bluuebunny/crossref_metadata_2025_split huggingface dataset:
C-fosAssessment as a Marker of Anti–Epidermal Growth Factor Receptor Effect
Authors: Jimeno Antonio , Kulesza Peter , Kincaid Erik , Bouaroud Nadia , Chan Audrey , Forastiere Arlene , Brahmer Julie , Clark Douglas P. , Hidalgo Manuel 
Published: February 2006

AbstractFactors predicting sensitivity to epidermal growth factor receptor (EGFR) blockade are largely unknown and new strategies are being sought to individualize cancer therapy. This study evaluated the variation in the expression of the early response gene c-fos as a distal effect of EGFR inhibition and its relationship to antitumor effects. The growth-inhibitory and c-fos–modulating effects of gefitinib and erlotinib in human cancer cell lines (A431, CAL27, HN11, HuCCT1, and Hep2) were determined. Next, these cell lines were xenografted in mice and treated for 14 days with gefitinib (A431 and HuCCT1) or erlotinib (CAL27, HN11, and Hep2). Fine needle aspiration biopsy of tumors was done at baseline and after 14 days of therapy for c-fos assessment. In addition, we tested the feasibility of analyzing this marker in five paired tumor samples from a clinical trial of gefitinib in patients with solid tumors. In culture, gefitinib and erlotinib decreased c-fos mRNA levels in the susceptible cell lines A431, CAL27, and HN11; however, both drugs failed to achieve c-fos inhibition in resistant cells. Gefitinib or erlotinib abrogated the increase in c-fos expression in vivo in EGFR-sensitive A431, CAL27, and HN11 tumors but not in resistant strains. Ex vivo evaluation was feasible and predicted in vivo effects. The feasibility study in paired human tumor biopsies showed that this biomarker can be reliably measured in clinical materials. In summary, variations in c-fos expression reflect the pharmacologic actions of EGFR inhibitors in in vitro and in vivo models. (Cancer Res 2006; 66(4): 2385-90)
Genetic and Epigenetic Analysis of von Hippel-Lindau (VHL) Gene Alterations and Relationship with Clinical Variables in Sporadic Renal Cancer
Authors: Banks Rosamonde E. , Tirukonda Prasanna , Taylor Claire , Hornigold Nick , Astuti Dewi , Cohen Dena , Maher Eamonn R. , Stanley Anthea J. , Harnden Patricia , Joyce Adrian , Knowles Margaret , Selby Peter J. 
Published: February 2006

Abstract
Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation–dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent. (Cancer Res 2006; 66(4): 2000-11)
Cell Adhesion to Fibronectin (CAM-DR) Influences Acquired Mitoxantrone Resistance in U937 Cells
Authors: Hazlehurst Lori A. , Argilagos Raul F. , Emmons Michael , Boulware David , Beam Craig A. , Sullivan Dan M. , Dalton William S. 
Published: February 2006

Abstract
Cell adhesion to fibronectin is known to confer a temporally related cell adhesion–mediated drug resistance (CAM-DR). However, it is unknown whether cell adhesion during drug selection influences the more permanent form of acquired drug resistance. To examine this question, we compared the acquisition of mitoxantrone resistance in U937 cells adhered to fibronectin versus cells selected in a traditional suspension culture. Our data show that acquired drug resistance levels of resistance to mitoxantrone are 2- to 3-fold greater for cells adhered to fibronectin compared with cells in suspension culture. We also compared mechanism(s) of resistance associated with drug selection in suspension versus fibronectin-adherent cultures. Drug resistance in both suspension and fibronectin-adhered cultures correlated with reduced drug-induced DNA damage and diminished topoisomerase II levels and activity; however, mechanisms regulating topoisomerase II levels differed depending on culture conditions. In suspension cultures, a reduction in topoisomerase IIβ levels was detected at both RNA and protein levels. Furthermore, the decreased expression of topoisomerase IIβ mRNA levels correlated with decreased expression of NF-YA. In contrast, in spite of no changes in NF-YA or topoisomerase IIβ RNA expression, topoisomerase IIβ protein levels were decreased in fibronectin-adherent, drug-resistant cells. In addition, topoisomerase IIα protein levels (but not RNA levels) were reduced in drug resistance cells selected on fibronectin; however, no change in topoisomerase IIα was observed in cells selected with mitoxantrone in suspension culture. Taken together, our results suggest that the development of drug resistance models must consider interactions with the microenvironment to identify clinically relevant targets and mechanisms associated with acquired drug resistance. (Cancer Res 2006; 66(4): 2338-45)
Reduction of Cytosolic p27Kip1 Inhibits Cancer Cell Motility, Survival, and Tumorigenicity
Authors: Wu Frederick Y. , Wang Shizhen Emily , Sanders Melinda E. , Shin Incheol , Rojo Federico , Baselga Jose , Arteaga Carlos L. 
Published: February 2006

