bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surfactant Protein A Gene Deletion and Prognostics for Patients with Stage I Non–Small Cell Lung Cancer
Authors: Jiang Feng , Caraway Nancy P. , Nebiyou Bekele Benjamin , Zhang Hua-Zhong , Khanna Abha , Wang Huijun , Li Ruiyun , Fernandez Ricardo L. , Zaidi Tanweer M. , Johnston Dennis A. , Katz Ruth L. 
Published: September 2005

Abstract
Purpose: The present study was conducted to determine clinical relevance of surfactant protein A (SP-A) genetic aberrations in early-stage non–small cell lung cancer (NSCLC).
Experimental Design: To determine whether SP-A aberrations are lung cancer–specific and indicate smoking-related damage, tricolor fluorescence in situ hybridization with SP-A and PTEN probes was done on touch imprints from the lung tumors obtained prospectively from 28 patients with primary NSCLC. To further define the clinical relevance of SP-A aberrations, fluorescence in situ hybridization was done on both tumor cells and adjacent bronchial tissue cells from paraffin-embedded tissue blocks from 130 patients NSCLC for whom we had follow-up information.
Results: SP-A was deleted from 89% of cancer tissues and the deletion was related to the smoking status of patients (P &lt; 0.001). PTEN was deleted from 16% in the cancer tissues and the deletion was not related to the smoking status of patients (P &gt; 0.05). In the cells isolated from paraffin-embedded tissue blocks, SP-A was deleted from 87% of the carcinoma tissues and 32% of the adjacent normal-appearing bronchial tissues. SP-A deletions in tumors and adjacent normal-appearing bronchial tissues were associated with increases in the risk of disease relapse (P = 0.0035 and P &lt; 0.001, respectively). SP-A deletions in the bronchial epithelium were the strongest prognostic indicators of disease-specific survival (P = 0.025).
Conclusions: Deletions of the SP-A gene are specific genomic aberrations in bronchial epithelial cells adjacent to and within NSCLC, and are associated with tumor progression and a history of smoking. SP-A deletions might be a useful biomarker to identify poor prognoses in patients with NSCLC who might therefore benefit from adjuvant treatment.
Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia
Authors: Tissing Wim J.E. , Meijerink Jules P.P. , den Boer Monique L. , Brinkhof Bas , van Rossum Elisabeth F.C. , van Wering Elisabeth R. , Koper Jan W. , Sonneveld Pieter , Pieters Rob 
Published: September 2005

Abstract
Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes. We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids.
Methods: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance.
Results: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.
FAS/FAS Ligand Ratio: A Marker of Oxaliplatin-Based Intrinsic and Acquired Resistance in Advanced Colorectal Cancer
Authors: Nadal Cristina , Maurel Joan , Gallego Rosa , Castells Antoni , Longarón Raquel , Marmol Maribel , Sanz Sergi , Molina Rafael , Martin-Richard Marta , Gascón Pere 
Published: September 2005

Abstract
Purpose: Oxaliplatin-5-fluorouracil combinations have increased responses in first-line therapy up to 40% in advanced colorectal cancer. Unfortunately, those patients who will respond are unknown and initially sensitive patients become rapidly resistant to current therapies. FAS (CD95) and FAS ligand (FASL; CD95L) have been implicated in chemosensitivity through leading to apoptosis in response to DNA-damaging drugs. Whereas the proapoptotic role of FAS and FASL is well characterized, the function of their soluble forms as predictors of chemosensitivity remains unknown.
Patients and Methods: Blood samples were obtained from 68 patients with advanced colorectal cancer who received oxaliplatin-5-fluorouracil combinations in first-line therapy. Computed tomographic scans were done every 3 months and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. ELISA soluble FAS and soluble FASL analysis were done before treatment and every 3 months until disease progression. Ratios between soluble FAS and soluble FASL were established and its values and variations through time were related to treatment responses.
Results: We found a significant increase in soluble FAS levels and a significant decrease in FASL at 3 months compared with baseline (13.2 versus 10.02 ng/mL; P = 0.0001; 0.07 versus 0.14 ng/mL; P = 0.007, respectively). A significant increase in the soluble FASL levels up to 9 months (fourth to fifth extractions; 0.26 ng/mL) of therapy compared with first to third extractions (0.11 ng/mL; P = 0.003) was also found. A random effect regression statistical model determined that &gt;1.2-fold increase in soluble FAS/soluble FASL ratio was a marker of chemosensitivity (P = 0.001).
Conclusions: These data strongly indicate that an increment of soluble FAS/soluble FASL ratio after treatment could be an excellent marker of chemosensitivity in colorectal cancer. On the other hand, a decreased ratio after treatment can be a predictor of chemoresistance despite an initial response.
In vivo Target Modulation and Biological Activity of CHIR-258, a Multitargeted Growth Factor Receptor Kinase Inhibitor, in Colon Cancer Models
Authors: Lee Sang Hoon , Lopes de Menezes Daniel , Vora Jayesh , Harris Alex , Ye Helen , Nordahl Lara , Garrett Evelyn , Samara Emil , Aukerman Sharon Lea , Gelb Arnold B. , Heise Carla 
Published: September 2005

