bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquisition of Epithelial-Mesenchymal Transition Phenotype of Gemcitabine-Resistant Pancreatic Cancer Cells Is Linked with Activation of the Notch Signaling Pathway
Authors: Wang Zhiwei , Li Yiwei , Kong Dejuan , Banerjee Sanjeev , Ahmad Aamir , Azmi Asfar Sohail , Ali Shadan , Abbruzzese James L. , Gallick Gary E. , Sarkar Fazlul H. 
Published: March 2009

Abstract
Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of “cancer stem-like cells”; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-κB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC. [Cancer Res 2009;69(6):2400–7]
GPR109A Is a G-protein–Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon
Authors: Thangaraju Muthusamy , Cresci Gail A. , Liu Kebin , Ananth Sudha , Gnanaprakasam Jaya P. , Browning Darren D. , Mellinger John D. , Smith Sylvia B. , Digby Gregory J. , Lambert Nevin A. , Prasad Puttur D. , Ganapathy Vadivel 
Published: March 2009

AbstractShort-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein–coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon. [Cancer Res 2009;69(7):2826–32]
Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors
Authors: Hochhauser Daniel , Meyer Timothy , Spanswick Victoria J. , Wu Jenny , Clingen Peter H. , Loadman Paul , Cobb Margaret , Gumbrell Lindsey , Begent Richard H. , Hartley John A. , Jodrell Duncan 
Published: March 2009

AbstractPurpose: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data.Experimental Design: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 μg/m2) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 μg/m2 due to unexpected toxicity.Results: The maximum tolerated dose of SJG-136 was 45 μg/m2. The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for &gt;6 weeks in 10 patients; in 2 patients this was maintained for &gt;12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive γ-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested.Conclusions: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.
Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model
Authors: Kadoch Cigall , Dinca Eduard B. , Voicu Ramona , Chen Lingjing , Nguyen Diana , Parikh Seema , Karrim Juliana , Shuman Marc A. , Lowell Clifford A. , Treseler Patrick A. , James C. David , Rubenstein James L. 
Published: March 2009

AbstractPurpose: The prospect for advances in the treatment of patients with primary central nervous system lymphoma (PCNSL) is likely dependent on the systematic evaluation of its pathobiology. Animal models of PCNSL are needed to facilitate the analysis of its molecular pathogenesis and for the efficient evaluation of novel therapeutics.Experimental Design: We characterized the molecular pathology of CNS lymphoma tumors generated by the intracerebral implantation of Raji B lymphoma cells in athymic mice. Lymphoma cells were modified for bioluminescence imaging to facilitate monitoring of tumor growth and response to therapy. In parallel, we identified molecular features of lymphoma xenograft histopathology that are evident in human PCNSL specimens.Results: Intracerebral Raji tumors were determined to faithfully reflect the molecular pathogenesis of PCNSL, including the predominant immunophenotypic state of differentiation of lymphoma cells and their reactive microenvironment. We show the expression of interleukin-4 by Raji and other B lymphoma cell lines in vitro and by Raji tumors in vivo and provide evidence for a role of this cytokine in the M2 polarization of lymphoma macrophages both in the murine model and in diagnostic specimens of human PCNSL.Conclusion: Intracerebral implantation of Raji cells results in a reproducible and invasive xenograft model, which recapitulates the histopathology and molecular features of PCNSL, and is suitable for preclinical testing of novel agents. We also show for the first time the feasibility and accuracy of tumor bioluminescence in the monitoring of a highly infiltrative brain tumor.
Aberrant Hyperactivation of Akt and Mammalian Target of Rapamycin Complex 1 Signaling in Sporadic Chordomas
Authors: Han Sangyeul , Polizzano Carolyn , Nielsen Gunnlaugur P. , Hornicek Francis J. , Rosenberg Andrew E. , Ramesh Vijaya 
Published: March 2009

