bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Pathology of Nerve Sheath Tumors in Mouse Models and Humans
Authors: Stemmer-Rachamimov Anat O. , Louis David N. , Nielsen Gunnlaugur P. , Antonescu Cristina R. , Borowsky Alexander D. , Bronson Roderick T. , Burns Dennis K. , Cervera Pascale , McLaughlin Margaret E. , Reifenberger Guido , Schmale Michael C. , MacCollin Mia , Chao Richard C. , Cichowski Karen , Kalamarides Michel , Messerli Shanta M. , McClatchey Andrea I. , Niwa-Kawakita Michiko , Ratner Nancy , Reilly Karlyne M. , Zhu Yuan , Giovannini Marco 
Published: September 2005

AbstractDespite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated to aid in the study of NF tumor biology and in the development of targeted therapies for NF patients. A single, universal pathological classification of the lesions generated in these murine models is essential for the validation of the models, for their analysis and comparison with other models, and for their future effective use in preclinical treatment trials. For the formulation of a pathological classification of these lesions, the WHO classification of human tumors was used as a reference. However, it was not adopted for the classification of the GEM lesions because of some important differences between the human and murine lesions. A novel classification scheme for peripheral nerve sheath tumors in murine models was therefore devised.
BRCA1 Interacts with and Is Required for Paclitaxel-Induced Activation of Mitogen-Activated Protein Kinase Kinase Kinase 3
Authors: Gilmore Paula M. , McCabe Nuala , Quinn Jennifer E. , Kennedy Richard D. , Gorski Julia J. , Andrews Heather N. , McWilliams Stewart , Carty Michael , Mullan Paul B. , Duprex W. Paul , Liu Edison T. , Johnston Patrick G. , Harkin D. Paul 
Published: September 2005

Abstract
BRCA1 has been implicated in a number of cellular processes, including transcriptional regulation, DNA damage repair, cell cycle arrest, and apoptosis. We identified mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3), an upstream regulator of the c-Jun NH2-terminal kinase/stress-activated protein kinase and p38/MAPK pathways, as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by coimmunoprecipitation in mammalian cells. Deletion mapping demonstrated that amino acids 1611–1863 are required to mediate the interaction with MEKK3 in yeast. BRCA1 disease-associated mutations abrogated the interaction in yeast, and BRCA1 failed to interact with MEKK3 in BRCA1 mutant HCC1937 breast cancer cells. We demonstrate that small interfering RNA-based inhibition of endogenous BRCA1 reduces MEKK3 kinase activity and conversely that inducible expression of BRCA1 activates MEKK3 and p38/MAPK. Finally, we demonstrate using complementary approaches that BRCA1 is required for paclitaxel-induced activation of MEKK3. These data indicate that BRCA1 is a key regulator of the paclitaxel-induced stress response pathway and suggest that the ability of BRCA1 to associate with, and mediate the activation of, MEKK3 represents a potential mechanism through which this pathway is regulated.
Pro-Matrix Metalloproteinase-2 Transfection Increases Orthotopic Primary Growth and Experimental Metastasis of MDA-MB-231 Human Breast Cancer Cells in Nude Mice
Authors: Tester Angus M. , Waltham Mark , Oh Se-Jeong , Bae Seog-Nyeon , Bills Margaret M. , Walker Emma C. , Kern Francis G. , Stetler-Stevenson William G. , Lippman Marc E. , Thompson Erik W. 
Published: September 2005

Abstract
The ability to activate pro-matrix metalloproteinase (pro-MMP)-2 via membrane type-MMP is a hallmark of human breast cancer cell lines that show increased invasiveness, suggesting that MMP-2 contributes to human breast cancer progression. To investigate this, we have stably transfected pro-MMP-2 into the human breast cancer cell line MDA-MB-231, which lacks MMP-2 expression but does express its cell surface activator, membrane type 1-MMP. Multiple clones were derived and shown to produce pro-MMP-2 and to activate it in response to concanavalin A. In vitro analysis showed that the pro-MMP-2-transfected clones exhibited an increased invasive potential in Boyden chamber and Matrigel outgrowth assays, compared with the parental cells or those transfected with vector only. When inoculated into the mammary fat pad of nude mice, each of the MMP-2-tranfected clones grew faster than each of the vector controls tested. After intracardiac inoculation into nude mice, pro-MMP-2-transfected clones showed a significant increase in the incidence of metastasis to brain, liver, bone, and kidney compared with the vector control clones but not lung. Increased tumor burden was seen in the primary site and in lung metastases, and a trend toward increased burden was seen in bone, however, no change was seen in brain, liver, or kidney. This data supports a role for MMP-2 in breast cancer progression, both in the growth of primary tumors and in their spread to distant organs. MMP-2 may be a useful target for breast cancer therapy when refinement of MMP inhibitors provides for MMP-specific agents.
Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3
Authors: George Prince , Bali Purva , Cohen Pamela , Tao Jianguo , Guo Fei , Sigua Celia , Vishvanath Anasuya , Fiskus Warren , Scuto Anna , Annavarapu Srinivas , Moscinski Lynn , Bhalla Kapil 
Published: September 2005

