bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE SU(2) ⊗ U(1) ELECTROWEAK MODEL BASED ON THE NONLINEARLY REALIZED GAUGE GROUP
Authors: BETTINELLI D. , FERRARI R. , QUADRI A. 
Published: June 2009

The electroweak model is formulated on the nonlinearly realized gauge group SU (2) ⊗ U (1). This implies that in perturbation theory no Higgs field is present. This paper provides the effective action at the tree level, the Slavnov–Taylor identity (necessary for the proof of physical unitarity), the local functional equation (used for the control of the amplitudes involving the Goldstone bosons) and the subtraction procedure (nonstandard, since the theory is not power-counting renormalizable). Particular attention is devoted to the number of independent parameters relevant for the vector mesons; in fact, there is the possibility of introducing two mass parameters. With this choice the relation between the ratio of the intermediate vector meson masses and the Weinberg angle depends on an extra free parameter. We briefly outline a method for dealing with γ5 in dimensional regularization. The model is formulated in the Landau gauge for sake of simplicity and conciseness. The QED Ward identity has a simple and intriguing form.
FORWARD PHYSICS AT THE LHC: ELASTIC SCATTERING
Authors: FIORE R. , JENKOVSZKY L. , ORAVA R. , PREDAZZI E. , PROKUDIN A. , SELYUGIN O. 
Published: June 2009

The following effects in the nearly forward ("soft") region of the LHC are proposed to be investigated: • At small |t| the fine structure of the cone (Pomeron) should be scrutinized: (a) a break of the cone near t ≈ -0.1 GeV 2, due to the two-pion threshold, and required by t-channel unitarity, and (b) possible small-period oscillations between t = 0 and the dip region. • In measuring the elastic pp scattering and total pp cross-section at the LHC, the experimentalists are urged to treat the total cross-section σt, the ratio ρ of real to imaginary part of the forward scattering amplitude, the forward slope B and the luminosity [Formula: see text] as free parameters, and to publish model-independent results on dN/dt. • Of extreme interest are the details of the expected diffraction minimum in the differential cross-section. Its position, expected in the interval 0.4 < -t < 1 GeV 2 at the level of about 10-2 mb · GeV -2–10-1 mb · GeV -2, cannot be predicted unambiguously, and its depth, i.e. the ratio of dσ/dt at the minimum to that at the subsequent maximum (about -t = 5 GeV 2, which is about 5) is of great importance. • The expected slow-down with increasing |t| of the shrinkage of the second cone (beyond the dip-bump), together with the transition from an exponential to a power decrease in -t, will be indicative of the transition from "soft" to "hard" physics. Explicit models are proposed to help in quantifying this transition. • In a number of papers a limiting behavior, or saturation of the black disk limit (BDL), was predicted. This controversial phenomenon shows that the BDL may not be the ultimate limit, instead a transition from shadow to antishadow scattering may by typical of the LHC energy scale.
Regulation of HSulf-1 Expression by Variant Hepatic Nuclear Factor 1 in Ovarian Cancer
Authors: Liu Peng , Khurana Ashwani , Rattan Ramandeep , He Xiaoping , Kalloger Steve , Dowdy Sean , Gilks Blake , Shridhar Viji 
Published: June 2009

