bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of overtopping reliability and benefits of a flood detention dam
Authors: Yanmaz A. Melih , Gunindi M. Engin 
Published: October 2008

There is a growing tendency to assess safety levels of existing dams and to design new dams using probabilistic approaches according to project characteristics and site-specific conditions. This study is a probabilistic assessment of the overtopping reliability of a dam, which will be designed for flood detention purpose, and will compute the benefits that can be gained as a result of the implementation of this dam. In a case study, a bivariate flood frequency analysis was carried out using a five-parameter bivariate gamma distribution. A family of joint return period curves relating the runoff peak discharges to the runoff volumes at the dam site was derived. A number of hydrographs were also obtained under a joint return period of 100 years to observe the variation of overtopping tendency. The maximum reservoir elevation and overtopping reliability were determined by performing a probabilistic reservoir routing based on Monte Carlo simulations.
Semaphorin 3B Inhibits the Phosphatidylinositol 3-Kinase/Akt Pathway through Neuropilin-1 in Lung and Breast Cancer Cells
Authors: Castro-Rivera Emely , Ran Sophia , Brekken Rolf A. , Minna John D. 
Published: October 2008

Abstract
Semaphorin 3B (SEMA3B), located at 3p21.3, is a secreted member of the semaphorin family important in axonal guidance. SEMA3B undergoes allele and expression loss in lung and breast cancer and can function as a tumor suppressor. Previously, we found that SEMA3B induces apoptosis in tumor cells either by reexpression or when applied as a soluble ligand. SEMA3B-induced apoptosis was mediated, in part, by blocking vascular endothelial growth factor autocrine activity in tumor cells. In the current study, treatment of lung and breast cancer cells with picomolar concentrations of soluble SEMA3B inhibited their growth; induced apoptosis; and was associated with decreased Akt phosphorylation, increase in cytochrome c release and caspase-3 cleavage, as well as increased phosphorylation of several proapoptotic proteins, including glycogen synthase kinase-3β, FKHR, and MDM-2. Lung and breast cancer lines resistant to SEMA3B did not show these signaling changes and a tumor-derived missense SEMA3B mutant was inactive in this regard, providing specificity. SEMA3B-mediated inhibition of proliferation and induction of apoptosis in cancer cells were blocked by expressing a constitutively active Akt mutant and are linked to tumor cell expression of neuropilin-1 (Np-1). SEMA3B-insensitive Np-1–negative tumor cells acquired sensitivity to SEMA3B after forced expression of Np-1, whereas SEMA3B-sensitive Np-1–positive tumor cells lost sensitivity to SEMA3B after knockdown of Np-1 by small interfering RNA. We conclude that SEMA3B is a potential tumor suppressor that induces apoptosis in SEMA3B-inactivated tumor cells through the Np-1 receptor by inactivating the Akt signaling pathway. [Cancer Res 2008;68(20):8295–303]
Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors
Authors: Buck Elizabeth , Eyzaguirre Alexandra , Rosenfeld-Franklin Maryland , Thomson Stuart , Mulvihill Mark , Barr Sharon , Brown Eric , O'Connor Mathew , Yao Yan , Pachter Jonathan , Miglarese Mark , Epstein David , Iwata Kenneth K. , Haley John D. , Gibson Neil W. , Ji Qun-Sheng 
Published: October 2008

Abstract
Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic growth inhibition has been reported for combined blockade of EGFR and IGF-IR. However, in preclinical models, only a subset of tumors exhibit high sensitivity to this combination, highlighting the potential need for patient selection to optimize clinical efficacy. Herein, we have characterized the molecular basis for cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide biomarkers that seem to differentiate response. We find for epithelial, but not for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in vitro and growth regression in vivo upon combined blockade of both receptors. We identified two molecular aspects contributing to synergy: (a) inhibition of EGFR or IGF-IR individually promotes activation of the reciprocal receptor; (b) inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. Mechanistically, we find that inhibition of the MAPK pathway circumvents a negative feedback loop imposed on the IGF-IR– insulin receptor substrate 1 (IRS-1) signaling complex, a molecular scenario that parallels the negative feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed IGF-IR signaling. Collectively, these data show that resistance to inhibition of MEK, mTOR, and EGFR is associated with enhanced IGF-IR–directed Akt signaling, where all affect feedback loops converging at the level of IRS-1. [Cancer Res 2008;68(20):8322–32]
Genetic Instability Caused by Loss of MutS Homologue 3 in Human Colorectal Cancer
Authors: Haugen Astrid C. , Goel Ajay , Yamada Kanae , Marra Giancarlo , Nguyen Thuy-Phuong , Nagasaka Takeshi , Kanazawa Shinsaku , Koike Junichi , Kikuchi Yoshinori , Zhong Xiaoling , Arita Michitsune , Shibuya Kazutoshi , Oshimura Mitsuo , Hemmi Hiromichi , Boland C. Richard , Koi Minoru 
Published: October 2008

