bluuebunny/crossref_metadata_2025_split huggingface dataset:
The 3D fault and vein architecture of strike-slip releasing- and restraining bends: evidence from volcanic-centre-related mineral deposits
Authors: Berger B. R. 
Published: December 2007

Abstract
High-temperature, volcanic-centre-related hydrothermal systems involve large fluid-flow volumes and are observed to have high discharge rates in the order of 100–400 kg/s. The flows and discharge occur predominantly on networks of critically stressed fractures. The coupling of hydrothermal fluid flow with deformation produces the volumes of veins found in epithermal mineral deposits. Owing to this coupling, veins provide information on the fault–fracture architecture in existence at the time of mineralization. They therefore provide information on the nature of deformation within fault zones, and the relations between different fault sets. The Virginia City and Goldfield mining districts, Nevada, were localized in zones of strike-slip transtension in an Early to Mid-Miocene volcanic belt along the western margin of North America. The Camp Douglas mining area occurs within the same belt, but is localized in a zone of strike-slip transpression. The vein systems in these districts record the spatial evolution of strike-slip extensional and contractional stepovers, as well as geometry of faulting in and adjacent to points along strike-slip faults where displacement has been interrupted and transferred into releasing and restraining stepovers.
Extensional deformation and development of deep basins associated with the sinistral transcurrent fault zone of the Scotia–Antarctic plate boundary
Authors: Bohoyo F. , Galindo-Zaldívar J. , Jabaloy A. , Maldonado A. , Rodríguez-Fernández J. , Schreider A. , Suriñach E. 
Published: December 2007

Abstract
The Scotia–Antarctic plate boundary extends along the southern branch of the Scotia Arc, between triple junctions with the former Phoenix plate to the west (57°W) and with the Sandwich plate to the east (30°W). The main mechanism responsible for the present arc configuration is the development of the Scotia and Sandwich plates from 30–35 Ma, related to breakup of the continental connection between South America and the Antarctic Peninsula. The Scotia–Antarctic plate boundary is a very complex tectonic zone, because both oceanic and continental elements are involved. Present-day sinistral transcurrent motion probably began 8 Ma ago. The main active structures that we observed in the area include releasing and restraining bends, with related deep extensional and compressional basins, and probable pull-apart basins. The western sector of the plate boundary crosses fragmented continental crust: the Western South Scotia Ridge, with widespread development of pull-apart basins and releasing bends deeper than 5000 m, filled by asymmetrical sedimentary wedges. The northern border of the South Orkney microcontinent, in the central sector, has oceanic and continental crust in contact along a large thrust zone. Finally, the eastern sector of the South Scotia Ridge is located within Discovery Bank, a piece of continental crust from a former arc. On its southern border, strike-slip and normal faults produce a 5500-m-deep trough that may be interpreted as a pull-apart basin. In the eastern and western South Scotia Ridge, despite extreme continental-crustal thinning, the basins show no development of oceanic crust. This geometry is conditioned by the distinctive rheological behaviour of the crust involved, with the bulk concentration of deformation within the rheologically weaker continental blocks.
Inhibition of RAS-Mediated Transformation and Tumorigenesis by Targeting the Downstream E3 Ubiquitin Ligase Seven in Absentia Homologue
Authors: Schmidt Rebecca L. , Park Cheol Hong , Ahmed Atique U. , Gundelach Justin H. , Reed Nanette R. , Cheng Shen , Knudsen Bruce E. , Tang Amy H. 
Published: December 2007

Abstract
Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer. [Cancer Res 2007;67(24):11798–810]
Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand
Authors: Gregory Meredith S. , Saff Rebecca R. , Marshak-Rothstein Ann , Ksander Bruce R. 
Published: December 2007

AbstractFas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions—membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage. [Cancer Res 2007;67(24):11951–58]
In vivo Imaging and Quantitation of Adoptively Transferred Human Antigen-Specific T Cells Transduced to Express a Human Norepinephrine Transporter Gene
Authors: Doubrovin Mikhail M. , Doubrovina Ekaterina S. , Zanzonico Pat , Sadelain Michel , Larson Steven M. , O'Reilly Richard J. 
Published: December 2007

