bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion
Authors: Gutiérrez-Fernández Ana , Fueyo Antonio , Folgueras Alicia R. , Garabaya Cecilia , Pennington Caroline J. , Pilgrim Simon , Edwards Dylan R. , Holliday Deborah L. , Jones J. Louise , Span Paul N. , Sweep Fred C.G.J. , Puente Xose S. , López-Otín Carlos 
Published: April 2008

Abstract
Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells. In this work, we have used mutant mice deficient in MMP-8 and syngenic melanoma and lung carcinoma tumor cells lines overexpressing this enzyme to further explore the putative antimetastatic potential of MMP-8. We report herein that MMP-8 prevents metastasis formation through the modulation of tumor cell adhesion and invasion. Thus, tumor cells overexpressing MMP-8 have an increased adhesion to extracellular matrix proteins, whereas their invasive ability through Matrigel is substantially reduced when compared with control cells. Analysis of MMP-8 in breast cancer patients revealed that the expression of this metalloproteinase by breast tumors correlates with a lower incidence of lymph node metastasis and confers good prognosis to these patients. On this basis, we propose that MMP-8 is a tumor protective factor, which also has the ability to reduce the metastatic potential of malignant cells in both mice and human. [Cancer Res 2008;68(8):2755–63]
Genome-Wide Promoter Analysis Uncovers Portions of the Cancer Methylome
Authors: Hoque Mohammad Obaidul , Kim Myoung Sook , Ostrow Kimberly Laskie , Liu Junwei , Wisman G. Bea A. , Park Hannah Lui , Poeta Maria Luana , Jeronimo Carmen , Henrique Rui , Lendvai Ágnes , Schuuring Ed , Begum Shahnaz , Rosenbaum Eli , Ongenaert Maté , Yamashita Keishi , Califano Joseph , Westra William , van der Zee Ate G.J. , Criekinge Wim Van , Sidransky David 
Published: April 2008

AbstractDNA methylation has a role in mediating epigenetic silencing of CpG island genes in cancer and other diseases. Identification of all gene promoters methylated in cancer cells “the cancer methylome” would greatly advance our understanding of gene regulatory networks in tumorigenesis. We previously described a new method of identifying methylated tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of re-expression on microarray analysis. In this study, we modified and greatly improved the selection of candidates based on new promoter structure algorithm and microarray data generated from 20 cancer cell lines of 5 major cancer types. We identified a set of 200 candidate genes that cluster throughout the genome of which 25 were previously reported as harboring cancer-specific promoter methylation. The remaining 175 genes were tested for promoter methylation by bisulfite sequencing or methylation-specific PCR (MSP). Eighty-two of 175 (47%) genes were found to be methylated in cell lines, and 53 of these 82 genes (65%) were methylated in primary tumor tissues. From these 53 genes, cancer-specific methylation was identified in 28 genes (28 of 53; 53%). Furthermore, we tested 8 of the 28 newly identified cancer-specific methylated genes with quantitative MSP in a panel of 300 primary tumors representing 13 types of cancer. We found cancer-specific methylation of at least one gene with high frequency in all cancer types. Identification of a large number of genes with cancer-specific methylation provides new targets for diagnostic and therapeutic intervention, and opens fertile avenues for basic research in tumor biology. [Cancer Res 2008;68(8):2661–70]
NOV-002, a Glutathione Disulfide Mimetic, as a Modulator of Cellular Redox Balance
Authors: Townsend Danyelle M. , He Lin , Hutchens Steven , Garrett Tracy E. , Pazoles Christopher J. , Tew Kenneth D. 
Published: April 2008