Abstract
Presence of the activating length mutation (LM) in the juxtamembrane domain or point mutation in the kinase domain of FMS-like tyrosine kinase-3 (FLT-3) mediates ligand-independent progrowth and prosurvival signaling in approximately one-third of acute myelogenous leukemia (AML). PKC412, an inhibitor of FLT-3 kinase activity, is being clinically evaluated in AML. Present studies demonstrate that treatment of human acute leukemia MV4-11 cells (containing a FLT-3 LM) with the heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin (17-AAG) attenuated the levels of FLT-3 by inhibiting its chaperone association with heat shock protein 90, which induced the poly-ubiquitylation and proteasomal degradation of FLT-3. Treatment with 17-AAG induced cell cycle G1 phase accumulation and apoptosis of MV4-11 cells. 17-AAG-mediated attenuation of FLT-3 and p-FLT-3 in MV4-11 cells was associated with decrease in the levels of p-AKT, p-ERK1/2, and p-STAT5, as well as attenuation of the DNA binding activity of STAT-5. Treatment with 17-AAG, downstream of STAT5, reduced the levels of c-Myc and oncostatin M, which are transactivated by STAT5. Cotreatment with 17-AAG and PKC412 markedly down-regulated the levels of FLT-3, p-FLT-3, p-AKT, p-ERK1/2, and p-STAT5, as well as induced more apoptosis of MV4-11 cells than either agent alone. Furthermore, the combination of 17-AAG and PKC412 exerted synergistic cytotoxic effects against MV4-11 cells. Importantly, 17-AAG and PKC412 induced more loss of cell viability of primary AML blasts containing FLT-3 LM, as compared with those that contained wild-type FLT-3. Collectively, these in vitro findings indicate that the combination of 17-AAG and PKC412 has high level of activity against AML cells with FLT-3 mutations.
Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract
Authors: Wentzensen Nicolas , Vinokurova Svetlana , Doeberitz Magnus von Knebel 
Published: September 2005

Abstract
Cancers of the anogenital tract as well as some head and neck cancers are caused by persistent infections with high-risk type human papillomaviruses (HPVs). Two viral oncogenes, E6 and E7, induce severe chromosomal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This occurs early in preneoplastic lesions, when the viral genome still persists in an episomal state. In most invasive cancers and also in a few high-grade dysplastic lesions, however, integration of high-risk HPV genomes into the host genome is observed. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of preneoplastic lesions. Disruption or deregulation of defined critical cellular gene functions by insertional mutagenesis by integrated HPV genome fragments has been hypothesized as one major promoting factor in the pathogenesis of HPV-associated cancers. This hypothesis was based on the detection of HPV integration events in the area of tumor-relevant genes in few cases. Here, we reviewed &gt;190 reported integration loci with respect to changes in the viral structure and the targeted genomic locus. This analysis confirms that HPV integration sites are randomly distributed over the whole genome with a clear predilection for genomic fragile sites. No evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.
Molecular Features of the Transition from Prostatic Intraepithelial Neoplasia (PIN) to Prostate Cancer
Authors: Ashida Shingo , Nakagawa Hidewaki , Katagiri Toyomasa , Furihata Mutsuo , Iiizumi Megumi , Anazawa Yoshio , Tsunoda Tatsuhiko , Takata Ryo , Kasahara Kotaro , Miki Tsuneharu , Fujioka Tomoaki , Shuin Taro , Nakamura Yusuke 
Published: September 2005

Abstract
To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.
The
HMG-I
Oncogene Causes Highly Penetrant, Aggressive Lymphoid Malignancy in Transgenic Mice and Is Overexpressed in Human Leukemia
Authors: Xu Yi , Sumter Takita Felder , Bhattacharya Raka , Tesfaye Abeba , Fuchs Ephraim J. , Wood Lisa J. , Huso David L. , Resar Linda M. S. 
Published: September 2005

