bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor–Associated PDGFRAD842V Mutation
Authors: Dewaele Barbara , Wasag Bartosz , Cools Jan , Sciot Raf , Prenen Hans , Vandenberghe Peter , Wozniak Agnieszka , Schöffski Patrick , Marynen Peter , Debiec-Rychter Maria 
Published: September 2008

Abstract
Purpose: Activating mutations in platelet-derived growth factor receptor-α (PDGFRA) have been reported in ∼5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRAD842V and PDGFRAΔDIM842-844. In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants.
Experimental Design: Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRAD842V or imatinib-sensitive PDGFRAΔDIM842-844 mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined.
Results: All inhibitors tested exhibited a high efficacy toward the PDGFRAΔDIM842-844 mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRAD842V isoform with an IC50 value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at &gt;1,000 and &gt;5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRAD842V mutant with an IC50 value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRAD842V and PDGFRAΔDIM842-844 at 256 and 182 nmol/L, respectively.
Conclusions: Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRAD842V mutant isoform.
Type III Transforming Growth Factor-β (TGF-β) Receptor Mediates Apoptosis in Renal Cell Carcinoma Independent of the Canonical TGF-β Signaling Pathway
Authors: Margulis Vitaly , Maity Tapati , Zhang Xiu-Ying , Cooper Simon J. , Copland John A. , Wood Christopher G. 
Published: September 2008

Abstract
Purpose: Alterations in transforming growth factor-β (TGF-β) signaling occur early during malignant transformation of renal epithelial cells and are associated with loss of type III TGF-β receptor (TβRIII) expression. We evaluated the role of TβRIII in mediation of apoptosis using in vitro cell culture and in vivo animal models of clear cell renal cell carcinoma.
Experimental Design: TβR3 expression was manipulated with adenoviral gene vector delivery system in vitro and in vivo. Induction of apoptosis and signaling through the Smad and mitogen-activated protein kinase (MAPK) pathways were examined at various time points after infection. To study viral oncolysis in vivo, human renal cell carcinoma cells were implanted s.c. in the flanks of nude mice and treated with intratumoral injections of adenovirus.
Results: Restoring TβRIII expression in clear cell renal cell carcinoma resulted in a marked induction of apoptosis using in vitro cell culture and in vivo animal models. The expression of the cytoplasmic domain, but not the extracellular domain, of TβRIII mimicked the induction of apoptosis by full-length TβRIII in cell culture and the growth inhibition of tumors in athymic nude mice. TβRIII-associated apoptosis was not dependent on signaling through the canonical TGF-β/Smad pathway but was mediated through p38 MAPK.
Conclusion: These findings indicate a novel mechanistic antitumor function for TβRIII and further support its role as an important tumor suppressor in clear cell renal cell carcinoma.
Pancreatic Cancer Stem Cells: Implications for the Treatment of Pancreatic Cancer
Authors: Simeone Diane M. 
Published: September 2008

Abstract
Pancreatic cancer is a highly lethal disease that is usually diagnosed at a late stage for which there are few effective therapies. Emerging evidence has suggested that malignant tumors are quite heterogeneous and that they are composed of a small subset of distinct cancer cells (usually defined by cell surface marker expression) that are responsible for tumor initiation and propagation, termed cancer stem cells. These cells are termed cancer stem cells because, like normal stem cells, they possess the ability to self-renew and make differentiated progeny. Recent studies of human pancreatic cancers have shown a population of pancreatic cancer stem cells that have aberrantly activated developmental signaling pathways, are resistant to standard chemotherapy and radiation, and have up-regulated signaling cascades that are integral for tumor metastasis. An improved understanding of the biological behavior of these cells may lead to more effective therapies to treat pancreatic cancer. In this review, approaches to develop and test therapeutics targeting pancreatic cancer stem cells are discussed.
Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN
Authors: Woodward Emma R. , Ricketts Christopher , Killick Pip , Gad Sophie , Morris M.R. , Kavalier Fred , Hodgson Shirley V. , Giraud Sophie , Bressac-de Paillerets Brigitte , Chapman Cyril , Escudier Bernard , Latif Farida , Richard Stéphane , Maher Eamonn R. 
Published: September 2008

