bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer Pricing for Corporate Treasury in the Multinational Enterprise
Authors: Curtis Stephen L. 
Published: July 2008

Intercompany financing transactions are becoming increasingly important to multinational enterprises (MNEs) as they expand internationally. Corporate treasurers of MNEs have many responsibilities, including the management of international capital structure and cost of capital, the financing of cross‐border acquisitions, foreign direct investment, international capital budgeting and cash management, management of foreign exchange and transactional risk, and port‐folio and investment management.This article focuses on a corporate function, transfer pricing, that is potentially relevant to each of these activities. Whenever a payment crosses borders in a treasury context—whether to provide a loan, purchase a receivable, provide a guarantee, sweep cash, factor a receivable, provide a hedge or insurance product—a transfer pricing issue is present. Transfer pricing is often viewed as a taxation issue and thus the responsibility of the corporate tax department. This article challenges that view, and makes the case that an integrated, multi‐functional approach to MNE treasury planning in the context of transfer pricing can be an important component in improving the efficiency of cross‐border financial management. The paper uses conceptual and empirical information as well as numerical examples to illustrate relevant tax and transfer pricing concepts for policy planners and others responsible for MNE treasury and tax planning.
In situ determination of a rock mass modulus using a high resolution tiltmeter
Authors: Saleh Bassam , Malkawi Abdallah I Husein , Blum Pierre A 
Published: July 2008

A very high resolution tiltmeter (108 rad, 0.002 s) developed by P.A. Blum, in 1957 was used to establish a new approach to directly evaluate the in situ average elastic rock-mass modulus. Five tiltmeters were installed on the facades of the Louvre museum to study the deformations induced by internal structural work and by the impact of the Paris metro traffic movement. The measured data from the tiltmeter were used to determine the elastic rock modulus of the museum's foundation using the Boussinesq model. The results obtained by the developed approach are consistent with the typical elastic rock-mass modulus for the rock found in the museum's foundations. Key words: rock-mass modulus, tiltmeter, deformation, Boussinesq model.
Tissue-Specific Promoters Active in CD44+CD24−/low Breast Cancer Cells
Authors: Bauerschmitz Gerd J. , Ranki Tuuli , Kangasniemi Lotta , Ribacka Camilla , Eriksson Minna , Porten Marius , Herrmann Isabell , Ristimäki Ari , Virkkunen Pekka , Tarkkanen Maija , Hakkarainen Tanja , Kanerva Anna , Rein Daniel , Pesonen Sari , Hemminki Akseli 
Published: July 2008

Abstract
It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44+CD24−/low population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44+CD24−/low cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44+CD24−/low cells. α-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44+CD24−/low cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44+CD24−/low cells in vitro. In vivo, these viruses had significant antitumor activity in CD44+CD24−/low–derived tumors. These findings may have relevance for elimination of cancer stem cells in humans. [Cancer Res 2008;68(14):5533–9]
Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development
Authors: Hu Zhishang , Liu Yuheng , Zhang Chunbo , Zhao Yun , He Wei , Han Lu , Yang Leilei , Hopkins Kevin M. , Yang Xiao , Lieberman Howard B. , Hang Haiying 
Published: July 2008

Abstract
The Rad9 gene is evolutionarily conserved from yeast to humans and plays crucial roles in genomic maintenance, DNA repair, and cell cycle checkpoint controls. However, the function of this gene with respect to tumorigenesis is not well-understood. A Rad9-null mutation in mice causes embryonic lethality. In this study, we created mice in which mouse Rad9, Mrad9, was deleted only in keratinocytes to permit examination of the potential function of the gene in tumor development. Mice with Mrad9+/− or Mrad9−/− keratinocytes showed no overt, spontaneous morphologic defects and seemed similar to wild-type controls. Painting the carcinogen 7,12-dimethylbenzanthracene (DMBA) onto the skin of the animals caused earlier onset and more frequent formation of tumors and senile skin plaques in Mrad9−/− mice, compared with Mrad9+/− and Mrad9+/+ littermates. DNA damage response genes p21, p53, and Mrad9B were expressed at higher levels in Mrad9−/− relative to Mrad9+/+ skin. Keratinocytes isolated from Mrad9−/− skin had more spontaneous and DMBA-induced DNA double strand breaks than Mrad9+/+ keratinocytes, and the levels were reduced by incubation with the antioxidant epigallocatechin gallate. These data suggest that Mrad9 plays an important role in maintaining genomic stability and preventing tumor development in keratinocytes. [Cancer Res 2008;68(14):5552–61]
Activation of Platelet-Activating Factor Receptor and Pleiotropic Effects on Tyrosine Phospho-EGFR/Src/FAK/Paxillin in Ovarian Cancer
Authors: Aponte Margarita , Jiang Wei , Lakkis Montaha , Li Ming-Jiang , Edwards Dale , Albitar Lina , Vitonis Allison , Mok Samuel C. , Cramer Daniel W. , Ye Bin 
Published: July 2008