Abstract
We recently identified HSulf-1 as a down-regulated gene in ovarian carcinomas. Our previous analysis indicated that HSulf-1 inactivation in ovarian cancers is partly mediated by loss of heterozygosity and epigenetic silencing. Here, we show that variant hepatic nuclear factor 1 (vHNF1), encoded by transcription factor 2 gene (TCF2, HNF1β), negatively regulates HSulf-1 expression in ovarian cancer. Immunoblot assay revealed that vHNF1 is highly expressed in HSulf-1–deficient OV207, SKOV3, and TOV-21G cell lines but not in HSulf-1–expressing OSE, OV167, and OV202 cells. By short hairpin RNA–mediated down-regulation of vHNF1 in TOV-21G cells and transient enhanced vHNF1 expression in OV202 cells, we showed that vHNF1 suppresses HSulf-1 expression in ovarian cancer cell lines. Reporter assay and chromatin immunoprecipitation experiments showed that vHNF1 is specifically recruited to HSulf-1 promoter at two different vHNF1-responsive elements in OV207 and TOV-21G cells. Additionally, down-regulation of vHNF1 expression in OV207 and TOV-21G cells increased cisplatin- or paclitaxel-mediated cytotoxicity as determined by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays and this effect was reversed by down-regulation of HSulf-1. Moreover, nude mice bearing TOV-21G cell xenografts with stably down-regulated vHNF1 were more sensitive to cisplatin- or paclitaxel-induced cytotoxicity compared with xenografts of TOV-21G clonal lines with nontargeted control short hairpin RNA. Finally, immunohistochemical analysis of 501 ovarian tumors including 140 clear-cell tumors on tissue microarrays showed that vHNF1 inversely correlates to HSulf-1 expression. Collectively, these results indicate that vHNF1 acts as a repressor of HSulf-1 expression and might be a molecular target for ovarian cancer therapy. [Cancer Res 2009;69(11):4843–50]
Promyelocytic Leukemia Protein is Required for Gain of Function by Mutant p53
Authors: Haupt Sue , di Agostino Silvia , Mizrahi Inbal , Alsheich-Bartok Osnat , Voorhoeve Mathijs , Damalas Alex , Blandino Giovanni , Haupt Ygal 
Published: June 2009

Abstract
Mutations in the p53 tumor suppressor are the most common genetic events in human cancer. These mutations not only result in a loss of wild-type p53 activity, but can also lead to a gain of new oncogenic properties. Understanding how these gained functions are regulated is in its infancy. In this study, we show that the promyelocytic leukemia (PML) protein is an important regulator of mutant p53. We show that PML interacts with mutant p53. Importantly, PML enhances the transcriptional activity of mutant p53. Unexpectedly, PML is required for the proliferation and colony formation of cancer cells bearing mutant p53. Down-regulation of PML expression inhibits the growth of mutant p53-expressing cancer cells, predominantly by promoting cell cycle arrest. Our results suggest that the tumor suppression function of PML depends on the status of p53. In the context of mutant p53, PML enhances its cancer-promoting activities. [Cancer Res 2009;69(11):4818–26]
Genomic Profiling of MicroRNAs in Bladder Cancer: miR-129 Is Associated with Poor Outcome and Promotes Cell Death In vitro
Authors: Dyrskjøt Lars , Ostenfeld Marie S. , Bramsen Jesper B. , Silahtaroglu Asli N. , Lamy Philippe , Ramanathan Ramshanker , Fristrup Niels , Jensen Jens L. , Andersen Claus L. , Zieger Karsten , Kauppinen Sakari , Ulhøi Benedicte P. , Kjems Jørgen , Borre Michael , Ørntoft Torben F. 
Published: June 2009

Abstract
microRNAs (miRNA) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Here, we profiled the expression of 290 unique human miRNAs in 11 normal and 106 bladder tumor samples using spotted locked nucleic acid–based oligonucleotide microarrays. We identified several differentially expressed miRNAs between normal urothelium and cancer and between the different disease stages. miR-145 was found to be the most down-regulated in cancer compared with normal, and miR-21 was the most up-regulated in cancer. Furthermore, we identified miRNAs that significantly correlated to the presence of concomitant carcinoma in situ. We identified several miRNAs with prognostic potential for predicting disease progression (e.g., miR-129, miR-133b, and miR-518c*). We localized the expression of miR-145, miR-21, and miR-129 to urothelium by in situ hybridization. We then focused on miR-129 that exerted significant growth inhibition and induced cell death upon transfection with a miR-129 precursor in bladder carcinoma cell lines T24 and SW780 cells. Microarray analysis of T24 cells after transfection showed significant miR-129 target down-regulation (P = 0.0002) and pathway analysis indicated that targets were involved in cell death processes. By analyzing gene expression data from clinical tumor samples, we identified significant expression changes of target mRNA molecules related to the miRNA expression. Using luciferase assays, we documented a direct link between miR-129 and the two putative targets GALNT1 and SOX4. The findings reported here indicate that several miRNAs are differentially regulated in bladder cancer and may form a basis for clinical development of new biomarkers for bladder cancer. [Cancer Res 2009;69(11):4851–60]
Intestinal Mucosal Inflammation Leads to Systemic Genotoxicity in Mice
Authors: Westbrook Aya M. , Wei Bo , Braun Jonathan , Schiestl Robert H. 
Published: June 2009

