bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smokers with theCHRNALung Cancer–Associated Variants Are Exposed to Higher Levels of Nicotine Equivalents and a Carcinogenic Tobacco-Specific Nitrosamine
Authors: Le Marchand Loïc , Derby Kiersten S. , Murphy Sharon E. , Hecht Stephen S. , Hatsukami Dorothy , Carmella Steven G. , Tiirikainen Maarit , Wang Hansong 
Published: November 2008

AbstractA locus at 15q24/15q25.1, which includes the nicotinic acetylcholine receptor A subunits 3 and 5 (CHRNA3 and CHRNA5) genes, has recently been associated with lung cancer risk, self-reported number of cigarettes smoked per day, and a nicotine dependence scale. It is not clear whether the association with lung cancer is direct or mediated through differences in smoking behavior. We used urinary biomarkers to test whether two linked lung cancer risk variants in CHRNA3 (rs1051730) and CHRNA5 (rs16969968) are associated with intensity of smoking and exposure to a tobacco-specific carcinogenic nitrosamine per cigarette dose. We studied 819 smokers and found that carriers of these variants extract a greater amount of nicotine (P = 0.003) and are exposed to a higher internal dose of 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (P = 0.03) per cigarette than noncarriers. Thus, smokers who carry the CHRNA3 and CHRNA5 variants are expected to be at increased risk for lung cancer compared with smokers who do not carry these alleles even if they smoked the same number of cigarettes. Number of cigarettes per day, even if it could be accurately assessed, is not an adequate measure of smoking dose. [Cancer Res 2008;68(22):9137–40]
Regulated Expression of a Tumor-Associated Antigen Reveals Multiple Levels of T-Cell Tolerance in a Mouse Model of Lung Cancer
Authors: Cheung Ann F. , DuPage Michel J.P. , Dong H. Katie , Chen Jianzhu , Jacks Tyler 
Published: November 2008

AbstractMaximizing the potential of cancer immunotherapy requires model systems that closely recapitulate human disease to study T-cell responses to tumor antigens and to test immunotherapeutic strategies. We have created a new system that is compatible with Cre-LoxP–regulatable mouse cancer models in which the SIY antigen is specifically overexpressed in tumors, mimicking clinically relevant TAAs. To show the utility of this system, we have characterized SIY-reactive T cells in the context of lung adenocarcinoma, revealing multiple levels of antigen-specific T-cell tolerance that serve to limit an effective antitumor response. Thymic deletion reduced the number of SIY-reactive T cells present in the animals. When potentially self-reactive T cells in the periphery were activated, they were efficiently eliminated. Inhibition of apoptosis resulted in more persistent self-reactive T cells, but these cells became anergic to antigen stimulation. Finally, in the presence of tumors overexpressing SIY, SIY-specific T cells required a higher level of costimulation to achieve functional activation. This system represents a valuable tool in which to explore sources contributing to T-cell tolerance of cancer and to test therapies aimed at overcoming this tolerance. [Cancer Res 2008;68(22):9459–68]
SM-164: A Novel, Bivalent Smac Mimetic That Induces Apoptosis and Tumor Regression by Concurrent Removal of the Blockade of cIAP-1/2 and XIAP
Authors: Lu Jianfeng , Bai Longchuan , Sun Haiying , Nikolovska-Coleska Zaneta , McEachern Donna , Qiu Su , Miller Rebecca S. , Yi Han , Shangary Sanjeev , Sun Yi , Meagher Jennifer L. , Stuckey Jeanne A. , Wang Shaomeng 
Published: November 2008

