bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Exercise on Serum Estrogens in Postmenopausal Women
Authors: McTiernan Anne , Tworoger Shelley S. , Ulrich Cornelia M. , Yasui Yutaka , Irwin Melinda L. , Rajan Kumar B. , Sorensen Bess , Rudolph Rebecca E. , Bowen Deborah , Stanczyk Frank Z. , Potter John D. , Schwartz Robert S. 
Published: September 2005

Abstract
Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index &gt; 24.0 kg/m2, body fat &gt; 33%), postmenopausal women, ages 50–75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P = 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by ≥2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.
Increased Susceptibility of Poly(ADP-Ribose) Polymerase-1 Knockout Cells to Antitumor Triazoloacridone C-1305 Is Associated with Permanent G2 Cell Cycle Arrest
Authors: Węsierska-Gądek Józefa , Schloffer Daniela , Gueorguieva Marieta , Uhl Maria , Skladanowski Andrzej 
Published: September 2005

Abstract
Triazoloacridone C-1305 is a novel inhibitor of DNA topoisomerase II, which exhibits potent antitumor activity toward solid tumors. In this study, antiproliferative action of C-1305 and its close analog C-1533 was investigated in nontransformed mouse fibroblasts and two mutant cell lines in which the PARP-1 gene was specifically disrupted. Unexpectedly, C-1305 very strongly affected proliferation of cells lacking poly(ADP-ribose) polymerase-1 (PARP-1), whereas the action of less active compound C-1533 toward normal and PARP-1-negative cells was comparable. The IC50 concentration of C-1305 determined for PARP-1 knockout cells was ∼150-fold lower than that determined for cells with functional PARP-1. Both studied triazoloacridones exhibited very low direct cytotoxicity as evidenced by accumulation of 7-amino-actinomycin D, and only low levels of apoptosis were observed after a 24-h exposure to studied drugs. Analysis of DNA damage induced by C-1305 by the Comet assay showed that this drug induced very low levels of DNA strand breaks. C-1305 strongly affected cell cycle progression in normal and PARP-1 mutant cells and arrested both cell types in G2-M phase. However, the G2-M arrest induced by C-1305 was greatly prolonged in PARP-1-deficient cells as compared with normal fibroblasts. Together, these results show that mouse cells lacking PARP-1 are extremely sensitive to C-1305, a new topoisomerase II inhibitor. This is in striking contrast with previous reports in which PARP-1-deficient cells were shown to be resistant to classical topoisomerase II inhibitors. Our data also suggest that the PARP-1 status might be essential for the maintenance of the G2 arrest induced by C-1305.
Mutation of
hCDC4
Leads to Cell Cycle Deregulation of Cyclin E in Cancer
Authors: Reed Susanna Ekholm , Spruck Charles H. , Sangfelt Olle , van Drogen Frank , Mueller-Holzner Elisabeth , Widschwendter Martin , Zetterberg Anders , Reed Steven I. 
Published: September 2005

Abstract
hCDC4, the gene that encodes the F-box protein responsible for targeting cyclin E for ubiquitin-mediated proteolysis, has been found to be mutated in a number of primary cancers and cancer-derived cell lines. We have observed that functional inactivation of hCDC4 does not necessarily correlate with elevated levels of cyclin E in tumors. Here we show, however, that hCDC4 mutation in primary tumors correlates strongly with loss of cell cycle regulation of cyclin E. Similarly, a breast carcinoma-derived cell line mutated for hCDC4 exhibits cell cycle deregulation of cyclin E, but periodic expression is restored by reintroducing hCDC4 via retroviral transduction. Conversely, small interfering RNA-mediated silencing of hCdc4 deregulates cyclin E with respect to the cell cycle. These results indicate that hCdc4 function is an absolute prerequisite for cell cycle regulation of cyclin E levels, and loss of hCdc4 function is sufficient to deregulate cyclin E.
Laminin-Induced Signaling in Tumor Cells
Authors: Givant-Horwitz Vered , Davidson Ben , Reich Reuven 
Published: September 2005