Abstract
Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, substantially increases the risk of colorectal cancer. However, mechanisms linking mucosal inflammation to the sequence of dysplasia are incompletely understood. Whereas studies have shown oxidative damage to the colon, this study tests whether genotoxicity is elicited systemically by acute and chronic intestinal inflammation. In this study, genotoxic endpoints were assessed in peripheral leukocytes (DNA single- and double-stranded breaks and oxidative DNA damage) and normochromatic erythrocytes (micronuclei) during chemical or immune-mediated colitis. During three consecutive cycles of intestinal inflammation induced by dextran sulfate sodium administration, genotoxicity to peripheral leukocytes and erythroblasts was detected in both acute and chronic phases of dextran sulfate sodium–induced inflammation. Reactive oxygen species–mediated oxidative stress and DNA damage was confirmed with positive 8-oxoguanine and nitrotyrosine staining in peripheral leukocytes. Levels of DNA damage generally decreased during remission and increased during treatment, correlating with clinical symptoms and systemic inflammatory cytokine levels. In Gαi2−/− and interleukin-10−/− transgenic mice susceptible to immune-mediated colitis and inflammation-associated adenocarcinoma, similar levels of peripheral leukocyte and erythroblast genotoxicity were also observed. Moreover, this systemic genotoxicity was observed in mice with subclinical inflammation, which was further elevated in those with severe mucosal inflammation. We propose that mucosal inflammation, by eliciting substantial and ongoing systemic DNA damage, contributes early on to genetic instability necessary for progression to inflammatory bowel disease–associated dysplasia and the development of cancer. [Cancer Res 2009;69(11):4827–34]
Proliferation of Immature Tumor Vessels Is a Novel Marker of Clinical Progression in Prostate Cancer
Authors: Gravdal Karsten , Halvorsen Ole J. , Haukaas Svein A. , Akslen Lars A. 
Published: June 2009

AbstractNestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α (HIF-1α) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1α. Vascular proliferation by Nestin/Ki-67–positive vessels was counted within “hotspot” areas. Median vascular proliferation counts were 4- to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P &lt; 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P &lt; 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1α expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1α expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients. [Cancer Res 2009;69(11):4708–15]
Transcript Level Modulates the Inherent Oncogenicity of RET/PTC Oncoproteins
Authors: Richardson Douglas S. , Gujral Taranjit S. , Peng Susan , Asa Sylvia L. , Mulligan Lois M. 
Published: June 2009

