bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Throughput Screening Identifies Novel Agents Eliciting Hypersensitivity in Fanconi Pathway–Deficient Cancer Cells
Authors: Gallmeier Eike , Hucl Tomas , Brody Jonathan R. , Dezentje David A. , Tahir Khola , Kasparkova Jana , Brabec Viktor , Bachman Kurtis E. , Kern Scott E. 
Published: March 2007

Abstract
Inactivation of the Fanconi anemia (FA) pathway occurs in diverse human tumors among the general population and renders those tumors hypersensitive to DNA interstrand-cross-linking (ICL) agents. The identification of novel agents to which FA pathway–deficient cells were hypersensitive could provide new therapeutic opportunities and improve our molecular understanding of the FA genes. Using high-throughput screening, we assessed the growth of isogenic human cancer cells that differed only in the presence or absence of single FA genes upon treatment with 880 active drugs and 40,000 diverse compounds. We identified several compounds to which FA pathway–deficient cells were more sensitive than FA pathway–proficient cells, including two groups of structurally related compounds. We further investigated the compound eliciting the strongest effect, termed 80136342. Its mechanism of action was distinct from that of ICL agents; 80136342 did not cause increased chromosomal aberrations, enhanced FANCD2 monoubiquitination, H2AX phosphorylation, p53 activation, or ICL induction. Similar to ICL agents, however, 80136342 caused a pronounced G2 arrest in FA pathway–deficient cells. When applied in combination with ICL agents, 80136342 had at least additive toxic effects, excluding interferences on ICL-induced toxicity and facilitating a combinational application. Finally, we identified one particular methyl group necessary for the effects of 80136342 on FA–deficient cells. In conclusion, using high-throughput screening in an isogenic human FA cancer model, we explored a novel approach to identify agents eliciting hypersensitivity in FA pathway–deficient cells. We discovered several attractive candidates to serve as lead compounds for evaluating structure-activity relationships and developing therapeutics selectively targeting FA pathway–deficient tumors. [Cancer Res 2007;67(5):2169–77]
Intersex-like (IXL) Is a Cell Survival Regulator in Pancreatic Cancer with 19q13 Amplification
Authors: Kuuselo Riina , Savinainen Kimmo , Azorsa David O. , Basu Gargi D. , Karhu Ritva , Tuzmen Sukru , Mousses Spyro , Kallioniemi Anne 
Published: March 2007

Abstract
Pancreatic cancer is a highly aggressive disease characterized by poor prognosis and vast genetic instability. Recent microarray-based, genome-wide surveys have identified multiple recurrent copy number aberrations in pancreatic cancer; however, the target genes are, for the most part, unknown. Here, we characterized the 19q13 amplicon in pancreatic cancer to identify putative new drug targets. Copy number increases at 19q13 were quantitated in 16 pancreatic cancer cell lines and 31 primary tumors by fluorescence in situ hybridization. Cell line copy number data delineated a 1.1 Mb amplicon, the presence of which was also validated in 10% of primary pancreatic tumors. Comprehensive expression analysis by quantitative real-time reverse transcription-PCR indicated that seven transcripts within this region had consistently elevated expression levels in the amplified versus nonamplified cell lines. High-throughput loss-of-function screen by RNA interference was applied across the amplicon to identify genes whose down-regulation affected cell viability. This screen revealed five genes whose down-regulation led to significantly decreased cell viability in the amplified PANC-1 cells but not in the nonamplified MiaPaca-2 cells, suggesting the presence of multiple biologically interesting genes in this region. Of these, the transcriptional regulator intersex-like (IXL) was consistently overexpressed in amplified cells and had the most dramatic effect on cell viability. IXL silencing also resulted in G0-G1 cell cycle arrest and increased apoptosis in PANC-1 cells. These findings implicate IXL as a novel amplification target gene in pancreatic cancer and suggest that IXL is required for cancer cell survival in 19q13-amplified tumors. [Cancer Res 2007;67(5):1943–9]
Lung Cancer Cell Lines HarboringMETGene Amplification Are Dependent on Met for Growth and Survival
Authors: Lutterbach Bart , Zeng Qinwen , Davis Lenora J. , Hatch Harold , Hang Gaozhen , Kohl Nancy E. , Gibbs Jackson B. , Pan Bo-Sheng 
Published: March 2007