AbstractSmall-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that Smac mimetics target cellular inhibitor of apoptosis protein (cIAP)-1/2 for degradation and induce tumor necrosis factor-α (TNFα)–dependent apoptosis in tumor cells. In this study, we have investigated the mechanism of action and therapeutic potential of two different types of novel Smac mimetics, monovalent SM-122 and bivalent SM-164. Our data showed that removal of cIAP-1/2 by Smac mimetics or small interfering RNA is not sufficient for robust TNFα-dependent apoptosis induction, and X-linked inhibitor of apoptosis protein (XIAP) plays a critical role in inhibiting apoptosis induction. Although SM-164 is modestly more effective than SM-122 in induction of cIAP-1/2 degradation, SM-164 is 1,000 times more potent than SM-122 as an inducer of apoptosis in tumor cells, which is attributed to its much higher potency in binding to and antagonizing XIAP. SM-164 induces rapid cIAP-1 degradation and strong apoptosis in the MDA-MB-231 xenograft tumor tissues and achieves tumor regression, but has no toxicity in normal mouse tissues. Our study provides further insights into the mechanism of action for Smac mimetics and regulation of apoptosis by inhibitor of apoptosis proteins. Furthermore, our data provide evidence that SM-164 is a promising new anticancer drug for further evaluation and development. [Cancer Res 2008;68(22):9384–93]
MUC4, a Multifunctional Transmembrane Glycoprotein, Induces Oncogenic Transformation of NIH3T3 Mouse Fibroblast Cells
Authors: Bafna Sangeeta , Singh Ajay P. , Moniaux Nicolas , Eudy James D. , Meza Jane L. , Batra Surinder K. 
Published: November 2008

Abstract
Numerous studies have established the association of MUC4 with the progression of cancer and metastasis. An aberrant expression of MUC4 is reported in precancerous lesions, indicating its early involvement in the disease process; however, its precise role in cellular transformation has not been explored. MUC4 contains many unique domains and is proposed to affect cell signaling pathways and behavior of the tumor cells. In the present study, to decipher the oncogenic potential of MUC4, we stably expressed the MUC4 mucin in NIH3T3 mouse fibroblast cells. Stable ectopic expression of MUC4 resulted in increased growth, colony formation, and motility of NIH3T3 cells in vitro and tumor formation in nude mice when cells were injected s.c. Microarray analysis showed increased expression of several growth-associated and mitochondrial energy production–associated genes in MUC4-expressing NIH3T3 cells. In addition, expression of MUC4 in NIH3T3 cells resulted in enhanced levels of oncoprotein ErbB2 and its phosphorylated form (pY1248-ErbB2). In conclusion, our studies provide the first evidence that MUC4 alone induces cellular transformation and indicates a novel role of MUC4 in cancer biology. [Cancer Res 2008;68(22):9231–8]
Monoclonal Antibody CC188 Binds a Carbohydrate Epitope Expressed on the Surface of Both Colorectal Cancer Stem Cells and their Differentiated Progeny
Authors: Xu Mai , Yuan Yuan , Xia Yang , Achilefu Samuel 
Published: November 2008

Abstract
Purpose: Recently, cancer stem cells (CSC), undifferentiated cancer progenitor cells, have been successfully isolated from colorectal tumors. Targeting both CSCs and differentiated, rapidly proliferating tumor cells with therapeutic drugs provides a focused strategy to treat cancer. In this study, we isolated the monoclonal antibody (mAb) CC188 and characterized the epitope recognized by mAb CC188, which is useful for developing biological reagents that target CSCs.
Experimental Design: We used a hybridoma technique to generate mAbs and an immunomagnetic method to isolate colon CSCs. We characterized mAb CC188 binding epitope and examined the epitope distribution in normal and tumor tissues, particularly in CSCs using tissue arrays and immunofluorescence staining method. We also evaluated the effect of mAb CC188 on invasiveness of NSY tumor cells.
Results: mAb CC188 was generated and 98.9% (187 of 189 cases) of colon cancer were positively stained by mAb CC188. “+”, “++,” and “+++” staining were 25.9%, 28.6%, and 43.4%, respectively. The mAb CC188 binding epitope was identified as a carbohydrate, which was expressed on the surface of colon CSCs (CD133+), differentiated colon cancer cells (CD133−), and cells from various types of epithelial tumors. In contrast, the expression of the carbohydrate epitope was low in normal prostate muscle and pancreatic acinar cells, as well as in some normal epithelial cells of the breast duct, cervix, and skin. A functional study indicated that mAb CC188 suppressed the invasiveness of NSY tumor cells.
Conclusion: mAb CC188 selectively targets a carbohydrate epitope expressed on cancer cells, providing a viable method for specific tumor imaging and targeted therapy.
Predictive Value of Plasma Hepatocyte Growth Factor/Scatter Factor Levels in Patients with Clinically Localized Prostate Cancer
Authors: Gupta Amit , Karakiewicz Pierre I. , Roehrborn Claus G. , Lotan Yair , Zlotta Alexandre R. , Shariat Shahrokh F. 
Published: November 2008