AbstractNOV-002 is a novel glutathione disulfide mimetic that when administered in combination with standard chemotherapeutic regimens has resulted in increased efficacy (survival, tumor response) and improved tolerance to chemotherapy (e.g., hematologic recovery) in advanced non–small cell lung cancer patients. We show that NOV-002, which is not cytotoxic as a single agent, generated time- and concentration-dependent oxidative signals at the cell surface (reduction in protein thiols) and intracellularly [altered oxidized glutathione (GSSG) and reduced glutathione levels and ratio; increased reactive oxygen species] in the premyeloid HL-60 cell line and that this was associated with an increase in S-glutathionylation of cell proteins, particularly actin. Commensurate with these effects, NOV-002 activated p38, c-Jun-NH2-kinase, and extracellular signal-regulated kinase and caused a dose-dependent increase in phosphorylation of three proteins that have previously been linked with hematopoiesis, AKT, JAK2, and STAT5. The effect of NOV-002 on enzymes involved in glutathione metabolism was evaluated. Relative to oxidized glutathione, NOV-002 was an equivalent substrate for glutathione reductase and was an inhibitor of protein disulfide isomerase, one of the components of the redox-sensitive unfolded protein response pathway. These redox-stimulated cell signaling actions occurred in the context of increased HL-60 cell proliferation after treatment with NOV-002. Overall, the pleiotropic pharmacologic effects of NOV-002 can be attributed to the GSSG component of the drug, and modulation of cellular redox balance is a feature central to the mechanism of action of NOV-002. Such modulation may underlie its clinical actions, including hematologic recovery and immunostimulation in the face of chemosuppression. [Cancer Res 2008;68(8):2870–7]
A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent Inhibition of mTOR Kinase Activity and Profound Repression of Global Protein Synthesis
Authors: Shor Boris , Zhang Wei-Guo , Toral-Barza Lourdes , Lucas Jessica , Abraham Robert T. , Gibbons James J. , Yu Ker 
Published: April 2008

Abstract
The mammalian target of rapamycin (mTOR) inhibitor CCI-779 (temsirolimus) is a recently Food and Drug Administration–approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies. In cell culture studies, CCI-779 at the commonly used nanomolar concentrations generally confers a modest and selective antiproliferative activity. Here, we report that, at clinically relevant low micromolar concentrations, CCI-779 completely suppressed proliferation of a broad panel of tumor cells. This “high-dose” drug effect did not require FKBP12 and correlated with an FKBP12-independent suppression of mTOR signaling. An FKBP12-rapamycin binding domain (FRB) binding–deficient rapamycin analogue failed to elicit both the nanomolar and micromolar inhibitions of growth and mTOR signaling, implicating FRB binding in both actions. Biochemical assays indicated that CCI-779 and rapamycin directly inhibited mTOR kinase activity with IC50 values of 1.76 ± 0.15 and 1.74 ± 0.34 μmol/L, respectively. Interestingly, a CCI-779–resistant mTOR mutant (mTOR-SI) displayed an 11-fold resistance to the micromolar CCI-779 in vitro (IC50, 20 ± 3.4 μmol/L) and conferred a partial protection in cells exposed to micromolar CCI-779. Treatment of cancer cells with micromolar but not nanomolar concentrations of CCI-779 caused a marked decline in global protein synthesis and disassembly of polyribosomes. The profound inhibition of protein synthesis was accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2α. These findings suggest that high-dose CCI-779 inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression. This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients. [Cancer Res 2008;68(8):2934–43]
DNA Methyltransferase 1 and 3B Activate BAG-1 Expression via Recruitment of CTCFL/BORIS and Modulation of Promoter Histone Methylation
Authors: Sun Lunching , Huang Lei , Nguyen Phuongmai , Bisht Kheem S. , Bar-Sela Gil , Ho Allen S. , Bradbury C. Matthew , Yu Wenqiang , Cui Hengmi , Lee Sunmin , Trepel Jane B. , Feinberg Andrew P. , Gius David 
Published: April 2008

Abstract
In a previous genomic analysis, using somatic methyltransferase (DNMT) knockout cells, we showed that hypomethylation decreased the expression of as many genes as were observed to increase, suggesting a previously unknown mechanism for epigenetic regulation. To address this idea, the expression of the BAG family genes was used as a model. These genes were used because their expression was decreased in DNMT1−/−, DNMT3B−/−, and double knockout cells and increased in DNMT1-overexpressing and DNMT3B-overexpressing cells. Chromatin immunoprecipitation analysis of the BAG-1 promoter in DNMT1-overexpressing or DNMT3B-overexpressing cells showed a permissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status associated with DNA-binding of CTCFL/BORIS, as well as increased BAG-1 expression. In contrast, a nonpermissive dimethyl-H3-K4/dimethyl-H3-K9 chromatin status was associated with CTCF DNA-binding and decreased BAG-1 expression in the single and double DNMT knockout cells. BORIS short hairpin RNA knockdown decreased both promoter DNA-binding, as well as BAG-1 expression, and changed the dimethyl-H3-K4/dimethyl-H3-K9 ratio to that characteristic of a nonpermissive chromatin state. These results suggest that DNMT1 and DNMT3B regulate BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation. [Cancer Res 2008;68(8):2726–35]
Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib
Authors: Weichsel Ralf , Dix Carolin , Wooldridge Linda , Clement Matthew , Fenton-May Angharad , Sewell Andrew K. , Zezula Josef , Greiner Elisabeth , Gostick Emma , Price David A. , Einsele Hermann , Seggewiss Ruth 
Published: April 2008

