bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular Retinoic Acid–Binding Protein II Is a Direct Transcriptional Target of MycN in Neuroblastoma
Authors: Gupta Anu , Williams Bryan R.G. , Hanash Samir M. , Rawwas Jawhar 
Published: August 2006

Abstract
Neuroblastoma is a heterogeneous disease in which 22% of tumors show MycN oncogene amplification and are associated with poor clinical outcome. MycN is a transcription factor that regulates the expression of a number of proteins that affect the clinical behavior of neuroblastoma. We report here that cellular retinoic acid–binding protein II (CRABP-II) is a novel MycN target, expressed at significantly higher levels in primary neuroblastoma tumors with mycN oncogene amplification as compared with non–MycN-amplified tumors. Moreover, regulated induction and repression of MycN in a neuroblastoma-derived cell line resulted in temporal and proportionate expression of CRABP-II. CRABP-II is expressed in several cancers, but its role in tumorigenesis has not been elucidated. We show that MycN binds to the promoter of CRABP-II and induces CRABP-II transcription directly. In addition, CRABP-II-transfected neuroblastoma cell lines show an increase in MycN protein levels resulting in increased cell motility. Gene expression profiling of CRABP-II-expressing cell lines uncovered increased expression of the HuB (Hel N1) gene. Hu proteins have been implicated in regulating the stability of MycN mRNA and other mRNAs by binding to their 3′ untranslated regions. We did not, however, observe any change in MycN mRNA stability or protein half-life in response to CRABP-II expression. In contrast, de novo MycN protein synthesis was increased in CRABP-II-expressing neuroblastoma cells, thereby suggesting an autoregulatory loop that might exacerbate the effects of MycN gene amplification and affect the clinical outcome. Our findings also suggest that CRABP-II may be a potential therapeutic target for neuroblastoma. (Cancer Res 2006; 66(16): 8100-8)
Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Promote Malignant Growth of Cells from Head and Neck Squamous Cell Carcinomas In vivo
Authors: Gutschalk Claudia M. , Herold-Mende Christel C. , Fusenig Norbert E. , Mueller Margareta M. 
Published: August 2006

Abstract
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are used to ameliorate cancer therapy-induced neutropenia and mucositis. Yet, first data in head and neck squamous cell carcinoma (HNSCC) indicate an impaired long-term prognosis on G-CSF treatment, and previous studies showed a contribution of both factors to the progression of human epithelial tumors. Therefore, we investigate the role of G-CSF and GM-CSF in progression of tumor cells from human HNSCC. Both factors stimulated proliferation and migration of tumor cell lines established from patient tumors expressing G-CSF and GM-CSF and/or their receptors. Blockade of G-CSF and GM-CSF inhibited tumor cell invasion in a three-dimensional organotypic culture model. The contribution of both factors to tumor malignancy was further confirmed in nude mouse transplants in vivo. Invasive and malignant growth yielding a similar tumor phenotype as the original patient tumor was exclusively observed in G-CSF- and GM-CSF-expressing tumors and was associated with enhanced and persistent angiogenesis and enhanced inflammatory cell recruitment. Although factor-negative tumors grew somewhat faster, they were characterized by lack of invasion, reduced and transient angiogenesis, and large necrotic areas. These data provide evidence for a progression-promoting effect of G-CSF and GM-CSF in human HNSCC and suggest further detailed evaluation of their use in the therapy of these tumors. (Cancer Res 2006; 66(16): 8026-36)
Different Lineages of P1A-Expressing Cancer Cells Use Divergent Modes of Immune Evasion for T-Cell Adoptive Therapy
Authors: Bai Xue-Feng , Liu Jin-Qing , Joshi Pramod S. , Wang Lizhong , Yin Lijie , Labanowska Jadwiga , Heerema Nyla , Zheng Pan , Liu Yang 
Published: August 2006