AbstractPurpose: Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that is involved in cancer growth, motility, invasion, and angiogenesis. We assessed whether preoperative plasma levels of HGF can enhance the accuracy of standard models for predicting pathologic features and clinical outcomes.Experimental Design: The study comprised 421 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma. HGF/SF was measured using a commercially available immunoassay. Multivariate logistic regression was used to assess the relationship between plasma HGF/SF and pathologic features. Multivariate Cox regression was used to predict disease recurrence. One thousand bootstrap replicates were created for internal validation and predictive accuracies were estimated for each model.Results: Plasma HGF/SF levels were significantly elevated in patients with lymph node and/or seminal vesicle invasion (P &lt; 0.0001 and P = 0.007, respectively). Preoperative plasma HGF/SF level was an independent predictor of lymph node invasion [odds ratio (OR) for every 100 pg/mL increase in HGF/SF, 1.82; 95% confidence interval (95% CI), 1.33-2.49] and seminal vesicle invasion (OR, 1.18; 95% CI, 1.06-1.3). Addition of HGF/SF increased the accuracy of a base model that included standard preoperative variables for prediction of lymph node invasion by 6.7% (predictive accuracy, 98.4%). HGF/SF also independently predicted disease recurrence after surgery (hazard ratio, 1.07; 95% CI, 1.0-1.15).Conclusions: Preoperative plasma level of HGF/SF is an independent predictor of prostate cancer metastasis to lymph nodes and disease recurrence after surgery. Use of HGF may help in therapeutic decision-making and enrollment into clinical trials.
The Use of Genetic Markers to Identify Lung Cancer in Fine Needle Aspiration Samples
Authors: Gill Rajbir K. , Vazquez Madeline F. , Kramer Arin , Hames Megan , Zhang Lijuan , Heselmeyer-Haddad Kerstin , Ried Thomas , Shilo Konstantin , Henschke Claudia , Yankelevitz David , Jen Jin 
Published: November 2008

Abstract
Purpose: We seek to establish a genetic test to identify lung cancer using cells obtained through computed tomography–guided fine needle aspiration (FNA).
Experimental Design: We selected regions of frequent copy number gains in chromosomes 1q32, 3q26, 5p15, and 8q24 in non–small cell lung cancer and tested their ability to determine the neoplastic state of cells obtained by FNA using fluorescent in situ hybridization. Two sets of samples were included. The pilot set included six paraffin-embedded, noncancerous lung tissues and 33 formalin-fixed FNA specimens. These 39 samples were used to establish the optimal fixation and single scoring criteria for the samples. The test set included 40 FNA samples. The results of the genetic test were compared with the cytology, pathology, and clinical follow-up for each case to assess the sensitivity and specificity of the genetic test.
Results: Nontumor lung tissues had ≤4 signals per nucleus for all tested markers, whereas tumor samples had ≥5 signals per nucleus in five or more cells for at least one marker. Among the 40 testing cases, 36 of 40 (90%) FNA samples were analyzable. Genetic analysis identified 15 cases as tumor and 21 cases as nontumor. Clinical and pathologic diagnoses confirmed the genetic test in 15 of 16 lung cancer cases regardless of tumor subtype, stage, or size and in 20 of 20 cases diagnosed as benign lung diseases.
Conclusions: A set of only four genetic markers can distinguish the neoplastic state of lung lesion using small samples obtained through computed tomography–guided FNA.
Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with EGFR-Mutant Lung Adenocarcinoma
Authors: Bean James , Riely Gregory J. , Balak Marissa , Marks Jenifer L. , Ladanyi Marc , Miller Vincent A. , Pao William 
Published: November 2008