AbstractThe expression of the Mr 67,000 laminin receptor, a nonintegrin laminin receptor, was found to be up-regulated in neoplastic cells and to directly correlate with invasion and metastatic potential. In the present study, we investigated the role of laminin receptor in mediating laminin effects and the involvement of the mitogen-activated protein kinases (MAPK) cascades and dual-specificity phosphatases in laminin signaling in human melanoma cells. Using stable transfection of A375SM melanoma cells, we established lines expressing reduced or elevated laminin receptor. The antisense-transfected cells demonstrated reduced attachment to laminin and reduced invasion through Matrigel-coated filters. In addition, both matrix metalloproteinase-2 (MMP-2) mRNA expression and activity were significantly reduced in the antisense-transfected cells. Antisense-transfected cells showed a reduction in mRNA level of the α6B integrin subunit isoform, whereas no change in the mRNA level of the α6A isoform was observed. We found that exogenous laminin reduced the phosphorylated (active) form of extracellular signal-regulated kinase, c-Jun NH2-terminal protein kinase, and p38 in all of the cells, irrespective of the expression of the laminin receptor. Furthermore, the phosphorylation of extracellular signal-regulated kinase, c-Jun NH2-terminal protein kinase, and p38 was significantly higher in the cell lines expressing reduced laminin receptor, regardless of the exposure to exogenous laminin. This increase of MAPK phosphorylation was accompanied by a significant reduction in MKP-1 phosphatase mRNA level and a significant increase in PAC-1 phosphatase mRNA level. In conclusion, our results confirm the involvement of the laminin receptor in different mechanisms related to tumor dissemination and provide first evidence of the involvement of MAPK and dual-specificity phosphatases in its signal transduction pathway.
Selectivity of an Oncolytic Herpes Simplex Virus for Cells Expressing the DF3/MUC1 Antigen
Authors: Kasuya Hideki , Pawlik Timothy M. , Mullen John T. , Donahue James M. , Nakamura Hideo , Chandrasekhar Soundararajalu , Kawasaki Hiroshi , Choi Enid , Tanabe Kenneth K. 
Published: September 2005

AbstractReplication-conditional viruses destroy tumors in a process referred to as viral oncolysis. An important prerequisite for this cancer therapy strategy is use of viruses that replicate preferentially in neoplastic cells. In this study the DF3/MUC1 promoter/enhancer sequence is used to regulate expression of γ134.5 to drive replication of a Herpes simplex virus 1 (HSV-1) mutant (DF3γ34.5) preferentially in DF3/MUC1-positive cells. HSV-1 γ134.5 functions to dephosphorylate elongation initiation factor 2α, which is an important step for robust HSV-1 replication. After DF3γ34.5 infection of cells, elongation initiation factor 2α phosphatase activity and viral replication were observed preferentially in DF3/MUC1-positive cells but not in DF3/MUC1-negative cells. Regulation of γ134.5 function results in preferential replication in cancer cells that express DF3/MUC1, restricted biodistribution in vivo, and less toxicity as assessed by LD50. Preferential replication of DF3γ34.5 was observed in DF3/MUC1-positive liver tumors after intravascular perfusion of human liver specimens. DF3γ34.5 was effective against carcinoma xenografts in nude mice. Regulation of γ134.5 by the DF3/MUC1 promoter is a promising strategy for development of HSV-1 mutants for viral oncolysis.
V599EB-RAF is an Oncogene in Melanocytes
Authors: Wellbrock Claudia , Ogilvie Lesley , Hedley Douglas , Karasarides Maria , Martin Jan , Niculescu-Duvaz Dan , Springer Caroline J. , Marais Richard 
Published: September 2005

Abstract
The oncogenic version of B-RAF, V599EB-RAF, is found in approximately 70% of human melanomas. However, the role that this oncogene plays in melanoma is unclear because V559EB-RAF is also found in approximately 80% of benign nevi. We have examined the role of oncogenic B-RAF in the early stages of melanoma by expressing V599EB-RAF in cultured melanocytes. In these cells, V599EB-RAF induced constitutive mitogen activated ERK-activating kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling, 12-O-tetradecanoylphorbol-13-acetate-independent growth, and tumorigenicity in nude mice. Intriguingly, in RAS-transformed melanocytes, B-RAF depletion did not block MEK-ERK signaling or cell cycle progression. Similarly, B-RAF depletion blocked MEK-ERK signaling in human melanoma cells harboring oncogenic B-RAF, but not in melanoma cells harboring oncogenic RAS. Thus, although B-RAF can act as a potent oncogene in the early stages of melanoma by signaling through MEK and ERK, it is not required for this signaling in RAS-transformed melanocytes due to innate redundancy within the pathway. These findings have important implications for future therapeutic strategies.
Loss of Heterozygosity Occurs via Mitotic Recombination in
Trp53
+/− Mice and Associates with Mammary Tumor Susceptibility of the BALB/c Strain
Authors: Blackburn Anneke C. , McLary S. Christine , Naeem Rizwan , Luszcz Jason , Stockton David W. , Donehower Lawrence A. , Mohammed Mansoor , Mailhes John B. , Soferr Tamar , Naber Stephen P. , Otis Christopher N. , Jerry D. Joseph 
Published: September 2005