Abstract
Among the proinflammatory mediators, platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a major primary and secondary messenger involved in intracellular and extracellular communication. Evidence suggests that PAF plays a significant role in oncogenic transformation, tumor growth, angiogenesis, and metastasis. However, PAF, with its receptor (PAFR) and their downstream signaling targets, has not been thoroughly studied in cancer. Here, we characterized the PAFR expression pattern in 4 normal human ovarian surface epithelial (HOSE) cell lines, 13 ovarian cancer cell lines, paraffin blocks (n = 84), and tissue microarrays (n = 230) from patients with ovarian cancer. Overexpression of PAFR was found in most nonmucinous types of ovarian cancer but not in HOSE and mucinous cancer cells. Correspondingly, PAF significantly induced cell proliferation and invasion only in PAFR-positive cells (i.e., OVCA429 and OVCA432), but not in PAFR-negative ovarian cells (HOSE and mucinous RMUG-L). The dependency of cell proliferation and invasion on PAFR was further confirmed using PAFR-specific small interfering RNA gene silencing probes, antibodies against PAFR and PAFR antagonist, ginkgolide B. Using quantitative multiplex phospho-antibody array technology, we found that tyrosine phosphorylation of EGFR/Src/FAK/paxilin was coordinately activated by PAF treatment, which was correlated with the activation of phosphatidylinositol 3-kinase and cyclin D1 as markers for cell proliferation, as well as matrix metalloproteinase 2 and 9 for invasion. Specific tyrosine Src inhibitor (PP2) reversibly blocked PAF-activated cancer cell proliferation and invasion. We suggest that PAFR is an essential upstream target of Src and other signal pathways to control the PAF-mediated cancer progression. [Cancer Res 2008;68(14):5839–48]
GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas
Authors: Rønneberg Jo Anders , Tost Jörg , Solvang Hiroko K. , Alnaes Grethe I.G. , Johansen Fredrik E. , Brendeford Elen M. , Yakhini Zohar , Gut Ivo G. , Lønning Per Eystein , Børresen-Dale Anne-Lise , Gabrielsen Odd S. , Kristensen Vessela N. 
Published: July 2008

Abstract
The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor–positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation. [Cancer Res 2008;68(14):5562–71]
Cathepsin G Enhances Mammary Tumor–Induced Osteolysis by Generating Soluble Receptor Activator of Nuclear Factor-κB Ligand
Authors: Wilson Thomas J. , Nannuru Kalyan C. , Futakuchi Mitsuru , Sadanandam Anguraj , Singh Rakesh K. 
Published: July 2008

Abstract
Breast cancer commonly causes osteolytic metastases in bone, a process that is dependent on tumor-stromal interaction. Proteases play an important role in modulating tumor-stromal interactions in a manner that favors tumor establishment and progression. Whereas several studies have examined the role of proteases in modulating the bone microenvironment, little is currently known about their role in tumor-bone interaction during osteolytic metastasis. In cancer-induced osteolytic lesions, cleavage of receptor activator of nuclear factor-κB ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with breast cancer–induced bone metastases, we identified cathepsin G, cathepsin K, matrix metalloproteinase (MMP)-9, and MMP13 to be proteases that are up-regulated at the tumor-bone interface using comparative cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G at the tumor-bone interface seems to be osteoclasts that up-regulate production of cathepsin G via interaction with tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of cathepsin G in a coculture model and that in vivo inhibition of cathepsin G reduces mammary tumor–induced osteolysis. Together, our data indicate that cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor–induced osteolysis and suggest that cathepsin G is a potentially novel therapeutic target in the treatment of breast cancer bone metastasis. [Cancer Res 2008;68(14):5803–11]
Vaccination Elicits Correlated Immune and Clinical Responses in Glioblastoma Multiforme Patients
Authors: Wheeler Christopher J. , Black Keith L. , Liu Gentao , Mazer Mia , Zhang Xiao-xue , Pepkowitz Samuel , Goldfinger Dennis , Ng Hiushan , Irvin Dwain , Yu John S. 
Published: July 2008

AbstractCancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-γ responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited ≥1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans. [Cancer Res 2008;68(14):5955–64]
The Novel Angiogenic Inhibitor, Angiocidin, Induces Differentiation of Monocytes to Macrophages
Authors: Gaurnier-Hausser Anita , Rothman Vicki L. , Dimitrov Svetoslav , Tuszynski George P. 
Published: July 2008

AbstractWe previously showed that angiocidin, a tumor and vascular associated protein, is a potent inhibitor of angiogenesis and tumor growth. Angiocidin is a multidomain protein that exerts its antiangiogenic activity through multiple mechanisms, including effects on cell matrix interaction. Here, we describe another activity of angiocidin that may contribute to its antitumor activity. We show that angiocidin activates monocytes to secrete a mixture of proinflammatory cytokines and induces them to differentiate into macrophage-like cells. Using the monocytic cell line THP-1, we show that angiocidin induces the cells to become adherent and phagocytic, express macrophage markers, and secrete matrix metalloproteinase-9. Microarray analysis of control and angiocidin-treated THP-1 cells revealed that angiocidin up-regulated p105/p50, p100/p52, and rel B, components of the nuclear factor-κB (NF-κB) pathway. We confirmed the microarray data and showed that angiocidin induced phosphorylation of Iκβ, p50, and p65 and translocation of p50 and p65 to the nucleus. We also showed that angiocidin activated up-stream mediators of NF-κB, such as the mitogen-activated protein kinase (MAPK) pathway and phosphoinositide-3 kinase (PI3K). Blockage of NF-κB and MAPK activation with small molecule inhibitors completely prevented angiocidin-mediated secretion of cytokines from THP-1 cells, but did not inhibit their adhesive phenotype. Blocking PI3K inhibited both secretion of cytokines, as well as the adhesive phenotype. These data suggest that angiocidin activates monocytes to secrete cytokines and differentiates them to a macrophage-like phenotype through at least two pathways mediated by MAPK and NF-κB, as well as PI3K. [Cancer Res 2008;68(14):5905–14]
Cell Lineage Analysis of a Mouse Tumor
Authors: Frumkin Dan , Wasserstrom Adam , Itzkovitz Shalev , Stern Tomer , Harmelin Alon , Eilam Raya , Rechavi Gideon , Shapiro Ehud 
Published: July 2008

Abstract
Revealing the lineage relations among cancer cells can shed light on tumor growth patterns and metastasis formation, yet cell lineages have been difficult to come by in the absence of a suitable method. We previously developed a method for reconstructing cell lineage trees from genomic variability caused by somatic mutations. Here, we apply the method to cancer and reconstruct, for the first time, a lineage tree of neoplastic and adjacent normal cells obtained by laser microdissection from tissue sections of a mouse lymphoma. Analysis of the reconstructed tree reveals that the tumor initiated from a single founder cell, ∼5 months before diagnosis, that the tumor grew in a physically coherent manner, and that the average number of cell divisions accumulated in cancerous cells was almost twice than in adjacent normal lung epithelial cells but slightly less than the expected figure for normal B lymphocytes. The cells were also genotyped at the TP53 locus, and neoplastic cells were found to share a common mutation, which was most likely present in a heterozygous state. Our work shows that the ability to obtain data regarding the physical appearance, precise anatomic position, genotypic profile, and lineage position of single cells may be useful for investigating cancer development, progression, and interaction with the microenvironment. [Cancer Res 2008;68(14):5924–31]
Inhibition of Glycogen Synthase Kinase 3β Attenuates Neurocognitive Dysfunction Resulting from Cranial Irradiation
Authors: Thotala Dinesh K. , Hallahan Dennis E. , Yazlovitskaya Eugenia M. 
Published: July 2008

