bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Functional Variant in the Transcriptional Regulatory Region of Gene LOC344967 Cosegregates with Disease Phenotype in Familial Nasopharyngeal Carcinoma
Authors: Jiang Ri-Cheng , Qin Hai-De , Zeng Mu-Sheng , Huang Wei , Feng Bing-Jian , Zhang Feng , Chen Han-Kui , Jia Wei-Hua , Chen Li-Zhen , Feng Qi-Sheng , Zhang Ru-Hua , Yu Xing-Juan , Zheng Mei-Zhen , Zeng Yi-Xin 
Published: January 2006

Abstract
Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma–associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism −32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The −32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this −32A variant creates an activator protein (AP-1)–binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the −32G/A genotype compared with nasopharyngeal carcinoma cells with the −32G/G genotype. Collectively, these results provide evidence that the −32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied. (Cancer Res 2006; 66(2): 693-700)
Selective Targeting of Antitumor Immune Responses with Engineered Live-Attenuated Listeria monocytogenes
Authors: Yoshimura Kiyoshi , Jain Ajay , Allen Heather E. , Laird Lindsay S. , Chia Christina Y. , Ravi Sowmya , Brockstedt Dirk G. , Giedlin Martin A. , Bahjat Keith S. , Leong Meredith L. , Slansky Jill E. , Cook David N. , Dubensky Thomas W. , Pardoll Drew M. , Schulick Richard D. 
Published: January 2006

Abstract
Improved immunization and ex vivo T-cell culture strategies can generate larger numbers and more potent tumor-specific effector cells than previously possible. Nonetheless, the capacity of these cells to eliminate established tumors is limited by their ability to efficiently enter tumor-bearing organs and mediate their effector function. In the current study, we show that the administration of an engineered organ-homing microbe selectively targets tumor-specific immune responses to metastases within that organ. Specifically, an attenuated Listeria monocytogenes strain, which preferentially infects the liver following systemic administration, dramatically enhances the activity of a cancer vaccine against liver metastases but not metastases in the lung. This enhanced activity results from both local recruitment of innate immune effectors as well as concentration and increased activation of vaccine-induced antitumor T cells within the liver. These findings show a general approach to focus systemic cancer immunotherapies to specific organs bearing tumor metastases by taking advantage of differential tropisms and the proinflammatory nature of microbes. (Cancer Res 2006; 66(2): 1096-104)
Down-Regulation of Stem Cell Genes, Including Those in a 200-kb Gene Cluster at 12p13.31, Is Associated withIn vivoDifferentiation of Human Male Germ Cell Tumors
Authors: Korkola James E. , Houldsworth Jane , Chadalavada Rajendrakumar S.V. , Olshen Adam B. , Dobrzynski Debbie , Reuter Victor E. , Bosl George J. , Chaganti R.S.K. 
Published: January 2006

AbstractAdult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray (∼83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell–associated genes in embryonal carcinoma, including several core “stemness” genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas. (Cancer Res 2006; 66(2): 820-7)
Efficient Induction of Tumor Antigen–Specific CD8+ Memory T Cells by Recombinant Lentivectors
Authors: Chapatte Laurence , Colombetti Sara , Cerottini Jean-Charles , Lévy Frédéric 
Published: January 2006

AbstractThe success of active cancer immunotherapy entails a robust induction of tumor-reactive effector and memory CD8+ T cells. We compared the in vivo immunogenicity of the melanoma-associated antigen Melan-A26-35 encoded by third-generation recombinant lentivector (rec. lv) or as peptide admixed with a strong adjuvant. Ex vivo analyses of immunized HLA-A2/H-2Kb mice showed that rec. lv triggered a stronger anti-Melan-A CD8+ T-cell response than peptide vaccine. Importantly, the majority of anti-Melan-A T cells elicited by rec. lv expressed the memory marker CD127 at the peak of the primary response. In those mice, memory T cells were detectable several months after priming and could be activated by recall peptide vaccination. These results show that immunization with rec. lv induces not only a strong antigen-specific CD8+ T-cell response but also a long-lasting T-cell memory against a bona fide tumor-associated antigen. (Cancer Res 2006; 66(2): 1155-60)
Roles of Myofibroblasts in Prostaglandin E2–Stimulated Intestinal Epithelial Proliferation and Angiogenesis
Authors: Shao Jinyi , Sheng George G. , Mifflin Randy C. , Powell Don W. , Sheng Hongmiao 
Published: January 2006

