bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Tumor Volume of [18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Predicts Short-Term Outcome to Radiotherapy With or Without Chemotherapy in Pharyngeal Cancer
Authors: Chung Man Ki , Jeong Han-Sin , Park Sang Gyu , Jang Jeon Yeob , Son Young-Ik , Choi Joon Young , Hyun Seung Hyup , Park Keunchil , Ahn Myung-Ju , Ahn Yong Chan , Kim Hyung-Jin , Ko Young-Hyeh , Baek Chung-Hwan 
Published: September 2009

Abstract
Purpose: This study aimed to investigate whether metabolic tumor volume (MTV) measured from [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) predicts short-term outcome to radiotherapy with or without chemotherapy and disease-free survival (DFS) in patients with pharyngeal cancers.
Experimental Design: The MTVs of primary sites with or without neck nodes were measured in 82 patients. Short-term outcome was assessed using the treatment response evaluation by the Response Evaluation Criteria in Solid Tumors and recurrence events during follow-up (complete response/no recurrence or residual disease/recurrence).
Results: A total of 64 patients had complete response/no recurrence as of the last follow-up. A cutoff of 40 mL for the MTV was the best discriminative value for predicting treatment response. By univariate analyses, patients with MTV &gt;40 mL showed a significantly lower number of complete response/no recurrence than did patients with MTV ≤40 mL [68.2% versus 87.8%; hazard ratio (HR), 3.34; 95% confidence interval (95% CI), 1.09-10.08; P = 0.03], as is the same in tumor-node-metastasis stage (87.5% for I-II versus 90% for III versus 63.8% for IV; P = 0.02). However, MTV was only a significant predictor of short-term outcome by multivariate analyses (HR, 4.09; 95% CI, 1.02-16.43; P = 0.04). MTV &gt;40 mL indicated a significantly worse DFS than MTV ≤40 mL (HR, 3.42; 95% CI, 1.04-11.26;P = 0.04). The standardized uptake value for the primary tumor did not show any correlation with treatment outcome or DFS.
Conclusion: MTV has a potential value in predicting short-term outcome and DFS in patients with pharyngeal cancers. (Clin Cancer Res 2009;15(18):5861–8)
MicroRNA Expression Signatures in Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Yang Hushan , Gu Jian , Wang Kenneth K. , Zhang Wei , Xing Jinliang , Chen Zhinan , Ajani Jaffer A. , Wu Xifeng 
Published: September 2009

Abstract
Purpose: Esophageal adenocarcinoma is a highly aggressive malignancy that frequently develops from Barrett's esophagus, a premalignant pathologic change occurring in the lower end of the esophagus. Identifying Barrett's esophagus patients at high risk of malignant transformation is essential to the prevention of esophageal adenocarcinoma. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of esophageal adenocarcinoma have not been extensively evaluated.
Experimental Design: In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with Barrett's esophagus of either low- or high-grade dysplasia, or esophageal adenocarcinoma.
Results: Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of Barrett's esophagus with high-grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for esophageal adenocarcinoma, but not for Barrett's esophagus with low-grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade-dysplasia Barrett's esophagus to esophageal adenocarcinoma.
Conclusions: We showed that miRNAs were involved in the development and progression of esophageal adenocarcinoma. The identified significant miRNAs that may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer. (Clin Cancer Res 2009;15(18):5744–52)
Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure
Authors: Demetri George D. , Heinrich Michael C. , Fletcher Jonathan A. , Fletcher Christopher D.M. , Van den Abbeele Annick D. , Corless Christopher L. , Antonescu Cristina R. , George Suzanne , Morgan Jeffrey A. , Chen Ming Hui , Bello Carlo L. , Huang Xin , Cohen Darrel P. , Baum Charles M. , Maki Robert G. 
Published: September 2009

Abstract
Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules.
Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed.
Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease ≥6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by &gt;25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity.
Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902–9)
Association of Inflammation-Related and microRNA Gene Expression with Cancer-Specific Mortality of Colon Adenocarcinoma
Authors: Schetter Aaron J. , Nguyen Giang Huong , Bowman Elise D. , Mathé Ewy A. , Yuen Siu Tsan , Hawkes Jason E. , Croce Carlo M. , Leung Suet Yi , Harris Curtis C. 
Published: September 2009