Abstract
There are now more than 10 million cancer survivors in the United States. With these numbers, chronic sequelae that result from cancer therapy have become a major health care problem. Although radiation therapy of the brain has improved cancer cure rates, learning disorders and memory deficits are a common consequence of this therapy. Here we show that glycogen synthase kinase 3β (GSK-3β) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. Inhibition of GSK-3β either by small molecules (SB216763 or SB415286) or by ectopic expression of kinase-inactive GSK-3β before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons. GSK-3β inhibition with SB216763 or SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. Studies of the molecular mechanisms of the cytoprotective effect showed that GSK-3β activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this enzyme in radiation-induced apoptosis. At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of GSK-3β activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by GSK-3β inhibitors. These findings identify GSK-3β signaling as a key regulator of radiation-induced damage in hippocampal neurons and suggest that GSK-3β inhibitors may have a therapeutic role in protecting both pediatric and adult cancer patients and may help to improve quality of life in cancer survivors. [Cancer Res 2008;68(14):5859–68]
A Role for the Cyclin Box in the Ubiquitin-Mediated Degradation of Cyclin G1
Authors: Piscopo Denise M. , Hinds Philip W. 
Published: July 2008

Abstract
Cyclin G1 was identified as a transcriptional target of p53 that encodes a protein with strong homology to the cyclin family of cell cycle regulators. We show that either ectopically expressed or endogenous cyclin G1 protein is very unstable, undergoes modification with ubiquitin, and is likely degraded by the proteasome. Ectopic cyclin G1 protein stability is increased by cyclin box mutation or by association with inactive cyclin-dependent kinase (CDK) subunits, suggesting that a function of cyclin G1 as a CDK regulator may be required for its rapid turnover. Furthermore, cyclin G1 and the cyclin box mutant interact with and are ubiquitinated by MDM2, another transcriptional target of p53 that acts as a negative regulator of p53 stability. These data suggest that the cyclin box has a role in the proteasome-mediated degradation of cyclin G1 and thus suggest a putative role for a CDK in cyclin G1 metabolism and function. [Cancer Res 2008;68(14):5581–90]
Noninvasive Assessment of E2F-1–Mediated Transcriptional Regulation In vivo
Authors: Monfared Parisa , Winkeler Alexandra , Klein Markus , Li Hongfeng , Klose Anke , Hoesel Marianna , Waerzeggers Yannic , Korsching Sigrun , Jacobs Andreas H. 
Published: July 2008

Abstract
Targeted therapies directed against individual cancer-specific molecular alterations offer the development of disease-specific and individualized treatment strategies. Activation of the transcription factor E2F-1 via alteration of the p16-cyclinD-Rb pathway is one of the key molecular events in the development of gliomas. E2F-1 binds to and activates the E2F-1 promoter in an autoregulatory manner. The human E2F-1 promoter has been shown to be selectively activated in tumor cells with a defect in the pRb pathway. Paradoxically, E2F-1 also carries tumor suppressor function. Our investigations focused on analyzing the dynamics of the activity of the E2F-1 responsive element under basal conditions and certain stimuli such as chemotherapy using molecular imaging technology. We constructed a retrovirus bearing the Cis-E2F-TA-LITG reporter system to noninvasively assess E2F-1–dependent transcriptional regulation in culture and in vivo. We show that our reporter system is sensitive to monitor various changes in cellular E2F-1 levels and its transcriptional control of our reporter system to follow the state of the Rb/E2F pathway and the DNA damage–induced up-regulation of E2F-1 activity in vivo. Exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea leads to increased E2F-1 expression levels in a dose- and time-dependent manner, which can be quantified by imaging in vivo, leading to an alteration of cell cycle progression and caspase 3/7 activity. In summary, noninvasive imaging of E2F-1 as a common downstream regulator of cell cycle progression using the Cis-E2F-TA-LUC-IRES-TKGFP reporter system is highly attractive for evaluating the kinetics of cell cycle regulation and the effects of novel cell cycle targeting anticancer agents in vivo. [Cancer Res 2008;68(14):5932–40]