Abstract
Purpose: To evaluate the therapeutic and biological effects of CHIR-258, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases, in colon cancer models.
Experimental Design: The pharmacologic activity of CHIR-258 was characterized by monitoring target modulation as well as by evaluating the antitumor and antiangiogenic effects in human colon xenograft models.
Results: CHIR-258 inhibits vascular endothelial growth factor receptor 1/2, fibroblast growth factor receptor 1/3, and platelet-derived growth factor receptor β (PDGFRβ) and shows both antitumor and antiangiogenic activities in vivo. Treatment of KM12L4a human colon cancer cells with CHIR-258 resulted in a dose-dependent inhibition of vascular endothelial growth factor receptor 1 and PDGFRβ phosphorylation and reduction of phosphorylated extracellular signal-regulated kinase (ERK) levels, indicating modulation of target receptors and downstream signaling. In vivo administration of CHIR-258 resulted in significant tumor growth inhibition and tumor regressions, including large, established tumors (500-1,000 mm3). Immunohistochemical analysis showed a reduction of phosphorylated PDGFRβ and phosphorylated ERK in tumor cells after oral dosing with CHIR-258 compared with control tumors. These changes were accompanied by decreased tumor cell proliferation rate and reduced intratumoral microvessel density. CHIR-258 inhibited the phosphorylation of PDGFRβ and ERK phosphorylation in tumors within 2 hours following dosing and the inhibitory activity was sustained for &gt;24 hours. Significant antitumor activity was observed with intermittent dosing schedules, indicating a sustained biological activity.
Conclusion: These studies provide evidence that biological activity of CHIR-258 in tumors correlates with efficacy and aids in the identification of potential biomarkers of this multitargeted receptor tyrosine kinase inhibitor. CHIR-258 exhibits properties that make it a promising candidate for clinical development in a variety of solid and hematologic malignancies.
Defects in the Human Leukocyte Antigen Class I Antigen Processing Machinery in Head and Neck Squamous Cell Carcinoma: Association with Clinical Outcome
Authors: Meissner Markus , Reichert Torsten E. , Kunkel Martin , Gooding William , Whiteside Theresa L. , Ferrone Soldano , Seliger Barbara 
Published: September 2005

AbstractPurpose: Human leukocyte antigen (HLA) class I antigen defects, which are frequently present in head and neck squamous cell carcinoma (HNSCC) cells may provide the tumor with an escape mechanism from immune surveillance. Scanty information is available about mechanisms underlying HLA class I antigen defects in both lesions and cell lines from HNSCC. In this study, we investigate the role of antigen processing machinery (APM) component abnormalities in the generation of deficient HLA class I surface expression of HNSCC cells.Experimental Design: Using immunohistochemistry, Western blot, and RT-PCR analyses we correlated the expression of the IFN-γ inducible proteasome subunits and of the peptide transporter TAP with that of HLA class I antigens in biopsies and cell lines from primary, recurrent, and metastatic HNSCC. Furthermore, APM component and HLA class I antigen expression in surgically removed lesions were correlated with the course of the disease in order to assess the clinical significance of deficient expression of these molecules.Results: A high frequency of LMP2, LMP7, and TAP1 down-regulation or loss was found in tumor lesions and cell lines obtained from HNSCC cancer patients. These defects could be corrected by incubating cells with IFN-γ. Furthermore, LMP2, LMP7, TAP1, TAP2, and HLA class I antigen expression rates in primary HNSCC lesions were found to predict overall survival. Lastly, the level of LMP7 expression was significantly associated with disease recurrence at 2 years.Conclusions: Our results suggest that the analysis of APM component expression in HNSCC lesions can provide useful prognostic information in patients with HNSCC.
Phase I Study of Immunization with Dendritic Cells Modified with Fowlpox Encoding Carcinoembryonic Antigen and Costimulatory Molecules
Authors: Morse Michael A. , Clay Timothy M. , Hobeika Amy C. , Osada Takuya , Khan Shubi , Chui Stephen , Niedzwiecki Donna , Panicali Dennis , Schlom Jeffrey , Lyerly H. Kim 
Published: September 2005

