bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Rejection of Mouse Tumors Expressing Mutated Self
Authors: Duan Fei , Lin Yun , Liu Cailian , Engelhorn Manuel E. , Cohen Adam D. , Curran Michael , Sakaguchi Shimon , Merghoub Taha , Terzulli Stephanie , Wolchok Jedd D. , Houghton Alan N. 
Published: April 2009

Abstract
How the immune system recognizes and responds to mutations expressed by cancer cells is a critical issue for cancer immunology. Mutated self-polypeptides are particularly strong tumor-specific rejection antigens for natural tumor immunity, but we know remarkably little about T-cell responses to mutated self during tumor growth in vivo, including levels of response, kinetics, and correlates that predict tumor rejection. To address these questions, a mutated self-antigen, designated tyrosinase-related protein 1 (Tyrp1)-WM, derived from Tyrp1 was expressed in the poorly immunogenic, spontaneously arising B16 melanoma and the immunogenic, chemically induced LiHa fibrosarcoma. Syngeneic mice challenged with LiHa fibrosarcoma cells expressing Tyrp1-WM, but not native Tyrp1, induced specific CD8+ and CD4+ T-cell responses against defined mutated epitopes in tumor-draining lymph nodes and in tumors. Subsequently, specific CD8+ T-cell responses contracted as a minority of tumors progressed. B16 melanomas expressing Tyrp1-WM induced minimal T-cell responses, and no tumor immunity was detected. Treatment with an agonist monoclonal antibody against glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR) increased the level of CD8+ T cells recognizing a peptide derived from the Tyrp1-WM sequence and the proportion of mice rejecting tumors. These results show that B16 tumors expressing mutations that generate strongly immunogenic epitopes naturally induce T-cell responses, which are insufficient to reject tumors. Immune modulation, such as inducing GITR signaling, is required to enhance CD8+ T-cell responses to specific mutations and to lead to tumor rejection. [Cancer Res 2009;69(8):3545–53]
Mirk/Dyrk1B Maintains the Viability of Quiescent Pancreatic Cancer Cells by Reducing Levels of Reactive Oxygen Species
Authors: Deng Xiaobing , Ewton Daina Z. , Friedman Eileen 
Published: April 2009

Abstract
The kinase Mirk/dyrk1B mediated the clonogenic growth of pancreatic cancer cells in earlier studies. It is now shown that Mirk levels increased 7-fold in SU86.86 pancreatic cancer cells when over a third of the cells were accumulated in a quiescent G0 state, defined by Hoechst/Pyronin Y staining. Depletion of Mirk by a doxycycline-inducible short hairpin RNA increased the G0 fraction to ∼50%, suggesting that Mirk provided some function in G0. Mirk reduced the levels of reactive oxygen species (ROS) in quiescent cultures of SU86.86 cells and of Panc1 cells by increasing transcription of the antioxidant genes ferroxidase, superoxide dismutase (SOD)2, and SOD3. These genes were functional antioxidant genes in pancreatic cancer cells because ectopic expression of SOD2 and ferroxidase in Mirk-depleted cells lowered ROS levels. Quiescent pancreatic cancer cells quickly lost viability when depleted of Mirk because of elevated ROS levels, exhibiting up to 4-fold less colony-forming activity and 4-fold less capability for dye exclusion. As a result, reduction of ROS by N-acetyl cysteine led to more viable cells. Mirk also destabilizated cyclin D1 and D3 in quiescent cells. Thus, quiescent pancreatic cancer cells depleted of Mirk became less viable because they were damaged by ROS, and had increased levels of G1 cyclins to prime cells to escape quiescence. [Cancer Res 2009;69(8):3317–24]
Osteoblast-Derived Factors Induce an Expression Signature that Identifies Prostate Cancer Metastasis and Hormonal Progression
Authors: Wang Gang , Haile Simon , Comuzzi Barbara , Tien Amy H. , Wang Jun , Yong Theresa M.K. , Jelescu-Bodos Anca E. , Blaszczyk Natalie , Vessella Robert L. , Masri Bassam A. , Sadar Marianne D. 
Published: April 2009