Abstract
Purpose: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance.
Experimental Design: Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then done to characterize the biological properties of a novel mutant EGFR allele.
Results: A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R–mutant lung adenocarcinoma after long-term treatment with tyrosine kinase inhibitors. The T854A mutation was not detected in a pretreatment tumor sample. The crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays show that the EGFR T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib. Such resistance seems to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW 2992.
Conclusions: The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket.
Microtubule Active Agents: Beyond the Taxane Frontier
Authors: Morris Patrick G. , Fornier Monica N. 
Published: November 2008

Abstract
Microtubules are essential to cell transport, signaling, and mitosis. An increasing range of anticancer drugs interferes with the normal formation and function of microtubules. Vinca alkaloids act as microtubule destabilizers and the taxanes act as microtubule stabilizers. Taxanes are widely used cytotoxic agents that are active in a range of solid tumor malignancies and are routinely used in a variety of settings. Significant limitations with the taxanes exist, including acquired and intrinsic tumor resistance through the expression of multidrug resistance proteins such as P-glycoprotein, risk of hypersensitivity reactions, dose-limiting hematopoietic toxicity, and cumulative neurotoxicity. Hence, there is a need to develop novel agents that act on the microtubules. Epothilones are macrolide antibiotics that bind near the taxane-binding site on microtubules and have been extensively studied in recent and ongoing clinical trials. A variety of other agents that act on the microtubules at different sites with a variety of structures are at varying stages of development.
Prognostic Relevance of Occult Nodal Micrometastases and Circulating Tumor Cells in Colorectal Cancer in a Prospective Multicenter Trial
Authors: Koyanagi Kazuo , Bilchik Anton J. , Saha Sukamal , Turner Roderick R. , Wiese David , McCarter Martin , Shen Perry , Deacon Linda , Elashoff David , Hoon Dave S.B. 
Published: November 2008

Abstract
Purpose: Nodal micrometastasis and circulating tumor cells detected by multimarker quantitative real-time reverse transcription-PCR (qRT-PCR) may have prognostic importance in patients with colorectal cancer.
Experimental Design: Paraffin-embedded sentinel lymph nodes from 67 patients and blood from 34 of these patients were evaluated in a prospective multicenter trial of sentinel lymph node mapping in colorectal cancer. Sentinel lymph nodes were examined by H&E staining and cytokeratin immunohistochemistry. Sentinel lymph nodes and blood were examined by a four-marker qRT-PCR assay (c-MET, melanoma antigen gene-A3 family, β1→4-N-acetylgalactosaminyltransferase, and cytokeratin-20); qRT-PCR results were correlated with disease stage and outcome.
Results: In H&E-negative sentinel lymph node patients that recurred, cytokeratin immunohistochemistry and qRT-PCR detected metastasis in 30% and 60% of patients, respectively. Disease-free survival differed significantly by multimarker qRT-PCR upstaged sentinel lymph node (P = 0.014). qRT-PCR analysis of blood for circulating tumor cells correlated with overall survival (P = 0.040).
Conclusion: Molecular assessment for micrometastasis in sentinel lymph node and blood specimens may help identify patients at high risk for recurrent colorectal cancer, who could benefit from adjuvant therapy.
[18F]Fluorothymidine Positron Emission Tomography before and 7 Days after Gefitinib Treatment Predicts Response in Patients with Advanced Adenocarcinoma of the Lung
Authors: Sohn Hee-Jung , Yang You-Jung , Ryu Jin-Sook , Oh Seung Jun , Im Ki Chun , Moon Dae Hyuk , Lee Dae Ho , Suh Cheolwon , Lee Jung-Shin , Kim Sang-We 
Published: November 2008