Abstract
Sequential imaging of genetically marked effector cells after adoptive transfer in vivo has greatly enhanced analyses of their biodistribution, growth, and activity both in animal models and in clinical trials of cellular immunotherapy. However, the immunogenicity of cells expressing xenogeneic reporter constructs limits their survival and clinical utility. To address this limitation, we have evaluated a human norepinephrine transporter (hNET) permitting imaging of transduced cells in vivo with a previously approved clinical grade radiolabeled probe, metaiodobenzylguanidine (MIBG). The hNET gene cDNA was cloned from the SK-N-SH cell line and inserted into a bicistronic retroviral vector also encoding green fluorescent protein. Following transfection, human EBV-specific T lymphocytes seemed fully functional in vitro and also selectively accumulated [123I]MIBG. In nonobese diabetic/severe combined immunodeficient mice bearing human EBV lymphoma xenografts, as few as 104 transduced T cells injected into the tumors could be imaged by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after i.v. infusion of [123I]MIBG or [124I]MIBG, respectively. When hNET+ EBV-specific T cells were infused i.v., their migration and specific accumulation in EBV+ tumors expressing their restricting HLA allele could be imaged by SPECT or PET over 28 days. Image intensity was closely correlated with the number of T cells accumulated in targeted tumors. The use of two reporter probes (MIBG and 2′-deoxy-2′-fluoro-β-d-arabinofuranosyl-5-iodouracil) permitted independent contemporaneous tracking of two distinct EBV-specific T-cell subpopulations expressing different reporter genes (hNET-CD4+ T cells and HSV-TK-CD8+ T cells) in the same animal using three-dimensional nuclear modalities (SPECT and PET). The hNET-based system described may thus have significant potential as a nonimmunogenic reporter for extended repeated quantitative in vivo imaging of transduced cells in man. [Cancer Res 2007;67(24):11959–69]
Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα
Authors: Lee Hong Jin , Ji Yan , Paul Shiby , Maehr Hubert , Uskokovic Milan , Suh Nanjoo 
Published: December 2007

AbstractBone morphogenetic proteins (BMP) are members of the transforming growth factor-β superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D3 analogue, Ro-438-3582 [Ro3582; 1α,25-dihydroxy-20S,21(3-hydroxy-3-methylbutyl)-23-yne-26,27-hexafluorocholecalciferol], inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKCα, but not PKCε, PKCδ or PKCζ isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKCα mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras–transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKCα to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKCα and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKCα pathway in breast epithelial cells. [Cancer Res 2007;67(24):11840–7]
mTORC2 Activity Is Elevated in Gliomas and Promotes Growth and Cell Motility via Overexpression of Rictor
Authors: Masri Janine , Bernath Andrew , Martin Jheralyn , Jo Oak D. , Vartanian Raffi , Funk Alexander , Gera Joseph 
Published: December 2007

Abstract
mTORC2 is a multimeric kinase composed of the mammalian target of rapamycin kinase (mTOR), mLST8, mSin1, and rictor. The complex is insensitive to acute rapamycin exposure and has shown functions in controlling cell growth and actin cytoskeletal assembly. mTORC2 has recently been shown to phosphorylate and activate Akt. Because ∼70% of gliomas harbor high levels of activated Akt, we investigated whether mTORC2 activity was elevated in gliomas. In this study, we found that mTORC2 activity was elevated in glioma cell lines as well as in primary tumor cells as compared with normal brain tissue (P &lt; 0.05). Moreover, we found that rictor protein and mRNA levels were also elevated and correlated with increased mTORC2 activity. Overexpression of rictor in cell lines led to increased mTORC2 assembly and activity. These lines exhibited increased anchorage-independent growth in soft agar, increased S-phase cell cycle distribution, increased motility, and elevated integrin β1 and β3 expression. In contrast, small interfering RNA–mediated knockdown of rictor inhibited these oncogenic activities. Protein kinase Cα (PKCα) activity was shown to be elevated in rictor-overexpressing lines but reduced in rictor-knockdown clones, consistent with the known regulation of actin organization by mTORC2 via PKCα. Xenograft studies using these cell lines also supported a role for increased mTORC2 activity in tumorigenesis and enhanced tumor growth. In summary, these data suggest that mTORC2 is hyperactivated in gliomas and functions in promoting tumor cell proliferation and invasive potential due to increased complex formation as a result of the overexpression of rictor. [Cancer Res 2007;67(24):11712–20]
A Role for Glial Cell–Derived Neurotrophic Factor–Induced Expression by Inflammatory Cytokines and RET/GFRα1 Receptor Up-regulation in Breast Cancer
Authors: Esseghir Selma , Todd S. Katrina , Hunt Toby , Poulsom Richard , Plaza-Menacho Ivan , Reis-Filho Jorge S. , Isacke Clare M. 
Published: December 2007