AbstractPurpose: Chordomas are rare, malignant bone neoplasms in which the pathogenic mechanisms remain unknown. Interestingly, tuberous sclerosis complex (TSC) is the only syndrome in which the incidence of chordomas has been described. We previously reported the pathogenic role of the TSC genes in TSC-associated chordomas. In this study, we investigated whether aberrant TSC/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is associated with sporadic chordomas.Experimental Design: We assessed the status of mTORC1 signaling in primary tumors/cell lines of sacral chordomas and further examined upstream of mTORC1 signaling, including the PTEN (phosphatase and tensin homologue deleted on chromosome ten) tumor suppressor. We also tested the efficacy of the mTOR inhibitor rapamycin on signaling and growth of chordoma cell lines.Results: Sporadic sacral chordoma tumors and cell lines examined commonly displayed hyperactivated Akt and mTORC1 signaling. Strikingly, expression of PTEN, a negative regulator of mTORC1 signaling, was not detected or significantly reduced in chordoma-derived cell lines and primary tumors. Furthermore, rapamycin inhibited mTORC1 activation and suppressed proliferation of chordoma-derived cell line.Conclusions: Our results suggest that loss of PTEN as well as other genetic alterations that result in constitutive activation of Akt/mTORC1 signaling may contribute to the development of sporadic chordomas. More importantly, a combination of Akt and mTORC1 inhibition may provide clinical benefits to chordoma patients.
MicroRNA-21 Regulates the Proliferation and Invasion in Esophageal Squamous Cell Carcinoma
Authors: Hiyoshi Yukiharu , Kamohara Hidenobu , Karashima Ryuichi , Sato Nobutaka , Imamura Yu , Nagai Youhei , Yoshida Naoya , Toyama Eiichiro , Hayashi Naoko , Watanabe Masayuki , Baba Hideo 
Published: March 2009

Abstract
Purpose: MicroRNAs are ∼22 nucleotide noncoding RNA molecules that posttranscriptionally regulate gene expression. The aim of this study was (a) to determine a role of microRNA-21 in esophageal squamous cell carcinoma and (b) to elucidate the regulation of the programmed cell death 4 (PDCD4) gene by microRNA-21.
Experimental Design: MicroRNA-21 expression was investigated in 20 matched normal esophageal epitheliums and esophageal squamous cell carcinomas and seven esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30) by TaqMan quantitative real-time PCR and in situ hybridization. To evaluate the role of microRNA-21, cell proliferation and invasion were analyzed with anti–microRNA-21–transfected cells. In addition, the regulation of PDCD4 by microRNA-21 was elucidated to identify the mechanisms of this regulation.
Results: Of 20 paired samples, 18 cancer tissues overexpressed microRNA-21 in comparison with matched normal epitheliums. Specifically, patients with lymph node metastasis or venous invasion showed significantly high expression of microRNA-21. In situ hybridization for microRNA-21 showed strong positive staining in paraffin-embedded esophageal squamous cell carcinoma tissues. All seven esophageal squamous cell carcinoma cell lines also overexpressed microRNA-21, and anti–microRNA-21–transfected cells showed significant reduction in cellular proliferation and invasion. The PDCD4 protein levels in esophageal squamous cell carcinoma cells have an inverse correlation with microRNA-21 expression. Anti–microRNA-21–transfected cells increased PDCD4 protein expression without changing the PDCD4 mRNA level and increased a luciferase-reporter activity containing the PDCD4-3′ untranslated region construct.
Conclusions: MicroRNA-21 targets PDCD4 at the posttranscriptional level and regulates cell proliferation and invasion in esophageal squamous cell carcinoma. It may serve as a novel therapeutic target in esophageal squamous cell carcinoma.
HER-2, Notch, and Breast Cancer Stem Cells: Targeting an Axis of Evil
Authors: Korkaya Hasan , Wicha Max S. 
Published: March 2009

Abstract
Increasing evidence indicates that tumor-initiating (cancer stem) cells may contribute to treatment resistance and relapse, suggesting that improved clinical outcome will require effective targeting of this cell population. Recent studies suggest that the remarkable clinical efficacy of trastuzumab may relate to its ability to target cancer stem cell populations.
Algorithmic guided screening of drug combinations of arbitrary size for activity against cancer cells
Authors: Zinner Ralph G. , Barrett Brittany L. , Popova Elmira , Damien Paul , Volgin Andrei Y. , Gelovani Juri G. , Lotan Reuben , Tran Hai T. , Pisano Claudio , Mills Gordon B. , Mao Li , Hong Waun K. , Lippman Scott M. , Miller John H. 
Published: March 2009