Abstract
Prostaglandins (PG) are produced throughout the gastrointestinal tract and are critical mediators for a complex array of physiologic and pathophysiologic processes in the intestine. Intestinal myofibroblasts, which express cyclooxygenase (COX) and generate PGE2, play important roles in intestinal epithelial proliferation, differentiation, inflammation, and neoplasia through secreting growth factors and cytokines. Here, we show that PGE2 activated human intestinal subepithelial myofibroblasts (18Co) through Gs protein–coupled E-prostanoid receptors and the cyclic AMP/protein kinase A pathway. 18Co cells and primary colonic myofibroblast isolates expressed a number of growth factors; several of them were dramatically regulated by PGE2. An epidermal growth factor–like growth factor, amphiregulin (AR), which was not expressed by untreated cells, was strongly induced by PGE2. Expression of vascular endothelial growth factor A (VEGFA) was rapidly increased by PGE2 exposure. Hepatocyte growth factor (HGF) was elevated in PGE2-treated myofibroblasts at both mRNA and protein levels. Thus, PGE2-activated myofibroblasts promoted the proliferation and migration of intestinal epithelial cells, which were attenuated by neutralizing antibodies to AR and HGF, respectively. Moreover, in the presence of PGE2, myofibroblasts strongly stimulated the migration and tubular formation of vascular endothelial cells. Neutralizing antibody to VEGFA inhibited the observed stimulation of migration. These results suggest that myofibroblast-generated growth factors are important mediators for PGE2-induced intestinal epithelial proliferation and angiogenesis, which play critical roles in intestinal homeostasis, inflammation, and neoplasia. (Cancer Res 2006; 66(2): 846-55)
Synergistic Effects of Gemcitabine and Gefitinib in the Treatment of Head and Neck Carcinoma
Authors: Chun Patrick Y. , Feng Felix Y. , Scheurer Ashley M. , Davis Mary A. , Lawrence Theodore S. , Nyati Mukesh K. 
Published: January 2006

Abstract
Although the combination of gemcitabine and radiation produces a high frequency of complete responses in the treatment of locally advanced head and neck cancer, substantial toxicity suggests that an improvement in the therapeutic index is required. The purpose of this study was to determine if gefitinib could improve the efficacy of gemcitabine and if drug schedule is important. We hypothesized that gemcitabine followed by gefitinib would be superior to the opposite order because of both cell cycle and growth factor signaling interactions. Using UMSCC-1 cells in vitro, we confirmed that gefitinib arrested cells in G1 and suppressed phospho-epidermal growth factor receptor (pY845EGFR) and that gemcitabine arrested cells in S phase and stimulated pY845EGFR. The schedule of gemcitabine followed by gefitinib caused arrest of cells in S phase. Gefitinib suppressed gemcitabine-mediated pY845EGFR stimulation. This schedule caused decreased pS473AKT, increased poly(ADP-ribose) polymerase cleavage, and increased apoptosis compared with gemcitabine alone. The schedule of gefitinib followed by gemcitabine also caused suppression of pY845EGFR but arrested cells in G1. This schedule in which gefitinib was used first was associated with stable levels of pS473AKT and minimal poly(ADP-ribose) polymerase cleavage and apoptosis. These results were reflected in experiments in nude mice bearing UMSCC-1 xenografts, in which there was greater tumor regression and apoptosis when animals received gemcitabine followed by gefitinib during the first week of therapy. These findings suggest that the schedule of gemcitabine followed by gefitinib may increase the therapeutic index over gemcitabine alone and, combined with clinical data, encourage exploration of combination of gemcitabine, EGFR inhibitors, and radiation. (Cancer Res 2006; 66(2): 981-8)
Activity of the Adenoviral E1A Deletion Mutant dl922-947 in Ovarian Cancer: Comparison with E1A Wild-type Viruses, Bioluminescence Monitoring, and Intraperitoneal Delivery in Icodextrin
Authors: Lockley Michelle , Fernandez Mario , Wang Yaohe , Li N. Fiona , Conroy Susan , Lemoine Nicholas , McNeish Iain 
Published: January 2006

