bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adipocytes Impair Leukemia Treatment in Mice
Authors: Behan James W. , Yun Jason P. , Proektor Marina P. , Ehsanipour Ehsan A. , Arutyunyan Anna , Moses Ara S. , Avramis Vassilios I. , Louie Stan G. , Butturini Anna , Heisterkamp Nora , Mittelman Steven D. 
Published: September 2009

Abstract
Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P &lt; 0.05). Interestingly, this protection was independent of cell-cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment. [Cancer Res 2009;69(19):7867–74]
c-Myc and eIF4F Constitute a Feedforward Loop That Regulates Cell Growth: Implications for Anticancer Therapy
Authors: Lin Chen-Ju , Malina Abba , Pelletier Jerry 
Published: September 2009

Abstract
The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. Recent findings indicate that the role of Myc during cell growth and proliferation is linked to an increase in eIF4F activity in a feedforward relationship, providing a possible molecular mechanism of cell transformation by Myc. Developing therapeutics to inhibit eIF4F and/or Myc could be a potential treatment for a wide range of human cancers. [Cancer Res 2009;69(19):7491–4]
Expression of IFN-β Enhances Both Efficacy and Safety of Oncolytic Vesicular Stomatitis Virus for Therapy of Mesothelioma
Authors: Willmon Candice L. , Saloura Vassiliki , Fridlender Zvi G. , Wongthida Phonphimon , Diaz Rosa Maria , Thompson Jill , Kottke Timothy , Federspiel Mark , Barber Glen , Albelda Steven M. , Vile Richard G. 
Published: September 2009

Abstract
Our preclinical and clinical trials using a replication-defective adenoviral vector expressing IFN-β have shown promising results for the treatment of malignant mesothelioma. Based on the hypotheses that a replication-competent vesicular stomatitis virus (VSV) oncolytic vector would transduce more tumor cells in vivo, that coexpression of the immunostimulatory IFN-β gene would enhance the immune-based effector mechanisms associated both with regression of mesotheliomas and with VSV-mediated virotherapy, and that virus-derived IFN-β would add further safety to the VSV platform, we tested the use of IFN-β as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma. VSV-IFN-β showed significant therapy against AB12 murine mesotheliomas in the context of both local and locoregional viral delivery. Biologically active IFN-β expressed from VSV added significantly to therapy compared with VSV alone, dependent in part on host CD8+ T-cell responses. Immune monitoring suggested that these antitumor T-cell responses may be due to a generalized T-cell activation rather than the priming of tumor antigen–specific T-cell responses. Finally, IFN-β also added considerable extra safety to the virus by providing protection from off-target viral replication in nontumor tissues and protected severe combined immunodeficient mice from developing lethal neurotoxicity. The enhanced therapeutic index provided by the addition of IFN-β to VSV therefore provides a powerful justification for the development of this virus for future clinical trials. [Cancer Res 2009;69(19):7713–20]
Rearrangements and Amplification of IER3 (IEX-1) Represent a Novel and Recurrent Molecular Abnormality in Myelodysplastic Syndromes
Authors: Steensma David P. , Neiger Jessemy D. , Porcher Julie C. , Keats J. Jonathan , Bergsagel P. Leif , Dennis Thomas R. , Knudson Ryan A. , Jenkins Robert B. , Santana-Davila Rafael , Kumar Rajiv , Ketterling Rhett P. 
Published: September 2009

Abstract
IER3 (formerly IEX-1) encodes a 27-kDa glycoprotein that regulates death receptor–induced apoptosis, interacts with NF-κB pathways, and increases expression rapidly in response to cellular stresses such as irradiation. Animal models, gene expression microarray experiments, and functional studies in cell lines have suggested a potential role for IER3 in oncogenesis, but, to date, no abnormalities of IER3 at the DNA level have been reported in patients with neoplasia. Here, we describe breakpoint cloning of a t(6;9)(p21;q34) translocation from a patient with a myelodysplastic syndrome (MDS), facilitated by conversion technology and array-based comparative genomic hybridization, which revealed a rearrangement translocating the IER3 coding region away from critical flanking/regulatory elements and to a transcript-poor chromosomal region, markedly decreasing expression. Using split-signal and locus-specific fluorescence in situ hybridization (FISH) probes, we analyzed 204 patients with diverse hematological malignancies accompanied by clonal chromosome 6p21 abnormalities, and found 8 additional patients with MDS with IER3 rearrangements (translocations or amplification). Although FISH studies on 157 additional samples from patients with MDS and a normal-karyotype were unrevealing, and sequencing the IER3 coding and proximal promoter regions of 74 MDS patients disclosed no point mutations, reverse transcription-PCR results suggested that dysregulated expression of IER3 is common in MDS (61% &gt;4-fold increase or decrease in expression with decreased expression primarily in early MDS and increased expression primarily in later MDS progressing toward leukemia), consistent with findings in previous microarray experiments. These data support involvement of IER3 in the pathobiology of MDS. [Cancer Res 2009;69(19):7518–23]
Identification of a Small Molecule Inhibitor of the Human DNA Repair Enzyme Polynucleotide Kinase/Phosphatase
Authors: Freschauf Gary K. , Karimi-Busheri Feridoun , Ulaczyk-Lesanko Agnieszka , Mereniuk Todd R. , Ahrens Ashley , Koshy Jonathan M. , Rasouli-Nia Aghdass , Pasarj Phuwadet , Holmes Charles F.B. , Rininsland Frauke , Hall Dennis G. , Weinfeld Michael 
Published: September 2009