Abstract
The standard treatment for most advanced cancers is multidrug therapy. Unfortunately, combinations in the clinic often do not perform as predicted. Therefore, to complement identifying rational drug combinations based on biological assumptions, we hypothesized that a functional screen of drug combinations, without limits on combination sizes, will aid the identification of effective drug cocktails. Given the myriad possible cocktails and inspired by examples of search algorithms in diverse fields outside of medicine, we developed a novel, efficient search strategy called Medicinal Algorithmic Combinatorial Screen (MACS). Such algorithms work by enriching for the fitness of cocktails, as defined by specific attributes through successive generations. Because assessment of synergy was not feasible, we developed a novel alternative fitness function based on the level of inhibition and the number of drugs. Using a WST-1 assay on the A549 cell line, through MACS, we screened 72 combinations of arbitrary size formed from a 19-drug pool across four generations. Fenretinide, suberoylanilide hydroxamic acid, and bortezomib (FSB) was the fittest. FSB performed up to 4.18 SD above the mean of a random set of cocktails or “too well” to have been found by chance, supporting the utility of the MACS strategy. Validation studies showed FSB was inhibitory in all 7 other NSCLC cell lines tested. It was also synergistic in A549, the one cell line in which this was evaluated. These results suggest that when guided by MACS, screening larger drug combinations may be feasible as a first step in combination drug discovery in a relatively small number of experiments. [Mol Cancer Ther 2009;8(3):521–32]
Comparative Analysis of DNA Repair in Stem and Nonstem Glioma Cell Cultures
Authors: Ropolo Monica , Daga Antonio , Griffero Fabrizio , Foresta Mara , Casartelli Gianluigi , Zunino Annalisa , Poggi Alessandro , Cappelli Enrico , Zona Gianluigi , Spaziante Renato , Corte Giorgio , Frosina Guido 
Published: March 2009

Abstract
It has been reported that cancer stem cells may contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. We have examined DNA repair in five stem and nonstem glioma cell lines. The population doubling time was significantly increased in stem compared with nonstem cells, and enhanced activation of Chk1 and Chk2 kinases was observed in untreated CD133+ compared with CD133− cells. Neither DNA base excision or single-strand break repair nor resolution of pH2AX nuclear foci were increased in CD133+ compared with CD133− cells. We conclude that glioma stem cells display elongated cell cycle and enhanced basal activation of checkpoint proteins that might contribute to their radioresistance, whereas enhanced DNA repair is not a common feature of these cells. (Mol Cancer Res 2009;7(3):383–92)
Stratospheric Communication of El Niño Teleconnections to European Winter
Authors: Bell C. J. , Gray L. J. , Charlton-Perez A. J. , Joshi M. M. , Scaife A. A. 
Published: March 2009

Abstract
The stratospheric role in the European winter surface climate response to El Niño–Southern Oscillation sea surface temperature forcing is investigated using an intermediate general circulation model with a well-resolved stratosphere. Under El Niño conditions, both the modeled tropospheric and stratospheric mean-state circulation changes correspond well to the observed “canonical” responses of a late winter negative North Atlantic Oscillation and a strongly weakened polar vortex, respectively. The variability of the polar vortex is modulated by an increase in frequency of stratospheric sudden warming events throughout all winter months. The potential role of this stratospheric response in the tropical Pacific–European teleconnection is investigated by sensitivity experiments in which the mean state and variability of the stratosphere are degraded. As a result, the observed stratospheric response to El Niño is suppressed and the mean sea level pressure response fails to resemble the temporal and spatial evolution of the observations. The results suggest that the stratosphere plays an active role in the European response to El Niño. A saturation mechanism whereby for the strongest El Niño events tropospheric forcing dominates the European response is suggested. This is examined by means of a sensitivity test and it is shown that under large El Niño forcing the European response is insensitive to stratospheric representation.
Synoptic-Statistical Approach to Regional Downscaling of IPCC Twenty-First-Century Climate Projections: Seasonal Rainfall over the Hawaiian Islands*
Authors: Timm Oliver , Diaz Henry F. 
Published: March 2009