Abstract
We generated a p27Kip1 mutant (p27ΔNLS) that localized exclusively in cell cytosol. Expression of p27ΔNLS in MCF7 breast cancer cells down-regulated RhoA and increased motility, survival, and Akt levels without an effect on cell cycle distribution. RNA interference of p27 in U87 glioma cells, which express p27 predominantly in the cytoplasm, inhibited motility and survival. Conversely, knockdown of p27 in COS7 cells, with &gt;95% nuclear p27 expression, accelerated proliferation but had no effect on motility or survival. U87 cells in which p27 had been eliminated by RNA interference exhibited lower Akt levels, shorter Akt turnover, and markedly impaired tumorigenicity in vivo. These xenografts were less invasive and exhibited increased apoptosis compared with p27-expressing tumors. Expression of cytosolic p27 in primary human breast carcinomas correlated linearly with Akt content as measured by immunohistochemistry. These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity. (Cancer Res 2006; 66(4): 2162-72)
Genetic and Histopathologic Evaluation ofBRCA1andBRCA2DNA Sequence Variants of Unknown Clinical Significance
Authors: Chenevix-Trench Georgia , Healey Sue , Lakhani Sunil , Waring Paul , Cummings Margaret , Brinkworth Ross , Deffenbaugh Amie M. , Burbidge Lynn Anne , Pruss Dmitry , Judkins Thad , Scholl Tom , Bekessy Anna , Marsh Anna , Lovelock Paul , Wong Ming , Tesoriero Andrea , Renard Helene , Southey Melissa , Hopper John L. , Yannoukakos Koulis , Brown Melissa ,   kConFab Investigators, Easton Douglas , Tavtigian Sean V. , Goldgar David , Spurdle Amanda B. 
Published: February 2006

AbstractClassification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that ∼80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants. (Cancer Res 2006; 66(4): 2019-27)
Haplotype Analysis of theHSD17B1Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies
Authors: Feigelson Heather Spencer , Cox David G. , Cann Howard M. , Wacholder Sholom , Kaaks Rudolf , Henderson Brian E. , Albanes Demetrius , Altshuler David , Berglund Goran , Berrino Franco , Bingham Sheila , Buring Julie E. , Burtt Noel P. , Calle Eugenia E. , Chanock Stephen J. , Clavel-Chapelon Francoise , Colditz Graham , Diver W. Ryan , Freedman Matthew L. , Haiman Christopher A. , Hankinson Susan E. , Hayes Richard B. , Hirschhorn Joel N. , Hunter David , Kolonel Laurence N. , Kraft Peter , LeMarchand Loic , Linseisen Jakob , Modi William , Navarro Carmen , Peeters Petra H. , Pike Malcolm C. , Riboli Elio , Setiawan V. Wendy , Stram Daniel O. , Thomas Gilles , Thun Michael J. , Tjonneland Anne , Trichopoulos Dimitrios 
Published: February 2006

AbstractThe 17β-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study. (Cancer Res 2006; 66(4): 2468-75)
A Prospective Study of Serum C-Reactive Protein and Colorectal Cancer Risk in Men
Authors: Gunter Marc J. , Stolzenberg-Solomon Rachael , Cross Amanda J. , Leitzmann Michael F. , Weinstein Stephanie , Wood Richard J. , Virtamo Jarmo , Taylor Philip R. , Albanes Demetrius , Sinha Rashmi 
Published: February 2006