Abstract
Purpose: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen.
Experimental Design: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2–restricted peptide derived from cytomegalovirus pp65 protein.
Results: Fourteen patients (11 with colorectal cancer and 3 with non–small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/105 peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4+ and CD8+ T cells in all immune responders.
Conclusion: This immunization strategy is safe and activates potent CEA-specific immune responses.
Automated Quantitative Analysis of E-Cadherin Expression in Lymph Node Metastases Is Predictive of Survival in Invasive Ductal Breast Cancer
Authors: Harigopal Malini , Berger Aaron J. , Camp Robert L. , Rimm David L. , Kluger Harriet M. 
Published: September 2005

Abstract
Purpose: The tumor suppressor adhesion molecule E-cadherin is believed to have an anti-invasive role in breast cancer. Lymph node involvement is the best prognostic marker known, yet there is variability in outcome among node-positive patients. We investigated the relationship between E-cadherin expression in primary invasive ductal tumors and corresponding nodal metastases, and determined the prognostic value of E-cadherin expression in node-positive breast cancer.
Experimental Design: Membrane E-cadherin expression was studied by immunohistochemical staining of tissue microarrays with fluorescent-labeled antibodies. An objective method of automated quantitative analysis (AQUA) was used. AQUA uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures E-cadherin expression using a Cy5-conjugated antibody within the mask.
Results: We employed a tissue microarray containing 207 primary and matched nodal metastases suitable for AQUA analysis. There was no significant difference in mean staining intensity between the primary and nodal specimens (P = 0.8). A scattergram was generated which identified a subset of patients (25%) with high E-cadherin expression in nodal metastases, and this top quartile had improved survival (P = 0.028). On univariate analysis, increased E-cadherin expression in nodal metastases was strongly associated with improved survival (P = 0.007), whereas expression in primary tumors was not (P = 0.13). On multivariate analysis, nodal E-cadherin expression retained its independent association with survival, as did tumor size and HER2/neu status.
Conclusions: Strong E-cadherin expression in lymph node metastases was highly predictive of improved survival. This suggests that expression of adhesion molecules at metastatic sites portends less aggressive tumor behavior.
Promoter Methylation of DAL-1/4.1B Predicts Poor Prognosis in Non–Small Cell Lung Cancer
Authors: Kikuchi Shinji , Yamada Daisuke , Fukami Takeshi , Masuda Mari , Sakurai-Yageta Mika , Williams Yuko N. , Maruyama Tomoko , Asamura Hisao , Matsuno Yoshihiro , Onizuka Masataka , Murakami Yoshinori 
Published: September 2005

Abstract
Purpose: DAL-1/4.1B is an actin-binding protein originally identified as a molecule whose expression is down-regulated in lung adenocarcinoma. We have previously shown that a lung tumor suppressor, TSLC1, associates with DAL-1, suggesting that both proteins act in the same cascade. The purpose of this study is to understand the molecular mechanisms and clinical significance of DAL-1 inactivation in lung cancer.
Experimental Design: We studied aberration of the DAL-1 in 103 primary non–small cell lung cancers (NSCLC) and 18 lung cancer cells. Expression and allelic and methylation status of DAL-1 was examined by reverse transcription-PCR, microsatellite analysis, and bisulfite sequencing or bisulfite single-strand conformational polymorphism, respectively.
Results: Loss of DAL-1 expression was strongly correlated with promoter methylation in lung cancer cells, whereas DAL-1 expression was restored by a demethylating agent, 5-aza-2′-deoxycytidine. The DAL-1 promoter was methylated in 59 (57%) primary NSCLC tumors, 37% of which were associated with loss of heterozygosity around the DAL-1 on chromosomal region 18p11.3. In squamous cell carcinomas, DAL-1 methylation was observed in 9 of 10 tumors at stage I, whereas the incidence of methylation gradually increased in adenocarcinomas as they progressed [13 of 36 (36%), 4 of 12 (33%), 14 of 17 (82%), and 3 of 3 (100%) tumors at stages I, II, III, and IV, respectively; P = 0.0026]. Furthermore, in adenocarcinomas, disease-free survival and overall survival were significantly shorter in patients with tumors harboring the methylated DAL-1 (P = 0.0011 and P = 0.045, respectively).
Conclusions: DAL-1 methylation is involved in the development and progression of NSCLC and provides an indicator for poor prognosis.
A Haplotype Analysis of HER-2 Gene Polymorphisms: Association with Breast Cancer Risk, HER-2 Protein Expression in the Tumor, and Disease Recurrence in Korea
Authors: Han Wonshik , Kang Daehee , Lee Jong Eun , Park In Ae , Choi Ji-Yeob , Lee Kyung-Mu , Bae Ji Yeon , Kim Sook , Shin Eun-Soon , Lee Jeong Eon , Shin Hyuk-Jae , Kim Seok Won , Kim Sung-Won , Noh Dong-Young 
Published: September 2005

