bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Molecular Classification of Papillary Renal Cell Carcinoma
Authors: Yang Ximing J. , Tan Min-Han , Kim Hyung L. , Ditlev Jonathon A. , Betten Mark W. , Png Carolina E. , Kort Eric J. , Futami Kunihiko , Furge Kyle A. , Takahashi Masayuki , Kanayama Hiro-omi , Tan Puay Hoon , Teh Bin Sing , Luan Chunyan , Wang Kim , Pins Michael , Tretiakova Maria , Anema John , Kahnoski Richard , Nicol Theresa , Stadler Walter , Vogelzang Nicholas G. , Amato Robert , Seligson David , Figlin Robert , Belldegrun Arie , Rogers Craig G. , Teh Bin Tean 
Published: September 2005

AbstractDespite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIα in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.
RNA Interference–Mediated Silencing of the Acetyl-CoA-Carboxylase-α Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells
Authors: Brusselmans Koen , De Schrijver Ellen , Verhoeven Guido , Swinnen Johannes V. 
Published: September 2005

Abstract
Overexpression of lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)–mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-α (ACC-α), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-α gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low lipogenic activity, no cytotoxic effects of knockdown of ACC-α or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-α is a potential target for cancer intervention.
Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling
Authors: Godl Klaus , Gruss Oliver J. , Eickhoff Jan , Wissing Josef , Blencke Stephanie , Weber Martina , Degen Heidrun , Brehmer Dirk , Őrfi László , Horváth Zoltán , Kéri György , Müller Stefan , Cotten Matt , Ullrich Axel , Daub Henrik 
Published: September 2005

Abstract
Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1–mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.
Novel Tumor-Specific Isoforms of BEHAB/Brevican Identified in Human Malignant Gliomas
Authors: Viapiano Mariano S. , Bi Wenya Linda , Piepmeier Joseph , Hockfield Susan , Matthews Russell T. 
Published: September 2005

Abstract
Malignant gliomas are deadly brain tumors characterized by diffuse invasion into the surrounding brain tissue. Understanding the mechanisms involved in glioma invasion could lead to new therapeutic strategies. We have previously shown that BEHAB/brevican, an extracellular matrix protein in the central nervous system, plays a role in the invasive ability of gliomas. The mechanisms that underlie BEHAB/brevican function are not yet understood, due in part to the existence of several isoforms that may have different functions. Here we describe for the first time the expression of BEHAB/brevican in human brain and characterize two novel glioma-specific isoforms, B/bsia and B/bΔg, which are generated by differential glycosylation and are absent from normal adult brain and other neuropathologies. B/bsia is an oversialylated isoform expressed by about half the high- and low-grade gliomas analyzed. B/bΔg lacks most of the carbohydrates typically present on BEHAB/brevican and is the major up-regulated isoform of this protein in high-grade gliomas but is absent in a specific subset of low-grade, indolent oligodendrogliomas. B/bΔg is detected on the extracellular surface, where it binds to the membrane by a mechanism distinct from the other BEHAB/brevican isoforms. The glioma-specific expression of B/bΔg, its restricted membrane localization, and its expression in all high-grade gliomas tested to date suggest that it may play a significant role in glioma progression and make it an important new potential therapeutic target. In addition, its absence from benign gliomas prompts its use as a diagnostic marker to distinguish primary brain tumors of similar histology but different pathologic course.
BLM Helicase Complements Disrupted Type II Telomere Lengthening in Telomerase-Negative sgs1 Yeast
Authors: Lillard-Wetherell Kate , Combs Kelly A. , Groden Joanna 
Published: September 2005

Abstract
Recombination-mediated pathways for telomere lengthening may be utilized in the absence of telomerase activity. The RecQ-like helicases, BLM and Sgs1, are implicated in recombination-mediated telomere lengthening in human cells and budding yeast, respectively. Here, we show that BLM expression rescues disrupted telomere lengthening in telomerase-negative sgs1 yeast. BLM helicase activity is required for this complementation, indicating BLM and Sgs1 resolve the same telomeric structures. These data support a conserved function for BLM and Sgs1 in recombination-mediated telomere lengthening.
CD26 Regulates p38 Mitogen-Activated Protein Kinase–Dependent Phosphorylation of Integrin β1, Adhesion to Extracellular Matrix, and Tumorigenicity of T-Anaplastic Large Cell Lymphoma Karpas 299
Authors: Sato Tsutomu , Yamochi Tadanori , Yamochi Toshiko , Aytac Ugur , Ohnuma Kei , McKee Kathryn S. , Morimoto Chikao , Dang Nam H. 
Published: September 2005