Abstract
Purpose: Inflammatory genes and microRNAs have roles in colon carcinogenesis; therefore, they may provide useful biomarkers for colon cancer. This study examines the potential clinical utility of an inflammatory gene expression signature as a prognostic biomarker for colon cancer in addition to previously examined miR-21 expression.
Experimental Design: Quantitative reverse transcriptase-PCR. was used to measure the expression of 23 inflammatory genes in colon adenocarcinomas and adjacent noncancerous tissues from 196 patients. These data were used to develop models for cancer-specific mortality on a training cohort (n = 57), and this model was tested in both a test (n = 56) and a validation (n = 83) cohort. Expression data for miR-21 were available for these patients and were compared and combined with inflammatory gene expression.
Results: PRG1, IL-10, CD68, IL-23a, and IL-12a expression in noncancerous tissue, and PRG1, ANXA1, IL-23a, IL-17a, FOXP3, and HLA-DRA expression in tumor tissues were associated with poor prognosis based on Cox regression (|Z-score| &gt;1.5) and were used to generate the inflammatory risk score (IRS). IRS was associated with cancer-specific mortality in the training, test (P = 0.01), and validation (P = 0.02) cohorts. This association was strong for stage II cases (P = 0.002). Expression of miR-21 was associated with IL-6, IL-8, IL-10, IL-12a, and NOS2a, providing evidence that the function of this microRNA and these inflammatory genes are linked. Both IRS and miR-21 expression were independently associated with cancer-specific mortality, including stage II patients alone.
Conclusion: IRS and miR-21 expression are independent predictors of colon cancer prognosis and may provide a clinically useful tool to identify high-risk patients. (Clin Cancer Res 2009;15(18):5878–87)
Guiding the Optimal Translation of New Cancer Treatments From Canine to Human Cancer Patients
Authors: Khanna Chand , London Cheryl , Vail David , Mazcko Christina , Hirschfeld Steven 
Published: September 2009

Abstract
On June 20, 2008, a meeting entitled “Translation of new cancer treatments from canine to human cancer patients,” sponsored by the National Cancer Institute in Bethesda, Maryland, was convened to discuss the potential value, opportunity, risks, and rewards of an integrated and comparative drug development path for new cancer therapeutics that includes naturally occurring cancers in pet animals. A summary of this meeting and subsequent discussion are provided here to afford clarity on the conduct of these studies so as to optimize the opportunities provided by this novel drug development and modeling strategy. (Clin Cancer Res 2009;15(18):5671–7)
Biomarkers in GIST: Partly Ready for Prime-Time Use
Authors: Blanke Charles D. 
Published: September 2009

Abstract
Gastrointestinal stromal tumors, or GISTs, are now among the most treatable of solid malignancies. Assessing actual tumor response remains challenging; however, in this issue of Clinical Cancer Research, two articles discuss biomarkers potentially helpful in predicting response or other long-term benefits with standard tyrosine kinase therapy use. (Clin Cancer Res 2009;15(18):5603–5)
Adenovirus-mediated down-regulation of X-linked inhibitor of apoptosis protein inhibits colon cancer
Authors: Dai Yun , Qiao Liang , Chan Kwok Wah , Yang Mo , Ye Jieyu , Zhang Rongxin , Ma Juan , Zou Bing , Lam Colin S.C. , Wang Jide , Pang Roberta , Tan Victoria P.Y. , Lan H.Y. , Wong Benjamin C.Y. 
Published: September 2009

Abstract
Our previous studies and those of others have indicated that X-linked inhibitor of apoptosis protein (XIAP) holds promise as a target gene in colon cancer gene therapy. In this study, we constructed an adenoviral vector to deliver small hairpin RNA (shRNA) against XIAP (XIAP-shRNA) into colon cancer cells and tested its therapeutic efficacy in vitro and in vivo. We first confirmed an overexpression of XIAP in colon cancer cells and human cancer tissues. We then designed XIAP-small interfering RNA (siRNA) and confirmed the knockdown effect of these siRNAs in colon cancer cells. The sequences of the effective siRNAs were converted into shRNA and then packed into replication-deficient adenoviral vectors using BLOCK-iT Adenoviral RNAi Expression System to generate Adv-XIAP-shRNA. Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Treatment of xenograft tumors with Adv-XIAP-shRNA did not affect the expressions of inflammatory cytokines in tumor-bearing mice. Thus, Adv-XIAP-shRNA–mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response. [Mol Cancer Ther 2009;8(9):2762–70]
Exon Array Profiling DetectsEML4-ALKFusion in Breast, Colorectal, and Non–Small Cell Lung Cancers
Authors: Lin Eva , Li Li , Guan Yinghui , Soriano Robert , Rivers Celina Sanchez , Mohan Sankar , Pandita Ajay , Tang Jerry , Modrusan Zora 
Published: September 2009