Abstract
Identification of gene expression signatures associated with metastases provides a tool to discern mechanisms and potential therapeutic targets and may lead toward a molecular classification system in pathology. Prostate cancer (CaP) frequently metastasizes to the bone to form osteoblastic lesions. Correlative clinical data and in vitro evidence have led to the hypothesis that osteoblast-derived factors promote hormonal progression of CaP cells. Here, the gene expression signature of CaP exposed to osteoblast-derived factors was identified. This signature included known androgen-regulated genes, oncogenes, tumor suppressors, and genes whose products are involved in apoptosis and cell cycle. A comparative functional genomic approach involved the application of this responsive gene expression signature to clinical samples of human CaP, melanomas, and oral cancers. Cluster analysis revealed that this gene expression signature had specificity for CaP and could resolve clinical specimens according to stage (benign, localized, and metastatic) and androgen sensitivity with an accuracy of 100% and 80%, respectively. Together, these results suggest that factors derived from osteoblasts induce a more advanced phenotype of CaP and promotes hormonal progression. [Cancer Res 2009;69(8):3433–42]
Identification of Copy Number Abnormalities and Inactivating Mutations in Two Negative Regulators of Nuclear Factor-κB Signaling Pathways in Waldenström's Macroglobulinemia
Authors: Braggio Esteban , Keats Jonathan J. , Leleu Xavier , Van Wier Scott , Jimenez-Zepeda Victor H. , Valdez Riccardo , Schop Roelandt F.J. , Price-Troska Tammy , Henderson Kimberly , Sacco Antonio , Azab Feda , Greipp Philip , Gertz Morie , Hayman Suzanne , Rajkumar S. Vincent , Carpten John , Chesi Marta , Barrett Michael , Stewart A. Keith , Dogan Ahmet , Bergsagel P. Leif , Ghobrial Irene M. , Fonseca Rafael 
Published: April 2009

Abstract
Waldenström's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor–associated factor 3 and TNFα-induced protein 3, two negative regulators of the nuclear factor-κB (NF-κB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-κB target genes. Mutational activation of the NF-κB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-κB pathway activation in the treatment of WM. [Cancer Res 2009;69(8):3579–88]
Attenuated Transforming Growth Factor β Signaling Promotes Nuclear Factor-κB Activation in Head and Neck Cancer
Authors: Cohen Jonah , Chen Zhong , Lu Shi-Long , Yang Xin Ping , Arun Pattatheyil , Ehsanian Reza , Brown Matthew S. , Lu Hai , Yan Bin , Diallo Oumou , Wang Xiao-Jing , Van Waes Carter 
Published: April 2009

AbstractAlthough constitutively activated nuclear factor-κB (NF-κB), attenuated transforming growth factor β (TGFβ) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-κB–related genes, reduced expression of TGFβ receptor (TβR) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGFβ1, both growth inhibition and TGFβ target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGFβ signaling, TGFβ1 inhibited both constitutive and tumor necrosis factor α–stimulated NF-κB activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced TβRII and knocking down mtTP53 induced TβRII, increasing TGFβ downstream gene expression while inhibiting proinflammatory NF-κB target gene expression. Transfection of ectopic TβRII directly restored TGFβ signaling while inhibiting inhibitor κBα degradation and suppressing serine-536 phosphorylation of NF-κB p65 and NF-κB transcriptional activation, linking these alterations. Finally, experiments with TβRII conditional knockout mice show that abrogation of TGFβ signaling promotes the sustained induction of NF-κB and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGFβ signaling promotes NF-κB activation and squamous epithelial malignancy in the setting of altered TP53 status. [Cancer Res 2009;69(8):3415–24]
The Cell Fate Determination Factor Dachshund Inhibits Androgen Receptor Signaling and Prostate Cancer Cellular Growth
Authors: Wu Kongming , Katiyar Sanjay , Witkiewicz Agnes , Li Anping , McCue Peter , Song Liang-Nian , Tian Lifeng , Jin Ming , Pestell Richard G. 
Published: April 2009