Abstract
Human polynucleotide kinase/phosphatase (hPNKP) is a 57.1-kDa enzyme that phosphorylates DNA 5′-termini and dephosphorylates DNA 3′-termini. hPNKP is involved in both single- and double-strand break repair, and cells depleted of hPNKP show a marked sensitivity to ionizing radiation. Therefore, small molecule inhibitors of hPNKP should potentially increase the sensitivity of human tumors to γ-radiation. To identify small molecule inhibitors of hPNKP, we modified a novel fluorescence-based assay to measure the phosphatase activity of the protein, and screened a diverse library of over 200 polysubstituted piperidines. We identified five compounds that significantly inhibited hPNKP phosphatase activity. Further analysis revealed that one of these compounds, 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), was the most effective, with an IC50 of 0.06 μmol/L. When tested for its specificity, A12B4C3 displayed no inhibition of two well-known eukaryotic protein phosphatases, calcineurin and protein phosphatase-1, or APTX, another human DNA 3′-phosphatase, and only limited inhibition of the related PNKP from Schizosaccharomyces pombe. At a nontoxic dose (1 μmol/L), A12B4C3 enhanced the radiosensitivity of human A549 lung carcinoma and MDA-MB-231 breast adenocarcinoma cells by a factor of two, which was almost identical to the increased sensitivity resulting from shRNA-mediated depletion of hPNKP. Importantly, A12B4C3 failed to increase the radiosensitivity of the hPNKP-depleted cells, implicating hPNKP as the principal cellular target of A12B4C3 responsible for increasing the response to radiation. A12B4C3 is thus a useful reagent for probing hPNKP cellular function and will serve as the lead compound for further development of PNKP-targeting drugs. [Cancer Res 2009;69(19):7739–46]
Metastamir: The Field of Metastasis-Regulatory microRNA Is Spreading
Authors: Hurst Douglas R. , Edmonds Mick D. , Welch Danny R. 
Published: September 2009

Abstract
Despite advancements in knowledge from more than a century of metastasis research, the genetic programs and molecular mechanisms required for cancer metastasis are still incompletely understood. Genes that specifically regulate the process of metastasis are useful tools to elucidate molecular mechanisms and may become markers and/or targets for antimetastatic therapy. Recently, several noncoding regulatory RNA genes, microRNA (miRNA), were identified, which play roles in various steps of metastasis, some without obvious roles in tumorigenesis. Understanding how these metastasis-associated miRNA, which we term metastamir, are involved in metastasis will help identify possible biomarkers or targets for the most lethal attribute of cancer: metastasis. [Cancer Res 2009;69(19):7495–8]
Combined Bcl-2/Mammalian Target of Rapamycin Inhibition Leads to Enhanced Radiosensitization via Induction of Apoptosis and Autophagy in Non–Small Cell Lung Tumor Xenograft Model
Authors: Kim Kwang Woon , Moretti Luigi , Mitchell Lauren Rhea , Jung Dae Kwang , Lu Bo 
Published: September 2009