AbstractRecent clinical successes of small-molecule epidermal growth factor receptor (EGFR) inhibitors in treating advanced non–small cell lung cancer (NSCLC) have raised hopes that the identification of other deregulated growth factor pathways in NSCLC will lead to new therapeutic options for NSCLC. Met, the receptor for hepatocyte growth factor, has been implicated in growth, invasion, and metastasis of many tumors including NSCLC. To assess the functional role for Met in NSCLC, we evaluated a panel of nine lung cancer cell lines for Met gene amplification, Met expression, Met pathway activation, and the sensitivity of the cell lines to short hairpin RNA (shRNA)–mediated Met knockdown. Two cell lines, EBC-1 and H1993, showed significant Met gene amplification and overexpressed Met receptors which were constitutively phosphorylated. The other seven lines did not exhibit Met amplification and expressed much lower levels of Met, which was phosphorylated only on addition of hepatocyte growth factor. We also found a strong up-regulation of tyrosine phosphorylation in β-catenin and p120/δ-catenin in the Met-amplified EBC-1 and H1993 cell lines. ShRNA-mediated Met knockdown induced significant growth inhibition, G1-S arrest, and apoptosis in EBC-1 and H1993 cells, whereas it had little or no effect on the cell lines that do not have Met amplification. These results strongly suggest that Met amplification identifies a subset of NSCLC likely to respond to new molecular therapies targeting Met. [Cancer Res 2007;67(5):2081–8]
Deletion of p37Ing1 in Mice Reveals a p53-Independent Role for Ing1 in the Suppression of Cell Proliferation, Apoptosis, and Tumorigenesis
Authors: Coles Andrew H. , Liang Huiling , Zhu Zhiqing , Marfella Concetta G.A. , Kang Joonsoo , Imbalzano Anthony N. , Jones Stephen N. 
Published: March 2007

Abstract
ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37Ing1, a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37Ing1-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37Ing1 inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37Ing1-deficient cells. In addition, loss of p37Ing1 induces Bax expression and increases DNA damage–induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37Ing1 suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that p53 does not require p37Ing1 to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37Ing1 can negatively regulate cell growth and apoptosis in a p53-independent manner. [Cancer Res 2007;67(5):2054–61]
Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma
Authors: Hjalgrim Henrik , Ekström Smedby Karin , Rostgaard Klaus , Molin Daniel , Hamilton-Dutoit Stephen , Chang Ellen T. , Ralfkiaer Elisabeth , Sundström Christer , Adami Hans-Olov , Glimelius Bengt , Melbye Mads 
Published: March 2007

AbstractInfectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18–44 years) and older (45–74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive [OR, 3.23; 95% confidence interval (95% CI) 1.89–5.55] but not EBV-negative HL (OR, 1.35; 95% CI, 0.86–2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19–7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8–4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (ORIM EBV+ HL versus EBV− HL, 2.68; 95% CI, 1.40–5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies. [Cancer Res 2007;67(5):2382–8]
GATA-1 Is Essential in EGF-Mediated Induction of Nucleotide Excision Repair Activity and ERCC1 Expression through ERK2 in Human Hepatoma Cells
Authors: Andrieux Lise O. , Fautrel Alain , Bessard Anne , Guillouzo André , Baffet Georges , Langouët Sophie 
Published: March 2007

Abstract
The nucleotide excision repair (NER) pathway and its leading gene excision-repair cross-complementary 1 (ERCC1) have been shown to be up-regulated in hepatocellular carcinomas even in the absence of treatment with chemotherapeutics. The aim of this study was to determine the mechanism involved in NER regulation during the liver cell growth observed in hepatocellular carcinoma. Both NER activity and ERCC1 expression were increased after exposure to the epidermal growth factor (EGF) in cultured normal and tumoral human hepatocytes. These increases correlated with the activation of the kinase signaling pathway mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK that is known to be a key regulator in the G1 phase of the hepatocyte cell cycle. Moreover, EGF-mediated activation of ERCC1 was specifically inhibited by either the addition of U0126, a MEK/ERK inhibitor or small interfering RNA-mediated knockdown of ERK2. Basal expression of ERCC1 was decreased in the presence of the phosphoinositide-3-kinase (PI3K) inhibitor and small hairpin RNA (shRNA) against the PI3K pathway kinase FKBP12-rapamycin-associated protein or mammalian target of rapamycin. Transient transfection of human hepatocytes with constructs containing different sizes of the 5′-flanking region of the ERCC1 gene upstream of the luciferase reporter gene showed an increase in luciferase activity in EGF-treated cells, which correlated with the presence of the nuclear transcription factor GATA-1 recognition sequence. The recruitment of GATA-1 was confirmed by chromatin immunoprecipitation assay. In conclusion, these results represent the first demonstration of an up-regulation of NER and ERCC1 in EGF-stimulated proliferating hepatocytes. The transcription factor GATA-1 plays an essential role in the induction of ERCC1 through the mitogen-activated protein kinase (MAPK) pathway, whereas the PI3K signaling pathway contributes to ERCC1 basal expression. [Cancer Res 2007;67(5):2114–23]
Insulin Receptor Substrate-1 Regulates the Transformed Phenotype of BT-20 Human Mammary Cancer Cells
Authors: Dalmizrak Ozlem , Wu An , Chen Jia , Sun Hongzhi , Utama Fransiscus E. , Zambelli Diana , Tran Thai H. , Rui Hallgeir , Baserga Renato 
Published: March 2007