Abstract
The adenoviral mutant dl922-947 has potent activity in a variety of tumors. We investigated the efficacy of dl922-947 in ovarian carcinoma; compared its activity to wild-type adenovirus, dl309, and dl1520; and investigated the use of icodextrin to enhance activity in vivo. We also assessed the utility of luciferase bioluminescence imaging to quantify the response of human ovarian carcinoma xenografts to dl922-947. Ovarian carcinoma cell lines were transfected in vitro with dl922-947, adenovirus 5 wild-type (Ad5 WT), dl309, and dl1520 and monitored for S-phase induction, viral protein expression, replication, and overall survival. In vivo, the efficacy of dl922-947 when delivered in PBS or icodextrin to female nude mice bearing IGROV1 xenografts was determined. In vitro, dl922-947 induced lysis with greater efficacy than Ad5 WT, dl309, or dl1520 in all ovarian carcinoma cell lines tested, which was associated with earlier expression of viral proteins and S-phase induction. The lytic effect in immortalized ovarian surface epithelial cells confirmed that cellular retinoblastoma pathway status is a strong determinant of dl922-947 activity. In vivo, i.p. delivery of dl922-947 (5 × 109 particles daily × 5) increased median survival from 20 to 96 days (P &lt; 0.0001) and delivery in icodextrin-enhanced survival further. However, delayed hepatic toxicity was evident in some dl922-947-treated mice, which was not dependent upon viral replication within tumor cells or the liver. dl922-947 has potency in ovarian carcinoma and i.p. delivery in icodextrin may enhance this activity. Immunocompetent models of ovarian carcinoma are required for further evaluation of hepatotoxicity. (Cancer Res 2006; 66(2): 989-98)
17-Allylamino-17-Demethoxygeldanamycin Synergistically Potentiates Tumor Necrosis Factor–Induced Lung Cancer Cell Death by Blocking the Nuclear Factor-κB Pathway
Authors: Wang Xia , Ju Wei , Renouard Jordan , Aden James , Belinsky Steven A. , Lin Yong 
Published: January 2006

AbstractNuclear factor-κB (NF-κB), a survival signal induced by tumor necrosis factor (TNF), contributes substantially to the resistance to TNF-induced cell death. Previous studies suggest that heat shock protein 90 (Hsp90) regulates the stability and function of receptor-interaction proteins (RIP) and IκB kinase β (IKKβ), the key components of the TNF-induced NF-κB activation pathway. In this study, we showed that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) was synergistic with TNF to induce apoptotic cell death in a panel of lung tumor-derived cell lines. Treatment with 17AAG caused degradation of RIP and IKKβ that, in turn, blocked TNF-induced NF-κB activation and antiapoptotic gene expression. The synergistic cytotoxicity was detected only when TNF treatment followed 17AAG preexposure. Importantly, the potentiation of cell death was abolished in NF-κB-disabled cells that express a nondegradable IκBα mutant (IκBαAA). These results suggest that the cytotoxicity seen with 17AAG and TNF treatment results from blocking TNF-induced NF-κB activation. The other components of the TNF receptor I signaling cascade were not altered, whereas TNF-induced c-Jun NH2-terminal kinase activation and apoptosis were potentiated. A similar synergism for inducing apoptosis was also observed in 17AAG-treated and TNF-related apoptosis-inducing ligand (TRAIL)–treated cancer cells. Our results suggest that NF-κB plays a key role in the resistance of lung cancer cells to TNF and TRAIL and that disabling this survival signal with 17AAG followed by TNF or TRAIL treatment could be an effective new therapeutic strategy for lung cancer. (Cancer Res 2006; 66(2): 1089-95)
MSF-A Interacts with Hypoxia-Inducible Factor-1α and Augments Hypoxia-Inducible Factor Transcriptional Activation to Affect Tumorigenicity and Angiogenesis
Authors: Amir Sharon , Wang Ruoxiang , Matzkin Haim , Simons Jonathan W. , Mabjeesh Nicola J. 
Published: January 2006

Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the signaling pathway that controls the hypoxic responses of cancer cells. Activation of the HIF system has been observed in carcinogenesis and numerous cancers. We found an interaction between a member of the mammalian septin gene family (MSF-A) and the HIF system. MSF-A is a nuclear protein that interacts with HIF-1α protein to prevent its ubiquitination and degradation, thus activating the HIF transcriptome. Cells overexpressing MSF-A protein exhibit increased HIF transcriptional activity and higher proliferation rates in vitro and in vivo. Xenograft-derived human tumors from these cells were larger and more vascular. These findings link a function of a septin protein with angiogenesis through activation of the HIF pathway. (Cancer Res 2006; 66(2): 856-66)
Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680
Authors: Young Matthew A. , Shah Neil P. , Chao Luke H. , Seeliger Markus , Milanov Zdravko V. , Biggs William H. , Treiber Daniel K. , Patel Hitesh K. , Zarrinkar Patrick P. , Lockhart David J. , Sawyers Charles L. , Kuriyan John 
Published: January 2006

Abstract
We present a high-resolution (2.0 Å) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His396Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the “gatekeeper” position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position. (Cancer Res 2006; 66(2): 1007-14)
Significance of Murine Retroviral Mutagenesis for Identification of Disease Genes in Human Acute Myeloid Leukemia
Authors: Erkeland Stefan J. , Verhaak Roel G.W. , Valk Peter J.M. , Delwel Ruud , Löwenberg Bob , Touw Ivo P. 
Published: January 2006