Abstract
CD26 is an antigen with key role in T-cell biology and is expressed on selected subsets of aggressive T-cell malignancies. To elucidate the role of CD26 in tumor behavior, we examine the effect of CD26 depletion by small interfering RNA transfection of T-anaplastic large cell lymphoma Karpas 299. We show that the resultant CD26-depleted clones lose the ability to adhere to fibronectin and collagen I. Because anti–integrin β1 blocking antibodies also prevent binding of Karpas 299 to fibronectin and collagen I, we then evaluate the CD26-integrin β1 association. CD26 depletion does not decrease integrin β1 expression but leads to dephosphorylation of both integrin β1 and p38 mitogen-activated protein kinase (MAPK). Moreover, our data showing that the p38MAPK inhibitor SB203580 dephosphorylates integrin β1 and that binding of the anti-CD26 antibody 202.36 dephosphorylates both p38MAPK and integrin β1 on Karpas 299, leading to loss of cell adhesion to the extracellular matrix, indicate that CD26 mediates cell adhesion through p38MAPK-dependent phosphorylation of integrin β1. Finally, in vivo experiments show that depletion of CD26 is associated with loss of tumorigenicity and greater survival. Our findings hence suggest that CD26 plays an important role in tumor development and may be a novel therapeutic target for selected neoplasms.
Array-Based Comparative Genomic Hybridization Analysis Identified Cyclin D1 as a Target Oncogene at 11q13.3 in Nasopharyngeal Carcinoma
Authors: Hui Angela Bik-Yu , Or Yvonne Yan-Yan , Takano Hirokuni , Tsang Raymond King-Yin , To Ka-Fai , Guan Xin-Yuen , Sham Jonathan Shun-Tong , Hung Katherine Wing-Ki , Lam Cleo Nga-Yee , van Hasselt Charles Andrew , Kuo Wen-Lin , Gray Joe W. , Huang Dolly P. , Lo Kwok-Wai 
Published: September 2005

Abstract
Nasopharyngeal carcinoma is highly prevalent in Southern China and Southeast Asia. To unveil the molecular basis of this endemic disease, high-resolution comparative genomic hybridization arrays were used for systematic investigation of genomic abnormalities in 26 nasopharyngeal carcinoma samples. A comprehensive picture of genetic lesions associated with tumorigenesis of nasopharyngeal carcinoma was generated. Consistent chromosomal gains were frequently found on 1q, 3q, 8q, 11q, 12p, and 12q. High incidences of nonrandom losses were identified on chromosomes 3p, 9p, 11q, 14q, and 16q. In addition to previously characterized regions, we have identified several novel minimal regions of gains, including 3q27.3-28, 8q21-24, 11q13.1-13.3, and 12q13, which may harbor candidate nasopharyngeal carcinoma–associated oncogenes. In this study, gain of 11q13.1-13.3 was the most frequently detected chromosomal aberration and a 5.3-Mb amplicon was delineated at this region. Within this 11q13 amplicon, concordant amplification and overexpression of cyclin D1 (CCND1) oncogene was found in nasopharyngeal carcinoma cell lines, xenografts, and primary tumors. Knockdown of cyclin D1 by small interfering RNA in nasopharyngeal carcinoma cell lines led to significant decrease of cell proliferation. The findings suggest that cyclin D1 is a target oncogene at 11q13 in nasopharyngeal carcinoma and its activation plays a significant role in nasopharyngeal carcinoma tumorigenesis.
The Fallacy of Epithelial Mesenchymal Transition in Neoplasia
Authors: Tarin David 
Published: September 2005