AbstractTumor evasion of T-cell immunity remains a significant obstacle to adoptive T-cell therapy. It is unknown whether the mode of immune evasion is dictated by the cancer cells or by the tumor antigens. Taking advantage of the fact that multiple lineages of tumor cells share the tumor antigen P1A, we adoptively transferred transgenic T cells specific for P1A (P1CTL) into mice with established P1A-expressing tumors, including mastocytoma P815, plasmocytoma J558, and fibrosarcoma Meth A. Although P1CTL conferred partial protection, tumors recurred in almost all mice. Analysis of the status of the tumor antigen revealed that all J558 tumors underwent antigenic drift whereas all P815 tumors experienced antigenic loss. Interestingly, although Meth A cells are capable of both antigenic loss and antigenic drift, the majority of recurrent Meth A tumors retained P1A antigen. The ability of Meth A to induce apoptosis of P1CTL in vivo alleviated the need for antigenic drift and antigenic loss. Our data showed that, in spite of their shared tumor antigen, different lineages of cancer cells use different mechanisms to evade T-cell therapy. (Cancer Res 2006; 66(16):8241-9)
Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase
Authors: Hobbs Cheryl A. , Wei Gang , DeFeo Karen , Paul Barry , Hayes Candace S. , Gilmour Susan K. 
Published: August 2006

Abstract
Elevated expression of ornithine decarboxylase (ODC) and increased synthesis of polyamines are hallmarks of epithelial tumorigenesis. The skin and tumors of K6/ODC and ODC/Ras transgenic mice, in which overexpression of ODC has been targeted to hair follicles, were found to exhibit intrinsically high histone acetyltransferase (HAT) activity. We identified Tip60 as a candidate enzyme for contributing significantly to this abnormally high HAT activity. Compared with normal littermate controls, the levels of Tip60 protein and an alternative splice variant Tip53 were found to be greater in K6/ODC mouse skin. Furthermore, skin tumors that spontaneously develop in ODC/Ras bigenic mice typically have substantially more Tip60 protein than adjacent non–tumor-bearing skin and exhibit a unique pattern of Tip60 size variants and chemically modified protein isoforms. Steady-state Tip60 and Tip53 mRNA levels were not affected in ODC-overexpressing skin and tumors, implying novel posttranscriptional regulation by polyamines. Given the diverse roles of Tip60, the overabundance of Tip60 protein is predicted to have biological consequences. Compared with normal littermate skin, we detected altered association of Tip60 with E2F1 and a subset of newly identified Tip60-interacting transcription factors in ODC transgenic mouse skin and tumors. E2F1 was shown to be bound in greater amounts to up-regulated target genes in ODC-overexpressing skin. Thus, up-regulation of Tip60 protein, influencing the expression of Tip60-regulated genes, could play a contributing role in polyamine-mediated tumor promotion. (Cancer Res 2006; 66(16): 8116-22)
Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib
Authors: Carey Kendall D. , Garton Andrew J. , Romero Maria S. , Kahler Jennifer , Thomson Stuart , Ross Sarajane , Park Frances , Haley John D. , Gibson Neil , Sliwkowski Mark X. 
Published: August 2006

AbstractWe show that two commonly occurring epidermal growth factor receptor (EGFR) somatic mutations, L858R and an in-frame deletion mutant, Del(746-750), exhibit distinct enzymatic properties relative to wild-type EGFR and are differentially sensitive to erlotinib. Kinetic analysis of the purified intracellular domains of EGFR L858R and EGFR Del(746-750) reveals that both mutants are active but exhibit a higher KM for ATP and a lower Ki for erlotinib relative to wild-type receptor. When expressed in NR6 cells, a cell line that does not express EGFR or other ErbB receptors, both mutations are ligand dependent for receptor activation, can activate downstream EGFR signaling pathways, and promote cell cycle progression. As expected from the kinetic analysis, the EGFR Del(746-752) is more sensitive to erlotinib inhibition than the EGFR L858R mutant. Further characterization shows that these mutations promote ligand-dependent and anchorage-independent growth, and cells harboring these mutant receptors form tumors in immunocompromised mice. Analysis of tumor lysates reveals that the tumorigenicity of the mutant EGFR cell lines may be due to a differential pattern of mutant EGFR autophosphorylation as compared with wild-type receptor. Significant inhibition of tumor growth, in mice harboring wild-type EGFR receptors, is only observed at doses of erlotinib approaching the maximum tolerated dose for the mouse. In contrast, the growth of mutant tumors is inhibited by erlotinib treatment at approximately one third the maximum tolerated dose. These findings suggest that EGFR somatic mutations directly influence both erlotinib sensitivity and cellular transformation. (Cancer Res 2006; 66(16): 8163-71)
Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression
Authors: Ai Lingbao , Kim Wan-Ju , Kim Tae-You , Fields C. Robert , Massoll Nicole A. , Robertson Keith D. , Brown Kevin D. 
Published: August 2006

