bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features
Authors: Bomben Riccardo , Dal-Bo Michele , Benedetti Dania , Capello Daniela , Forconi Francesco , Marconi Daniela , Bertoni Francesco , Maffei Rossana , Laurenti Luca , Rossi Davide , Del Principe Maria Ilaria , Luciano Fabrizio , Sozzi Elisa , Cattarossi Ilaria , Zucchetto Antonella , Rossi Francesca Maria , Bulian Pietro , Zucca Emanuele , Nicoloso Milena S. , Degan Massimo , Marasca Roberto , Efremov Dimitar G. , Del Poeta Giovanni , Gaidano Gianluca , Gattei Valter 
Published: January 2010

Abstract
Purpose: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL.
Experimental Design: Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23–expressing CLL.
Results: IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non–IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non–IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non–IGHV3-23 CLL.
Conclusions: Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features. Clin Cancer Res; 16(2); 620–8
MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer
Authors: Landi Maria Teresa , Zhao Yingdong , Rotunno Melissa , Koshiol Jill , Liu Hui , Bergen Andrew W. , Rubagotti Maurizia , Goldstein Alisa M. , Linnoila Ilona , Marincola Francesco M. , Tucker Margaret A. , Bertazzi Pier Alberto , Pesatori Angela C. , Caporaso Neil E. , McShane Lisa M. , Wang Ena 
Published: January 2010

AbstractPurpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non–small cell lung cancer.Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics.Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (Pglobal &lt; 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ.Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. Clin Cancer Res; 16(2); 430–41
Antibodies to TWEAK Receptor Inhibit Human Tumor Growth through Dual Mechanisms
Authors: Culp Patricia A. , Choi Donghee , Zhang Yongke , Yin Johnny , Seto Pui , Ybarra Suzanne E. , Su Mian , Sho Mien , Steinle Roxanne , Wong Melanie H.L. , Evangelista Ferdinand , Grove Jennifer , Cardenas Marie , James Marjorie , Hsi Eric D. , Chao Debra T. , Powers David B. , Ramakrishnan Vanitha , Dubridge Robert 
Published: January 2010

AbstractPurpose: Targeted therapeutics have significantly changed the outcome for patients diagnosed with cancer. Still, effective therapeutic intervention does not exist for many cancers and much remains to be done. The objective of this study was to identify novel genes that potentially regulate tumor growth, to target these gene products with monoclonal antibodies, and to examine the therapeutic potential of these antibodies.Experimental Design: Using cDNA microarray analysis, we identified genes overexpressed in several solid malignancies. We generated a mouse monoclonal antibody, 19.2.1, and its humanized counterpart, PDL192, to one such target, TweakR (TWEAK receptor, Fn14, TNFRSF12A, CD266), and characterized the antitumor activities in vitro and in mouse xenograft models.Results: Both 19.2.1 (mouse IgG2a) and PDL192 (human IgG1), like TWEAK, the natural ligand of TweakR, inhibited the growth of several TweakR-expressing cancer cell lines in anchorage-dependent and anchorage-independent assays in vitro. Both antibodies showed significant antitumor activity in multiple mouse xenograft models. PDL192 and 19.2.1 also induced antibody-dependent cellular cytotoxicity (ADCC) of cancer cell lines in vitro. A chimeric version of 19.2.1 containing the mouse IgG1 Fc region (19.2.1×G1) exhibited significantly less ADCC than 19.2.1. However, 19.2.1×G1 showed differential activity in vivo, with activity equivalent to 19.2.1 in one model, but significantly less efficacy than 19.2.1 in a second model. These results indicate that PDL192 and 19.2.1 mediate their antitumor effects by signaling through TweakR, resulting in reduced tumor cell proliferation, and by ADCC. Clin Cancer Res; 16(2); 497–508
Romidepsin and Belinostat Synergize the Antineoplastic Effect of Bortezomib in Mantle Cell Lymphoma
Authors: Paoluzzi Luca , Scotto Luigi , Marchi Enrica , Zain Jasmine , Seshan Venkatraman E. , O'Connor Owen A. 
Published: January 2010

Abstract
Purpose: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non–Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1.
Experimental Design: Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL.
Results: In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-XL, and an increase in accumulation of acetylated histone H3, acetylated α-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone.
Conclusions: Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL. Clin Cancer Res; 16(2); 554–65
Glioma-Associated Cancer-Initiating Cells Induce Immunosuppression
Authors: Wei Jun , Barr Jason , Kong Ling-Yuan , Wang Yongtao , Wu Adam , Sharma Amit K. , Gumin Joy , Henry Verlene , Colman Howard , Sawaya Raymond , Lang Frederick F. , Heimberger Amy B. 
Published: January 2010

