bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in Targeting IKK and IKK-Related Kinases for Cancer Therapy
Authors: Lee Dung-Fang , Hung Mien-Chie 
Published: September 2008

AbstractIκB kinases (IKK) and IKK-related kinases play critical roles in regulating the immune response through nuclear factor-κB and IFN regulatory factor–dependent signaling transduction cascades. Recently, these kinases have been implicated in the pathogenesis of many human diseases, including cancer. In fact, dysregulation of IKK activities promotes tumor survival, proliferation, migration, metastasis, and angiogenesis—common characteristics of many types of human cancers. Because of their oncogenic effects in human cancer development, targeting IKK and IKK-related kinases is becoming an increasingly popular avenue for the development of novel therapeutic interventions for cancer. This review will briefly cover the recent discovery of the downstream substrates of IKK and IKK-related kinases, and outline the strategies used for targeting IKK as a therapeutic intervention for cancer.
Tris (Dibenzylideneacetone) Dipalladium, aN-Myristoyltransferase-1 Inhibitor, Is Effective against Melanoma GrowthIn vitroandIn vivo
Authors: Bhandarkar Sulochana S. , Bromberg Jacqueline , Carrillo Carol , Selvakumar Ponniah , Sharma Rajendra K. , Perry Betsy N. , Govindarajan Baskaran , Fried Levi , Sohn Allie , Reddy Kalpana , Arbiser Jack L. 
Published: September 2008

AbstractPurpose: Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA.Experimental Design: Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed.Results: Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma.Conclusion: Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.
Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma
Authors: Riely Gregory J. , Kris Mark G. , Rosenbaum Daniel , Marks Jenifer , Li Allan , Chitale Dhananjay A. , Nafa Khedoudja , Riedel Elyn R. , Hsu Meier , Pao William , Miller Vincent A. , Ladanyi Marc 
Published: September 2008

Abstract
Purpose: KRAS mutations are found in ∼25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib.
Experimental Design: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas.
Results: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G→A) rather than the transversion mutations known to be smoking-related (G→T or G→C; P &lt; 0.0001).
Conclusions: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.
Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival
Authors: van Cruijsen Hester , van der Veldt Astrid A.M. , Vroling Laura , Oosterhoff Dinja , Broxterman Henk J. , Scheper Rik J. , Giaccone Giuseppe , Haanen John B.A.G. , van den Eertwegh Alfons J.M. , Boven Epie , Hoekman Klaas , de Gruijl Tanja D. 
Published: September 2008

AbstractPurpose: A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients.Experimental Design: Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data.Results: Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1+ MDC frequencies were predictive for tumor regression and improved progression-free survival.Conclusion: The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.
Prognostic Effect of Epithelial Cell Adhesion Molecule Overexpression in Untreated Node-Negative Breast Cancer
Authors: Schmidt Marcus , Hasenclever Dirk , Schaeffer Mitra , Boehm Daniel , Cotarelo Cristina , Steiner Eric , Lebrecht Antje , Siggelkow Wulf , Weikel Wolfgang , Schiffer-Petry Ilka , Gebhard Susanne , Pilch Henryk , Gehrmann Mathias , Lehr Hans-Anton , Koelbl Heinz , Hengstler Jan G. , Schuler Martin 
Published: September 2008

Abstract
Purpose: Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention not only as a prognostic factor in breast cancer but also as a potential target for immunotherapy. We examined Ep-CAM expression in 402 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting.
Experimental Design: Ep-CAM expression was evaluated by immunostaining. Its prognostic effect was estimated relative to overexpression/amplification of HER-2, histologic grade, tumor size, age, and hormone receptor expression.
Results: Ep-CAM status was positive in 106 (26.4%) patients. In multivariate analysis, Ep-CAM status was associated with disease-free survival independent of age, pT stage, histologic grade, estrogen receptor (ER), progesterone receptor (PR), as well as HER2 status (P = 0.028; hazard ratio, 1.60; 95% confidence interval, 1.05-2.44). Recently, so-called triple-negative (HER-2, ER, and PR) breast cancer has received increased attention. We noticed a similar association of Ep-CAM with disease-free survival in the triple-negative group as for the entire cohort.
Conclusion: In this study of untreated breast cancer patients, Ep-CAM overexpression was associated with poor survival in the entire cohort and in the subgroup of triple-negative breast cancer. This suggests that Ep-CAM may be a well-suited target for specific therapies particularly in HER-2–, ER-, and PR-negative tumors.
The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival
Authors: Quaye Lydia , Gayther Simon A. , Ramus Susan J. , Di Cioccio Richard A. , McGuire Valerie , Hogdall Estrid , Hogdall Claus , Blaakr Jan , Easton Douglas F. , Ponder Bruce A.J. , Jacobs Ian , Kjaer Susanne Kruger , Whittemore Alice S. , Pearce Celeste Leigh , Pharoah Paul D.P. , Song Honglin 
Published: September 2008