Abstract
Loss of heterozygosity (LOH) occurs commonly in cancers causing disruption of tumor suppressor genes and promoting tumor progression. BALB/c-Trp53+/− mice are a model of Li-Fraumeni syndrome, exhibiting a high frequency of mammary tumors and other tumor types seen in patients. However, the frequency of mammary tumors and LOH differs among strains of Trp53+/− mice, with mammary tumors occurring only on a BALB/c genetic background and showing a high frequency of LOH, whereas Trp53+/− mice on a 129/Sv or (C57BL/6 × 129/Sv) mixed background have a very low frequency of mammary tumors and show LOH for Trp53 in only ∼50% of tumors. We have performed studies on tumors from Trp53+/− mice of several genetic backgrounds to examine the mechanism of LOH in BALB/c-Trp53+/− mammary tumors. By Southern blotting, 96% (24 of 25) of BALB/c-Trp53+/− mammary tumors displayed LOH for Trp53. Karyotype analysis indicated that cells lacking one copy of chromosome 11 were present in all five mammary tumors analyzed but were not always the dominant population. Comparative genomic hybridization analysis of these five tumors indicated either loss or retention of the entire chromosome 11. Thus chromosome loss or deletions within chromosome 11 do not account for the LOH observed by Southern blotting. Simple sequence length polymorphism analysis of (C57BL/6 × BALB/c) F1-Trp53+/− mammary tumors showed that LOH occurred over multiple loci and that a combination of maternal and paternal alleles were retained, indicating that mitotic recombination is the most likely mechanism of LOH. Nonmammary tumors of BALB/c mice also showed a high frequency of LOH (22 of 26, 85%) indicating it was not a mammary tumor specific phenomenon but rather a feature of the BALB/c strain. In (C57BL/6 × BALB/c) F1-Trp53+/− mice LOH was observed in 93% (13 of 14) of tumors, indicating that the high frequency of LOH was a dominant genetic trait. Thus the high frequency of LOH for Trp53 in BALB/c-Trp53+/− mammary tumors occurs via mitotic recombination and is a dominant genetic trait that associates with the occurrence of mammary tumors in (C57BL/6 × BALB/c) F1-Trp53+/− mice. These results further implicate double-strand DNA break repair machinery as important contributors to mammary tumorigenesis.
CX3CR1-Fractalkine Expression Regulates Cellular Mechanisms Involved in Adhesion, Migration, and Survival of Human Prostate Cancer Cells
Authors: Shulby Shannon A. , Dolloff Nathan G. , Stearns Mark E. , Meucci Olimpia , Fatatis Alessandro 
Published: September 2005

Abstract
Chemokines and their receptors might be involved in the selection of specific organs by metastatic cancer cells. For instance, the CXCR4-SDF-1α pair regulates adhesion and migration of breast as well as prostate cancer cells to metastatic sites. In this study, we present the first evidence for the expression of CX3CR1—the specific receptor for the chemokine fractalkine—by human prostate cancer cells, whereas human bone marrow endothelial cells and differentiated osteoblasts express fractalkine. The adhesion of prostate cancer cells to human bone marrow endothelial cells in flow conditions is significantly reduced by a neutralizing antibody against fractalkine, and they migrate toward a medium conditioned by osteoblasts, which secrete the soluble form of the chemokine. Finally, fractalkine activates the PI3K/Akt survival pathway in human prostate cancer cells.
GW112, A Novel Antiapoptotic Protein That Promotes Tumor Growth
Authors: Zhang Xiuwu , Huang Qian , Yang Zhonghui , Li Yongping , Li Chuan-Yuan 
Published: September 2005