Abstract
Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator.
Experimental Design: Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNγ, and tumor necrosis factor α), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction.
Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations.
Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell–driven autoimmune diseases.
Up-Regulation of Peroxiredoxin 1 in Lung Cancer and Its Implication as a Prognostic and Therapeutic Target
Authors: Kim Joo-Heon , Bogner Paul N. , Baek Sun-Hee , Ramnath Nithya , Liang Ping , Kim Hak-Ryul , Andrews Chris , Park Young-Mee 
Published: April 2008

Abstract
Purpose: Peroxiredoxin 1 and 2 are highly homologous members of the Prx (or Prdx) protein family. Prx1 and Prx2 are elevated in several human cancers, and this seems to confer increased treatment resistance and aggressive phenotypes. This study was undertaken to examine the expression profiles of Prx1 and Prx2 in non–small cell lung cancer (NSCLC), and to test their prognostic value in predicting patient survival.
Experimental Design: To gain insight into the regulatory mechanisms of Prx1 and Prx2 expression in NSCLC, their respective transcript profiles were examined in NSCLC cell lines from the NCI-60 panel Affymetrix database sets, and the promoter compositions of the two genes were investigated using computer-based multiple sequence alignment analyses. Immunohistochemical analyses of Prx1 and Prx2 were done on a total of 235 NSCLC specimens with stage I through IV disease. The expression profiles of Prx1 and Prx2 in tumor specimens, and their associations with survival, were investigated.
Results and Conclusion: The levels of prx1 transcript were higher than those of prx2 in NSCLC cell lines, and the upstream regulatory sequences of the two genes display striking differences. The relative risk of death increased as Prx1 expression levels increased (P = 0.036) in a multivariate Cox model, independent of other clinicopathologic variables associated with survival. No statistically significant correlation was observed between Prx2 and survival. These results suggest that Prx1 may possess unique functions and regulatory mechanisms in NSCLC which are not shared with Prx2, and that Prx1 may serve as a new prognostic biomarker and therapeutic target in NSCLC.
Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells
Authors: Serova Maria , Ghoul Aïda , Benhadji Karim A. , Faivre Sandrine , Le Tourneau Christophe , Cvitkovic Esteban , Lokiec Francois , Lord Janet , Ogbourne Steven M. , Calvo Fabien , Raymond Eric 
Published: April 2008

AbstractPEP005 (ingenol-3-angelate) is a novel anticancer agent extracted from Euphorbia peplus that was previously shown to modulate protein kinase C (PKC), resulting in antiproliferative and proapoptotic effects in several human cancer cell lines. In Colo205 colon cancer cells, exposure to PEP005 induced a time- and concentration-dependent decrease of cells in S phase of cell cycle and apoptosis. In Colo205 cells exposed to PEP005, a variety of signaling pathways were activated as shown by increased phosphorylation of PKCδ, Raf1, extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase, p38 MAPK, and PTEN. PEP005-induced activation of PKCδ was associated with its translocation from the cytosol to the nucleus and other cellular membranes. Interestingly, PEP005 treatment also resulted in reduced expression of PKCα and reduced levels of phosphorylated active form of AKT/protein kinase B. These data suggest that PEP005-induced activation of PKCδ and reduced expression of PKCα resulted in apoptosis by mechanisms mediated by activation of Ras/Raf/MAPK and inhibition of the phosphatidylinositol 3-kinase/AKT signaling pathways. This study supports ongoing efforts targeting PKC isoforms in cancer therapy with PEP005 alone and in combination with other cytotoxic agents. [Mol Cancer Ther 2008;7(4):915–22]
Two-Sample Kalman Filter for Steady-State Data Assimilation
Authors: Sumihar Julius H. , Verlaan Martin , Heemink Arnold W. 
Published: April 2008