Abstract
Chronic inflammation has been implicated in the etiology of colorectal cancer. C-reactive protein (CRP), a sensitive marker of inflammation, has been investigated with regard to colorectal cancer in only three previous studies, and the results from these investigations were inconsistent. We examined serum CRP levels in relation to colorectal cancer incidence in a nested case-control study within the Alpha Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study, a cohort of 29,133 Finnish males enrolled from 1985 to 1988 with follow-up through April 2002. Colorectal cancer cases were ascertained by the Finnish Cancer Registry; this analysis included 130 cases of colorectal cancer (with available blood), which occurred between 1990 and April 30, 2002, and 260 matched controls. Baseline median CRP levels were ∼25% higher among colorectal cancer cases (3.4 mg/L) than controls (2.6 mg/L; P = 0.04). Relative to men in the lowest quartile of CRP concentration, men in the highest quartile had an odds ratio of 2.9 (95% confidence interval, 1.4-6.0) for developing colorectal cancer with a dose-response relationship supported (Ptrend = 0.006). The relation between CRP and incident colorectal cancer was modified by body mass index such that the association was stronger among lean individuals than in heavier individuals (Pinteraction = 0.018). These results support the notion that chronic low-grade inflammation is a marker for increased risk of colorectal cancer. (Cancer Res 2006; 66(4): 2483-7)
Ex vivoDetectable Human CD8 T-Cell Responses to Cancer-Testis Antigens
Authors: Baumgaertner Petra , Rufer Nathalie , Devevre Estelle , Derre Laurent , Rimoldi Donata , Geldhof Christine , Voelter Verena , Liénard Danielle , Romero Pedro , Speiser Daniel E. 
Published: February 2006

AbstractClinical trials have shown that strong tumor antigen–specific CD8 T-cell responses are difficult to induce but can be achieved for T-cells specific for melanoma differentiation antigens, upon repetitive vaccination with stable emulsions prepared with synthetic peptides and incomplete Freund's adjuvant. Here, we show in four melanoma patients that ex vivo detectable T-cells and thus strong T-cell responses can also be induced against the more universal cancer-testis antigens NY-ESO-1 and Mage-A10. Interestingly, all patients had ex vivo detectable T-cell responses against multiple antigens after serial vaccinations with three peptides emulsified in incomplete Freund's adjuvant. Antigen-specific T-cells displayed an activated phenotype and secreted IFNγ. The robust immune responses provide a solid basis for further development of human T-cell vaccination. (Cancer Res 2006; 66(4): 1912-6)
The Metastasis-Associated Gene CD24 Is Regulated by Ral GTPase and Is a Mediator of Cell Proliferation and Survival in Human Cancer
Authors: Smith Steven C. , Oxford Gary , Wu Zhong , Nitz Matthew D. , Conaway Mark , Frierson Henry F. , Hampton Garret , Theodorescu Dan 
Published: February 2006

Abstract
Ral GTPases are important mediators of transformation, tumorigenesis, and cancer progression. We recently identified the metastasis-associated protein CD24, a glycosyl phosphatidyl inositol–linked surface protein, as a downstream target of Ral signaling by profiling the expression of RalA/B–depleted bladder carcinoma cells. Because CD24 is highly expressed in bladder and many other tumor types, we sought to determine if this protein plays an essential role in maintaining the malignant phenotype. Here, we show that loss of CD24 function in cell lines derived from common tumor types is associated with decreased rates of cell proliferation, clonogenicity in soft agar, changes in the actin cytoskeleton, and induction of apoptosis. Given these phenotypes, we evaluated a human bladder cancer tissue microarray by immunohistochemistry for CD24 to determine if CD24 is a prognostic cancer biomarker. Multivariate analysis showed that increased CD24 expression correlated with shorter patient disease-free survival (P = 0.07). In conclusion, we show that CD24 is a novel and functionally relevant Ral-regulated target and a potentially important prognostic marker. We suggest that these insights may lead to future therapeutic approaches that seek to eliminate CD24 function in cancer cells. (Cancer Res 2006; 66(4): 1917-22)
Multiple Robust Signatures for Detecting Lymph Node Metastasis in Head and Neck Cancer
Authors: Roepman Paul , Kemmeren Patrick , Wessels Lodewijk F.A. , Slootweg Piet J. , Holstege Frank C.P. 
Published: February 2006

Abstract
Genome-wide mRNA expression measurements can identify molecular signatures of cancer and are anticipated to improve patient management. Such expression profiles are currently being critically evaluated based on an apparent instability in gene composition and the limited overlap between signatures from different studies. We have recently identified a primary tumor signature for detection of lymph node metastasis in head and neck squamous cell carcinomas. Before starting a large multicenter prospective validation, we have thoroughly evaluated the composition of this signature. A multiple training approach was used for validating the original set of predictive genes. Based on different combinations of training samples, multiple signatures were assessed for predictive accuracy and gene composition. The initial set of predictive genes is a subset of a larger group of 825 genes with predictive power. Many of the predictive genes are interchangeable because of a similar expression pattern across the tumor samples. The head and neck metastasis signature has a more stable gene composition than previous predictors. Exclusion of the strongest predictive genes could be compensated by raising the number of genes included in the signature. Multiple accurate predictive signatures can be designed using various subsets of predictive genes. The absence of genes with strong predictive power can be compensated by including more genes with lower predictive power. Lack of overlap between predictive signatures from different studies with the same goal may be explained by the fact that there are more predictive genes than required to design an accurate predictor. (Cancer Res 2006; 66(4): 2361-6)
Ethical Challenges: To Participate or Not to Participate?
Authors: Cooksy Leslie J. 
Published: February 2006