Abstract
HMG-I/Y is overexpressed in human cancer, although a direct role for this gene in transformation has not been established. We generated transgenic mice with HMG-I targeted to lymphoid cells. All seven informative founder HMG-I mice developed aggressive lymphoma by a mean age of 4.8 months. Tumors express T-cell markers and are transplantable. We also demonstrate that HMG-I mRNA and protein are increased in human acute lymphocytic leukemia samples. Our results show that HMG-I functions as an oncogene and suggest that it contributes to the pathogenesis of leukemia and other cancers with increased HMG-I expression.
X-Linked Inhibitor of Apoptosis Protein (XIAP) Is a Nonredundant Modulator of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)- Mediated Apoptosis in Human Cancer Cells
Authors: Cummins Jordan M. , Kohli Manu , Rago Carlo , Kinzler Kenneth W. , Vogelstein Bert , Bunz Fred 
Published: September 2005

Abstract
Although the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to play an important role in the immunosurveillance of neoplasia, apoptotic factors that modulate the sensitivity of cancer cells to TRAIL are poorly understood. The inhibitor of apoptosis proteins (IAPs) have generated considerable interest as potential targets for cancer therapy, but the lack of a phenotype in X-linked IAP (XIAP) knockout mice has generated speculation that IAP function may be redundant. Using gene targeting technology, we show that disruption of the gene encoding XIAP in human cancer cells did not interfere with basal proliferation, but caused a remarkable sensitivity to TRAIL. These results demonstrate that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis and provide a rationale for XIAP as a therapeutic target.
Uterine Leiomyomata with t(10;17) Disrupt the Histone Acetyltransferase
MORF
Authors: Moore Steven D. P. , Herrick Steven R. , Ince Tan A. , Kleinman Michael S. , Cin Paola Dal , Morton Cynthia C. , Quade Bradley J. 
Published: September 2005

Abstract
Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histones H1 and H5 and the PHD zinc fingers, the CH2CH zinc finger, or the CoA binding site, which is distinct from the breakpoints reported in AML. Mapping of the 17q21 breakpoint by fluorescence in situ hybridization within a specific region in three tumors revealed several positional candidates including GCN5L2, a gene with histone acetyltransferase activity similar to those fused to MORF in AML. Of note, two of three uterine leiomyomata were of the cellular subtype. Involvement of MORF in four uterine leiomyomata with chromosomal rearrangements involving 10q22 and 17q21 suggests a role for this histone acetyltransferase and altered chromatin regulation in uterine mesenchymal neoplasia.
Steps Involved in Immortalization and Tumorigenesis in Human B-Lymphoblastoid Cell Lines Transformed by Epstein-Barr Virus
Authors: Sugimoto Masanobu , Tahara Hidetoshi , Ide Toshinori , Furuichi Yasuhiro 
Published: September 2005

Abstract
Epstein-Barr virus (EBV) is closely associated with the generation of various tumors, including Burkitt’s lymphoma. Human resting B cells from peripheral blood are easily transformed by EBV to actively proliferating B-lymphoblastoid cell lines (LCLs). These LCLs with normal diploid karyotypes have been believed to be “immortal”, without becoming tumorigenic. A series of recent studies, however, indicate that this initial, simple concept needs extensive reconsideration. Most LCLs from normal individuals are mortal because their telomeres shorten. Some LCLs are truly immortalized by developing strong telomerase activity and aneuploidy, accompanied by various other changes: down-regulation of p16/Rb; mutation of the p53 gene; modulation of apoptosis; and sensitivity to various chemical agents. Some post-immortal LCLs additionally develop the ability to form colonies in agarose and even become tumorigenic by developing the ability to grow in nude mice. The genetic background of LCLs markedly affects the frequency of immortalization. In summary, changes of B cells after infection by EBV are roughly divided into two steps: (a) transformation of B cells into LCLs caused by EBV proteins; and (b) immortalization and tumorigenesis of LCLs mainly regulated by the factors of host cells in cooperation with EBV proteins. The new concept as reviewed here is essential for the future study of tumorigenesis by EBV.
Disruption of Cancer Cell Replication by Alternating Electric Fields
Authors: Kirson Eilon D. , Gurvich Zoya , Schneiderman Rosa , Dekel Erez , Itzhaki Aviran , Wasserman Yoram , Schatzberger Rachel , Palti Yoram 
Published: September 2005