Abstract
Purpose: Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility.
Experimental Design: We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility.
Results: FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility.
Conclusions: We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.
Cytochrome P450 2D6 and Homeobox 13/Interleukin-17B Receptor: Combining Inherited and Tumor Gene Markers for Prediction of Tamoxifen Resistance
Authors: Goetz Matthew P. , Suman Vera J. , Couch Fergus J. , Ames Matthew M. , Rae James M. , Erlander Mark G. , Ma Xiao-Jun , Sgroi Dennis C. , Reynolds Carol A. , Lingle Wilma L. , Weinshilboum Richard M. , Flockhart David A. , Desta Zeruesenay , Perez Edith A. , Ingle James N. 
Published: September 2008

Abstract
Purpose: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer.
Experimental Design: Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling.
Results: CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% CI, 1.17-8.52; P = 0.024).
Conclusions: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
Chlamydia Infection and Lymphomas: Association Beyond Ocular Adnexal Lymphomas Highlighted by Multiple Detection Methods
Authors: Ponzoni Maurilio , Ferreri Andrés J.M. , Guidoboni Massimo , Lettini Antonia A. , Cangi Maria Giulia , Pasini Elisa , Sacchi Luciano , Pecciarini Lorenza , Grassi Stefano , Dal Cin Elena , Stefano Rosalba , Magnino Simone , Dolcetti Riccardo , Doglioni Claudio 
Published: September 2008

Abstract
Purpose: Chlamydia psittaci (Cp) has been associated to ocular adnexal lymphomas (OAL) with variable geographic distribution. Herein, we used multiple Chlamydia detection tools to identify Cp elementary bodies–containing cell and to assess Cp prevalence in both nodal and extranodal lymphomas.
Experimental Design: TETR-PCR, immunohistochemistry, immunofluorescence, electron microscopy, and laser-capture microdissection were done in 35 OALs to define their effect in Chlamydia detection and, moreover, to identify the Cp cellular carrier. Cp prevalence was screened by TETR-PCR in 205 extraorbital lymphomas and 135 nonneoplastic controls.
Results: Twenty-six (74%) OALs were associated with Cp infection: immunohistochemistry, immunofluorescence, and laser-capture microdissection-assisted PCR showed that monocytes/macrophages were the Cp carriers; electron microscopy showed the presence of intact Cp elementary bodies into these cells. Immunohistochemistry and TETR-PCR showed a 70% concordance rate (P = 0.001). Cp DNA was equally prevalent in non-OAL, nodal, and extranodal lymphomas: among the latter, it was more common in diffuse large B-cell lymphomas of the skin (P = 0.03) and Waldeyer's ring.
Conclusions: This multiparametric approach shows, for the first time, that monocytes/macrophages are the carriers of Cp, Cp seems preferentially associated with lymphomas arising in organs primarily exposed to antigens. The clinical implications of these findings deserve to be prospectively investigated.
High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies
Authors: Prassas Ioannis , Paliouras Miltiadis , Datti Alessandro , Diamandis Eleftherios P. 
Published: September 2008

Abstract
Purpose: Human tissue kallikreins (KLK) comprise a subgroup of 15 homologous secreted serine proteases. Primarily known for their clinical use as cancer biomarkers (e.g., PSA), KLKs have recently been directly implicated in cancer-related processes, including invasion, angiogenesis, and tumor growth regulation. Therefore, the identification of compounds that would modulate expression of KLKs might be of considerable therapeutic value.
Experimental Design: A cell-based high-throughput screening (HTS) of three small molecule libraries (∼4,500 compounds) was undertaken; KLK expression in the breast cancer cell line MDA-MB-468 was assessed with sensitive ELISAs.
Results: The initial screening resulted in 66 “putative hits” that decreased KLK5 expression by at least 50% over control. Secondary screening and mini-dose-response assays resulted in 21 “validated hits.” These 21 compounds were clustered in only three distinct functional families and were further analyzed in vitro to determine their effectiveness (IC50s). Hits that failed to show dose-responsiveness or interfered with the viability of the cells were excluded. Multiple members of the cardiac glycoside family were found to be novel inhibitors of KLK expression, acting at low concentrations (10-50 nmol/L). Furthermore, members of the same family induced marked decreases in c-MYC and c-FOS expression, in a dose-dependent manner that correlated the KLK inhibition, suggesting a transcriptional mechanism of regulation of KLK expression.
Conclusions: We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (c-myc/fos) expression. These findings may partially explain the recently realized antineoplastic actions of cardiac glycosides.
Elevated Expression of GlutathioneS-Transferase π and p53 Confers Poor Prognosis in Head and Neck Cancer Patients Treated with Chemoradiotherapy but not Radiotherapy Alone
Authors: Schumaker Lisa , Nikitakis Nikolaos , Goloubeva Olga , Tan Ming , Taylor Rodney , Cullen Kevin J. 
Published: September 2008