This issue's scenario, “To Participate or Not to Participate,” describes an evaluator's shift in method from nonparticipant to participant observation. Although evaluation theorists differ on the extent to which methods decisions are ethical decisions (Morris, 1998), neither of the two commentators considers the methodological decision problematic; however, both raise issues about the process surrounding the change in observational approach. The first commentator focuses on how the methodological shift affects the responsibilities of the evaluator to the evaluation client. The second commentator notes that the scenario reflects the tension between evaluation for program improvement and evaluation for accountability. The evaluator's responsibility for capacity building among the group that he or she becomes a part of is a consideration that is touched on in both commentaries but is not the focus of either statement. Scott Rosas, whose response to the scenario is presented first, is a senior program and policy analyst with Nemours Health and Prevention Services in the Center for Children's Health Innovation. Dr. Rosas has a background in human development and family studies, with a focus on mental health preventive intervention models. His particular interest and expertise are in the area of assessment, problem identification, and theory-driven program evaluation. Valerie J. Caracelli, the second commentator, is a senior social science analyst at the U.S. Government Accountability Office. She is a past president of the Topical Interest Group on Evaluation Utilization and is known for her work on mixed-method evaluation.
Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis
Authors: Schade Andrew E. , Powers Jennifer J. , Wlodarski Marcin W. , Maciejewski Jaroslaw P. 
Published: February 2006

AbstractT-cell large granular lymphocytic leukemia (T-LGL) is characterized by chronic clonal lymphoproliferation of cytotoxic T lymphocytes (CTLs). Despite exhibiting phenotypic properties of antigen-activated cells, including expression of Fas and FasL, T-LGL cells accumulate and demonstrate resistance to apoptosis. We propose that increased activity of a prosurvival signaling pathway in T-LGL is responsible for attenuated apoptosis in T-LGL. Given the importance of the phosphatidylinositol-3 kinase (PI3K)–AKT pathway in regulating the balance between survival and apoptosis, we analyzed AKT activity in T-LGL cells. Compared with resting CTLs from healthy donors, patients' T-LGL cells showed higher levels of phosphorylated AKT. We demonstrate that phospho-AKT induction is dependent on the upstream activity of a Src family kinase. Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis, we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL. Inhibition of the PI3K-AKT pathway alone led to brisk spontaneous apoptosis of T-LGL. These results suggest that T-LGL pathogenesis is dependent on activity of the PI3K-AKT pathway, without which the leukemic cells will begin to undergo spontaneous apoptosis. We propose that novel therapeutics inhibiting the PI3K-AKT axis may provide effective treatment for T-LGL.
Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia
Authors: Schafer Andrew I. 
Published: February 2006

AbstractRecent insights into the molecular mechanisms of polycythemia vera (PV) and essential thrombocythemia (ET) are challenging the traditional diagnostic classification of these myeloproliferative disorders (MPDs). Clonality analysis using X-chromosome inactivation patterns has revealed apparent heterogeneity among the MPDs. The recently discovered single somatic activating point mutation in the JAK2 gene (JAK2-V617F) is found in the great majority of patients with PV, but also in many patients with phenotypically classified ET and other MPDs. In contrast to the acquired MPDs, mutations of the erythropoietin receptor and thrombopoietin receptor have been identified in familial forms of nonclonal erythrocytosis and thrombocytosis, respectively. The mechanisms of major clinical complications of PV and ET remain poorly understood. Quantitative or qualitative abnormalities of red cells and platelets do not provide clear explanations for the thrombotic and bleeding tendency in these MPDs, suggesting the need for entirely new lines of research in this area. Recently reported randomized clinical trials have demonstrated the efficacy and safety of low-dose aspirin in PV, and an excess rate of arterial thrombosis, major bleeding, and myelofibrotic transformation, but decreased venous thrombosis, in patients with ET treated with anagrelide plus aspirin compared to hydroxyurea plus aspirin.