Abstract
Although originating from a human breast cancer, BT-20 cells do not form colonies in soft agar. BT-20 cells do not express insulin receptor substrate-1 (IRS-1), which is known to promote both normal and abnormal growth and to inhibit differentiation. Stable expression of IRS-1 confers to BT-20 cells the ability to form colonies in soft agar. BT-20 cells form tumors in xenografts in mice, but the size of tumors is twice as large when the cells express IRS-1. The increased transformed phenotype is characterized by occupancy of the rDNA and cyclin D1 promoters by IRS-1 and the activation of the cyclin D1, c-myc, and rDNA promoters. In addition, the retinoblastoma protein, which is detectable in the rDNA promoter of quiescent BT-20/IRS-1 cells, is replaced by IRS-1 after insulin-like growth factor-I stimulation. Our results indicate that in BT-20 human mammary cancer cells, expression of IRS-1 activates promoters involved in cell growth and cell proliferation, resulting in a more transformed phenotype. Targeting of IRS-1 could be effective in inhibiting the proliferation of mammary cancer cells. [Cancer Res 2007;67(5):2124–30]
Immunoediting Sculpts Tumor Epitopes during Immunotherapy
Authors: Singh Reshma , Paterson Yvonne 
Published: March 2007

Abstract
Immunoediting of tumor-associated antigens occurs in response to immune pressure. We show that the mutation of residues within epitopes of HER-2/neu leads to the outgrowth of autochthonous tumors after immunizing HER-2/neu transgenic mice with Listeria monocytogenes therapeutic vaccines expressing fragments of HER-2/neu. Three of these vaccines target the extracellular domain (LmLLO-EC1, LmLLO-EC2, and LmLLO-EC3), and two of these vaccines target the intracellular domain (Lm-LLO-IC1 and Lm-LLO-IC2). Mutations occurred in the regions of the HER-2/neu molecule targeted by the Listeria strain expressing that region, which suggests that the rate of generation of escape mutants was a significant factor in the efficacy of each vaccine. A longer delay in the onset of tumors after immunotherapy occurred with the vaccine that targeted the kinase domain. We verified that the mutations in this domain occurred within novel CD8+ T-cell epitopes, and that the mutation of these residues abrogated CTL responses to these epitopes. The long delay in the onset of tumors after immunotherapy targeting the kinase domain may be because this region of HER-2/neu cannot undergo extensive mutations without impairing its ability to signal cell growth. [Cancer Res 2007;67(5):1887–92]
The Adaptive Immunologic Microenvironment in Colorectal Cancer: A Novel Perspective
Authors: Galon Jérôme , Fridman Wolf-Herman , Pagès Franck 
Published: March 2007

AbstractColorectal cancer is one of the most common malignancies, often presenting with a poor prognosis. To date, the anatomic extent of disease has been by far the most important prognostic factor. Recently, we obtained evidence that the type, density, and location of immune cells in colorectal cancer could provide a prognostic factor superior and independent to that of criteria related to the anatomic extent of the tumor. Here, we discuss the meaning and potential implications of this novel finding. [Cancer Res 2007;67(5):1883–6]
Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor
Authors: Yeh Tammie C. , Marsh Vivienne , Bernat Bryan A. , Ballard Josh , Colwell Heidi , Evans Ron J. , Parry Janet , Smith Darin , Brandhuber Barbara J. , Gross Stefan , Marlow Allison , Hurley Brian , Lyssikatos Joe , Lee Patrice A. , Winkler James D. , Koch Kevin , Wallace Eli 
Published: March 2007