AbstractPurpose: To examine the prognostic significance of expression of glutathione s-transferase π (GST-π) and p53 in patients treated with radiation alone for locally advanced head and neck cancer [Radiation Therapy Oncology Group (RTOG), trial 9003] or radiation ± concomitant chemotherapy as postoperative adjuvant therapy (RTOG trial 9501).Experimental Design: Immunohistochemical staining for p53 and GST-π was done on tissue samples from 393 patients in RTOG 9003 and 142 patients in RTOG 9501. Kaplan-Meier survival analyses were done.Results: Patients who had low expression of both markers had longer survival than patients who had high expression of both markers. In trial 9003, median survival was 2.4 years for patients with low expression of both markers versus 1.4 years for patients who had elevated expression of both markers (P = 0.07). These differences were highly significant in trial 9501 and were accounted for by the chemotherapy treated arm. In this group, patients with low expression of both markers had a median survival of 7.0 years compared with 1.4 years for patients with elevated expression of both markers (P = 0.006). In both trials, black patients had lower survival rates than did white patients and there was a trend toward higher expression of both markers in blacks compared with whites.Conclusion: Given the poor outcome of chemoradiotherapy treatment patients with elevated expression of both p53 and GST-π, these patients may not be appropriate candidates for chemoradiotherapy based on standard protocols. Some of the adverse outcome for black patients in both studies may be attributed to elevated expression of p53 and GST-π.
The Translational Research Working Group Developmental Pathway for Lifestyle Alterations
Authors: Hawk Ernest T. , Greenwood Addison , Gritz Ellen R. , McTiernan Anne , Sellers Thomas , Hursting Stephen D. , Leischow Scott , Grad Oren ,   for the Translational Research Working Group
Published: September 2008

Abstract
The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of lifestyle alterations, which can, variously, be recommended to prevent cancer, modify a patient's adherence and response to cancer treatment, ameliorate side effects of cancer treatments, or improve prognosis and quality of life in cancer patients and survivors. The lifestyle alteration pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate lifestyle alteration through the translational process up to the point where it could be handed off for definitive testing, when appropriate. This article discusses key issues associated with the development of lifestyle alterations in light of the pathway.
The Translational Research Working Group Developmental Pathway for Interventive Devices
Authors: Dorfman Gary S. , Lawrence Theodore S. , Matrisian Lynn M. ,   for the Translational Research Working Group
Published: September 2008

Abstract
The interventive device pathway refers to one of six pathways developed by the Translational Research Working Group (TRWG) that, together, describe the core domains of early translational cancer research. This pathway focuses on the development of devices (as classified by the Food and Drug Administration), designed for local ablation of cancer or precancerous lesions (e.g., radiation therapy, microwave, radiofrequency ablation, and high-intensity focused ultrasound systems). This article describes the distinctive features of the pathway and issues that are encountered in the real-world development of interventive devices for the treatment of cancer. The interventive device pathway is envisioned to be a general guideline of the steps required for effective development, optimization, testing, and validation of developing devices, to be dynamic and adaptable, and to form a framework for discussions focused on improving the efficiency and effectiveness of new device development.
Urokinase-Type Plasminogen Activator Receptor: A Beacon of Malignancy?
Authors: Drapkin Ronny , Clauss Adam , Skates Steven 
Published: September 2008

Abstract
Discriminating between benign and malignant disease is a pivotal diagnostic issue in the care of women with pelvic masses. Identification of serum biomakers that can rellably make the distinction would aid in the proper referral for patient care and may provide leads in the development of early detection strategies.
Religion of Reason Revised: David Koigen on the Jewish Ethos
Authors: Urban Martina 
Published: September 2008

AbstractWhereas some of the critics of Hermann Cohen's strictly rational foundation of religious consciousness promoted a turn to subjectivism, others endorsed an ethicotheology while seeking to revise the "Religion of Reason." Among the latter was the Ukrainian-born social philosopher David Koigen (1877–1933), author of Der moralische Gott. Eine Abhandlung über die Beziehungen zwischen Kultur und Religion/The Moral God: An essay on the relations between culture and religion (Berlin: Jüdischer Verlag, 1922). This article examines Koigen's reevaluation of Jewish monotheism as a culture-forming religion (Kulturreligion) grounded in a religious ethos which integrates the rational will, ethics and emotion.
On Becoming the Righteousness of God: Another Look at 2 Cor 5:21
Authors: Hooker Morna 
Published: September 2008