Abstract
Initially isolated as the dominant suppressor of the mutant epidermal growth factor receptor (ellipse), the Dachshund gene plays a key role in metazoan development regulating the Retinal Determination Gene Network. Herein, the DACH1 gene was expressed in normal prostate epithelial cells with reduced expression in human prostate cancer. DACH1 inhibited prostate cancer cellular DNA synthesis, growth in colony forming assays, and blocked contact-independent growth in soft agar assays. DACH1 inhibited androgen receptor (AR) activity, requiring a conserved DS Domain (Dachshund domain conserved with Ski/Sno) that bound NCoR/HDAC and was recruited to an androgen-responsive gene promoter. DACH1 inhibited ligand-dependent activity of AR mutations identified in patients with androgen-insensitive prostate cancer. The DS domain was sufficient for repression of the AR wild-type but failed to repress an AR acetylation site point mutant. These studies show a role for the Retinal Determination Gene Network in regulating cellular growth and signaling in prostate cancer. [Cancer Res 2009;69(8):3347–55]
Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Authors: Wakimoto Hiroaki , Kesari Santosh , Farrell Christopher J. , Curry William T. , Zaupa Cecile , Aghi Manish , Kuroda Toshihiko , Stemmer-Rachamimov Anat , Shah Khalid , Liu Ta-Chiang , Jeyaretna Deva S. , Debasitis Jason , Pruszak Jan , Martuza Robert L. , Rabkin Samuel D. 
Published: April 2009

Abstract
Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem–like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although ICP6 (UL39)–deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of γ34.5 significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of α47. Infection with oHSV G47Δ (ICP6−, γ34.5−, α47−) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Δ significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis. [Cancer Res 2009;69(8):3472–81]
Oxidation Status of Human OGG1-S326C Polymorphic Variant Determines Cellular DNA Repair Capacity
Authors: Bravard Anne , Vacher Monique , Moritz Eva , Vaslin Laurence , Hall Janet , Epe Bernd , Radicella J. Pablo 
Published: April 2009

Abstract
The hOGG1 gene encodes the DNA glycosylase that removes the mutagenic lesion 7,8-dihyro-8-oxoguanine (8-oxoG) from DNA. A frequently found polymorphism resulting in a serine to cysteine substitution at position 326 of the OGG1 protein has been associated in several molecular epidemiologic studies with cancer development. To investigate whether the variant allele encodes a protein with altered OGG1 function, we compared the 8-oxoG repair activity, both in vivo and in cell extracts, of lymphoblastoid cell lines established from individuals carrying either Ser/Ser or Cys/Cys genotypes. We show that cells homozygous for the Cys variant display increased genetic instability and reduced in vivo 8-oxoG repair rates. Consistently, their extracts have an almost 2-fold lower basal 8-oxoG DNA glycosylase activity when compared with the Ser variant. Treatment with reducing agents of either the Cys variant cells directly or of protein extracts from these cells increases the repair capacity to the level of the Ser variant, whereas it does not affect the activity in cells or extracts from the latter. Furthermore, the DNA glycosylase activity of cells carrying the Cys/Cys alleles is more sensitive to inactivation by oxidizing agents when compared with that of the Ser/Ser cells. Analysis of the redox status of the OGG1 protein in the cells confirms that the lower activity of OGG1-Cys326 is associated with the oxidation of Cys326 to form a disulfide bond. Our findings support the idea that individuals homozygous for the OGG1-Cys variant could more readily accumulate mutations under conditions of oxidative stress. [Cancer Res 2009;69(8):3642–9]
Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out
Authors: Neumann Hartmut P.H. , Erlic Zoran , Boedeker Carsten C. , Rybicki Lisa A. , Robledo Mercedes , Hermsen Mario , Schiavi Francesca , Falcioni Maurizio , Kwok Pingling , Bauters Catherine , Lampe Karen , Fischer Markus , Edelman Emily , Benn Diana E. , Robinson Bruce G. , Wiegand Stefanie , Rasp Gerd , Stuck Boris A. , Hoffmann Michael M. , Sullivan Maren , Sevilla Maria A. , Weiss Marjan M. , Peczkowska Mariola , Kubaszek Agata , Pigny Pascal , Ward Robyn L. , Learoyd Diana , Croxson Michael , Zabolotny Dmitry , Yaremchuk Svetlana , Draf Wolfgang , Muresan Mihaela , Lorenz Robert R. , Knipping Stephan , Strohm Michael , Dyckhoff Gerhard , Matthias Christoph , Reisch Nicole , Preuss Simon F. , Eβer Dirk , Walter Martin A. , Kaftan Holger , Stöver Timo , Fottner Christian , Gorgulla Harald , Malekpour Mahdi , Zarandy Masoud Motasaddi , Schipper Jörg , Brase Christoph , Glien Alexander , Kühnemund Matthias , Koscielny Sven , Schwerdtfeger Peter , Välimäki Matti , Szyfter Witold , Finckh Ulrich , Zerres Klaus , Cascon Alberto , Opocher Giuseppe , Ridder Gerd J. , Januszewicz Andrzej , Suarez Carlos , Eng Charis 
Published: April 2009