Abstract
Purpose: Glioblastoma multiforme is a lethal cancer that responds poorly to therapy. Glioblastoma multiforme cancer-initiating cells have been shown to mediate resistance to both chemotherapy and radiation; however, it is unknown to what extent these cells contribute to the profound immunosuppression in glioblastoma multiforme patients and if strategies that alter their differentiation state can reduce this immunosuppression.
Experimental Design: We isolated a subpopulation of cells from glioblastoma multiforme that possessed the capacity for self-renewal, formed neurospheres in vitro, were capable of pluripotent differentiation, and could initiate tumors in vivo. The immune phenotype of these cells was characterized including the elaboration of immunosuppressive cytokines and chemokines by ELISA. Functional immunosuppressive properties were characterized based on the inhibition of T-cell proliferation and effector responses, triggering of T-cell apoptosis, and induction of FoxP3+ regulatory T cells. On altering their differentiation state, the immunosuppressive phenotype and functional assays were reevaluated.
Results: We found that the cancer-initiating cells markedly inhibited T-cell proliferation and activation, induced regulatory T cells, and triggered T-cell apoptosis that was mediated by B7-H1 and soluble Galectin-3. These immunosuppressive properties were diminished on altering the differentiation of the cancer-initiating cells.
Conclusion: Cancer-initiating cells contribute to tumor evasion of the immunosurveillance and approaches that alter the differentiation state may have immunotherapeutic potential. Clin Cancer Res; 16(2); 461–73
Prospective Comparison of Clinical and Genomic Multivariate Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer
Authors: Lee Jae K. , Coutant Charles , Kim Young-Chul , Qi Yuan , Theodorescu Dan , Symmans W. Fraser , Baggerly Keith , Rouzier Roman , Pusztai Lajos 
Published: January 2010

Abstract
Purpose: Several different multivariate prediction models using routine clinical variables or multigene signatures have been proposed to predict pathologic complete response to combination chemotherapy in breast cancer. Our goal was to compare the performance of four conceptually different predictors in an independent cohort of patients.
Experimental Design: Gene expression profiling was done on fine-needle aspirations of 100 stage I to III breast cancers before preoperative paclitaxel, 5-fluorouracil, doxorubicin, and cyclophosphamide combination chemotherapy. Pathologic response was correlated with prediction results from a clinical nomogram, a human cancer–derived genomic predictor (DLDA30), a cell line–based genomic predictor [in vitro coexpression extrapolation (COXEN)], and an optimized cell line–derived (in vivo COXEN) predictor. None of the 100 test cases were used in the development of these predictors.
Results: The in vitro COXEN using a combination of four individual drug sensitivity predictions derived from cell lines was not predictive [area under the receiver operator characteristic curve (AUC), 0.5; 95% confidence interval, (95% CI), 0.41-0.59]. The clinical nomogram (AUC, 0.73; 95% CI, 0.65-0.80) and the DLDA30 (AUC, 0.73; 95% CI, 0.66-0.80) genomic predictor had similar performances. The in vivo COXEN that used informative genes from cell lines but was trained on a separate human data set also showed significant predictive value (AUC, 0.67; 95% CI, 0.60-0.74). These three different prediction scores correlated with each other and were significant in univariate but not in multivariate analysis.
Conclusions: Three conceptually different predictors performed similarly in this validation study and tended to identify the same patients as responders. A genomic predictor that relied solely on a composite of individual drug sensitivity predictions from cell lines did not show any predictive value. Clin Cancer Res; 16(2); 711–8
Antitumor Effect of NK012, a 7-Ethyl-10-Hydroxycamptothecin–Incorporating Polymeric Micelle, on U87MG Orthotopic Glioblastoma in Mice Compared with Irinotecan Hydrochloride in Combination with Bevacizumab
Authors: Kuroda Jun-ichiro , Kuratsu Jun-ichi , Yasunaga Masahiro , Koga Yoshikatsu , Kenmotsu Hirotsugu , Sugino Takashi , Matsumura Yasuhiro 
Published: January 2010