Abstract
Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR) deficiency. High levels of MSI at mononucleotide and dinucleotide repeats in colorectal cancer (CRC) are attributed to inactivation of the MMR genes, hMLH1 and hMSH2. CRC with low levels of MSI (MSI-L) exists; however, its molecular basis is unclear. There is another type of MSI—elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)—where loci containing [AAAG]n or [ATAG]n repeats are unstable. EMAST is frequent in non-CRCs; however, the incidence of EMAST and its cause in CRC is not known. Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low levels of mutations at dinucleotide repeats. About 60% of 117 sporadic CRC cases exhibit EMAST. All of the cases defined as MSI-H (16 cases) exhibited high levels of EMAST. Among 101 non–MSI-H cases, all 19 cases of MSI-L and 35 of 82 cases of MSS exhibited EMAST. Although non–MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the total tumor cell population, the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissues not exhibiting EMAST (8.4%). Taken together, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of MSI at loci with dinucleotide repeats in CRC. [Cancer Res 2008;68(20):8465–72]
Oncolytic Semliki Forest Virus Vector as a Novel Candidate against Unresectable Osteosarcoma
Authors: Ketola Anna , Hinkkanen Ari , Yongabi Felicitas , Furu Petra , Määttä Ann-Marie , Liimatainen Timo , Pirinen Risto , Björn Marko , Hakkarainen Tanja , Mäkinen Kimmo , Wahlfors Jarmo , Pellinen Riikka 
Published: October 2008

Abstract
Oncolytic viruses are a promising tool for treatment of cancer. We studied an oncolytic Semliki Forest virus (SFV) vector, VA7, carrying the enhanced green fluorescent protein gene (EGFP), as a novel virotherapy candidate against unresectable osteosarcoma. The efficiency and characteristics of the VA7-EGFP treatment were compared with a widely studied oncolytic adenovirus, Ad5Δ24, both in vitro and in vivo. VA7-EGFP resulted in more rapid oncolysis and was more efficient at low multiplicities of infection (MOI) when compared with Ad5Δ24 in vitro. Yet, in MG-63 cells, a subpopulation resistant to the VA7-EGFP vector emerged. In subcutaneous human osteosarcoma xenografts in nude mice treatment with either vector reduced tumor size, whereas tumors in control mice expanded quickly. The VA7-EGFP–treated tumors were either completely abolished or regressed to pinpoint size. The efficacy of VA7-EGFP vector was studied also in an orthotopic osteosarcoma nude mouse model characterized by highly aggressive tumor growth. Treatment with oncolytic SFV extended survival of the animals significantly (P &lt; 0.01), yet none of the animals were finally cured. Sera from SFV-treated mice contained neutralizing antibodies, and as nude mice are not able to establish IgG response, the result points out the role of IgM class antibodies in clearance of virus from peripheral tumors. Furthermore, biodistribution analysis at the survival end point verified the presence of virus in some of the brain samples, which is in line with previous studies demonstrating that IgG is required for clearance of SFV from central nervous system. [Cancer Res 2008;68(20):8342–50]
IFN-α and Bortezomib Overcome Bcl-2 and Mcl-1 Overexpression in Melanoma Cells by Stimulating the Extrinsic Pathway of Apoptosis
Authors: Lesinski Gregory B. , Raig Ene T. , Guenterberg Kristan , Brown Lloyd , Go Michael R. , Shah Nisha N. , Lewis Adrian , Quimper Megan , Hade Erinn , Young Gregory , Chaudhury Abhik Ray , Ladner Katherine J. , Guttridge Denis C. , Bouchard Page , Carson William E. 
Published: October 2008

AbstractWe hypothesized that IFN-α would enhance the apoptotic activity of bortezomib on melanoma cells. Combined treatment with bortezomib and IFN-α induced synergistic apoptosis in melanoma and other solid tumor cell lines. Apoptosis was associated with processing of procaspase-3, procaspase-7, procaspase-8, and procaspase-9 and with cleavage of Bid and poly(ADP-ribose) polymerase. Bortezomib plus IFN-α was effective at inducing apoptosis in melanoma cells that overexpressed Bcl-2 or Mcl-1, suggesting that this treatment combination can overcome mitochondrial pathways of cell survival and resistance to apoptosis. The proapoptotic effects of this treatment combination were abrogated by a caspase-8 inhibitor, led to increased association of Fas and FADD before the onset of cell death, and were significantly reduced in cells transfected with a dominant-negative FADD construct or small interfering RNA targeting Fas. These data suggest that bortezomib and IFN-α act through the extrinsic pathway of apoptosis via FADD-induced caspase-8 activation to initiate cell death. Finally, bortezomib and IFN-α displayed statistically significant antitumor activity compared with either agent alone in both the B16 murine model of melanoma and in athymic mice bearing human A375 xenografts. These data support the future clinical development of bortezomib and IFN-α for malignant melanoma. [Cancer Res 2008;68(20):8351–60]
Activated Gα13 Impairs Cell Invasiveness through p190RhoGAP-Mediated Inhibition of RhoA Activity
Authors: Bartolomé Rubén A. , Wright Natalia , Molina-Ortiz Isabel , Sánchez-Luque Francisco J. , Teixidó Joaquin 
Published: October 2008