AbstractA linear statistical downscaling technique is applied to the projection of the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) climate change scenarios onto Hawaiian rainfall for the late twenty-first century. Hawaii’s regional rainfall is largely controlled by the strength of the trade winds. During the winter months, disturbances in the westerlies can produce heavy rainfall throughout the islands. A diagnostic analysis of sea level pressure (SLP), near-surface winds, and rainfall measurements at 134 weather observing stations around the islands characterize the correlations between the circulation and rainfall during the nominal wet season (November–April) and dry season (May–October). A comparison of the base climate twentieth-century AR4 model simulations with reanalysis data for the period 1970–2000 is used to define objective selection criterion for the AR4 models. Six out of 21 available models were chosen for the statistical downscaling. These were chosen on the basis of their ability to more realistically simulate the modern large-scale circulation fields in the Hawaiian Islands region.For the AR4 A1B emission scenario, the six analyzed models show important changes in the wind fields around Hawaii by the late twenty-first century. Two models clearly indicate opposite signs in the anomalies. One model projects 20%–30% rainfall increase over the islands; the other model suggests a rainfall decrease of about 10%–20% during the wet season. It is concluded from the six-model ensemble that the most likely scenario for Hawaii is a 5%–10% reduction of the wet-season precipitation and a 5% increase during the dry season, as a result of changes in the wind field. The authors discuss the sources of uncertainties in the projected rainfall changes and consider future improvements of the statistical downscaling work and implications for dynamical downscaling methods.
A novel method for producing target cells and assessing cytotoxic T lymphocyte activity in outbred hosts
Authors: Bonci Francesca , Zabogli Elisa , Conti Francesca , Merico Antonio , Freer Giulia , Bendinelli Mauro , Pistello Mauro 
Published: March 2009

Abstract

Background
Cytotoxic T lymphocytes play a crucial role in the immunological control of microbial infections and in the design of vaccines and immunotherapies. Measurement of cytotoxic T lymphocyte activity requires that the test antigen is presented by target cells having the same or compatible class I major hystocompatibility complex antigens as the effector cells. Conventional assays use target cells labeled with 51chromium and infer cytotoxic T lymphocyte activity by measuring the isotope released by the target cells lysed following incubation with antigen-specific cytotoxic T lymphocytes. This assay is sensitive but needs manipulation and disposal of hazardous radioactive reagents and provides a bulk estimate of the reporter released, which may be influenced by spontaneous release of the label and other poorly controllable variables. Here we describe a novel method for producing target in outbred hosts and assessing cytotoxic T lymphocyte activity by flow cytometry.

Results
The method consists of culturing skin fibroblasts, immortalizing them with a replication defective clone of simian virus 40, and finally transducing them with a bicistronic vector encoding the target antigen and the reporter green fluorescent protein. When used in a flow cytometry-based assay, the target cells obtained with this method proved valuable for assessing the viral envelope protein specific cytotoxic T lymphocyte activity in domestic cats acutely or chronically infected with feline immunodeficiency virus, a lentivirus similar to human immunodeficiency virus and used as animal model for AIDS studies.

Conclusion
Given the versatility of the bicistronic vector used, its ability to deliver multiple and large transgenes in target cells, and its extremely wide cell specificity when pseudotyped with the vesicular stomatitis virus envelope protein, the method is potentially exploitable in many animal species.
Therapy monitoring of multiple sclerosis1
Authors: Deisenhammer Florian 
Published: March 2009

Abstract
The variety of pharmacological therapy of multiple sclerosis (MS) has increased substantially in the past couple of years with differing mechanisms of action. Reduction of clinical activity in terms of relapses is the main effect of these therapies; however, the delay of disease progression can be achieved from time to time. Owing to the rare clinical event rate with less than one relapse per year and slow progression, the clinical evaluation of therapeutic efficacy seems difficult. Therefore, laboratory supported therapy monitoring would be desirable and can from time to time be supportive of clinical decision-making. Also, most of the therapies are associated with side effects and these need to be evaluated by laboratory supported monitoring. The various possibilities and the usefulness of laboratory supported monitoring of MS therapy will be discussed in the present article.