Abstract
Cystatin M is a secreted inhibitor of lysosomal cysteine proteases. Several lines of evidence indicate that cystatin M is a tumor suppressor important in breast malignancy; however, the mechanism(s) that leads to inactivation of cystatin M during cancer progression is unknown. Inspection of the human cystatin M locus uncovered a large and dense CpG island within the 5′ region of this gene (termed CST6). Analysis of cultured human breast tumor lines indicated that cystatin M expression is either undetectable or in low abundance in several lines; however, enhanced gene expression was measured in cells cultured on the DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC). Increased cystatin M expression does not correlate with a cytotoxic response to 5-aza-dC; rather, various molecular approaches indicated that the CST6 gene was aberrantly methylated in these tumor lines as well as in primary breast tumors. Moreover, 60% (12 of 20) of primary tumors analyzed displayed CST6 hypermethylation, indicating that this aberrant characteristic is common in breast malignancies. Finally, preinvasive and invasive breast tumor cells were microdissected from nine archival breast cancer specimens. Of the five tumors displaying CST6 gene methylation, four tumors displayed methylation in both ductal carcinoma in situ and invasive breast carcinoma lesions and reduced expression of cystatin M in these tumors was confirmed by immunohistochemistry. In summary, this study establishes that the tumor suppressor cystatin M is a novel target for epigenetic silencing during mammary tumorigenesis and that this aberrant event can occur before development of invasive breast cancer. (Cancer Res 2006; 66(16): 7899-909)
Switching on Chromosomal Translocations
Authors: Ramiro Almudena R. , Nussenzweig Michel C. , Nussenzweig André 
Published: August 2006

Abstract
Activation-induced deaminase initiates three different antibody diversification reactions: class switch recombination, somatic hypermutation (SHM), and gene conversion. We have shown that, in addition to antibody diversification, activation-induced deaminase can also initiate Burkitt's lymphoma–like c-myc/IgH translocations. However, distinct DNA damage- and oncogene-induced checkpoints operate in B cells to produce a normal intrachromosomal class switch recombination event or an aberrant interchromosomal fusion. These findings open the way to study the molecular pathways taking place at the early stages of malignant transformation. (Cancer Res 2006; 66(16): 7837-9)
Disruption of Scaffold Attachment Factor B1 Leads to TBX2 Up-regulation, Lack of p19ARF Induction, Lack of Senescence, and Cell Immortalization
Authors: Dobrzycka Klaudia M. , Kang Kaiyan , Jiang Shiming , Meyer Rene , Rao Pulivarthi H. , Lee Adrian V. , Oesterreich Steffi 
Published: August 2006

Abstract
Scaffold attachment factor B1 (SAFB1) is a multifunctional protein, which has previously been implicated in breast cancer. Here, we show that genetic deletion of SAFB1 in mouse embryonic fibroblasts (MEF) leads to spontaneous immortalization and altered expression of two proteins involved in immortalization and escape from senescence: low levels of p19ARF and high levels of TBX2. Inactivation of TBX2 using a dominant-negative TBX2 resulted in up-regulation of p19ARF in SAFB1 knockout MEFs. SAFB1 loss also caused lack of contact inhibition, increased foci formation, and increased oncogene-induced anchorage-independent growth. These findings suggest that SAFB1 is a novel player in cellular immortalization and transformation. (Cancer Res 2006; 66(16): 7859-63)
Neutrophil Granulocytes Are Required for EffectiveBacillus Calmette-GuérinImmunotherapy of Bladder Cancer and Orchestrate Local Immune Responses
Authors: Suttmann Henrik , Riemensberger Josef , Bentien Gabriele , Schmaltz Dominik , Stöckle Michael , Jocham Dieter , Böhle Andreas , Brandau Sven 
Published: August 2006

AbstractThe role of polymorphonuclear neutrophil granulocytes (PMN) in antitumoral immune responses displays a striking dichotomy. Under inflammatory conditions, PMN may promote tumor growth and progression. In contrast, especially in the context of therapeutic interventions, PMN can exert important antitumor functions. However, until now, the mechanisms of PMN-mediated activation of tumor immunity are poorly defined. Based on a murine model of Bacillus Calmette-Guérin (BCG) immunotherapy of bladder cancer, we provide evidence for a novel immunoregulatory role of this leukocyte subset. PMN immigrate into the bladder after intravesical BCG instillation and depletion of PMN from tumor-bearing mice completely abrogated antitumor efficacy of BCG. PMN stimulated with BCG in vitro as well as PMN isolated from the urine of BCG-treated patients were a major source of the chemokines interleukin-8, growth-related oncogene-α, macrophage inflammatory protein-1α and of the inflammatory cytokine migration inhibitory factor. In vitro, BCG-stimulated PMN indirectly induced T-cell chemotaxis via the accessory function of activated monocytes. In vivo, depletion of PMN from BCG-treated mice significantly impaired CD4+ T-cell trafficking to the bladder. These data show that PMN direct the migration of effector cells to the bladder and by this means are indispensable for effective tumor immunotherapy. Thus, our findings provide evidence for a novel early immunoregulatory role of these innate immune cells in local antitumor immunity. (Cancer Res 2006; 66(16): 8250-7)
Presence ofEpidermal Growth Factor ReceptorGene T790M Mutation as a Minor Clone in Non–Small Cell Lung Cancer
Authors: Inukai Michio , Toyooka Shinichi , Ito Sachio , Asano Hiroaki , Ichihara Shuji , Soh Junichi , Suehisa Hiroshi , Ouchida Mamoru , Aoe Keisuke , Aoe Motoi , Kiura Katsuyuki , Shimizu Nobuyoshi , Date Hiroshi 
Published: August 2006

AbstractThe threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene has been reported in progressing lesions after gefitinib treatment in non–small cell lung cancer (NSCLC) that causes sensitive tumors to become resistant to gefitinib. Alternatively, the EGFR T790M mutation might be present in small fractions of tumor cells before drug treatment, and the tumor cells harboring the T790M mutation might be enriched during the proliferation after drug treatment. We developed a mutant-enriched PCR assay to detect small fractions of cells with T790M mutation and used this technique to detect mutations in 280 NSCLCs, including gefitinib-treated 95 cases. Although the direct sequencing detected only 1 T790M mutant case, the mutant-enriched PCR (confirmed to enrich one mutant out of 1 × 103 wild-type alleles) detected 9 additional cases among 280 cases. As linkage to clinicopathologic factors, the T790M mutation showed no bias for sex, smoking status, or histology but was significantly more frequent in advanced tumors (9 of 111 cases) than in early-stage tumors (1 of 169 cases; P = 0.0013). Among gefitinib-treated cases, gefitinib-sensitive mutations were found in 30 cases. The T790M mutation was present in 3 of 7 no-responders with the gefitinib-sensitive mutation and was not present in 19 responders (P = 0.014). Our results indicate that the T790M mutation is sometimes present in a minor population of tumor cells during the development of NSCLC and suggest that the detection of small fractions of T790M mutant alleles may be useful for predicting gefitinib resistance of NSCLCs with sensitive EGFR mutations. (Cancer Res 2006; 66(16): 7854-8)
Characterising the System of the International Criminal Court: An Exploration of the Role of the Court Through the Elements of Crimes and the Crime of Genocide
Authors: McKay Leanne 
Published: August 2006

AbstractThis paper examines the nature of the legislative system of the International Criminal Court, as established by the Rome Statute and the Elements of Crimes. It asks, to what extent can this system be seen as self-contained and self-sustaining or is its role better described as one of global harmonisation of existing and developing international criminal law? By examining the Elements of Crimes and their operation through the case study of the crime of genocide, the paper identifies some of the contradictions and challenges facing both the judges and parties who are obliged to work within this system, and also national jurisdictions that simultaneously seek to maintain their sovereignty and be included within the International Criminal Court system.
International Sentencing Law: In Search of a Justification and Coherent Framework
Authors: Bagaric Mirko , Morss John 
Published: August 2006