Abstract
In this paper, a new iterative algorithm for computing a steady-state Kalman gain is proposed. This algorithm utilizes two model forecasts with statistically independent random perturbations to determine the error covariance used to define a Kalman gain matrix for steady-state data assimilation. It is based on the assumption that the error process is weakly stationary and ergodic. The algorithm consists of an iterative procedure for improving the covariance estimate, which requires a fixed observation network. Two twin experiments using a simple wave model and an operational storm surge prediction model are performed to demonstrate the performance of the proposed algorithm. The experiments show that the results obtained by using the proposed algorithm converge to the ones produced by the classic Kalman filter algorithm. An additional experiment using the three-variable Lorenz model is also performed to demonstrate its potential applicability in unstable dynamical systems.
Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab
Authors: Khouri Issa F. , McLaughlin Peter , Saliba Rima M. , Hosing Chitra , Korbling Martin , Lee Ming S. , Medeiros L. Jeffrey , Fayad Luis , Samaniego Felipe , Alousi Amin , Anderlini Paolo , Couriel Daniel , de Lima Marcos , Giralt Sergio , Neelapu Sattva S. , Ueno Naoto T. , Samuels Barry I. , Hagemeister Fredrick , Kwak Larry W. , Champlin Richard E. 
Published: April 2008

Abstract
Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.
Analysis of bacterial DNA in synovial tissue of Tunisian patients with reactive and undifferentiated arthritis by broad-range PCR, cloning and sequencing
Authors: Siala Mariam , Jaulhac Benoit , Gdoura Radhouane , Sibilia Jean , Fourati Hela , Younes Mohamed , Baklouti Sofien , Bargaoui Naceur , Sellami Slaheddine , Znazen Abir , Barthel Cathy , Collin Elody , Hammami Adnane , Sghir Abdelghani 
Published: April 2008

Abstract
Introduction
Bacteria and/or their antigens have been implicated in the pathogenesis of reactive arthritis (ReA). Several studies have reported the presence of bacterial antigens and nucleic acids of bacteria other than those specified by diagnostic criteria for ReA in joint specimens from patients with ReA and various arthritides. The present study was conducted to detect any bacterial DNA and identify bacterial species that are present in the synovial tissue of Tunisian patients with reactive arthritis and undifferentiated arthritis (UA) using PCR, cloning and sequencing.

Methods
We examined synovial tissue samples from 28 patients: six patients with ReA and nine with UA, and a control group consisting of seven patients with rheumatoid arthritis and six with osteoarthritis (OA). Using broad-range bacterial PCR producing a 1,400-base-pair fragment from the 16S rRNA gene, at least 24 clones were sequenced for each synovial tissue sample. To identify the corresponding bacteria, DNA sequences were compared with sequences from the EMBL (European Molecular Biology Laboratory) database.

Results
Bacterial DNA was detected in 75% of the 28 synovial tissue samples. DNA from 68 various bacterial species were found in ReA and UA samples, whereas DNA from 12 bacteria were detected in control group samples. Most of the bacterial DNAs detected were from skin or intestinal bacteria. DNA from bacteria known to trigger ReA, such as Shigella flexneri and Shigella sonnei, were detected in ReA and UA samples of synovial tissue and not in control samples. DNA from various bacterial species detected in this study have not previously been found in synovial samples.

Conclusion
This study is the first to use broad-range PCR targeting the full 16S rRNA gene for detection of bacterial DNA in synovial tissue. We detected DNA from a wide spectrum of bacterial species, including those known to be involved in ReA and others not previously associated with ReA or related arthritis. The pathogenic significance of some of these intrasynovial bacterial DNAs remains unclear.
Using Accelerated Learning to Engage Employees and Deliver Results
Authors: Grant Fiona Louise 
Published: April 2008

Abstract
Organizations in the oil and gas industry around the world have placed an enormous importance on HS&E training as a way to help make employees more risk aware and, consequently, to reduce incidents from occurring. Traditionally, training methodologies have been conventional with limited active participation.
It is widely acknowledged that students engaging in this type of passive learning typically retain only 5–20% of the information conveyed. So, how do we close the gap on the 85%, increase effectiveness, and reduce time?
This paper will describe and demonstrate an accelerated learning methodology that actively engages students in learning and gives them ownership of the learning process.
Accelerated learning is activity-based and uses all the senses. It involves learning through sight, hearing, touch, and sometimes even smell and taste. In essence, it is highly participative and is only facilitated by the instructor.
This paper describes how this methodology has been used in the workplace to energize HS&E training and effect some real behavioral changes in employees. Because trainees take ownership of learning for themselves through a variety of interactive, facilitated activities, they retain more information and are more likely to apply it correctly in the workplace. This paper draws on case studies in over 15 countries, on 4 continents where this methodology has been used to:Develop the competence of HS&E SpecialistsInduct Graduate Engineers into a positive safety cultureCommunicate key HS&E requirements to supervisors & managersImprove the quality of risk/impact assessmentsTranscend cultural & language barriers
Results delivered include:100% positive trainee feedbackaverage 20% increase in perceived performance levelbetter quality risk/impact assessmentsincreased number of observation cards submitted