Abstract
The GTPase RhoA is a downstream target of heterotrimeric G13 proteins and plays key roles in cell migration and invasion. Here, we show that expression in human melanoma cells of a constitutively active, GTPase-deficient Gα13 form (Gα13QL) or lysophosphatidylcholine (LPC)-promoted signaling through Gα13-coupled receptors led to a blockade of chemokine-stimulated RhoA activation and cell invasion that was rescued by active RhoA. Melanoma cells expressing Gα13QL or cells stimulated with LPC displayed an increase in p190RhoGAP activation, and defects in RhoA activation and invasion were recovered by knocking down p190RhoGAP expression, thus identifying this GTPase-activating protein (GAP) protein as a downstream Gα13 target that is responsible for these inhibitory responses. In addition, defective stress fiber assembly and reduced migration speed underlay inefficient invasion of Gα13QL melanoma cells. Importantly, Gα13QL expression in melanoma cells led to impairment in lung metastasis associated with prolonged survival in SCID mice. The data indicate that Gα13-dependent downstream effects on RhoA activation and invasion tightly depend on cell type–specific GAP activities and that Gα13-p190RhoGAP signaling might represent a potential target for intervention in melanoma metastasis. [Cancer Res 2008;68(20):8221–30]
Fetal Cell Microchimerism in Papillary Thyroid Cancer: A Possible Role in Tumor Damage and Tissue Repair
Authors: Cirello Valentina , Recalcati Maria Paola , Muzza Marina , Rossi Stefania , Perrino Michela , Vicentini Leonardo , Beck-Peccoz Paolo , Finelli Palma , Fugazzola Laura 
Published: October 2008

Abstract
Fetal cells enter the maternal circulation during pregnancy and can persist in the maternal blood or tissues for decades, creating a physiologic microchimerism. Because papillary thyroid cancer (PTC) is more frequent in women, the role of persisting fetal male cells in this tumor has been investigated. Tumor tissue specimens were obtained from 63 women with PTC who had a male pregnancy before the diagnosis. Male cells, identified by PCR amplification of a male-specific gene, the sex-determining region Y, was detected in 47.5% of women. By fluorescence in situ hybridization (FISH) analyses, the total number of microchimeric cells was significantly higher in neoplastic tissue than in controlateral normal sections. By combined FISH and immunohistochemistry (immuno-FISH), male cells expressing thyroglobulin were found in tumor and normal tissues, whereas male microchimeric cells stained with the CD45 antigen were detected only in tumor sections. Microchimeric cells negative for either marker were detected both in tumor and normal tissues. Moreover, both CD45+ and Tg+ fetal cells did not express MHC II antigens. In conclusion, fetal microchimerism has been documented in a high proportion of women with PTC. The immuno-FISH studies indicate that CD45+/MHC II− male cells found in neoplastic tissues might be committed to destroy tumor cells, whereas Tg+/MHC II− cells could have a repair function. Finally, microchimeric cells negative for either CD45 or Tg could have “progenitor-like” properties able to transdifferentiate in different cellular types. Although a pathogenetic mechanism cannot be excluded, the whole of the present results indicates a protective role of microchimerism in thyroid cancer. [Cancer Res 2008;68(20):8482–8]
Noninvasive Molecular Imaging of Hypoxia in Human Xenografts: Comparing Hypoxia-Induced Gene Expression with Endogenous and Exogenous Hypoxia Markers
Authors: He Fuqiu , Deng Xuelong , Wen Bixiu , Liu Yueping , Sun Xiaorong , Xing Ligang , Minami Akiko , Huang Yunhong , Chen Qing , Zanzonico Pat B. , Ling C. Clifton , Li Gloria C. 
Published: October 2008