Abstract
Purpose: A single-nucleotide polymorphism (SNP) in codon 655 of HER-2 has been extensively studied with inconclusive results. The purpose of this study was to investigate the association between common variants of HER-2 and breast cancer risk, HER-2 expression, and survival using a haplotype-based stepwise approach.
Experimental Design: Twenty-nine SNPs listed in the National Center for Biotechnology Information database were screened to identify novel polymorphisms of HER-2 gene in 90 healthy Korean women. Six of 29 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Using these six SNPs, linkage disequilibrium and haplotype patterns were characterized. We tested association between the haplotypes and breast cancer in a large case–control study (n = 1,039 cases and 995 controls). Six-hundred two breast cancer patients with follow-up at least 24 months were analyzed for outcome in relation to haplotype. Expression of HER-2 protein was determined by immunohistochemistry in 1,094 cases of invasive breast cancer.
Results: All six SNPs showed a strong linkage disequilibrium pattern and were considered to belong to one haplotype block. Two haplotype-tagging SNPs (I655V and P1170A) for three common haplotypes (&gt;5%) were genotyped in cases and controls. The haplotypes and individual SNPs were not associated with breast cancer risk. In patients with at least one copy of haplotype I (the most common haplotype), HER-2 expression was 1.5 times higher (P = 0.009) and the prognosis was worse (P = 0.032) compared with patients without having that haplotype.
Conclusions: Our results suggest that the currently identified genetic polymorphisms of HER-2 are not associated with an increased risk of breast cancer in Korean women, whereas one haplotype does affect protein expression of the tumor and disease outcome.
Translational Crossroads for Biomarkers
Authors: Bast Robert C. , Lilja Hans , Urban Nicole , Rimm David L. , Fritsche Herbert , Gray Joe , Veltri Robert , Klee George , Allen Andrew , Kim Nam , Gutman Steven , Rubin Mark A. , Hruszkewycz Andrew 
Published: September 2005

Abstract
A group of investigators met at a Specialized Programs of Research Excellence Workshop to discuss key issues in the translation of biomarker discovery to the development of useful laboratory tests for cancer care. Development and approval of several new markers and technologies have provided informative examples that include more specific markers for prostate cancer, more sensitive tests for ovarian cancer, more objective analysis of tissue architecture and an earlier indication of response to treatment in breast cancer. Although there is no clear paradigm for biomarker development, several principles are clear. Marker development should be driven by clinical needs, including early cancer detection, accurate pretreatment staging, and prediction of response to treatment, as well as monitoring disease progression and response to therapy. Development of a national repository that uses carefully preserved, well-annotated tissue specimens will facilitate new marker development. Reference standards will be an essential component of this process. Both hospital-based and commercial laboratories can play a role in developing biomarkers from discovery to test validation. Partnering of academe and industry should occur throughout the process of biomarker development. The National Cancer Institute is in a unique position to bring together academe, industry, and the Food and Drug Administration to (a) define clinical needs for biomarkers by tumor type, (b) establish analytic and clinical paradigms for biomarker development, (c) discuss ways in which markers from different companies might be evaluated in combination, (d) establish computational methods to combine data from multiple biomarkers, (e) share information regarding promising markers developed in National Cancer Institute–supported programs, and (f) exchange data regarding new platforms and techniques that can accelerate marker development.
Gene Signatures of Progression and Metastasis in Renal Cell Cancer
Authors: Jones Jon , Otu Hasan , Spentzos Dimitrios , Kolia Shakirahmed , Inan Mehmet , Beecken Wolf D. , Fellbaum Christian , Gu Xuesong , Joseph Marie , Pantuck Allan J. , Jonas Dietger , Libermann Towia A. 
Published: September 2005

AbstractPurpose: To address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC).Experimental Design: Transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived.Results: Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern (“metastatic signature”) derived from primary tumor was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described “global” metastatic signature derived by another group from various non-RCC tumors was validated in RCC.Conclusion: Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC.