , Chan WaiKin , Heymach John , Wilkinson Miles , McConkey David J. 
Published: February 2009

Abstract
Hypoxia inducible factor 1α (HIF-1α) plays a central role in regulating tumor angiogenesis via its effects on vascular endothelial growth factor (VEGF) transcription, and its expression is regulated through proteasome-mediated degradation. Paradoxically, previous studies have shown that proteasome inhibitors (PI) block tumor angiogensis by reducing VEGF expression, but the mechanisms have not been identified. Here, we report that PIs down-regulated HIF-1α protein levels and blocked HIF-1α transcriptional activity in human prostate cancer cells. PIs induced phosphorylation of the translation initiation factor 2α (eIF2α), which caused general translational repression to inhibit HIF-1α expression. Furthermore, PIs induced HIF-1α accumulation in LNCaP-Pro5 cells depleted of eIF2α via siRNA transfection and in MEFs expressing a phosphorylation-deficient mutant form of eIF2α. Finally, PIs failed to induce eIF2α phosphorylation or translational attenuation in DU145 or 253JB-V cells, and, in these cells, PIs promoted HIF-1α accumulation. Our data established that PIs down-regulated HIF-1α expression in cells that display activation of the unfolded protein response by stimulating phosphorylation of eIF2α and inhibiting HIF-1α translation. [Cancer Res 2009;69(5):1836–43]
Resistance to Chemotherapy Is Associated with Fibroblast Growth Factor Receptor 4 Up-Regulation
Authors: Roidl Andreas , Berger Hans-Jürgen , Kumar Sushil , Bange Johannes , Knyazev Pjotr , Ullrich Axel 
Published: February 2009

Abstract
Purpose: Establishment of antiapoptotic signaling pathways in tumor cells is a major cause for the failure of chemotherapy against cancer. To investigate the underlying mechanisms, we developed an experimental approach that is based on the genetic plasticity of cancer cells and the selection for cell survival on treatment with chemotherapeutic agents.
Experimental Design: Gene expression changes of surviving cell clones were analyzed by macroarrays. Involvement of fibroblast growth factor receptor 4 (FGFR4) in antiapoptotic pathways was elucidated by apoptosis assays, small interfering RNA experiments, and an antagonistic antibody.
Results: We show that FGFR4 gene expression is up-regulated in doxorubicin-treated, apoptosis-resistant cancer cell clones. Ectopic expression of FGFR4 in cancer cells led to reduced apoptosis sensitivity on treatment with doxorubicin or cyclophosphamide, whereas knockdown of endogenous FGFR4 expression in breast cancer cell lines had the opposite effect. FGFR4 overexpression resulted in Bcl-xl up-regulation at both mRNA and protein levels. Knockdown of FGFR4 expression by small interfering RNA caused a decrease in phospho-extracellular signal-regulated kinase 1/2 levels and reduced Bcl-xl expression. Moreover, an antagonistic FGFR4 antibody suppressed the resistance of cancer cells with endogenous FGFR4 expression against apoptosis-inducing chemotherapeutic agents.
Conclusion: Based on these findings, we propose an antiapoptotic signaling pathway that is initiated by FGFR4 and regulating the expression of Bcl-xl through the mitogen-activated protein kinase cascade. Our findings are exemplary for a novel strategy toward the elucidation of diverse signaling pathways that define antiapoptotic potential in cancer cells. These observations open new avenues toward the diagnosis of chemoresistant tumors and therapies targeting FGFR4-overexpressing cancers.
High VEGFR-3–positive Circulating Lymphatic/Vascular Endothelial Progenitor Cell Level Is Associated with Poor Prognosis in Human Small Cell Lung Cancer
Authors: Bogos Krisztina , Renyi-Vamos Ferenc , Dobos Judit , Kenessey Istvan , Tovari Jozsef , Timar Jozsef , Strausz Janos , Ostoros Gyula , Klepetko Walter , Ankersmit Hendrik Jan , Lang Gyorgy , Hoda Mir AliReza , Nierlich Patrick , Dome Balazs 
Published: February 2009

