bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib
Authors: Morgillo Floriana , Woo Jong Kyu , Kim Edward S. , Hong Waun Ki , Lee Ho-Young 
Published: October 2006

AbstractEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat non–small cell lung cancer (NSCLC). However, the overall response rate to EGFR TKIs is limited, and the mechanisms mediating resistance to the drugs are poorly understood. Here, we report that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of erlotinib, an EGFR TKI. Treatment with erlotinib increased the levels of EGFR/IGF-IR heterodimer localized on cell membrane, activated IGF-IR and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)–mediated de novo protein synthesis of EGFR and survivin in NSCLC cells. Inhibition of IGF-IR activation, suppression of mTOR-mediated protein synthesis, or knockdown of survivin expression abolished resistance to erlotinib and induced apoptosis in NSCLC cells in vitro and in vivo. Our data suggest that enhanced synthesis of survivin protein mediated by the IGFR/EGFR heterodimer counteracts the antitumor action of erlotinib, indicating the needs of integration of IGF-IR–targeted agents to the treatment regimens with EGFR TKI for patients with lung cancer. (Cancer Res 2006; 66(20): 10100-11)
A t(1;19)(q10;p10) Mediates the Combined Deletions of 1p and 19q and Predicts a Better Prognosis of Patients with Oligodendroglioma
Authors: Jenkins Robert B. , Blair Hilary , Ballman Karla V. , Giannini Caterina , Arusell Robert M. , Law Mark , Flynn Heather , Passe Sandra , Felten Sara , Brown Paul D. , Shaw Edward G. , Buckner Jan C. 
Published: October 2006

Abstract
Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/19p12 fusion (P &lt; 0.001, χ2 test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients. (Cancer Res 2006; 66(20): 9852-61)
Targeting Liposomal Chemotherapy via Both Tumor Cell–Specific and Tumor Vasculature–Specific Ligands Potentiates Therapeutic Efficacy
Authors: Pastorino Fabio , Brignole Chiara , Di Paolo Daniela , Nico Bice , Pezzolo Annalisa , Marimpietri Danilo , Pagnan Gabriella , Piccardi Federica , Cilli Michele , Longhi Renato , Ribatti Domenico , Corti Angelo , Allen Theresa M. , Ponzoni Mirco 
Published: October 2006

Abstract
Neuroblastoma, the most common solid tumor of infancy derived from the sympathetic nervous system, continues to present a formidable clinical challenge. Sterically stabilized immunoliposomes (SIL) have been shown to enhance the selective localization of entrapped drugs to solid tumors, with improvements in therapeutic indices. We showed that SIL loaded with doxorubicin (DXR) and targeted to the disialoganglioside receptor GD2 [aGD2-SIL(DXR)] led to a selective inhibition of the metastatic growth of experimental models of human neuroblastoma. By coupling NGR peptides that target the angiogenic endothelial cell marker aminopeptidase N to the surface of DXR-loaded liposomes [NGR-SL(DXR)], we obtained tumor regression, pronounced destruction of the tumor vasculature, and prolonged survival of orthotopic neuroblastoma xenografts. Here, we showed good liposome stability, long circulation times, and enhanced time-dependent tumor accumulation of both the carrier and the drug. Antivascular effects against animal models of lung and ovarian cancer were shown for formulations of NGR-SL(DXR). In the chick embryo chorioallantoic assay, NGR-SL(DXR) substantially reduced the angiogenic potential of various neuroblastoma xenografts, with synergistic inhibition observed for the combination of NGR-SL(DXR) with aGD2-SIL(DXR). A significant improvement in antitumor effects was seen in neuroblastoma-bearing animal models when treated with the combined formulations compared with control mice or mice treated with either tumor- or vascular-targeted liposomal formulations, administered separately. The combined treatment resulted in a dramatic inhibition of tumor endothelial cell density. Long-term survivors were obtained only in animals treated with the combined tumor- and vascular-targeted formulations, confirming the pivotal role of combination therapies in treating aggressive metastatic neuroblastoma. (Cancer Res 2006; 66(20): 10073-82)
Effective Treatment of Tumors with Strong β-Catenin/T-Cell Factor Activity by Transcriptionally Targeted Oncolytic Herpes Simplex Virus Vector
Authors: Kuroda Toshihiko , Rabkin Samuel D. , Martuza Robert L. 
Published: October 2006

