bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role for Caspase-8 in Epidermal Growth Factor Signaling
Authors: Finlay Darren , Howes Amy , Vuori Kristiina 
Published: May 2009

Abstract
Caspase-8 has a well-defined canonical role as an apical protease of the extrinsic apoptosis pathway. Evidence is growing, however, that the protein has numerous other nonapoptotic functions. We have previously shown that caspase-8 is required for efficient adhesion-induced activation of the extracellular signal–regulated kinase (Erk)-1/2 pathway. We now show that caspase-8 is also necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling. This promotion of EGF-induced Erk1/2 activation is independent of the proteolytic activity of caspase-8 and can be recapitulated using only the pro-domains of the protein. In addition, we identify specific residues within the caspase-8 “RXDLL motif” that are essential for Erk pathway activation. Furthermore, these residues are also involved in forming a complex with the tyrosine kinase Src. Caspase-8 null cells and cells reconstituted with caspase-8 harboring point mutations of these critical amino acids also show defective EGF-induced migration as compared with cells reconstituted with the wild-type protein. In sum, we provide the first evidence for caspase-8 as an essential component of growth factor signaling and suggest that this may be due to its association with Src. As the EGF/Src pathway activity has been shown to promote oncogenic events, our findings that caspase-8 is necessary for these activities may help explain why it is rarely deleted or silenced in tumors. [Cancer Res 2009;69(12):5023–9]
Patterns of Gene Expression and Copy-Number Alterations in von-Hippel Lindau Disease-Associated and Sporadic Clear Cell Carcinoma of the Kidney
Authors: Beroukhim Rameen , Brunet Jean-Philippe , Di Napoli Arianna , Mertz Kirsten D. , Seeley Apryle , Pires Maira M. , Linhart David , Worrell Robert A. , Moch Holger , Rubin Mark A. , Sellers William R. , Meyerson Matthew , Linehan W. Marston , Kaelin William G. , Signoretti Sabina 
Published: May 2009

AbstractRecent insights into the role of the von-Hippel Lindau (VHL) tumor suppressor gene in hereditary and sporadic clear-cell renal cell carcinoma (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of three genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into two groups: one group with genomic profiles highly dissimilar to the majority of ccRCC and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL. [Cancer Res 2009;69(11):4674–81]
Extranuclear Coactivator Signaling Confers Insensitivity to Tamoxifen
Authors: Kumar Rakesh , Zhang Hao , Holm Caroline , Vadlamudi Ratna K. , Landberg Goran , Rayala Suresh K. 
Published: May 2009

Abstract
Purpose: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-α–positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.
Experimental Design: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid–, and leucine-rich protein–1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness.
Results: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1.
Conclusions: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling.
Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma
Authors: Hui Angela B.Y. , Yue Shijun , Shi Wei , Alajez Nehad M. , Ito Emma , Green Simon R. , Frame Sheelagh , O'Sullivan Brian , Liu Fei-Fei 
Published: May 2009

Abstract
Purpose: Seliciclib is a small-molecule cyclin-dependent kinase inhibitor, which has been reported to induce apoptosis and cell cycle arrest in EBV-negative nasopharyngeal carcinoma cell lines. Because most nasopharyngeal carcinoma patients harbor EBV, we proceeded to evaluate the cytotoxic effects of seliciclib in EBV-positive nasopharyngeal carcinoma models.
Experimental Design: Cytotoxicity of seliciclib was investigated in the EBV-positive cell line C666-1 and the C666-1 and C15 xenograft models. Caspase activities and cell cycle analyses were measured by flow cytometry. Efficacy of combined treatment of seliciclib with radiation therapy was also evaluated.
Results: Seliciclib caused significant cytotoxicity in the C666-1 cells in a time- and dose-dependent manner, with accumulation of cells in both sub-G1 and G2-M phases, indicative of apoptosis and cell cycle arrest, respectively. Caspase-2, -3, -8, and -9 activities were all increased, with caspase-3 being the most significantly activated at 48 h after treatment. These cells also showed a reduction of Mcl-1 mRNA and protein levels. Combined treatment of seliciclib with radiation therapy showed a synergistic interaction with enhanced cytotoxicity in C666-1 cells and delayed repair of double-strand DNA breaks. For in vivo models, significant delays in tumor growth were observed for both C666-1 and C15 tumors, which were associated with enhanced apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry analyses.
Conclusions: Seliciclib enhanced the antitumor efficacy of radiation therapy in EBV-positive nasopharyngeal carcinoma, characterized by G2-M arrest, and apoptosis, associated with an induction in caspase activity. This process is mediated by reduction in Mcl-1 expression and by attenuation of double-strand DNA break repair.
Activation of the Unfolded Protein Response Is Associated with Favorable Prognosis in Acute Myeloid Leukemia
Authors: Schardt Julian A. , Weber Daniel , Eyholzer Marianne , Mueller Beatrice U. , Pabst Thomas 
Published: May 2009