Abstract
Retroviral insertion mutagenesis is considered a powerful tool to identify cancer genes in mice, but its significance for human cancer has remained elusive. Moreover, it has recently been debated whether common virus integrations are always a hallmark of tumor cells and contribute to the oncogenic process. Acute myeloid leukemia (AML) is a heterogeneous disease with a variable response to treatment. Recurrent cytogenetic defects and acquired mutations in regulatory genes are associated with AML subtypes and prognosis. Recently, gene expression profiling (GEP) has been applied to further risk stratify AML. Here, we show that mouse leukemia genes identified by retroviral insertion mutagenesis are more frequently differentially expressed in distinct subclasses of adult and pediatric AML than randomly selected genes or genes located more distantly from a virus integration site. The candidate proto-oncogenes showing discriminative expression in primary AML could be placed in regulatory networks mainly involved in signal transduction and transcriptional control. Our data support the validity of retroviral insertion mutagenesis in mice for human disease and indicate that combining these murine screens for potential proto-oncogenes with GEP in human AML may help to identify critical disease genes and novel pathogenetic networks in leukemia. (Cancer Res 2006; 66(2): 622-6)
Antitumor Activity of Epidermal Growth Factor Receptor–Related Protein Is Mediated by Inactivation of ErbB Receptors and Nuclear Factor-κB in Pancreatic Cancer
Authors: Zhang Yuxiang , Banerjee Sanjeev , Wang Zhiwei , Xu Hu , Zhang Liyue , Mohammad Ramzi , Aboukameel Amro , Adsay Nazmi V. , Che Mingxin , Abbruzzese James L. , Majumdar Adhip P.N. , Sarkar Fazlul H. 
Published: January 2006

Abstract
The erbB family of receptor tyrosine kinases plays critical roles in human cancers, including pancreatic cancer. Discovering a specific agent, which targets multiple members of the erbB family, would be important in pancreatic cancer therapy. Recently, we isolated a novel negative regulator of epidermal growth factor receptor (EGFR), termed EGFR-related protein (ERRP), whose expression attenuates EGFR activation. In the current study, we examined the effects of recombinant ERRP on the growth and ligand-induced activation of multiple members of erbB family in three pancreatic cancer cell lines that express varying levels of EGFR and other member(s) of its family, specifically HER-2. Additionally, we compared the growth inhibitory effect of ERRP with that of Erbitux or Herceptin. Our results showed that ERRP is most effective in inhibiting proliferation of BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. ERRP also inhibited ligand-induced activation of EGFR, HER-2, and HER-3 (ErbB3). In contrast, Erbitux and Herceptin only partially or modestly inhibited activation of EGFR, HER-2, and HER-3. Most importantly, ERRP was found to inhibit pancreatic tumor growth in a severe combined immunodeficient mouse xenograft model. The antitumor activity of ERRP correlates well with tumor differentiation and down-regulation of nuclear factor-κB activity. In summary, our results suggest that ERRP is an effective pan-erbB inhibitor, which could be a potential therapeutic agent for pancreatic cancers expressing different levels and subclasses of erbB family of proteins. (Cancer Res 2006; 66(2): 1025-32)
Polymorphisms in RET and Its Coreceptors and Ligands as Genetic Modifiers of Multiple Endocrine Neoplasia Type 2A
Authors: Lesueur Fabienne , Cebrian Arancha , Robledo Mercedes , Niccoli-Sire Patricia , Svensson Karl-Axel , Pinson Stephane , Leyland Jean , Whittaker Joanne , Pharoah Paul D. , Ponder Bruce A.J. 
Published: January 2006

Abstract
Germ line missense mutations in the RET proto-oncogene are responsible for the inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). The clinical presentation of the disease and the age at onset varies even within families, where patients carry the same mutation. These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset. Here, we investigate whether this observed association could be confirmed in a larger set of 384 individuals from MEN2 families from four different European populations. In addition, we tested as modifiers four other single nucleotide polymorphisms (SNPs), which we have found in a previous association study of RET, its coreceptors, and ligands to be associated with the risk of developing sporadic medullary thyroid carcinoma. We could not replicate the association between G691S/S904S and modifier effects in MEN2A families in any of the four European families analyzed. Of the other SNPs tested, only RET A432A showed a positive weak effect on tumor spectrum within MEN2A, which requires replication in a larger series. (Cancer Res 2006; 66(2): 1177-80)