Abstract
GW112 is a novel gene that has little homology to other known genes. It is overexpressed in a number of human tumor types, especially in those of the digestive system. We show here that GW112 is associated with GRIM-19, a protein known to be involved in regulating cellular apoptosis. Functionally, GW112 could significantly attenuate the ability of GRIM19 to mediate retinoic acid-IFN-β-mediated cellular apoptosis and apoptosis-related gene expression. In addition, GW112 demonstrated strong antiapoptotic effects in tumor cells treated with other stress exposures such as hydrogen peroxide. Finally, forced overexpression of GW112 in murine prostate tumor cells led to more rapid tumor formation in a syngeneic host. Taken together, our data suggest that GW112 is an important regulator of cell death that plays important roles in tumor cell survival and tumor growth.
Identification of Channels Promoting Calcium Spikes and Waves in HT1080 Tumor Cells
Authors: Huang Ji-Biao , Kindzelskii Andrei L. , Clark Andrea J. , Petty Howard R. 
Published: September 2005

Abstract
Intracellular Ca2+ signals have been associated with cell polarization and locomotion. As cell motility underlies metastasis, we have sought to better characterize the Ca2+ signaling events in HT1080 fibrosarcoma cells. We have tested the hypothesis that low voltage-activated (LVA) and nonvoltage-gated (NVG) channels of HT1080 cells participate in dynamic Ca2+-signaling events leading to cell migration and invasion. Immunofluorescence microscopy has shown that HT1080 cells express LVA T-type Ca2+ channels uniformly about the cell periphery, whereas the transient receptor potential-1 (a NVG cation channel) protein appears as punctate spots about a cell’s periphery. HT1080 cells exhibit periodic intracellular Ca2+ spikes. High-speed imaging revealed that the Ca2+ spikes were composed of a single Ca2+ wave traveling unidirectionally about the periphery of the cytoplasm in a clockwise fashion (as viewed from basal to apical surfaces). The T-type Ca2+ channel blocker mibefradil inhibited Ca2+ spikes and waves on cells and, in parallel, inhibited cell motility and invasion in a dose-dependent manner. Similar changes were noted with the NVG cation channel blockers Gd3+ and carboxyamido-triazole. The combination of LVA and NVG blockers further reduced Matrigel invasiveness. However, the Ca2+ channel blockers nicardipine, SKF96365, diltiazem, and verapamil had no effect at appropriate doses. These results indicate that certain LVA and NVG channels regulate HT1080 cell motility. In addition to providing novel information regarding cancer cell motility, we suggest that it may be possible to design drugs that inhibit a key Ca2+ wave, thereby enhancing the efficacy of emerging therapeutic protocols.
Vaccination with Tumor Lysate-Pulsed Dendritic Cells Elicits Antigen-Specific, Cytotoxic T-Cells in Patients with Malignant Glioma
Authors: Yu John S. , Liu Gentao , Ying Han , Yong William H. , Black Keith L. , Wheeler Christopher J. 
Published: September 2005

AbstractThe primary goal of this Phase I study was to assess the safety and bioactivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens were measured. Fourteen patients were thrice vaccinated 2 weeks apart with autologous DCs pulsed with tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed DCs was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quantitative PCR-based assay. Six of 10 patients demonstrated robust systemic cytotoxicity as demonstrated by IFN-γ expression by peripheral blood mononuclear cells in response to tumor lysate after vaccination. Using HLA-restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones against one or more of tumor-associated antigens MAGE-1, gp100, and HER-2 after DC vaccination in four of nine patients. A significant CD8+ T-cell infiltrate was noted intratumorally in three of six patients who underwent reoperation. The median survival for patients with recurrent glioblastoma multiforme in this study (n = 8) was 133 weeks. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate-pulsed DC vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
Oncogene Expression and Genetic Background Influence the Frequency of DNA Copy Number Abnormalities in Mouse Pancreatic Islet Cell Carcinomas
Authors: Hager Jeffrey H. , Hodgson J. Graeme , Fridlyand Jane , Hariono Sujatmi , Gray Joe W. , Hanahan Douglas 
Published: September 2005