Abstract
Purpose: To evaluate the usefulness of 3′-deoxy-3′-[18F]fluorothymidine (FLT)-positron emission tomography (PET) for predicting response and patient outcome of gefitinib therapy in patients with adenocarcinoma of the lung.
Experimental Design: Nonsmokers with advanced or recurrent adenocarcinoma of the lung were eligible. FLT-PET images of the thorax were obtained before and 7 days after the start of gefitinib (250 mg/d) therapy, the maximum standardized uptake values (SUVmax) of primary tumors were measured, and the percent changes in SUVmax were calculated. After 6 weeks of therapy, the responses were assessed by computed tomography of the chest.
Results: Among 31 patients who were enrolled, we analyzed 28 patients for whom we had complete data. Chest computed tomography revealed partial response in 14 (50%), stable disease in 4 (14%), and progressive disease in 10 (36%) after 6 weeks of treatment. Pretreatment SUVmax of the tumors did not differ between responders and nonresponders. At 7 days after the initiation of therapy, the percent changes in SUVmax were significantly different (−36.0 ± 15.4% versus 10.1 ± 19.5%; P &lt; 0.001). Decrease of &gt;10.9% in SUVmax was used as the criterion for predicting response. The positive and negative predictive values were both 92.9%. The time to progression was significantly longer in FLT-PET responders than nonresponders (median, 7.9 versus 1.2 months; P = 0.0041).
Conclusion: FLT-PET can predict response to gefitinib 7 days after treatment in nonsmokers with advanced adenocarcinoma of the lung. The change in tumor SUVmax obtained by FLT-PET seems to be a promising predictive variable.
Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors
Authors: Veltkamp Stephan A. , Witteveen Els O. , Capriati Angela , Crea Attilio , Animati Fabio , Voogel-Fuchs Marja , van den Heuvel Ingeborg J.G.M. , Beijnen Jos H. , Voest Emile E. , Schellens Jan H.M. 
Published: November 2008

Abstract
Purpose: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites.
Experimental Design: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m2, followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity.
Results: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m2 (n = 1), 3,600 mg/m2 (n = 1), and 2,400 mg/m2 (n = 2). The dose level of 1,800 mg/m2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m2) and head and neck cancer (2400 mg/m2). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan.
Conclusions: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m2 in a phase II study.
Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme
Authors: Veeravagu Anand , Liu Zhaofei , Niu Gang , Chen Kai , Jia Bing , Cai Weibo , Jin Cunjing , Hsu Andrew R. , Connolly Andrew J. , Tse Victor , Wang Fan , Chen Xiaoyuan 
Published: November 2008

Abstract
Purpose: Abegrin is a monoclonal antibody to human integrin αVβ3, a cell adhesion molecule highly expressed on actively angiogenic endothelium and glioblastoma multiforme tumor cells. The purpose of this study was to evaluate the efficacy of a novel 90Y-Abegrin radioimmunotherapeutic agent in murine xenograft glioblastoma models with noninvasive in vivo molecular imaging modalities.
Experimental Design: A s.c. U87MG human glioblastoma xenograft model was used to determine maximum tolerated dose (MTD), biodistribution, dose response, and efficacy of 90Y-Abegrin. Antitumor efficacy was also characterized in an orthotopic U87MG and in a HT-29 colorectal cancer model, a low integrin-expressing carcinoma. Small-animal positron emission tomography imaging was used to correlate histologic findings of treatment efficacy.
Results: MTD and dose response analysis revealed 200 μCi per mouse as appropriate treatment dose with hepatic clearance and no organ toxicity. 90Y-Abegrin–treated U87MG tumor mice showed partial regression of tumor volume, with increased tumor volumes in 90Y-IgG, Abegrin, and saline groups. 18F-FDG imaging revealed a reduction of cell proliferation and metabolic activity whereas 18F-FLT reflected decreased DNA synthesis in the 90Y-Abegrin group. Ki67 analysis showed reduced proliferative index and quantitative terminal deoxynucleotidyl transferase dUTP nick-end labeling–positive analysis revealed increased DNA fragmentation and apoptosis in 90Y-Abegrin animals. CD31 and 4′,6-diamidino-2-phenylindole staining showed increased vascular fragmentation and dysmorphic vessel structure in 90Y-Abegrin animals only. Orthotopic U87MG tumors treated with 90Y-Abegrin displayed reduced tumor volume. HT-29 tumors showed no significant difference among the various groups.
Conclusion: Radioimmunotherapy with 90Y-labeled Abegrin may prove promising in the treatment of highly vascular, invasive, and heterogeneous malignant brain tumors.