Abstract
The Wnt/β-catenin/T-cell factor (Tcf) pathway is aberrantly up-regulated in the majority of colorectal cancers (CRC) and hepatoblastomas due to either an APC or β-catenin gene mutation. We constructed synthetic promoters, T and TE, which contain tandem repeats of a Tcf responsive element without and with the human 4F2 gene intronic enhancer, respectively. Although the T and TE promoters showed higher transcriptional activity than a control promoter in all CRC and hepatoblastoma cell lines tested, with low activities in most other tumor cell lines, the level of transcription varied considerably among the CRC and hepatoblastoma cell lines. In some CRC cell lines, the TE promoter displayed higher levels of transcription than even the human CMVIE promoter. In those CRC cells, the APC gene mutations were located within a small segment between the first and second 20-amino-acid repeats in the mutation cluster region of the APC protein. We created a transcriptionally targeted oncolytic herpes simplex virus vector (bM24-TE) in which replication is driven by the TE promoter. This vector efficiently and specifically replicated in and killed tumor cells with strong β-catenin/Tcf signaling. Intratumoral injection of bM24-TE significantly reduced the growth of highly β-catenin active SW480 CRC tumors and induced a complete response in half of them, whereas it had no effect on the growth of β-catenin-inactive A549 tumors. Our results suggest that a transcriptionally regulated oncolytic herpes vector targeting β-catenin/Tcf signal is very efficacious against CRC tumors carrying an APC gene mutation between the first and second 20-amino-acid repeats. (Cancer Res 2006; 66(20): 10127-35)
Essential Role of T-Cell Factor/β-Catenin in Regulation of Rad6B: A Potential Mechanism for Rad6B Overexpression in Breast Cancer Cells
Authors: Shekhar Malathy P.V. , Tait Larry , Gerard Brigitte 
Published: October 2006

Abstract
We have previously shown that the postreplication DNA repair gene Rad6B plays a critical role in the maintenance of genomic integrity of human breast cells. Whereas normal breast cells express low levels of Rad6B, increases in Rad6B expression occur in hyperplasia with overexpression in breast carcinomas. Here, we show that the human Rad6B gene is a transcriptional target of T-cell factor (TCF)-4/β-catenin/p300. Rad6B promoter activity is subject to negative regulation in normal human MCF10A breast cells whereas it is constitutively active in metastatic MDA-MB-231 breast cancer cells. Derepression and activation of Rad6B promoter in MCF10A cells require coexpression of β-catenin and p300. Using electrophoresis mobility shift assay, Western blot analysis of electrophoresis mobility shift assay, UV cross-linking, and chromatin immunoprecipitation assay, we show that Rad6B transcriptional repression in MCF10A cells is due to paucity of transcriptionally active β-catenin assembled on the TCF binding sequence in the Rad6B promoter rather than to a deficit/decreased affinity of TCF-4 for the TCF binding element in Rad6B promoter. Three-dimensional epithelial acini generated in vitro from MCF10A cells cotransfected with β-catenin and p300 showed β-catenin expression on the membrane, cytoplasm, and/or nuclei with concomitant Rad6 overexpression, whereas control acini showed β-catenin on the membranes and negligible Rad6 expression. Immunohistochemical analysis of 12 breast carcinomas showed an ∼80% correlation between Rad6 and β-catenin expression, and combined nuclear and cytoplasmic staining of β-catenin and Rad6 was detected in 25% of the breast carcinomas. In vivo implantation of MCF10A-Rad6B cells produced hyperplastic lesions. These data reveal a potentially important role for transcriptionally active β-catenin in the regulation of Rad6B gene expression, and link aberrant β-catenin signaling with transcriptional deregulation of Rad6B and breast cancer development. (Mol Cancer Res 2006;4(10):729–45)
Genetic and Expression Aberrations of E3 Ubiquitin Ligases in Human Breast Cancer
Authors: Chen Ceshi , Seth Arun K. , Aplin Andrew E. 
Published: October 2006

AbstractRecent studies revealed that E3 ubiquitin ligases play important roles in breast carcinogenesis. Clinical research studies have found that (epi)-genetic (deletion, amplification, mutation, and promoter methylation) and expression aberration of E3s are frequent in human breast cancer. Furthermore, many studies have suggested that many E3s are either oncogenes or tumor suppressor genes in breast cancer. In this review, we provide a comprehensive summary of E3s, which have genetic and/or expression aberration in breast cancer. Most cancer-related E3s regulate the cell cycle, p53, transcription, DNA repair, cell signaling, or apoptosis. An understanding of the oncogenic potential of the E3s may facilitate identifying and developing individual E3s as diagnosis markers and drug targets in breast cancer. (Mol Cancer Res 2006;4(10):695–707)
A Theory of Cultural Value Orientations: Explication and Applications
Authors: Schwartz Shalom 
Published: October 2006