AbstractThe echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as an oncogene in a subset of non–small cell lung cancers (NSCLC). We used profiling of cancer genomes on an exon array to develop a novel computational method for the global search of gene rearrangements. This approach led to the detection of EML4-ALK fusion in breast and colorectal carcinomas in addition to NSCLC. Screening of a large collection of patient tumor samples showed the presence of EML4-ALK fusion in 2.4% of breast (5 of 209), 2.4% of colorectal (2 of 83), and in 11.3% of NSCLC (12 of 106). Besides previously known EML4-ALK variants 1 (E13; A20) and 2 (E20; A20), a novel variant E21; A20 was found in colorectal carcinoma. The presence of an EML-ALK rearrangement was verified by identifying genomic fusion points in tumor samples representative of breast, colon, and NSCLC. EML4-ALK translocation was also confirmed by fluorescence in situ hybridization assay, which revealed its substantial heterogeneity in both primary tumors and tumor-derived cell lines. To elucidate the functional significance of EML4-ALK, we examined the growth of cell lines harboring the fusion following EML4 and ALK silencing by small interfering RNA. Significant growth inhibition was observed in some but not all cell lines, suggesting their variable dependence on ALK-mediated cell survival signaling. Collectively, these findings show the recurrence of EML4-ALK fusion in multiple solid tumors and further substantiate its role in tumorigenesis. (Mol Cancer Res 2009;7(9):1466–76)
Leukotriene B4 Creates a Favorable Microenvironment for Murine Melanoma Growth
Authors: Bachi André Luis Lacerda , Kim Fabiana Jin Kyung , Nonogaki Suely , Carneiro Célia Regina Whitaker , Lopes José Daniel , Jasiulionis Miriam Galvonas , Correa Mariangela 
Published: September 2009

AbstractChronic inflammation has long been associated with neoplastic progression. Our group had recently shown that the addition of a large number of apoptotic tumor cells to the tumor microenvironment induces a potent acute inflammatory reaction capable of promoting melanoma growth; however, primarily necrotizing cells do not cause such a reaction. Here, we show that potent inflammatory agents, such as lipopolysaccharide (LPS) and carrageenan, also promote growth of subtumorigenic doses of melanoma cells, having no effect on melanoma proliferation in vitro. Inhibition of 5-lipoxygenase (5-LOX) seems to have a pivotal role in this model because caffeic acid and MK886, a FLAP (5-LOX–activating protein) inhibitor, partially hindered tumor growth induced by apoptotic cells or LPS. Other enzymes of the arachidonic acid pathway, cyclooxygenase-1 and cyclooxygenase-2, seem to have no participation in this tumor promoter effect, as the inhibitor of both enzymes (indomethacin) did not alter melanoma growth. Leukotriene B4 (LTB4), the main product of the 5-LOX pathway, was able to induce growth of subtumorigenic inocula of melanoma cells, and a LTB4 receptor antagonist inhibited acute inflammation-associated tumor growth. Addition to the tumor inflammatory microenvironment of eicosapentaenoic acid, an ω3-polyunsaturated fatty acid with anti-inflammatory properties, or leukotriene B5, an eicosapentaenoic acid–derived leukotriene, significantly inhibited tumor development. These results give new insights to the mechanisms through which inflammation may contribute to tumor progression and suggest that LOX has an important role in tumor progression associated with an inflammatory state in the presence of apoptosis, which may be a consideration for apoptosis-inducing treatments, such as chemotherapy and radiotherapy. (Mol Cancer Res 2009;7(9):1417–24)
Pharmacologic p53 Activation Blocks Cell Cycle Progression but Fails to Induce Senescence in Epithelial Cancer Cells
Authors: Huang Baoying , Deo Dayanand , Xia Mingxuan , Vassilev Lyubomir T. 
Published: September 2009