Abstract
Purpose: Radiotherapy has a central role in the treatment of non–small cell lung cancer. Effectiveness of this modality, however, is often limited as resistance results from defects in cell death.
Experimental Design: We investigated whether simultaneous up-regulation of apoptosis, via Bcl-2 inhibitor ABT-737, and autophagy, via mammalian target of rapamycin inhibitor rapamycin, can be used to enhance radiosensitivity of H460 cells in vitro and growth delay in a xenograft model.
Results: In vitro studies confirmed that ABT-737 and rapamycin induce apoptosis and autophagy, respectively. ABT-737 induced cleaved caspase-3, a marker of apoptosis, and rapamycin correlated with an increase in punctate localization of green fluorescent protein-LC3, characteristic of autophagy. The combination ABT-737/rapamycin markedly enhanced sensitivity of H460 cells to radiation (dose enhancement ratio = 2.47; P = 0.002) in clonogenic assay. In addition, the combination ABT-737/rapamycin/radiation showed a dramatic tumor growth delay in a mouse xenograft model. In vivo immunohistochemistry staining showed that combination therapy yielded over a 100% increase in caspase-3 activity (apoptosis) and a 6-fold decrease in p62 protein level (indicative of autophagic flux) compared with radiation alone control group. Moreover, cell proliferation (Ki-67 staining) was reduced by 77% (P = 0.001) and vascular density (von Willebrand factor staining) by 67.5% (P = 0.09) compared with radiation alone. Additional in vitro studies in human umbilical vein endothelial cells indicated that combined therapy also significantly decreases tubule formation.
Conclusion: These results suggest that concurrent induction of apoptosis and autophagy enhances radiation therapy both in vitro and in lung cancer xenograft models. Further investigations are warranted to assess the clinical potential of such strategy in lung cancer patients. (Clin Cancer Res 2009;15(19):6096–105)
Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma
Authors: Pandha Hardev S. , Heinemann Lucy , Simpson Guy R. , Melcher Alan , Prestwich Robin , Errington Fiona , Coffey Matt , Harrington Kevin J. , Morgan Richard 
Published: September 2009

Abstract
Purpose: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murine melanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects.
Experimental Design: The effects of reovirus ± chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting–based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murine melanoma.
Results: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mouse melanoma cells, most significantly with cisplatin (combination index of 0.42 ± 0.03 at ED50). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up-regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P &lt; 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo.
Conclusion: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murine melanoma cell lines in vitro and murine tumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic. (Clin Cancer Res 2009;15(19):6158–66)
Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival
Authors: Grochola Lukasz F. , Vazquez Alexei , Bond Elisabeth E. , Würl Peter , Taubert Helge , Müller Thomas H. , Levine Arnold J. , Bond Gareth L. 
Published: September 2009

Abstract
Purpose: A regulated p53-dependent stress response is crucial in suppressing tumor formation and mediating the response to commonly used cancer therapeutics. However, little is known about the human, inherited genetics of this important signaling pathway.
Experimental Design: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown that single nucleotide polymorphisms (SNP) can affect p53 signaling, confer cancer risk, and alter outcome, and also suggest that the pathway is under evolutionary selective pressure. Here, we attempt to accelerate the identification of functional p53 pathway SNPs by incorporating these characteristics into an analysis of 142 genes that are known to affect p53 signaling.
Results: We report that a genomic scan for recent natural selection denotes that of the 142 genes studied, the PPP2R5E gene that encodes a regulatory subunit of the tumor suppressing protein phosphatase 2A resides in a naturally selected genomic region. We go on to show that a selected SNP in PPP2R5E (ϵ-SNP2) associates with significant allelic differences in the onset (up to 19.2 years; P = 0.0002) and risk (odds ratio, up to 8.1; P = 0.0009) of soft tissue sarcoma development, as well as overall survival (relative risk, up to 3.04; P = 0.026).
Conclusions: The PPP2R5E gene is identified as harboring genetic variants that can affect human cancer and are possibly under evolutionary selection pressure. (Clin Cancer Res 2009;15(19):6301–8)
Effect of sex difference on platelet adhesion, spreading and aggregate formation under flow
Authors: Eshel-Green Tal , Berny Michelle , Conley Robert , McCarty Owen 
Published: September 2009

SummaryThere are clear but poorly understood differences in the etiology and prognosis of thrombotic diseases in men and women. Due to the fact that platelets play a central role in the formation of occlusive thrombi in atherosclerotic coronary arteries, previous studies have examined whether sex differences exist for platelets, and have obtained conflicting results. Additionally, due to the increased use of genetically modified mouse models to explore the molecular mechanisms underlying platelet activation and thrombotic disorders, it is critical to determine if sex is a confounding variable. Our study of the role of sex differences in platelet function was designed to utilise purified platelets from inbred paired female/male littermates in order to minimise genetic and environmental variability. In the current study, we demonstrate that platelet adhesion to and spreading on immobilised fibrinogen, thrombin or collagen was equivalent for both female and male mouse platelets. The ability of the soluble agonist thrombin or convulxin to potentiate platelet Pselectin exposure, fibrinogen binding, or adhesion and spreading on immobilised fibrinogen was equivalent for both female and male mouse platelets. Our data show that an equivalent degree of platelet adhesion and aggregation on collagen or fibrinogen under shear flow was observed for both female and male mouse platelets. In conclusion, our data would argue against an intrinsic difference for female mouse platelets in regulating the major functional platelet responses: platelet adhesion, spreading, or aggregation under flow.
Factor VIII-eGFP fusion proteins with preserved functional activity for the analysis of the early secretory pathway of factor VIII
Authors: Heinz Stefan , Schüttrumpf Jörg , Simpson Jeremy , Pepperkok Rainer , Nicolaes Gerry , Abriss Daniela , Milanov Peter , Roth Stefanie , Seifried Erhard , Tonn Torsten 
Published: September 2009