AbstractThis article presents a theory of seven cultural value orientations that form three cultural value dimensions. This theory permits more finely tuned characterization of cultures than other theories. It is distinctive in deriving the cultural orientations from a priori theorizing. It also specifies a coherent, integrated system of relations among the orientations, postulating that they are interdependent rather than orthogonal. Analyses of data from 73 countries, using two different instruments, validate the 7 cultural orientations and the structure of interrelations among them. Conceptual and empirical comparisons of these orientations with Inglehart's two dimensions clarify similarities and differences. Using the cultural orientations, I generate a worldwide empirical mapping of 76 national cultures that identifies 7 transnational cultural groupings: West European, English-speaking, Latin American, East European, South Asian, Confucian influenced, and African and Middle Eastern. I briefly discuss distinctive cultural characteristics of these groupings. I then examine examples of socioeconomic, political, and demographic factors that give rise to national differences on the cultural value dimensions, factors that are themselves reciprocally influenced by culture. Finally, I examine consequences of prevailing cultural value orientations for attitudes and behavior (e.g., conventional morality, opposition to immigration, political activism) and argue that culture mediates the effects of major social structural variables on them.
Globalization, "McDonaldization" and Values: Quo Vadis?
Authors: Esmer Yilmaz 
Published: October 2006

AbstractIt is frequently asserted that the ongoing process that is commonly referred to as globalization should bring about wide-spread changes in values. Furthermore, it is hypothesized that the unparalleled increases in the flow of capital, goods, services and information coupled with the revolutionary developments in information and communication technologies should result in a convergence of values.This paper is attempt to assess the direction and the magnitude of value change between 1981, when the first WVS/EVS surveys were conducted, and 2001, the last year for which data are available. Data from some 20 countries are analyzed to follow possible changes in values. Furthermore, the paper offers a test of the convergence hypothesis by examining the standard deviations and the coefficients of variation of a wide-ranging list of values.The conclusion is that cultural value change has been rather limited during this period at least for this sample of countries. Among the dimensions studied, marriage, family and gender relations seem to be the area of most significant change. On the other hand, we have found almost no evidence for even a slow convergence of values.
From Text to Talisman: Al-Būsīrī's Qasīdat al-Burdah (Mantle Ode) and the Supplicatory Ode
Authors: Stetkevych Suzanne Pinckney 
Published: October 2006

AbstractAccording to popular and literary tradition, when the Mamlūk period poet al-Būsīrī (d. 694-6/1294-7) was stricken with semi-paralysis that confounded his physicians, he turned in despair to compose a poem of praise to the Prophet Muhammad (madīh nabawī). He then saw the Prophet in a dream and recited the poem to him, upon which the Prophet bestowed his mantle (burdah) upon him, and the poet awoke miraculously cured. The present study argues that the story of the miraculous cure, the talismanic uses of various verses of the Burdah, and the extraordinary power of the poem to generate a vast body of imitations, expansions, translations and commentaries, cannot be understood except through a literary analysis of the text of the poem itself. After analyzing the structural and generic differences between the Burdah and the Sufi ghazal of Ibn al-Fārid of which it is technically a contrafaction (mu'āradah), this study argues that the overall ritual-poetic structure of the Burdah, as contained in Parts 1-3 and 9-10 of the poem, is that of the supplicatory panegyric ode as practiced by such poets as the pre-Islamic al-Nābighah al-Dhubyānī or the poet of the Prophet, Ka'b ibn Zuhayr. It then proceeds to demonstrate that the Burdah exhibits the same structural elements as the supplicatory qasīdat al-madh: 1) Lyric-Elegiac Prelude (nasīb); 2) Self-Abasement; 3) Praise of the One Supplicated (mamdūh); and 4) Supplication (including benediction). It notes that in post-classical madīh nabawī the mamdūh is no longer of this world, and therefore the ritual exchange between poet and patron is essentially a spiritual one: what the supplicant is asking for is shafā'ah, the intercession of the Prophet on the Day of Judgment. The myth of the miraculous cure then serves, above all, as a symbol, a physical sign of a spiritual transformation or cure, that is, of the poem's ritual and spiritual efficacy. Taking these stories literally, believers engaged the poem, as text and talisman, to procure a wide range of physical and spiritual boons.
Cultural Representation in Literary Translation: Translators as Mediators/Creators
Authors: Ettobi Mustapha 
Published: October 2006

AbstractThis article examines the French and English translations of Mohamed Choukri's Al-Khubz al-Hāfī (For Bread Alone), by Tahar Ben Jelloun and Paul Bowles respectively, and the impact on the representation of Moroccan (Arab) culture. It explores the roles of these translators in the emergence and promotion of Choukri's controversial book. It also shows how they used this text to convey different views on various issues and, therefore, change the representation of cultural aspects. Giving specific examples of these shifts and the probable motivations for making them, the article proves that nuanced readings of these translations cannot ignore the presence of these mediators/creators.
The International Covenant on Civil and Political Rights: One Covenant, Two Chinese Texts?
Authors: Shiyan Sun 
Published: October 2006