Abstract
Purpose: The unfolded protein response is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum. Previous studies suggest that the unfolded protein response is activated in some cancer cell lines and involved in tumor development. The role of the unfolded protein response during leukemogenesis is unknown thus far.
Experimental Design: Here, we assessed the induction of key effectors of the unfolded protein response in leukemic cells at diagnosis of 105 acute myeloid leukemia (AML) patients comprising all subtypes. We determined the formation of the spliced variant of the X-box–binding protein 1 (XBP1) mRNA, as well as expression levels of calreticulin, GRP78, and CHOP mRNA.
Results: The formation of the spliced variant of XBP1s was detectable in 16.2% (17 of 105) of AML patients. Consistent with activated unfolded protein response, this group also had significantly increased expression of calreticulin, GRP78, and CHOP. AML patients with activated unfolded protein response had lower WBC counts, lactate dehydrogenase levels, and more frequently, secondary AML. The incidence of fms-related tyrosine kinase 3 (FLT3) mutations was significantly lower in patients with activated unfolded protein response. In addition, an association was observed between activated unfolded protein response and deletion of chromosome 7. Finally, the clinical course of AML patients with activated unfolded protein response was more favorable with lower relapse rate (P = 0.0182) and better overall (P = 0.041) and disease-free survival (P = 0.022).
Conclusions: These results suggest that the unfolded protein response is activated in a considerable subset of AML patients. AML patients with activated unfolded protein response present specific clinical characteristics and a more favorable course of the disease.
Imaging a Genetically Engineered Oncolytic Vaccinia Virus (GLV-1h99) Using a Human Norepinephrine Transporter Reporter Gene
Authors: Brader Peter , Kelly Kaitlyn J. , Chen Nanhai , Yu Yong A. , Zhang Qian , Zanzonico Pat , Burnazi Eva M. , Ghani Rashid E. , Serganova Inna , Hricak Hedvig , Szalay Aladar A. , Fong Yuman , Blasberg Ronald G. 
Published: May 2009

Abstract
Purpose: Oncolytic viral therapy continues to be investigated for the treatment of cancer, and future studies in patients would benefit greatly from a noninvasive modality for assessing virus dissemination, targeting, and persistence. The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [123I]metaiodobenzylguanidine (MIBG) γ-camera and [124I]MIBG positron emission tomography (PET) imaging.
Experimental Design: GLV-1h99 was tested in human malignant mesothelioma and pancreatic cancer cell lines for cytotoxicity, expression of the hNET protein using immunoblot analysis, and [123I]MIBG uptake in cell culture assays. In vivo [123I]MIBG γ-camera and serial [124I]MIBG PET imaging was done in MSTO-211H orthotopic pleural mesothelioma tumors.
Results: GLV-1h99 successfully infected and provided dose-dependent levels of transgene hNET expression in human malignant mesothelioma and pancreatic cancer cells. The time course of [123I]MIBG accumulation showed a peak of radiotracer uptake at 48 hours after virus infection in vitro. In vivo hNET expression in MSTO-211H pleural tumors could be imaged by [123I]MIBG scintigraphy and [124I]MIBG PET 48 and 72 hours after GLV-1h99 virus administration. Histologic analysis confirmed the presence of GLV-1h99 in tumors.
Conclusion: GLV-1h99 shows high mesothelioma tumor cell infectivity and cytotoxic efficacy. The feasibility of imaging virus-targeted tumor using the hNET reporter system with [123I]MIBG γ-camera and [124I]MIBG PET was shown in an orthotopic pleural mesothelioma tumor model. The inclusion of human reporter genes into recombinant oncolytic viruses enhances the potential for translation to clinical monitoring of oncolytic viral therapy.
HGF and c-Met Participate in Paracrine Tumorigenic Pathways in Head and Neck Squamous Cell Cancer
Authors: Knowles Lynn M. , Stabile Laura P. , Egloff Ann Marie , Rothstein Mary E. , Thomas Sufi M. , Gubish Christopher T. , Lerner Edwina C. , Seethala Raja R. , Suzuki Shinsuke , Quesnelle Kelly M. , Morgan Sarah , Ferris Robert L. , Grandis Jennifer R. , Siegfried Jill M. 
Published: May 2009