Abstract
Low-intensity, intermediate-frequency (100–300 kHz), alternating electric fields, delivered by means of insulated electrodes, were found to have a profound inhibitory effect on the growth rate of a variety of human and rodent tumor cell lines (Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26) and malignant tumors in animals. This effect, shown to be nonthermal, selectively affects dividing cells while quiescent cells are left intact. These fields act in two modes: arrest of cell proliferation and destruction of cells while undergoing division. Both effects are demonstrated when such fields are applied for 24 h to cells undergoing mitosis that is oriented roughly along the field direction. The first mode of action is manifested by interference with the proper formation of the mitotic spindle, whereas the second results in rapid disintegration of the dividing cells. Both effects, which are frequency dependent, are consistent with the computed directional forces exerted by these specific fields on charges and dipoles within the dividing cells. In vivo treatment of tumors in C57BL/6 and BALB/c mice (B16F1 and CT-26 syngeneic tumor models, respectively), resulted in significant slowing of tumor growth and extensive destruction of tumor cells within 3–6 days. These findings demonstrate the potential applicability of the described electric fields as a novel therapeutic modality for malignant tumors.
A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors
Authors: Chen Lei L. , Trent Jonathan C. , Wu Elsie F. , Fuller Gregory N. , Ramdas Latha , Zhang Wei , Raymond Austin K. , Prieto Victor G. , Oyedeji Caroline O. , Hunt Kelly K. , Pollock Raphael E. , Feig Barry W. , Hayes Kimberly J. , Choi Haesun , Macapinlac Homer A. , Hittelman Walter , Velasco Marco A. , Patel Shreyaskumar , Burgess Michael A. , Benjamin Robert S. , Frazier Marsha L. 
Published: September 2005

Abstract
KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.
Preexisting Lymphatic Endothelium but not Endothelial Progenitor Cells Are Essential for Tumor Lymphangiogenesis and Lymphatic Metastasis
Authors: He Yulong , Rajantie Iiro , Ilmonen Maritta , Makinen Taija , Karkkainen Marika J. , Haiko Paula , Salven Petri , Alitalo Kari 
Published: September 2005

Abstract
Endothelial progenitor cells have been shown to contribute to angiogenesis in various tumor models. Here, we have studied the relative contributions of bone marrow (BM)-derived endothelial progenitors and pre-existing lymphatic vessels to tumor lymphangiogenesis. We did not find significant incorporation of genetically marked BM-derived cells in lymphatic vessels during tumor- or vascular endothelial growth factor C-induced lymphangiogenesis. The degree of tumor lymphangiogenesis correlated with lymphatic vessel density in the peritumoral area, and despite tumor lymphangiogenesis, lymphatic metastasis failed to occur in gene-targeted vascular endothelial growth factor C+/− mice that have hypoplasia of the lymphatic network. Our data demonstrate that during tumor lymphangiogenesis and cancer cell dissemination via the lymphatics, the newly formed lymphatic vessels sprout from the pre-existing local lymphatic network with little if any incorporation of BM-derived endothelial progenitor cells.
The Biological and Therapeutic Importance of Gastrin Gene Expression in Pancreatic Adenocarcinomas
Authors: Harris Joseph C. , Gilliam Andrew D. , McKenzie Andrew J. , Evans Sean A. , Grabowska Anna M. , Clarke Philip A. , McWilliams Daniel F. , Watson Sue A. 
Published: September 2005

Abstract
The gastrin gene is expressed widely in pancreatic adenocarcinomas and the study aimed to assess its role in both the resistance of cancer cells to apoptosis and the sensitivity of cells to chemotherapeutic agents.
Two human pancreatic cell lines, PAN1 and BXPC3, expressed gastrin at both the RNA and protein levels and are shown to be representative of human pancreatic adenocarcinomas in terms of gastrin expression. Inhibition of endogenous gastrin production by tumor cells was achieved with neutralizing gastrin antiserum and transfection with a gastrin antisense plasmid.
Gastrin antiserum synergized with both taxotere and gemcitabine in inhibiting the in vitro growth of the PAN1 cell line with the inhibitory effect of the antiserum increasing from 12.7% to 70.2% with taxotere (P &lt; 0.05) and 28.6% with gemcitabine (P &lt; 0.01) after controlling for the effects of the cytotoxics. Synergy was only achieved with taxotere in BXPC3 cells with the inhibitory effect of gastrin antiserum increasing from 22.9% to 50.0% (P &lt; 0.005). Cells transfected with gastrin antisense had reduced in vitro growth in low serum conditions and were poorly tumorigenic in nude mice at an orthotopic site. Gastrin antisense-transfected PAN1 cells had increased sensitivity to the antiproliferative effects of both gemcitabine (IC50 of &gt;100 μg/ml reduced to 0.1 μg/ml) and taxotere (IC50 of 20 μg/ml reduced to &lt;0.01 μg/ml) when compared with vector controls. The increased sensitivity of PAN1 antisense coincided with increased caspase-3 activity and reduced protein kinase B/Akt phosphorylation in response to both gemcitabine and taxotere.
Gastrin gene circumvention may be an optimal adjunct to chemotherapeutic agents, such as taxotere and gemcitabine, in pancreatic adenocarcinoma.