Abstract
Mutations to the RET proto-oncogene occur in as many as one in three cases of thyroid cancer and have been detected in both the medullary (MTC) and the papillary (PTC) forms of the disease. Of the nearly 400 chromosomal rearrangements resulting in oncogenic fusion proteins that have been identified to date, the rearrangements that give rise to RET fusion oncogenes in PTC remain the paradigm for chimeric oncoprotein involvement in solid tumors. RET-associated PTC tumors are phenotypically indolent and relatively less aggressive than RET-related MTCs. The mechanism(s) contributing to the differences in oncogenicity of RET-related MTC and PTC remains unexplained. Here, through cellular and molecular characterization of the two most common RET/PTC rearrangements (PTC1 and PTC3), we show that RET/PTC oncoproteins are highly oncogenic when overexpressed, with the ability to increase cell proliferation and transformation. Further, RET/PTCs activate similar downstream signaling cascades to wild-type RET, although at different levels, and are relatively more stable as they avoid lysosomal degradation. Absolute quantitation of transcript levels of RET, CCDC6, and NCOA4 (the 5′ fusion genes involved in PTC1 and PTC3, respectively) suggest that these rearrangements result in lower RET expression in PTCs relative to MTCs. Together, our findings suggest PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo. [Cancer Res 2009;69(11):4861–9]
Estrogen Receptor-β Affects the Prognosis of Human Malignant Mesothelioma
Authors: Pinton Giulia , Brunelli Elisa , Murer Bruno , Puntoni Riccardo , Puntoni Matteo , Fennell Dean A. , Gaudino Giovanni , Mutti Luciano , Moro Laura 
Published: June 2009

AbstractMalignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERβ staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERα. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERβ expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17β-estradiol led to an ERβ-mediated inhibition of malignant mesothelioma cell proliferation as well as p21CIP1 and p27KIP1 up-regulation. Consistently cell growth was suppressed by ERβ overexpression, causing a G2-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERβ acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients. [Cancer Res 2009;69(11):4598–604]
AKR1C Isoforms Represent a Novel Cellular Target for Jasmonates alongside Their Mitochondrial-Mediated Effects
Authors: Davies Nicholas J. , Hayden Rachel E. , Simpson Paul J. , Birtwistle Jane , Mayer Katarina , Ride Jonathan P. , Bunce Chris M. 
Published: June 2009

Abstract
Members of the aldo-keto reductase (AKR) superfamily, particularly the AKR1C subfamily, are emerging as important mediators of the pathology of cancer. Agents that inhibit these enzymes may provide novel agents for either the chemoprevention or treatment of diverse malignancies. Recently, jasmonates, a family of plant stress hormones that bear a structural resemblance to prostaglandins, have been shown to elicit anticancer activities both in vitro and in vivo. In this study, we show that jasmonic acid (JA) and methyl jasmonate (MeJ) are capable of inhibiting all four human AKR1C isoforms. Although JA is the more potent inhibitor of recombinant AKR1C proteins, including the in vitro prostaglandin F synthase activity of AKR1C3, MeJ displayed greater potency in cellular systems that was, at least in part, due to increased cellular uptake of MeJ. Moreover, using the acute myelogenous leukemia cell lines HL-60 and KG1a, we found that although both jasmonates were able to induce high levels of reactive oxygen species in a dose-dependent fashion, only MeJ was able to induce high levels of mitochondrial superoxide (MSO), possibly as an epiphenomenon of mitochondrial damage. There was a strong correlation observed between MSO formation at 24 hours and reduced cellularity at day 5. In conclusion, we have identified AKR1C isoforms as a novel target of jasmonates in cancer cells and provide further evidence of the promise of these compounds, or derivatives thereof, as adjunctive therapies in the treatment of cancer. [Cancer Res 2009;69(11):4769–75]
Selective Killing of Cancer Cells by Suppression of Geminin Activity
Authors: Zhu Wenge , DePamphilis Melvin L. 
Published: June 2009