Abstract
Purpose: We determined hepatocyte growth factor (HGF) and c-Met expression and signaling in human head and neck squamous cell carcinoma (HNSCC) cells and primary tissues and tested the ability of c-Met tyrosine kinase inhibitors (TKI) to block HGF-induced biological signaling.
Experimental Design: Expression and signaling were determined using immunoblotting, ELISA, and immunohistochemistry. Biological end points included wound healing, cell proliferation, and invasion. c-Met TKIs were tested for their ability to block HGF-induced signaling and biological effects in vitro and in xenografts established in nude mice.
Results: c-Met was expressed and functional in HNSCC cells. HGF was secreted by HNSCC tumor-derived fibroblasts, but not by HNSCC cells. Activation of c-Met promoted phosphorylation of AKT and mitogen-activated protein kinase as well as release of the inflammatory cytokine interleukin-8. Cell growth and wound healing were also stimulated by HGF. c-Met TKIs blocked HGF-induced signaling, interleukin-8 release, and wound healing. Enhanced invasion of HNSCC cells induced by the presence of tumor-derived fibroblasts was completely blocked with a HGF-neutralizing antibody. PF-2341066, a c-Met TKI, caused a 50% inhibition of HNSCC tumor growth in vivo with decreased proliferation and increased apoptosis within the tumors. In HNSCC tumor tissues, both HGF and c-Met protein were increased compared with expression in normal mucosa.
Conclusions: These results show that HGF acts mainly as a paracrine factor in HNSCC cells, the HGF/c-Met pathway is frequently up-regulated and functional in HNSCC, and a clinically relevant c-Met TKI shows antitumor activity in vivo. Blocking the HGF/c-Met pathway may be clinically useful for the treatment of HNSCC.
Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration
Authors: Schwartz Anthony L. , Malgor Ramiro , Dickerson Eric , Weeraratna Ashani T. , Slominski Andrzej , Wortsman Jacobo , Harii Norikazu , Kohn Aimee D. , Moon Randall T. , Schwartz Frank L. , Goetz Douglas J. , Kohn Leonard D. , McCall Kelly D. 
Published: May 2009

AbstractPurpose: To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo.Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated.Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation.Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma.
Association between Plasma 25-Hydroxyvitamin D and Breast Cancer Risk
Authors: Crew Katherine D. , Gammon Marilie D. , Steck Susan E. , Hershman Dawn L. , Cremers Serge , Dworakowski Elzbieta , Shane Elizabeth , Terry Mary Beth , Desai Manisha , Teitelbaum Susan L. , Neugut Alfred I. , Santella Regina M. 
Published: May 2009