Abstract
Tumor hypoxia is important in the development and treatment of human cancers. We have developed a novel xenograft model for studying and imaging of hypoxia-induced gene expression. A hypoxia-inducible dual reporter herpes simplex virus type 1 thymidine kinase and enhanced green fluorescence protein (HSV1-TKeGFP), under the control of hypoxia response element (9HRE), was stably transfected into human colorectal HT29 cancer cells. Selected clones were further enriched by repeated live cell sorting gated for hypoxia-induced eGFP expression. Fluorescent microscopy, fluorescence-activated cell sorting, and radioactive substrate trapping assays showed strong hypoxia-induced expression of eGFP and HSV1-tk enzyme in the HT29-9HRE cells in vitro. Sequential micropositron emission tomography (PET) imaging of tumor-bearing animals, using the hypoxic cell tracer 18F-FMISO and the reporter substrate 124I-FIAU, yielded similar tumor hypoxia images for the HT29-9HRE xenograft but not in the parental HT29 tumor. Using autoradiography and IHC, detailed spatial distributions in tumor sections were obtained and compared for the following hypoxia-associated biomarkers in the HT29-9HRE xenograft: 124I-FIAU, 18F-FMISO, Hoechst (perfusion), lectin-TRITC (functional blood vessels), eGFP, pimonidazole, EF5, and CA9. Intratumoral distributions of 124I-FIAU and 18F-FMISO were similar, and eGFP, pimonidazole, EF5, and CA9 colocalized in the same areas but not in well-perfused regions that were positive for Hoechst and lectin-TRITC. In enabling the detection of hypoxia-induced molecular events and mapping their distribution in vivo with serial noninvasive positron emission tomography imaging, and multiple variable analysis with immunohistochemistry and fluorescence microscopy, this human xenograft model provides a valuable tool for studying tumor hypoxia and in validating existing and future exogenous markers for tumor hypoxia. [Cancer Res 2008;68(20):8597–606]
Dual Inhibition of PI3Kα and mTOR as an Alternative Treatment for Kaposi's Sarcoma
Authors: Chaisuparat Risa , Hu Jiadi , Jham Bruno C. , Knight Zachary A. , Shokat Kevan M. , Montaner Silvia 
Published: October 2008

Abstract
Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathologic angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus–encoded G protein–coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here, we show that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the up-regulation of several Akt proliferative and survival pathways. However, use of a novel dual phosphatidylinositol 3-kinase α (PI3Kα)/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathologic angiogenesis, our results further provide the basis for the early assessment of PI-103 as an antiangiogenic chemotherapeutic. [Cancer Res 2008;68(20):8361–8]
Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1α during Hypoxia in Human Cancer Cells
Authors: Ader Isabelle , Brizuela Leyre , Bouquerel Pierre , Malavaud Bernard , Cuvillier Olivier 
Published: October 2008

Abstract
Here, we provide the first evidence that sphingosine kinase 1 (SphK1), an oncogenic lipid kinase balancing the intracellular level of key signaling sphingolipids, modulates the transcription factor hypoxia inducible factor 1α (HIF-1α), master regulator of hypoxia. SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1α levels is mediated by the Akt/glycogen synthase kinase-3β signaling pathway that prevents its von Hippel-Lindau protein–mediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1α and its transcriptional activity in several human cancer cell lineages (prostate, brain, breast, kidney, and lung), suggesting a canonical pathway. Therefore, we propose that SphK1 can act as a master regulator for hypoxia, giving support to its inhibition as a valid strategy to control tumor hypoxia and its molecular consequences. [Cancer Res 2008;68(20):8635–42]
Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a Population-Based Series of 582 Cases
Authors: Barault Ludovic , Charon-Barra Céline , Jooste Valérie , de la Vega Mathilde Funes , Martin Laurent , Roignot Patrick , Rat Patrick , Bouvier Anne-Marie , Laurent-Puig Pierre , Faivre Jean , Chapusot Caroline , Piard Francoise 
Published: October 2008

Abstract
The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P &lt; 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37–2.51; CIMP-High, HR, 2.90; 95% CI, 1.53–5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer. [Cancer Res 2008;68(20):8541–6]
Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability
Authors: Maxwell Christopher A. , Fleisch Markus C. , Costes Sylvain V. , Erickson Anna C. , Boissière Arnaud , Gupta Rishi , Ravani Shraddha A. , Parvin Bahram , Barcellos-Hoff Mary Helen 
Published: October 2008

Abstract
Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. We investigated the mechanism of this nontargeted effect in human mammary epithelial cells (HMEC) exposed to low doses of radiation. We identified a centrosome-associated expression signature in irradiated HMEC and show here that centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy, and aneuploidy. Clonal analysis of genomic instability showed a threshold of &gt;10 cGy. Treatment with transforming growth factor β1 (TGFβ), which is implicated in regulation of genomic stability and is activated by radiation, reduced both the centrosome expression signature and centrosome aberrations in irradiated HMEC. Furthermore, TGFβ inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFβ selectively deleted unstable cells via p53-dependent apoptosis. Together, these studies show that radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that this can be opposed by radiation-induced TGFβ signaling. [Cancer Res 2008;68(20):8304–11]