Abstract
By screening a tissue microarray of invasive breast tumors, we have shown that the receptor tyrosine kinase RET (REarranged during Transfection) and its coreceptor GFRα1 (GDNF receptor family α-1) are overexpressed in a subset of estrogen receptor–positive tumors. Germ line–activating oncogenic mutations in RET allow this receptor to signal independently of GFRα1 and its ligand glial cell–derived neurotrophic factor (GDNF) to promote a spectrum of endocrine neoplasias. However, it is not known whether tumor progression can also be driven by receptor overexpression and whether expression of GDNF, as has been suggested for other neurotrophic factors, is regulated in response to the inflammatory microenvironment surrounding many epithelial cancers. Here, we show that GDNF stimulation of RET+/GFRα1+ MCF7 breast cancer cells in vitro enhanced cell proliferation and survival, and promoted cell scattering. Moreover, in tumor xenografts, GDNF expression was found to be up-regulated on the infiltrating endogenous fibroblasts and to a lesser extent by the tumor cells themselves. Finally, the inflammatory cytokines tumor necrosis factor-α and interleukin-1β, which are involved in tumor promotion and development, were found to act synergistically to up-regulate GDNF expression in both fibroblasts and tumor cells. These data indicate that GDNF can act as an important component of the inflammatory response in breast cancers and that its effects are mediated by both paracrine and autocrine stimulation of tumor cells via signaling through the RET and GFRα1 receptors. [Cancer Res 2007;67(24):11732–41]
Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin
Authors: Jin Quanri , Feng Lei , Behrens Carmen , Bekele B. Nebiyou , Wistuba Ignacio I. , Hong Waun-Ki , Lee Ho-Young 
Published: December 2007

Abstract
Survivin plays important roles in maintaining cell proliferation and survival and promoting tumorigenesis. The present study was conducted to determine the stage of lung carcinogenesis at which survivin expression is induced and to investigate how survivin affects the chemopreventive action of deguelin. In in vitro studies, we observed higher levels of survivin expression in a subset of premalignant and malignant human bronchial epithelial (HBE) and non–small-cell lung cancer (NSCLC) cell lines than in normal HBE cells, and in in vivo studies, a higher level of survivin expression in specimen of human lung dysplasia than in normal lung specimens. Treatment with deguelin inhibited de novo synthesis of survivin protein and induced apoptosis, resulting in suppression of transformation phenotypes, in the premalignant and malignant HBE and NSCLC cell lines. Deguelin inhibited survivin expression in tuberous sclerosis complex 2 (TSC2) wild-type mouse embryonic fibroblasts (MEF) but not in TSC2-knockout MEFs in which mammalian target of rapamycin (mTOR) is constitutively active. Deguelin induced activation of AMP-activated protein kinase (AMPK) and inactivation of Akt. Overexpression of constitutively active Akt abolished deguelin-induced modulation of AMPK activity and survivin expression. Conversely, inactivation of AMPK by compound C or AMPKα1/2 small interfering RNA restored Akt and mTOR activities and survivin expression in deguelin-treated HBE cells. These results suggest that survivin expression is induced as an early event in lung carcinogenesis, and deguelin acts as a chemopreventive agent by inducing a reciprocal regulation between AMPK and Akt, resulting in the inhibition of mTOR-mediated survivin. [Cancer Res 2007;67(23):11630–9]
CDC25B Involvement in the Centrosome Duplication Cycle and in Microtubule Nucleation
Authors: Boutros Rose , Lobjois Valérie , Ducommun Bernard 
Published: December 2007