Abstract
Epithelial mesenchymal transition has been postulated as a versatile mechanism which facilitates cellular repositioning and redeployment during embryonic development, tissue reconstruction after injury, carcinogenesis, and tumor metastasis. The hypothesis originates from parallels drawn between the morphology and behavior of locomotory and sedentary cells in vitro and in various normal and pathologic processes in vivo. This review analyzes data from several studies on embryonic development, wound healing, and the pathology of human tumors, including work from our own laboratory, to assess the validity of the proposal. It is concluded that there is no convincing evidence for conversion of epithelial cells into mesenchymal cell lineages in vivo and that the biological repertoire of normal and malignant cells is sufficient to account for the events and processes observed, without needing to invoke radical changes in cell identity.
Akt Phosphorylates Tal1 Oncoprotein and Inhibits Its Repressor Activity
Authors: Palamarchuk Alexey , Efanov Alexey , Maximov Vadim , Aqeilan Rami I. , Croce Carlo M. , Pekarsky Yuri 
Published: September 2005

Abstract
The helix-loop-helix transcription factor Tal1 is required for blood cell development and its activation is a frequent event in T-cell acute lymphoblastic leukemia. The Akt (protein kinase B) kinase is a key player in transduction of antiapoptotic and proliferative signals in T cells. Because Tal1 has a putative Akt phosphorylation site at Thr90, we investigated whether Akt regulates Tal1. Our results show that Akt specifically phosphorylates Thr90 of the Tal1 protein within its transactivation domain in vitro and in vivo. Coimmunoprecipitation experiments showed the presence of Tal1 in Akt immune complexes, suggesting that Tal1 and Akt physically interact. We further showed that phosphorylation of Tal1 by Akt causes redistribution of Tal1 within the nucleus. Using luciferase assay, we showed that phosphorylation of Tal1 by Akt decreased repressor activity of Tal1 on EpB42 (P4.2) promoter. Thus, these data indicate that Akt interacts with Tal1 and regulates Tal1 by phosphorylation at Thr90 in a phosphatidylinositol 3-kinase–dependent manner.
Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents
Authors: Vearing Christopher , Lee Fook-Thean , Wimmer-Kleikamp Sabine , Spirkoska Violeta , To Catherine , Stylianou Con , Spanevello Mark , Brechbiel Martin , Boyd Andrew W. , Scott Andrew M. , Lackmann Martin 
Published: September 2005

Abstract
The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact–mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the “low-affinity” ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents.
The Glycosphingolipid, Lactosylceramide, Regulates β1-Integrin Clustering and Endocytosis
Authors: Sharma Deepak K. , Brown Jennifer C. , Cheng Zhijie , Holicky Eileen L. , Marks David L. , Pagano Richard E. 
Published: September 2005

Abstract
Glycosphingolipids are known to play roles in integrin-mediated cell adhesion and migration; however, the mechanisms by which glycosphingolipids affect integrins are unknown. Here, we show that addition of the glycosphingolipid, C8-lactosylceramide (C8-LacCer), or free cholesterol to human fibroblasts at 10°C causes the formation of glycosphingolipid-enriched plasma membrane domains as shown by visualizing a fluorescent glycosphingolipid probe, BODIPY-LacCer, incorporated into the plasma membrane of living cells. Addition of C8-LacCer or cholesterol to cells initiated the clustering of β1-integrins within these glycosphingolipid-enriched domains and the activation of the β1-integrins as assessed using a HUTS antibody that only binds activated integrin. On warming to 37°C, β1-integrins were rapidly internalized via caveolar endocytosis in cells treated with C8-LacCer or cholesterol, whereas little β1-integrin was endocytosed in untreated fibroblasts. Incubation of cells with C8-LacCer or cholesterol followed by warm-up caused src activation, a reorganization of the actin cytoskeleton, translocation of RhoA GTPase away from the plasma membrane as visualized using total internal reflection fluorescence microscopy, and transient cell detachment. These studies show that LacCer can regulate integrin function both by modulating integrin clustering in microdomains and by regulating integrin endocytosis via caveolae. Our findings suggest the possibility that aberrant levels of glycosphingolipids found in cancer cells may influence cell attachment events by direct effects on integrin clustering and internalization.
Chromosomal Instability in Unirradiated Hemopoietic Cells Resulting from a Delayed In vivo Bystander Effect of γ Radiation
Authors: Lorimore Sally A. , McIlrath Joanne M. , Coates Philip J. , Wright Eric G. 
Published: September 2005