Abstract
Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs ∼US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age ≤40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]
A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by CultureIn vitro
Authors: Daniel Vincent C. , Marchionni Luigi , Hierman Jared S. , Rhodes Jonathan T. , Devereux Wendy L. , Rudin Charles M. , Yung Rex , Parmigiani Giovanni , Dorsch Marion , Peacock Craig D. , Watkins D. Neil 
Published: April 2009

AbstractTraditional approaches to the preclinical investigation of cancer therapies rely on the use of established cell lines maintained in serum-based growth media. This is particularly true of small-cell lung cancer (SCLC), where surgically resected tissue is rarely available. Recent attention has focused on the need for better models that preserve the integrity of cancer stem cell populations, as well as three-dimensional tumor-stromal interactions. Here we describe a primary xenograft model of SCLC in which endobronchial tumor specimens obtained from chemo-naive patients are serially propagated in vivo in immunodeficient mice. In parallel, cell lines grown in conventional tissue culture conditions were derived from each xenograft line, passaged for 6 months, and then reimplanted to generate secondary xenografts. Using the Affymetrix platform, we analyzed gene expression in primary xenograft, xenograft-derived cell line, and secondary xenograft, and compared these data to similar analyses of unrelated primary SCLC samples and laboratory models. When compared with normal lung, primary tumors, xenografts, and cell lines displayed a gene expression signature specific for SCLC. Comparison of gene expression within the xenograft model identified a group of tumor-specific genes expressed in primary SCLC and xenografts that was lost during the transition to tissue culture and that was not regained when the tumors were reestablished as secondary xenografts. Such changes in gene expression may be a common feature of many cancer cell culture systems, with functional implications for the use of such models for preclinical drug development. [Cancer Res 2009;69(8):3364–71]
The miR-17/92 Polycistron Is Up-regulated in Sonic Hedgehog–Driven Medulloblastomas and Induced by N-myc in Sonic Hedgehog–Treated Cerebellar Neural Precursors
Authors: Northcott Paul A. , Fernandez-L Africa , Hagan John P. , Ellison David W. , Grajkowska Wesia , Gillespie Yancey , Grundy Richard , Van Meter Timothy , Rutka James T. , Croce Carlo M. , Kenney Anna Marie , Taylor Michael D. 
Published: April 2009

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. [Cancer Res 2009;69(8):3249–55]
Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia
Authors: Chiarini Francesca , Falà Federica , Tazzari Pier Luigi , Ricci Francesca , Astolfi Annalisa , Pession Andrea , Pagliaro Pasqualepaolo , McCubrey James A. , Martelli Alberto M. 
Published: April 2009

Abstract
Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G0-G1 phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3β. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth. [Cancer Res 2009;69(8):3520–28]