Abstract
Centrosome amplification is frequently reported in human cancers, although the molecular mechanisms that are responsible for this remain unclear. There is significant evidence to support a role for cyclin-dependent kinase (CDK)–cyclin complexes in centrosome duplication. The activities of CDK-cyclin complexes are, in turn, regulated by the CDC25 family of phosphatases in a strict spatiotemporal manner, and we have recently reported that CDC25B localizes to the centrosomes from early S phase. In the present study, we have investigated the role of centrosomally localized CDC25B in centrosome duplication. We first observed that overexpression of CDC25B under an inducible promoter in S phase results in centrosome overduplication. We found that forced expression of wild-type but not phosphatase-inactive CDC25B at the centrosomes results in centrosome amplification, aberrant microtubule organization, and abnormal accumulation of γ-tubulin. In contrast, inhibition of CDC25B phosphatase activity inhibits the assembly of interphase microtubules and the centrosomal localization of γ-tubulin. We propose that CDC25B is part of the pathway that controls the localization of γ-tubulin to the centrosomes, thereby regulating centrosome duplication during S phase and the nucleation of microtubules. We speculate that abnormal expression of CDC25B in numerous human tumors might therefore have a critical role in centrosome amplification and genomic instability. [Cancer Res 2007;67(24):11557–64]
Integrated Profiling of Basal and Luminal Breast Cancers
Authors: Adélaïde José , Finetti Pascal , Bekhouche Ismahane , Repellini Laetitia , Geneix Jeannine , Sircoulomb Fabrice , Charafe-Jauffret Emmanuelle , Cervera Nathalie , Desplans Jérôme , Parzy Daniel , Schoenmakers Eric , Viens Patrice , Jacquemier Jocelyne , Birnbaum Daniel , Bertucci François , Chaffanet Max 
Published: December 2007

Abstract
Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 × 10−5) and ZNF703 (P = 7 × 10−4) were the most significant basal and luminal potential oncogenes, respectively. Finally, among 10p candidate oncogenes associated with basal subtype, we validated CDC123/C10orf7 protein as a basal marker. [Cancer Res 2007;67(24):11565–75]
Ada3 Requirement for HAT Recruitment to Estrogen Receptors and Estrogen-Dependent Breast Cancer Cell Proliferation
Authors: Germaniuk-Kurowska Aleksandra , Nag Alo , Zhao Xiangshan , Dimri Manjari , Band Hamid , Band Vimla 
Published: December 2007

Abstract
We have previously shown that evolutionarily conserved alteration/deficiency in activation (Ada) protein associates with and promotes estrogen receptor (ER)–mediated target gene expression. Here, we examined the role of endogenous Ada3 to recruit histone acetyl transferases (HAT) to an ER-responsive promoter and its role in estrogen-dependent cell proliferation and malignant phenotype. Using a combination of glycerol gradient cosedimentation and immunoprecipitation analyses, we show that Ada3, ER, and three distinct HATs [p300, (p300/CBP-associated factor) PCAF, and general control nonrepressed 5 (Gcn5)] are present in a complex. Using chromatin immunoprecipitation analysis, we show that short hairpin RNA (shRNA)–mediated knockdown of Ada3 in ER-positive breast cancer cells significantly reduced the ligand-dependent recruitment of p300, PCAF, and Gcn5 to the ER-responsive pS2 promoter. Finally, we use shRNA knockdown to show that Ada3 is critical for estrogen-dependent proliferation of ER-positive breast cancer cell lines in two-dimensional, as well as three-dimensional, culture. Knockdown of Ada3 in ER-positive MCF-7 cells induced reversion of the transformed phenotype in three-dimensional culture. Thus, our results show an important role of Ada3 in HAT recruitment to estrogen-responsive target gene promoters and for estrogen-dependent proliferation of breast cancer cells. [Cancer Res 2007;67(24):11789–97]