Abstract
Untargeted effects of ionizing radiation (de novo effects in the unirradiated descendants or neighbors of irradiated cells) challenge widely held views about the mechanisms of radiation-induced DNA damage with implications for the health consequences of radiation exposures particularly in the context of the induction of malignancy. To investigate in vivo untargeted effects of sparsely ionizing (low linear energy transfer) radiation, a congenic sex-mismatch bone marrow transplantation protocol has been used to repopulate the hemopoietic system from a mixture of γ-irradiated and nonirradiated hemopoietic stem cells such that host-, irradiated donor– and unirradiated donor–derived cells can be distinguished. Chromosomal instability in the progeny of irradiated hemopoietic stem cells accompanied by a reduction in their contribution to the repopulated hemopoietic system is consistent with a delayed genomic instability phenotype being expressed in vivo. However, chromosomal instability was also shown in the progeny of the nonirradiated hemopoietic stem cells implicating a bystander mechanism. Studies of the influence of irradiated recipient stromal microenvironment and experiments replacing irradiated cells with irradiated cell–conditioned medium reveal the source of the in vivo bystander effect to be the descendants of irradiated cells, rather than irradiated cell themselves. Thus, it is possible that a radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of inflammatory-type damaging signals as a long-term unexpected consequence of the initial single radiation exposure.
Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins
Authors: Shimamura Takeshi , Lowell April M. , Engelman Jeffrey A. , Shapiro Geoffrey I. 
Published: September 2005

Abstract
Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR), including L858R and exon 19 deletions, underlie responsiveness to gefitinib and erlotinib in non–small cell lung cancer (NSCLC). Acquired resistance to these tyrosine kinase inhibitors is in some cases mediated by a second mutation, T790M. Ansamycin antibiotics, such as geldanamycin, potently inhibit heat shock protein 90 (Hsp90), promoting ubiquitin-mediated degradation of oncogenic kinases that require the chaperone for proper conformational folding. Here, we show that L858R and deletion mutant EGFR proteins found in NSCLC interact with the chaperone and are sensitive to degradation following Hsp90 inhibition. In NIH/3T3 cells expressing either wild-type or mutant EGFR, diminution of expression of both L858R and EGFR delL747-S752, P753S occurred following exposure to 50 nmol/L geldanamycin over 24 hours, whereas partial diminution of wild-type EGFR required a minimum of 200 nmol/L drug. In time course experiments, mutant EGFR expression was depleted after only 4 hours of exposure to 1 μmol/L geldanamycin, whereas diminution of wild-type EGFR was less substantial and seen only following 12 hours. Similarly, EGFR proteins in NSCLC cell lines harboring EGFR mutations, including NCI-H1650, NCI-H3255, and NCI-H1975, were also more sensitive to geldanamycin-induced degradation compared with the protein in wild-type cells. Exposure of EGFR-mutant cell lines to geldanamycin induced marked depletion of phospho-Akt and cyclin D1 as well as apoptosis. These data suggest mutational activation of EGFR is associated with dependence on Hsp90 for stability and that Hsp90 inhibition may represent a novel strategy for the treatment of EGFR-mutant NSCLC.
Targeting of Antigens to Activated Dendritic Cells In vivo Cures Metastatic Melanoma in Mice
Authors: Mahnke Karsten , Qian Yingjie , Fondel Sabine , Brueck Juergen , Becker Christian , Enk Alexander H. 
Published: September 2005

Abstract
Anti (α)-DEC-205 antibodies target to the DEC-205 receptor that mediates antigen presentation to T cells by dendritic cells. To exploit these properties for immunization purposes, we conjugated the melanoma antigen tyrosinase-related protein (TRP)-2 to αDEC-205 antibodies and immunized mice with these conjugates together with dendritic cell–activating oligonucleotides (CpG). Upon injection of the melanoma cell line B16, αDEC-TRP immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted B16 cells by injection of αDEC-TRP2 conjugates into tumor bearing hosts. Approximately 70% of the animals were cured from existing tumors by treatment with αDEC conjugates carrying two different melanoma antigens (TRP-2 and gp100). This protection was due to induction of melanoma-specific CD4 and CD8 responses. Thus, these data show that targeting of dendritic cells in situ by the means of antibody-antigen conjugates may be a novel way to induce long-lasting antitumor immunity.