Abstract
Purpose: The 5-year survival rate for invasive epithelial ovarian cancer is &lt;35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer.
Experimental Design: We evaluated the association between 34 tagging single nucleotide polymorphisms and survival in 1,480 cases of invasive epithelial ovarian cancer cases from three different studies. Cox regression analysis, stratified by study, was used to estimate per rare allele hazard ratios (HR).
Results: The minor allele rs6944385 in BRAF was significantly associated with poor survival [HR, 1.19; 95% confidence intervals (95% CI), 1.02-1.39; P = 0.024]. The association remained after adjusting for prognostic factors (adjusted HR, 1.20; 95 CI, 1.03-1.40; P = 0.018). A haplotype of BRAF was also associated with poor survival (HR, 1.24; 95% CI, 1.02-1.51; P = 0.029) and was more significant after adjustment (HR, 1.44; 95% CI, 1.15-1.81; P = 0.001). We also found evidence of an association between a KRAS haplotype and poor survival in serous subtype (HR, 1.69; 95% CI, 1.21-2.38; P = 0.002), but this was no longer significant after adjustment. Finally, when analyses were restricted to the serous histologic subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007).
Conclusion: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.
Gene Expression Profiling Reveals Similarities between theIn vitroandIn vivoResponses of Immune Effector Cells to IFN-α
Authors: Zimmerer Jason M. , Lesinski Gregory B. , Ruppert Amy S. , Radmacher Michael D. , Noble Carl , Kendra Kari , Walker Michael J. , Carson William E. 
Published: September 2008

AbstractPurpose: The precise molecular targets of IFN-α therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1 signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-α would be similar to the in vivo response to treatment with high-dose IFN-α.Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-α were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-α.Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-α in vitro for 18 hours (&gt;2-fold, P &lt; 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-α–treated T cells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-α-2b (20 MU/m2 i.v.) revealed significant up-regulation (&gt;2-fold) of 21 genes (P &lt; 0.001). Also, the gene expression profile of in vitro IFN-α–stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-α therapy.Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-α and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-α immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-α may be a useful predictor of the in vivo response of immune cells to IFN-α immunotherapy.
Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease
Authors: Xu Jianfeng , Isaacs Sarah D. , Sun Jielin , Li Ge , Wiley Kathleen E. , Zhu Yi , Hsu Fang-Chi , Wiklund Fredrik , Turner Aubrey R. , Adams Tamara S. , Liu Wennuan , Trock Bruce J. , Partin Alan W. , Chang Baoli , Walsh Patrick C. , Grönberg Henrik , Isaacs William , Zheng Siqun 
Published: September 2008

Abstract
Purpose: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain.
Experimental Design: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested.
Results: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening.
Conclusions: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.
Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Neutropenia during Phase I Development of Liposome-Entrapped Paclitaxel
Authors: Fetterly Gerald J. , Grasela Thaddeus H. , Sherman Jeffrey W. , Dul Jeanne L. , Grahn Amy , Lecomte Diane , Fiedler-Kelly Jill , Damjanov Nevena , Fishman Mayer , Kane Michael P. , Rubin Eric H. , Tan Antoinette R. 
Published: September 2008