AbstractAn international sentencing jurisprudence is emerging from the decisions by the International Criminal Tribunal for the Former Yugoslavia (ICTY or the Yugoslav tribunal) and the International Criminal Tribunal for Rwanda (ICTR or the Rwanda tribunal) (collectively, 'the tribunals'). This article examines international sentencing law and practice and discusses the justification for the practice. International sentencing law has several objectives. The main goals are reconciliation, deterrence, retribution and rehabilitation. The sentencing inquiry is marked by a high degree of discretion and has resulted in sentencers developing a large amount of aggravating and mitigating considerations, such as being in a position of authority, remorse and good character. It is argued that the current international sentencing approach is flawed – fundamentally so. Most of the stated goals of international sentencing in the form of reconciliation, retribution and rehabilitation are either highly speculative or misguided. The only justification for the practice is general deterrence. This is, however, significantly undermined by the selective and infrequent enforcement of crimes within the jurisdiction of such tribunals. The stated aggravated and mitigating considerations are not valid given that they are not justified by reference to the stated aims of sentencing and only serve to undermine the search for a penalty which is commensurate the serious of the offence. This article suggests a coherent framework for international sentencing policy and practice.
A high-density consensus map of barley linking DArT markers to SSR, RFLP and STS loci and agricultural traits
Authors: Wenzl Peter , Li Haobing , Carling Jason , Zhou Meixue , Raman Harsh , Paul Edie , Hearnden Phillippa , Maier Christina , Xia Ling , Caig Vanessa , Ovesná Jaroslava , Cakir Mehmet , Poulsen David , Wang Junping , Raman Rosy , Smith Kevin P , Muehlbauer Gary J , Chalmers Ken J , Kleinhofs Andris , Huttner Eric , Kilian Andrzej 
Published: August 2006

AbstractBackgroundMolecular marker technologies are undergoing a transition from largely serial assays measuring DNA fragment sizes to hybridization-based technologies with high multiplexing levels. Diversity Arrays Technology (DArT) is a hybridization-based technology that is increasingly being adopted by barley researchers. There is a need to integrate the information generated by DArT with previous data produced with gel-based marker technologies. The goal of this study was to build a high-density consensus linkage map from the combined datasets of ten populations, most of which were simultaneously typed with DArT and Simple Sequence Repeat (SSR), Restriction Enzyme Fragment Polymorphism (RFLP) and/or Sequence Tagged Site (STS) markers.ResultsThe consensus map, built using a combination of JoinMap 3.0 software and several purpose-built perl scripts, comprised 2,935 loci (2,085 DArT, 850 other loci) and spanned 1,161 cM. It contained a total of 1,629 'bins' (unique loci), with an average inter-bin distance of 0.7 ± 1.0 cM (median = 0.3 cM). More than 98% of the map could be covered with a single DArT assay. The arrangement of loci was very similar to, and almost as optimal as, the arrangement of loci in component maps built for individual populations. The locus order of a synthetic map derived from merging the component maps without considering the segregation data was only slightly inferior. The distribution of loci along chromosomes indicated centromeric suppression of recombination in all chromosomes except 5H. DArT markers appeared to have a moderate tendency toward hypomethylated, gene-rich regions in distal chromosome areas. On the average, 14 ± 9 DArT loci were identified within 5 cM on either side of SSR, RFLP or STS loci previously identified as linked to agricultural traits.ConclusionOur barley consensus map provides a framework for transferring genetic information between different marker systems and for deploying DArT markers in molecular breeding schemes. The study also highlights the need for improved software for building consensus maps from high-density segregation data of multiple populations.
Identification of the ancestral killer immunoglobulin-like receptor gene in primates
Authors: Sambrook Jennifer G , Bashirova Arman , Andersen Hanne , Piatak Mike , Vernikos George S , Coggill Penny , Lifson Jeff D , Carrington Mary , Beck Stephan 
Published: August 2006

AbstractBackgroundKiller Immunoglobulin-like Receptors (KIR) are essential immuno-surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving. Since few KIR remain orthologous between species, with only one of them,KIR2DL4, shown to be common to human, apes and monkeys, the evolution of the KIR gene family in primates remains unclear.ResultsUsing comparative analyses, we have identified the ancestral KIR lineage (provisionally namedKIR3DL0) in primates. We showKIR3DL0to be highly conserved with the identification of orthologues in human (Homo sapiens), common chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), rhesus monkey (Macaca mulatta) and common marmoset (Callithrix jacchus). We predictKIR3DL0to encode a functional molecule in all primates by demonstrating expression in human, chimpanzee and rhesus monkey. Using the rhesus monkey as a model, we further show the expression profile to be typical of KIR by quantitative measurement ofKIR3DL0from an enriched population of natural killer cells.ConclusionOne reason whyKIR3DL0may have escaped discovery for so long is that, in human, it maps in between two related leukocyte immunoglobulin-like receptor clusters outside the known KIR gene cluster on Chromosome 19. Based on genomic, cDNA, expression and phylogenetic data, we report a novel lineage of immunoglobulin receptors belonging to the KIR family, which is highly conserved throughout 50 million years of primate evolution.