Abstract
Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies. (Mol Cancer Res 2009;7(9):1497–509)
Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding
Authors: Dutton Richard , Hauser Carl , Boffard Kenneth , Dimsitts Jeannett , Bernard Gordon , Holcomb John , Leppäniemi Ari , Tortella Bartholemew , Bouillon Bertil , CONTROL Steering Committee  
Published: September 2009

Background Clinical research in trauma patients poses multiple challenges in study design. These reflect the heterogeneity of injury and treatment, the paucity of acceptable study endpoints aside from mortality, and the difficulties inherent in obtaining informed consent in acutely ill populations. A current example of this problem is the study of recombinant factor VIIa (rFVIIa), which has attracted considerable interest as a systemic procoagulant agent for use in trauma patients with exsanguinating hemorrhage. Purpose To report on the implementation of an international trial — CONTROL — intended to assess the efficacy and safety of rFVIIa in trauma, and discuss trauma research study design in light of this experience. Methods The CONTROL trial international steering committee confronted a number of barriers in the design of the CONTROL trial. They addressed methodologies for (1) standardizing entry criteria for trauma patients suffering inherently heterogeneous injuries, (2) obtaining informed consent in an acutely injured population with altered levels of consciousness, (3) avoiding futile care, while recruiting subjects with incompletely diagnosed injuries, (4) standardizing trauma intensive care across different investigating sites and countries, and (5) establishing study endpoints that were both clinically relevant and convincing to regulatory authorities. The resulting study methodology is reported. Results The CONTROL trial began active recruitment in October 2005, and was halted on June 11, 2008 because the observed mortality in the 576 enrolled patients was so far below expectations that the study would lack sufficient statistical power at the planned number of subjects to demonstrate a benefit. The utility of the endpoints selected for study will not be known until completion of data analysis. Limitations Any clinical trial in trauma patients must cope with the urgency of care required, issues of patient heterogeneity, standardization of care across multiple centers, and the difficulties of obtaining informed consent. Conclusion Research in acutely hemorrhaging trauma patients presents numerous scientific and ethical challenges. The methodology of the CONTROL study is presented as an example of how some of these challenges can be approached and managed, and of the pitfalls that may arise. Clinical Trials 2009; 6: 467—479. http://ctj.sagepub.com
Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis
Authors: Kim Ha-Jeong , Kim Pan-Kyung , Bae Sang Mun , Son Hye-Nam , Thoudam Debraj Singh , Kim Jung-Eun , Lee Byung-Heon , Park Rang-Woon , Kim In-San 
Published: September 2009

Abstract
Transforming growth factor-β–induced protein (TGFBIp)/βig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, α-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.
BMS-214662 induces mitochondrial apoptosis in chronic myeloid leukemia (CML) stem/progenitor cells, including CD34+38− cells, through activation of protein kinase Cβ
Authors: Pellicano Francesca , Copland Mhairi , Jorgensen Heather G. , Mountford Joanne , Leber Brian , Holyoake Tessa L. 
Published: September 2009

AbstractChronic myeloid leukemia (CML) is a hematopoietic stem cell disorder maintained by cancer stem cells. To target this population, we investigated the mechanism of action of BMS-214662, developed as a farnesyl transferase inhibitor (FTI) and unique in inducing apoptosis in these cells. By contrast, a related congener and equally effective FTI, BMS-225975 does not induce apoptosis, indicating a novel mechanism of action. BMS-214662 significantly and selectively induced apoptosis in primitive CD34+38− CML compared with normal cells. Apoptosis proceeded via the intrinsic pathway: Bax conformational changes, loss of mitochondrial membrane potential, generation of reactive oxygen species, release of cytochrome c, and caspase-9/3 activation were noted. Up-regulation of protein kinase Cβ (PKCβ), down-regulation of E2F1, and phosphorylation of cyclin A–associated cyclin-dependent kinase 2 preceded these changes. Cotreatment of CML CD34+ and CD34+38− cells with PKC modulators, bryostatin-1, or hispidin markedly decreased these early events and the subsequent apoptosis. None of these events was elicited by BMS-214662 in normal CD34+ cells or by BMS-225975 in CML CD34+ cells. These data suggest that BMS-214662 selectively elicits a latent apoptotic pathway in CML stem cells that is initiated by up-regulation of PKCβ and mediated by Bax activation, providing a molecular framework for development of novel therapeutics.