Abstract
Quantitative measurements of tumor genome composition show remarkable heterogeneity in tumors arising from the same anatomical location and/or histopathological class and stage. The factors that contribute to genomic heterogeneity are not clear, but germ-line allelic variation and timing of initiating oncogenic events are likely candidates. We investigated these factors by using array comparative genomic hybridization to measure genomic aberrations in genetically engineered mouse models of pancreatic islet cell carcinoma, in which oncogenic transformation is elicited by the SV40 T antigens expressed under the control of the rat insulin promoter (RIP-Tag). Two distinct transgenic RIP-Tag lines, and three polymorphic sublines of one, enabled us to investigate the effects of genetic background and differing age of oncogene induction. Both parameters were found to bias the spectrum of genomic copy number abnormalities. Specifically, the frequency of losing portions of chromosomes 9 and 16 was significantly modulated by genetic background, with the former being lost at highest rates in the FVB/N background and the latter being lost to greatest extent in both FVB/N and C57Bl/6 tumors compared with C3HeB/Fe tumors. The frequency of losing a region of chromosome 6 varied according to the age when tumorigenesis was initiated; loss of chromosome 6 was significantly higher when oncogene expression was first activated in adulthood. These studies illustrate the utility of transgenic animal models for investigation of factors influencing genomic heterogeneity despite the commonalty of target cell type and initiating oncogene.
Somatic Mutation of
p53
Leads to Estrogen Receptor α-Positive and -Negative Mouse Mammary Tumors with High Frequency of Metastasis
Authors: Lin Suh-Chin J. , Lee Kuo-Fen , Nikitin Alexander Yu. , Hilsenbeck Susan G. , Cardiff Robert D. , Li Aihua , Kang Keon-Wook , Frank Steven A. , Lee Wen-Hwa , Lee Eva Y-H. P. 
Published: September 2005

Abstract
Approximately 70% of human breast cancers are estrogen receptor α (ERα)-positive, but the origins of ERα-positive and -negative tumors remain unclear. Hormonal regulation of mammary gland development in mice is similar to that in humans; however, most mouse models produce only ERα-negative tumors. In addition, these mouse tumors metastasize at a low rate relative to human breast tumors. We report here that somatic mutations of p53 in mouse mammary epithelial cells using the Cre/loxP system leads to ERα-positive and -negative tumors. p53 inactivation under a constitutive active WAPCrec in prepubertal/pubertal mice, but not under MMTVCre in adult mice, leads to the development of ERα-positive tumors, suggesting that target cells or developmental stages can determine ERα status in mammary tumors. Importantly, these tumors have a high rate of metastasis. An inverse relationship between the number of targeted cells and median tumor latency was also observed. Median tumor latency reaches a plateau when targeted cell numbers exceed 20%, implying the existence of saturation kinetics for breast carcinogenesis. Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors. Thus, this tumor system reproduces many important features of human breast cancer and provides tools for the study of the origins of ERα-positive and -negative breast tumors in mice.
Conditionally Replicating Adenoviruses Expressing Short Hairpin RNAs Silence the Expression of a Target Gene in Cancer Cells
Authors: Carette Jan E. , Overmeer Renée M. , Schagen Frederik H. E. , Alemany Ramon , Barski Oleg A. , Gerritsen Winald R. , van Beusechem Victor W. 
Published: September 2005

Abstract
RNA interference (RNAi) is a posttranscriptional silencing mechanism triggered by double-stranded RNA that was recently shown to function in mammalian cells. Expression of cancer-associated genes was knocked down by expressing short hairpin RNAs (shRNAs) in cancer cells. By virtue of its excellent target specificity, RNAi may be used as a new therapeutic modality for cancer. The success of this approach will largely depend on efficient delivery of shRNAs to tumor cells. Tumor-selective replication competent viruses are especially suited to efficiently deliver anticancer genes to tumors. In addition, their intrinsic capacity to kill cancer cells makes these viruses promising anticancer agents per se. In this study, conditionally replicating adenoviruses were constructed encoding shRNAs targeted against firefly luciferase. These replicating viruses were shown to specifically silence the expression of the target gene in human cancer cells down to 30% relative to control virus. This finding offers the promise of using RNAi in the context of cancer gene therapy with oncolytic viruses.