Abstract
Purpose: The newly identified bone marrow–derived cell population, called lymphatic/vascular endothelial progenitor cells (LVEPC), has been shown to contribute to lymph capillary growth in experimental tumor systems. The clinical significance of these cells has not yet been investigated in a human malignancy. Our aim was to study whether peripheral blood circulating LVEPCs participate in the progression of human small cell lung cancer (SCLC).
Experimental Design: A total of 88 patients with limited-stage SCLC and 32 tumor-free control subjects were included. Peripheral blood circulating LVEPC labeled with CD34 and vascular endothelial growth factor receptor-3 (VEGFR3) antibodies and the serum levels of the key lymphangiogenic molecule VEGF-C were measured by flow cytometry and ELISA, respectively.
Results: CD34-positive/VEGFR3-positive LVEPC levels were significantly increased in patients (versus controls; P &lt; 0.01), and there was also a significant relationship between LVEPC counts and lymph node metastasis (P &lt; 0.01). High pretreatment circulating LVEPC numbers correlated with poor overall survival (P &lt; 0.01). Although we observed significantly elevated VEGF-C concentrations in patients (versus controls; P &lt; 0.01), there was no significant correlation between VEGF-C and LVEPC levels. Moreover, no significant differences in peripheral blood VEGF-C levels were seen between patients subgrouped by clinicopathologic variables including tumor and lymph node stages and survival.
Conclusions: Peripheral blood levels of bone marrow–derived LVEPCs are significantly increased in patients with SCLC and correlate with lymphatic involvement and prognosis. This is the first study that shows evidence of increased numbers of circulating LVEPC in patients with a malignant tumor.
Radiotherapy Decreases Vascular Density and Causes Hypoxia with Macrophage Aggregation in TRAMP-C1 Prostate Tumors
Authors: Chen Fang-Hsin , Chiang Chi-Shiun , Wang Chun-Chieh , Tsai Chien-Sheng , Jung Shih-Ming , Lee Chung-Chi , McBride William H. , Hong Ji-Hong 
Published: February 2009

Abstract
Purpose: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors with respect to vascularity, hypoxia, and macrophage infiltrates.
Experimental Design: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays.
Results: Tumor growth was delayed for 1 week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed.
Conclusion: Irradiation of TRAMP-C1 tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.
Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins
Authors: Lemos Clara , Kathmann Ietje , Giovannetti Elisa , Beliën Jeroen A.M. , Scheffer George L. , Calhau Conceição , Jansen Gerrit , Peters Godefridus J. 
Published: February 2009

Abstract
As cellular folate levels seem to have a different effect on cancer cells from different origins, we extended our initial study to a broader panel of cancer cells. BCRP and MRP1-5 expression was determined in KB, OVCAR-3, IGROV-1, ZR75-1/R/MTX, SCC-11B, SCC-22B, and WiDr either grown in standard RPMI 1640 containing 2.3 μmol/L supraphysiologic concentration of folic acid [high folate (HF)] or adapted to more physiologic concentrations [1-5 nmol/L folic acid or leucovorin; low folate (LF)]. Compared with the HF counterparts, KB LF cells displayed 16.1-fold increased MRP3 and OVCAR-3 LF cells showed 4.8-fold increased MRP4 mRNA levels along with increased MRP3 and MRP4 protein expression, respectively. A marked increase on BCRP protein and mRNA expression was observed in WiDr LF cells. These cells acquired ∼2-fold resistance to mitoxantrone compared with the HF cell line, a phenotype that could be reverted by the BCRP inhibitor Ko143. Of note, WiDr cells expressed BCRP in the intracellular compartment, similarly to what we have described for Caco-2 cells. Our results provide further evidence for an important role of cellular folate status in the modulation of the expression of multidrug resistance transporters in cancer cells. We show that up-regulation of intracellularly localized BCRP in response to adaptation to LF conditions may be a common feature within a panel of colon cancer cell lines. Under these circumstances, folate supplementation might improve the efficacy of chemotherapeutic drugs by decreasing BCRP expression. [Mol Cancer Ther 2009;8(3):655–64]
p53 Deficiency Leads to Compensatory Up-Regulation of p16INK4a
Authors: Leong Wai Fook , Chau Jenny Fung Ling , Li Baojie 
Published: February 2009

Abstract
p53-p21-cyclin-dependent kinase and p16INK4a-cyclin-dependent kinase pathways have parallel functions in preventing tumorigenesis. In cancer patients, tumor suppressor p53 is frequently inactivated through mutations, whereas p16INK4a is silenced through promoter methylation. However, the interaction between these two pathways is less well understood. Here, we report that p53 controls p16INK4a expression in a unique way. p53 deficiency led to up-regulation of p16INK4a in primary mouse embryonic fibroblasts, osteoblasts, and various mouse organs, and an increase in the p16INK4a promoter activity, without affecting the half-life of p16INK4a. Reconstitution of p53, but not mutant p53, restored the proper expression of p16INK4a. These results indicate that p53 is necessary in repressing p16INK4a expression. However, up-regulation of p53 in response to genotoxic stress or nutlin-3 treatment did not down-regulate p16INK4a. p53 did not repress the p16INK4a promoter activity either. These findings suggest that p53 has a necessary but not sufficient role in repressing p16INK4a expression. p16INK4a elevation in p53−/− cells is, at least partially, mediated by Ets1, a known positive regulator of p16INK4a, as p53 deficiency up-regulated Ets1 through protein stabilization and knockdown of Ets1 down-regulated p16INK4a expression in p53−/− mouse embryonic fibroblasts. These studies uncover a compensatory mechanism for the loss of p53 and provide a basis for targeting both p53 and p16INK4a in cancer therapy. (Mol Cancer Res 2009;7(3):354–63)
Race, Genetic West African Ancestry, and Prostate Cancer Prediction by Prostate-Specific Antigen in Prospectively Screened High-Risk Men
Authors: Giri Veda N. , Egleston Brian , Ruth Karen , Uzzo Robert G. , Chen David Y.T. , Buyyounouski Mark , Raysor Susan , Hooker Stanley , Torres Jada Benn , Ramike Teniel , Mastalski Kathleen , Kim Taylor Y. , Kittles Rick 
Published: February 2009