AbstractAt the end of 2 Corinthians 5, in which he is defending his style of ministry, Paul appeals three times to the gospel which he proclaims (vv. 14-15, 18-19, 21). These summaries are worded in ways that indicate the implications of the gospel for his ministry. At the same time, however, what is true of Paul should be true of all believers: they, too, should be living for the one who died and was raised for them (v. 15) and passing on the message of reconciliation to others (vv. 18-19). In the final summary, Christians are said to "become the righteousness of God" (v. 21). Käsemann's understanding of δικαιoσυνη Θεoν here as a reference to God's active power of salvation fits the context well: "in Christ", believers become what he is, and God's righteousness is manifested through them.
Intervention Debating Lebowitz: Is Class Conflict the Moral and Historical Element in the Value of Labour-Power?
Authors: Fine Ben 
Published: September 2008

AbstractPrompted by the debate over Michael Lebowitz's contributions on the relative absence of class struggle in Marx's Capital (and, in particular, the determining if subjective role played by labour in resisting capital), this paper seeks to push analysis forward by closer examination of the notion of the value of labour-power. It does so by arguing that labour markets are structured, reproduced and transformed in complex and differentiated ways, whilst the moral and historical elements that make up the use-value interpretation of the value of labour-power also need to be addressed in a differentiated manner rather than as a fixed bundle.
Cloning and characterization of α-pinene synthase from Chamaecyparis formosensis Matsum
Authors: Chu Fang-Hua , Kuo Pei-Min , Chen Yu-Rong , Wang Sheng-Yang 
Published: September 2008

Abstract
Analyzing the gene sequences of terpene synthase (TPS) may contribute to a better understanding of terpenes biosynthesis and evolution of phylogenetic taxonomy. Chamaecyparis formosensis is an endemic and precious conifer of Taiwan. To understand the biosynthesis mechanism of terpenes in this tree, a full length of putative mono-TPS, named as Cf-Pin (GeneBank accession no. EU099434), was obtained by PCR method and RACE extension. The Cf-Pin has an 1887-bp open reading frame and encodes 628 amino acids. To identify the function of Cf-Pin, the recombinant protein from Escherichia coli was incubated with geranyl diphosphate, produced one major product, the structure of which was elucidated. GC/MS analysis and matching of retention time and mass spectrum with authentic standards revealed that this product is α-pinene. This is the first report of cloning of a mono-TPS and functionally expressed in E. coli and which could be identified as α-pinene synthase from a Cupressaceae conifer.
Die Entstehung der modernen Landschaftswahrnehmung (1580–1730) (The Making of a New Landscape Perception)
Authors: Schramm Manuel 
Published: September 2008

Zusammenfassung
Der Aufsatz vertritt die These, daß vor allem das 17. Jahrhundert den Beginn der neuen Naturwahrnehmung in West- und Mitteleuropa markiert, wobei freilich von einer längeren Übergangszeit von ca. 1580–1730 auszugehen ist. In methodischer Hinsicht wird ein breiter Ansatz gewählt, der neuere Erkenntnisse aus der Ideen- und Kunstgeschichte mit technik- und wirtschaftshistorischen Veränderungen im Umgang mit der Natur in Beziehung setzt. Abschnitt I setzt sich mit den Positionen der bisherigen Forschung auseinander, die den Beginn der modernen Naturwahrnehmung entweder in der italienischen Renaissance (14./15. Jahrhundert), der „Wissenschaftlichen Revolution” des 17. Jahrhunderts oder der Romantik des späten 18. Jahrhunderts verorten. Abschnitt II versucht die These zu belegen, daß bereits um 1600 entscheidende Wandlungsprozesse in der Wahrnehmung von Natur und Landschaft in Semantik, Wissenschaft, Technik und Kunst stattfanden. Abschnitt III schildert die weitere Entwicklung in der zweiten Hälfte des 17. und dem ersten Drittel des 18. Jahrhunderts, die besonders durch das Aufkommen der Physikotheologie und der ästhetischen Kategorie des „Erhabenen” geprägt wurde. Abschnitt IV bietet einen kursorischen Ausblick auf die wichtigsten Veränderungen im 19. und 20. Jahrhundert.