SummaryConsidering the difficulty in detecting factor (F)VIII in vivo, fluorescently labelled FVIII protein provides a tool to analyse the intracellular localisation, bio distribution, and pharmacokinetics of the protein in living organisms. Here, we report the use of FVIII full length and B-domain deleted proteins, fused to enhanced green fluorescent protein (eGFP) at the C-terminus of the coagulation protein via a nine amino acid spanning linker. Comparison of the FVIII-eGFP fusion proteins to their unlabelled counterparts showed no impairment with respect to recombinant expression levels, intracellular processing, specific coagulant activity and decay at physiological temperature. Confocal live cell imaging demonstrated ER-Golgi-transport of B-domain deleted FVIII-eGFP in vesicular tubular carriers. Using temperature blocks and release experiments, imaging of FVIII-eGFP fusion proteins enabled for the first time the visualisation of the early secretory pathway of B-domain deleted FVIII in living cells and in particular highlighted the apparent deficit of active transport carriers, an observation consistent with the low rates of FVIII secretion seen in recombinant expression systems.
Effects of a semi-synthetic N-,O-sulfated glycosaminoglycan K5 polysaccharide derivative in a rat model of cerebral ischaemia/ reperfusion injury
Authors: Castiglia Sara , Manoni Marco , Salsini Liana , Chini Jacopo , Masini Emanuela , Fantozzi Roberto , Collino Massimo 
Published: September 2009

SummaryHeparin and low molecular weight heparins may reduce brain damage evoked by ischaemia/reperfusion (I/R) injury, although their use is hampered by the risk of haemorrhage. Chemical and enzymatic modifications of K5 polysaccharide have shown the possibility to produce heparin-like compounds with low anticoagulant activity and strong anti-inflammatory effects. Using a rat model of transient cerebral I/R, we investigated the effects of an epimerised N-,O-sulfated K5 polysaccharide derivative, K5-N,OSepi, on the infarct size, motor activity and injury caused by ischaemia (30 min) and reperfusion. Reperfusion was allowed for 60 min or 1–5 days. Rats reperfused for 5 days showed an infarct volume of 30.7 ±3.1% and K5-N,OSepi (0.1–1 mg/kg) caused dose-dependent reduction in infarct size (maximum at 1 mg/kg: 13.1 ±2.1% infarct volume). This effect was associated with a significant improvement in motor performance. In the rat hippocampus, one of the brain areas most sensitive to I/R injury, I/R induced a robust increase in myeloperoxidase (MPO) activity, a marker of neutrophil infiltration, that was halved by K5-N,OSepi administration (66.38 ±7.75 µU MPO/tissue g, 30.78 ±5.67 µU MPO/tissue g, respectively). K5-N,OSepi drastically reduced the expression of cyclooxygenase-2,inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1. I/R-induced activation of nuclear factor-kB was attenuated by drug treatment. Furthermore, K5-N,OSepi administration was associated with a significant modulation of apoptosis markers, such as Bid and Bcl-2. In conclusion, the results demonstrated that the sulfated semi-synthetic K5 derivative K5-N,OSepi protects the brain against I/R injury by disrupting multiple levels of the apoptotic and inflammatory cascade, including inhibition of NF-κB activation.
Heparins: Process-related physico-chemical and compositional characteristics, fingerprints and impurities
Authors: Mascellani Giuseppe , Spelta Franco , Liverani Lino 
Published: September 2009

SummaryDuring the past 25 years, heparin extraction and purification processes have changed. The results of these changes are reflected by the continuous increase in potency of the International Standard for heparin. This increase is due not only to a higher purity, but also to a number of changes in the physicochemical characteristics of heparin. For long time, all these changes have been disregarded as non-critical by regulatory authorities. Heparin marketing authorisation was reviewed only two years ago and Pharmacopoeia monographs were reviewed just for the addition of new tests, mainly aimed at tackling the oversulfated chondroitin sulfate (OSCS) crisis. Currently, heparin monographs are again under revision. Such changes, different for each manufacturer, have caused a further increase in the heterogeneity of individual batches of heparin. This review aims at showing that chemical, physical and biological characteristics of heparin (such as disaccharide composition, amount of low sulfated and high sulfated sequences, molecular weight profiles [MW], activities, structural artifacts, fingerprints and glycosaminoglycans impurities) are all process-dependent and may significantly vary when different processes are used to minimise the content of dermatan sulfate. The wide heterogeneity of the physico-chemical characteristics of currently marketed heparin and the lack of suitable and shareable reference standards for the identification/quantification of process-related impurities caused, and are still causing, heated debates among scientific institutions, companies and authorities.