AbstractVitamin D has been associated with decreased risk of several cancers. In experimental studies, vitamin D has been shown to inhibit cell proliferation and induce differentiation and apoptosis in normal and malignant breast cells. Using a population-based case-control study on Long Island, New York, we examined the association of breast cancer with plasma 25-hydroxyvitamin D (25-OHD) levels, a measure of vitamin D body stores. In-person interviews and blood specimens were obtained from 1,026 incident breast cancer cases diagnosed in 1996 to 1997 and 1,075 population-based controls. Plasma 25-OHD was measured in batched, archived specimens by Diasorin RIA. The mean (SD) plasma 25-OHD concentration was 27.1 (13.0) and 29.7 (15.1) ng/mL in the cases and controls, respectively (P &lt; 0.0001). Plasma 25-OHD was inversely associated with breast cancer risk in a concentration-dependent fashion (Ptrend = 0.002). Compared with women with vitamin D deficiency (25-OHD, &lt;20 ng/mL), levels above 40 ng/mL were associated with decreased breast cancer risk (odds ratio, 0.56; 95% confidence interval, 0.41-0.78). The reduction in risk was greater among postmenopausal women (odds ratio, 0.46; 95% confidence interval, 0.09-0.83), and the effect did not vary according to tumor hormone receptor status. In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of &gt;32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is ≥40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.
Lung Cancer Inhibitory Effect of Epigallocatechin-3-Gallate Is Dependent on Its Presence in a Complex Mixture (Polyphenon E)
Authors: Fu Huijing , He Jun , Mei Fan , Zhang Qi , Hara Yukihiko , Ryota Seto , Lubet Ronald A. , Chen Ruth , Chen Da-Ren , You Ming 
Published: May 2009

Abstract
Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. However, (−)-epigallocatechin-3-gallate (EGCG) alone was shown to be ineffective in preventing lung tumorigenesis in mice by aerosol administration. In this study, Polyphenon E and Polyphenon E without EGCG were administered by aerosol delivery to A/J mice 2 weeks after carcinogen treatment and continuing daily throughout the remainder of the study (20 weeks). An improved aerosol delivery system with a custom-built atomizer, an efficient solvent remove system, and a nose-only exposure chamber was used to provide aerosols with stable size distribution. There were no significant differences in the size distributions of Polyphenon E and Polyphenon E without EGCG. With a relatively low dose level (4.19 mg/kg), Polyphenon E decreased tumor multiplicity by 53%, whereas Polyphenon E without EGCG at the same dose failed to inhibit lung carcinogenesis. These results indicate that aerosol administration can be an effective approach in chemoprevention study, and aerosolized Polyphenon E can significantly inhibit pulmonary adenoma formation and growth in A/J mice. Furthermore, in aerosolized form, EGCG, which is thought to be the most active component of Polyphenon E, has to be present with other tea catechins to show chemopreventive activity on lung tumorigenesis.
Negotiations Over Water and Other Natural Resources in the La Plata River Basin: A Model for Other Transboundary Basins?
Authors: Pinard Margaret , Kempkey Natalie , Dinar Ariel , Pochat Víctor 
Published: May 2009

AbstractThe La Plata River Basin in South America, whose waters are shared by Argentina, Bolivia, Brazil, Paraguay and Uruguay, provides important lessons from the long history of negotiations over its shared water and other natural resources. In particular, innovative resource management practices developed over time have led to the relative harmony in which the riparian countries coexist. In this article, we analyze negotiation techniques within the La Plata River Basin by examining in detail the processes leading to the two seminal agreements – the 1969 Treaty of La Plata Basin and the 1979 Itaipú-Corpus Agreement. Based upon our analysis of the complex and often contradictory relationships between the riparian states, we evaluate the outcomes of both treaties from the standpoint of cooperation in the region and sustainable development. In doing so, we extend the relevance of the analysis to other basins with similar issues of regional management. The article extends the basin cooperation, through negotiation, to include trade agreements and development via project partnerships that draw in regional and global actors, including non-governmental organizations, environmental lobbies in foreign countries, and multinational development banks. The above actors are relevant for many parts of the world in today's era of globalization.
Hydrosolidarity and International Water Governance
Authors: Varady Robert , Gerlak Andrea , Haverland Arin 
Published: May 2009

AbstractIn the first decade of the 21st century, 'hydrosolidarity,' the notion that water management should include considerations of ethics and equity, has influenced international approaches to conducting environmental research and formulating water policy. Since its inception in the 1990s, the term appears frequently across a spectrum of water-related research. It has accordingly permeated discourses and publications on water management. Such rapid proliferation of the concept has helped usher in a wave of transition from conflict management to cooperative efforts between upstream and downstream basin users, as well as a complex paradigm that links both human and environmental welfare. In this paper, we trace the intellectual origins and changing conceptions of hydrosolidarity. We outline some of its applications as well as various reactions to the concept. We close by discussing how the concept can help frame negotiations between riparian states and influence treaty-making and institution-building in river basin settings.