Abstract
Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.
Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models.
Results: The IC50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor–induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate–induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells. Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line. When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday.
Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.
Oral Lactoferrin Results in T Cell–Dependent Tumor Inhibition of Head and Neck Squamous Cell Carcinoma In vivo
Authors: Wolf Jeffrey S. , Li Guoyan , Varadhachary Atul , Petrak Karel , Schneyer Mark , Li Daqing , Ongkasuwan Julina , Zhang Xiaoyu , Taylor Rodney J. , Strome Scott E. , O'Malley Bert W. 
Published: March 2007

Abstract
Purpose: Human lactoferrin is a naturally occurring glycoprotein that inhibits cancer growth. Our purpose was to evaluate recombinant human lactoferrin as a chemotherapeutic agent against head and neck squamous cell carcinoma.
Experimental Design: Controlled experiments both in vitro and in the murine model evaluating both the effect and mechanism of lactoferrin on cancer growth.
Results: In both human and murine cell lines, lactoferrin induced dose-dependent growth inhibition. Using flow cytometric analysis, lactoferrin was shown to induce G1-G0 growth arrest. This arrest seemed to be modulated by down-regulation of cyclin D1. In the in vitro model, luminex data revealed that lactoferrin inhibited cellular release of proinflammatory and prometastatic cytokines, including interleukin-8, interleukin-6, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-α. Lactoferrin up-regulated the cellular activation of nuclear factor-κB within 4 h of cellular exposure. In C3h/HeJ mice implanted with SCCVII tumors, orally delivered lactoferrin inhibited tumor growth by 75% compared with control mice. Immunohistochemical analysis of harvested tumors revealed up to 20-fold increases of lymphocytes within treated animals. When mice were depleted of CD3+ cells, all lactoferrin-induced tumor inhibition was abrogated.
Conclusion: We conclude that human recombinant lactoferrin can inhibit the growth of head and neck squamous cell carcinoma via direct cellular inhibition as well as systemically via immunomodulation. Our data support the study of human lactoferrin as an immunomodulatory compound with therapeutic potential.
Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications
Authors: Huang Suyun 
Published: March 2007

Abstract
Numerous cytokines, growth factors, and oncogenic proteins activate signal transducer and activator of transcription 3 (Stat3), which has been recognized as one of the common pathways in cancer cells. Stat3 signaling affects the expression and function of a variety of genes that are critical to cell survival, cell proliferation, invasion, angiogenesis, and immune evasion. Evidently, the Stat3 signaling pathway regulates cancer metastasis and constitutes a potential preventive and therapeutic target for cancer metastasis.
How to Compare Two Quantities? A Computational Model of Flutter Discrimination
Authors: Verguts Tom 
Published: March 2007

Abstract
A task that has been intensively studied at the neural level is f lutter discrimination. I argue that f lutter discrimination entails a combination of a temporal assignment problem and a quantity comparison problem, and propose a neural network model of how these problems are solved. The network combines unsupervised and one-layer supervised training. The unsupervised part clusters input features (stimulus + time window) and the supervised part categorizes the resulting clusters. After training, the model shows a good fit with both neural and behavioral properties. New predictions are outlined and links with other cognitive domains are pointed out.
Topography and Dynamics of Associative Long-term Memory Retrieval in Humans
Authors: Khader Patrick , Knoth Kathrin , Burke Michael , Ranganath Charan , Bien Siegfried , Rösler Frank 
Published: March 2007

Abstract
The present study investigated the neurophysiological processes underlying associative long-term memory retrieval of objects and spatial positions by means of a modified fan paradigm with cued recall and two neuroimaging methods (electroencephalogram [EEG] and functional magnetic resonance imaging). In an acquisition phase, either one stimulus or two stimuli became associated with a noun. During retrieval, probe stimuli comprising noun pairs were presented, and participants had to recall the respective associations and decided whether the nouns are linked to each other via a commonly associated stimulus. With this design, the quality and quantity of recalled associations was systematically varied, whereas the triggering stimuli and response requirements were held constant in all experimental conditions. Recall time proved to be directly related to the number of associations fanning out from a retrieval cue. Correspondingly, the hemodynamic response (blood oxygen level-dependent [BOLD] signal) and the amplitude of slow negative EEG potentials increased monotonically with the number of associations in both left anterior and bilateral posterior cortical areas. These effects were consistently observed with content-specific topographies for the two distinct materials. Furthermore, the multimethod approach revealed a close temporal link between response times and event-related slow potential changes on the one side and a close topographical and amplitude correspondence between slow potentials and BOLD signal changes on the other. The integrated results suggest that the neuronal dynamics of associative memory retrieval are equivalent for different types of associations, but that the structural basis is clearly content-specific.