AbstractThis article discloses the fact that there have coexisted two Chinese texts of the International Covenant on Civil and Political Rights. One of the texts has been widely used by the United Nations and in China for more than three decades. However, it is not the authentic Chinese text of ICCPR. The authentic Chinese text of the Covenant, as published in the United Nations Treaty Series, has been rarely referred to in Chinese literature on human rights. The article compares the two texts and points out a number of mistakes in the widely used text in the light of the object and purpose of the Covenant. The article also analyses the legal and practical consequences of the situation, and proposes both a legally justifiable and practically acceptable solution to the problem.
Whither survey research?
Authors: Gerrish Kate , Guillaume Louise 
Published: October 2006

In April 2004 new requirements for research governance were introduced in England. In order to safeguard the interests of research participants, research involving NHS patients, their tissues or NHS staff has to be registered with each organisation from where data will be collected and authorisation obtained before the study can commence. NHS Trusts/Primary Care Trusts (PCTs) have set up individual mechanisms for research governance approval with the result that there are no standardised procedures or documentation. Drawing upon data derived from making research governance applications for a postal survey involving nurses in 90 NHS Trusts/PCTs in seven strategic health authorities in England, this paper examines the implications of introducing research governance for this research method. An analysis of the application process, and the time and resources required suggests that undertaking survey research is increasingly problematic. Moreover, implications arising from the Data Protection Act and the need to complete commissioned research within contractual arrangements led to methodological compromises being made. Recommendations for changes in research governance policy are proposed, most notably the need to standardise procedures, provide greater clarification for R&D managers on the interpretation of research governance procedures and apportion the level of scrutiny according to risk.
Continuous delivery of human type I interferons (α/β) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model
Authors: Benjamin Reuben , Khwaja Asim , Singh Nalini , McIntosh Jenny , Meager Anthony , Wadhwa Meenu , Streck Christian , Ng Catherine , Davidoff Andrew M. , Nathwani Amit C. 
Published: October 2006

AbstractIn this study, we focused primarily on the antileukemic activity of interferon-β (IFN-β) in a murine xenograft model of acute myeloid leukemia (AML). Bolus administration of recombinant IFN-β via the subcutaneous or intravenous route failed to show efficacy in mice injected with AML cells despite achieving peak plasma IFN-β levels of more than 200 IU/mL. In contrast, stable expression of IFN-β following adeno-associated virus (AAV) vector–mediated gene transfer resulted in significant antileukemic activity against primary AML cells derived from patients with poor prognostic markers. An almost linear relationship was observed with stable plasma levels of IFN-β and antileukemic activity in mice. Even levels below 10 IU/mL were able to reduce tumor load by 50-fold when compared with control animals. These levels of IFN-β are likely to be nontoxic in humans. Therefore, approaches capable of maintaining stable plasma levels of IFN-β merit further clinical evaluation in patients with AML.
Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways
Authors: Piloto Obdulio , Wright Melissa , Brown Patrick , Kim Kyu-Tae , Levis Mark , Small Donald 
Published: October 2006

Abstract
Continuous treatment of malignancies with tyrosine kinase inhibitors (TKIs) may select for resistant clones (ie, imatinib mesylate). To study resistance to TKIs targeting FLT3, a receptor tyrosine kinase that is frequently mutated in acute myelogenous leukemia (AML), we developed resistant human cell lines through prolonged coculture with FLT3 TKIs. FLT3 TKI-resistant cell lines and primary samples still exhibit inhibition of FLT3 phosphorylation on FLT3 TKI treatment. However, FLT3 TKI-resistant cell lines and primary samples often show continued activation of downstream PI3K/Akt and/or Ras/MEK/MAPK signaling pathways as well as continued expression of genes involved in FLT3-mediated cellular transformation. Inhibition of these signaling pathways restores partial sensitivity to FLT3 TKIs. Mutational screening of FLT3 TKI-resistant cell lines revealed activating N-Ras mutations in 2 cell lines that were not present in the parental FLT3 TKI-sensitive cell line. Taken together, these data indicate that FLT3 TKI-resistant cells most frequently become FLT3 independent because of activation of parallel signaling pathways that provide compensatory survival/proliferation signals when FLT3 is inhibited. Anti-FLT3 mAb treatment was still cytotoxic to FLT3 TKI-resistant clones. An approach combining FLT3 TKIs with anti-FLT3 antibodies and/or inhibitors of important pathways downstream of FLT3 may reduce the chances of developing resistance.