Abstract
Eukaryotic cells normally restrict genome duplication to once per cell division. In metazoa, re-replication of DNA during a single S phase seems to be prevented solely by suppressing CDT1 activity, a protein required for loading the replicative MCM DNA helicase. However, siRNA suppression of geminin (a specific inhibitor of CDT1) arrested proliferation only of cells derived from cancers by inducing DNA re-replication and DNA damage that spontaneously triggered apoptosis. None of these effects were detected either in cells derived from normal human tissues or in cells immortalized by a viral oncogene. To induce these effects in noncancer cells required suppression of both geminin and cyclin A, another cell cycle regulator. Therefore, initiating DNA replication in some cancer cells is limited solely by regulating the level of CDT1 activity with geminin, whereas noncancer cells contain additional safeguards that prevent DNA re-replication. These results show that inhibition of geminin activity could be used to selectively kill cancer cells without harming other cells. [Cancer Res 2009;69(11):4870–7]
Industasis, a Promotion of Tumor Formation by Nontumorigenic Stray Cells
Authors: Pajer Petr , Karafiát Vít , Pec̆enka Vladimír , Pru̇ková Dana , Dudlová Jana , Plachý Jiří , Kašparová Petra , Dvořák Michal 
Published: June 2009

Abstract
A tumor cell is formed when a critical amount of endogenous and/or exogenous tumorigenic stimuli is exceeded. We have shown that the transient presence of nontumorigenic stray cells in tissues of experimental animals that contain cells with a subcritical set of genetic mutations can act as a tumor-promoting stimulus. To induce somatic mutations in all chicken tissues, we have used the MAV-2 retroviral insertion system that almost exclusively generates nephroblastomas. MAV-2 mutagenized animals i.v. inoculated with nonmalignant cells developed early clonal lung tumors before nephroblastomas. Importantly, the injected cells did not become a component of resultant tumors. Lung tumors displayed specific mutational signature characterized by an insertion of MAV-2 provirus into the fyn-related kinase (frk) promoter that results in the overexpression of the frk gene. In contrast, plag1, foxP, and twist genes were most often mutagenized in nephroblastomas. Based on such observations, we propose the mechanism termed industasis, a promotion of fully malignant phenotype of incipient tumor cell by stray cells, and hypothesize that it might be the underlying cause of human multiple primary tumors. [Cancer Res 2009;69(11):4605–12]
Angiopoietin-1 Overexpression Modulates Vascular Endothelium to Facilitate Tumor Cell Dissemination and Metastasis Establishment
Authors: Holopainen Tanja , Huang Huilian , Chen Caiping , Kim Kyung Eun , Zhang Luqing , Zhou Fei , Han Wencan , Li Chaojun , Yu Jun , Wu Jun , Koh Gou Young , Alitalo Kari , He Yulong 
Published: June 2009

Abstract
The angiopoietin-1 (Ang1)/Tie2 signaling pathway is known to play an important role in the regulation of vascular maturation and maintenance of vessel integrity. In this study, we have investigated the effect of systemic Tie2 activation or inhibition on tumor growth and metastasis. We found that treatment with Ang1 delivered via an adenoviral vector promoted s.c. implanted tumor metastasis to the lungs. Ang1 treatment did not significantly increase vascular density in the tumors but induced enlargement of blood vessels in both the tumor and normal tissues, which increased tumor cell dissemination into the blood circulation. Ang1 also enhanced the formation of metastatic foci in the lungs when tumor cells were injected into the circulation via the tail vein. The effect of Ang1 on metastasis was validated by a simultaneous treatment with a soluble form of Tie2 (sTie2), which led to the suppression of Ang1-induced increase of tumor metastasis. Furthermore, using a highly metastatic tumor model, we confirmed that systemic treatment with sTie2 suppressed tumor metastasis to the lungs and lymph nodes, whereas tumor-associated angiogenesis and lymphangiogenesis were not significantly affected. This suggests that the Ang1/Tie2 signals contribute to tumor progression by increasing vascular entry and exit of tumor cells to facilitate tumor dissemination and establishment of metastases. [Cancer Res 2009;69(11):4656–64]
Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus–Infected Cells
Authors: Wei Lanlan , Gravitt Patti E. , Song Hebin , Maldonado Anastacia M. , Ozbun Michelle A. 
Published: June 2009

Abstract
High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.[Cancer Res 2009;69(11):4878–84]