Abstract“Race-specific” prostate-specific antigen (PSA) needs evaluation in men at high risk for prostate cancer for optimizing early detection. Baseline PSA and longitudinal prediction for prostate cancer were examined by self-reported race and genetic West African (WA) ancestry in the Prostate Cancer Risk Assessment Program, a prospective high-risk cohort. Eligibility criteria were age 35 to 69 years, family history of prostate cancer, African American race, or BRCA1/2 mutations. Biopsies were done at low PSA values (&lt;4.0 ng/mL). WA ancestry was discerned by genotyping 100 ancestry informative markers. Cox proportional hazards models evaluated baseline PSA, self-reported race, and genetic WA ancestry. Cox models were used for 3-year predictions for prostate cancer. Six hundred forty-six men (63% African American) were analyzed. Individual WA ancestry estimates varied widely among self-reported African American men. Race-specific differences in baseline PSA were not found by self-reported race or genetic WA ancestry. Among men with ≥1 follow-up visit (405 total, 54% African American), 3-year prediction for prostate cancer with a PSA of 1.5 to 4.0 ng/mL was higher in African American men with age in the model (P = 0.025) compared with European American men. Hazard ratios of PSA for prostate cancer were also higher by self-reported race (1.59 for African American versus 1.32 for European American, P = 0.04). There was a trend for increasing prediction for prostate cancer with increasing genetic WA ancestry. “Race-specific” PSA may need to be redefined as higher prediction for prostate cancer at any given PSA in African American men. Large-scale studies are needed to confirm if genetic WA ancestry explains these findings to make progress in personalizing prostate cancer early detection.
Comprehensive Proteome Analysis of an Apc Mouse Model Uncovers Proteins Associated with Intestinal Tumorigenesis
Authors: Hung Kenneth E. , Faca Vitor , Song Kenneth , Sarracino David A. , Richard Larissa Georgeon , Krastins Bryan , Forrester Sara , Porter Andrew , Kunin Alexandra , Mahmood Umar , Haab Brian B. , Hanash Samir M. , Kucherlapati Raju 
Published: February 2009

Abstract
Tumor-derived proteins may occur in the circulation as a result of secretion, shedding from the cell surface, or cell turnover. We have applied an in-depth comprehensive proteomic strategy to plasma from intestinal tumor–bearing Apc mutant mice to identify proteins associated with tumor development. We used quantitative tandem mass spectrometry of fractionated mouse plasma to identify differentially expressed proteins in plasma from intestinal tumor–bearing Apc mutant mice relative to matched controls. Up-regulated proteins were assessed for the expression of corresponding genes in tumor tissue. A subset of proteins implicated in colorectal cancer were selected for further analysis at the tissue level using antibody microarrays, Western blotting, tumor immunohistochemistry, and novel fluorescent imaging. We identified 51 proteins that were elevated in plasma with concordant up-regulation at the RNA level in tumor tissue. The list included multiple proteins involved in colon cancer pathogenesis: cathepsin B and cathepsin D, cullin 1, Parkinson disease 7, muscle pyruvate kinase, and Ran. Of these, Parkinson disease 7, muscle pyruvate kinase, and Ran were also found to be up-regulated in human colon adenoma samples. We have identified proteins with direct relevance to colorectal carcinogenesis that are present both in plasma and in tumor tissue in intestinal tumor–bearing mice. Our results show that integrated analysis of the plasma proteome and tumor transcriptome of genetically engineered mouse models is a powerful approach for the identification of tumor-related plasma proteins.
A Proposed Modification to the Robert–Asselin Time Filter*
Authors: Williams Paul D. 
Published: February 2009

Abstract
The Robert–Asselin time filter is widely used in numerical models of weather and climate. It successfully suppresses the spurious computational mode associated with the leapfrog time-stepping scheme. Unfortunately, it also weakly suppresses the physical mode and severely degrades the numerical accuracy. These two concomitant problems are shown to occur because the filter does not conserve the mean state, averaged over the three time slices on which it operates. The author proposes a simple modification to the Robert–Asselin filter, which does conserve the three-time-level mean state. When used in conjunction with the leapfrog scheme, the modification vastly reduces the impacts on the physical mode and increases the numerical accuracy for amplitude errors by two orders, yielding third-order accuracy. The modified filter could easily be incorporated into existing general circulation models of the atmosphere and ocean. In principle, it should deliver more faithful simulations at almost no additional computational expense. Alternatively, it may permit the use of longer time steps with no loss of accuracy, reducing the computational expense of a given simulation.