Abstract
Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients.
Experimental Design: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m2). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection.
Results: The MTD of LEP-ETU was identified as 325 mg/m2. DLTs occurring at 375 mg/m2 consisted of febrile neutropenia and neuropathy. The Cmax and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 μg/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m2 q3w. For a dose of 110 mg/m2 given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w.
Conclusions: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m2 LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m2 Taxol q3w. A 275 mg/m2 dose may offer an improved therapeutic index.
The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics)
Authors: Schilsky Richard L. , Gordon Gary , Gilmer Tona M. , Courtneidge Sara A. , Matrisian Lynn M. , Grad Oren , Nelson William G. ,   on behalf of 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 the 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 agents—both small molecules and biologics—for the treatment and prevention of cancer. The Agents Developmental Pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of an agent through the translational process to the point where it can begin definitive clinical testing. This article presents the Agents Developmental Pathway and discusses key challenges associated with the processes described.
Translational Research Working Group Developmental Pathway for Immune Response Modifiers
Authors: Cheever Martin A. , Schlom Jeffrey , Weiner Louis M. , Lyerly H. Kim , Disis Mary L. , Greenwood Addison , Grad Oren , Nelson William G. ,   for the Translational Research Working Group
Published: September 2008

AbstractThe Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the investment of National Cancer Institute in translational research and envision its future. The Translational Research Working Group 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 immune response modifiers such as vaccines and cytokines. A hallmark of the Immune Response Modifier Developmental Pathway is the coordinated development of multiple components. The Immune Response Modifier 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 assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper discusses key challenges associated with the immune response modifier agent development process in light of the pathway.
A New Transcription of P. Oxy. 2383 (P69)
Authors: Wayment Thomas 
Published: September 2008

AbstractAlthough not listed in the critical apparatus of Luke 22:41-44 in NA27, P. Oxy. 2383 (P69) is an important early witness to the omission of these verses. Since the publication of the editio princeps in 1957 of this small papyrus fragment, no new editions have appeared. In light of recently completed images, this edition offers several significant new and improved readings, while at the same time confirming that this fragment witnesses the omission of Luke 22:41-44. Based on the new images, it is also apparent that the fragment was subject to subsequent scribal correction in at least two instances.
"Simon Son of John, Do You Love Me?" Some Reflections on John 21:15
Authors: Ramelli Ilaria 
Published: September 2008

AbstractIn John 21:15 the much-debated expression αγαπας με πλεoν τoυτων; ought to be interpreted "Do you love me more than you love these things?," i.e. all the rest. This conclusion is strongly supported by compelling arguments concerning grammar (primarily the absence of συ as a subject and the frequently attested use of πλεoν τoυτων in the sense of πλεoν η ταυτα [accusative]), Johannine, NT and first-century linguistic usage (in John and the NT nominative personal pronouns are always expressed whenever emphasis lies on them, even when they are not particularly stressed, and in John the only other occurrence of πλεoν + genitive precisely corresponds to πλεoν η + plural accusative neuter pronoun), context and sense, ancient versions of this passage (Latin, Coptic, and Syriac), and some Patristic interpretations.
Rebellion to Reform in Bolivia. Part II: Revolutionary Epoch, Combined Liberation and the December 2005 Elections
Authors: Webber Jeffery 
Published: September 2008

AbstractThis article presents a broad analysis of the political economy and dynamics of social change during the first year (January 2006–January 2007) of the Evo Morales government in Bolivia. It situates this analysis in the wider historical context of left-indigenous insurrection between 2000 and 2005, the changing character of contemporary capitalist imperialism, and the resurgence of anti-neoliberalism and anti-imperialism elsewhere in Latin America. It considers at a general level the overarching dilemmas of revolution and reform. Part II of this three-part essay addresses four major themes. First, it reviews the literature on revolution in contemporary Bolivia. Second, it explains why the 2000 to 2005 period is best conceived as a revolutionary epoch in which left-indigenous social forces were engaged in a combined liberation struggle against racial oppression and class exploitation. However, it argues that this revolutionary epoch has not led to social revolution. Third it examines in detail the electoral rise of Evo Morales and his Movimiento al Socialismo (Movement Towards Socialism, MAS) party in the December 2005 elections. Fourth, it explores the historical trajectory of the MAS in terms of its changing class composition, ideology, and political strategies since the party's inception in the late 1990s.