AbstractPurpose: To clarify the effect of bevacizumab on NK012 therapy in mice bearing U87MG glioblastoma orthotopic xenografts in comparison with the combination therapy of irinotecan hydrochloride (CPT-11) with bevacizumab.Experimental Design: NK012 at 7-ethyl-10-hydroxycamptothecin (SN-38) equivalent dose of 30 mg/kg was administered intravenously three times every 4 days with or without bevacizumab. CPT-11 at 66.7 mg/kg was administered intravenously three times every 4 days or CPT-11 at 40 mg/kg/d over 5 consecutive days with or without bevacizumab. Bevacizumab was administered intraperitoneally six times every 4 days in each experiment. In vivo antitumor effects were evaluated by bioluminescence imaging, histopathologic evaluation, and immunohistochemistry. To evaluate interaction with bevacizumab, free SN-38 concentration in tumor tissues was examined by high-performance liquid chromatography.Results: CPT-11 in combination with bevacizumab showed significantly more potent antitumor activity and longer survival than CPT-11 monotherapy (P &lt; 0.05). However, there was no difference between NK012 monotherapy and NK012 in combination with bevacizumab. Concentration of free SN-38 released from NK012 in tumor tissue decreased in combination with bevacizumab (P = 0.027). NK012 monotherapy or NK012 with bevacizumab showed potent antitumor activity and longer survival than any dosing method of CPT-11 in combination with bevacizumab (P &lt; 0.05). Orthotopic tumors treated with NK012 showed decreased tumor cellularity and lower Ki-67 index (P &lt; 0.001) relative to those treated with CPT-11/bevacizumab.Conclusions: The present study using orthotopic glioblastoma model in mice may warrant further preclinical evaluation of NK012 before conducting the clinical trial of the drug, because the antitumor activity of NK012 monotherapy was superior to the combination therapy of CPT-11 with bevacizumab. Clin Cancer Res; 16(2); 521–9
Analysis of Genetic Variants in Never-Smokers with Lung Cancer Facilitated by an Internet-Based Blood Collection Protocol: A Preliminary Report
Authors: Girard Nicolas , Lou Emil , Azzoli Christopher G. , Reddy Rekha , Robson Mark , Harlan Megan , Orlow Irene , Yatabe Yasushi , Nafa Khedoudja , Ladanyi Marc , Viale Agnes , Kris Mark G. , Riely Gregory , Miller Vincent , Klein Robert J. , Matsuo Keitaro , Pao William 
Published: January 2010

Abstract
Purpose: Germ line polymorphisms may confer susceptibility to lung cancer in never smokers, but studies in the United States have been limited by the low number of cases seen at single institutions. We hypothesized that we could use the Internet to bolster the accrual of appropriate patients.
Experimental Design: We established an Internet-based protocol to collect blood and information from patients throughout the United States. To illustrate the power of this approach, we used these samples, plus additional cases and age-matched controls from the Memorial Sloan-Kettering Cancer Center (New York, NY) and the Aichi Cancer Center (Nagoya, Japan), to analyze germ line DNA for genetic variants reportedly associated with lung cancer susceptibility. The genotypes for the polymorphisms rs763317 (intron 1) and T790M (exon 20) in the EGFR gene were determined by direct sequencing, and CHRNA3 nicotinic acetylcholine receptor single nucleotide polymorphisms (rs8034191 and rs1051730) were genotyped as part of a pilot genome-wide association study.
Results: We successfully analyzed germ line DNA from 369 cases, including 45 obtained via the Internet, and 342 controls. A germ line EGFR T790M variant was identified in 2 of the 369 cases (0.54%; 95% confidence interval, 0.21-1.29%), and in none of the 292 controls (P = 0.21). No difference was observed in EGFR rs763317 frequency between cases and controls. Similarly, neither CHRNA3 rs8034191 nor rs1051730 were associated with lung cancer risk.
Conclusions: The Internet provides a way to recruit patients throughout the country for minimal risk studies. This approach could be used to facilitate studies of germ line polymorphisms in specific groups of patients with cancer. Clin Cancer Res; 16(2); 755–63
A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages
Authors: Wahlin Björn Engelbrekt , Aggarwal Mohit , Montes-Moreno Santiago , Gonzalez Luis Francisco , Roncador Giovanna , Sanchez-Verde Lidia , Christensson Birger , Sander Birgitta , Kimby Eva 
Published: January 2010

AbstractPurpose: The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors.Experimental Design: Seventy follicular lymphoma patients with extreme clinical outcome (“poor” and “good” cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in ≤5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used.Results: Independently of the Follicular Lymphoma International Prognostic Index, CD4+ cells were associated with poor outcome and programmed death-1–positive and CD8+ cells were associated with good outcome. The prognostic values of CD4+ and programmed death-1–positive cells were accentuated when they were follicular and that of CD8+ cells were accentuated when they were interfollicular. Follicular FOXP3+ cells were associated with good outcome and interfollicular CD68+ cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome.Conclusion: There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets. Clin Cancer Res; 16(2); 637–50.
Clusterin Facilitates COMMD1 and I-κB Degradation to Enhance NF-κB Activity in Prostate Cancer Cells
Authors: Zoubeidi Amina , Ettinger Susan , Beraldi Eliana , Hadaschik Boris , Zardan Anousheh , Klomp Leo W.J. , Nelson Colleen C. , Rennie Paul S. , Gleave Martin E. 
Published: January 2010

Abstract
Secretory clusterin (sCLU) is a stress-activated, cytoprotective chaperone that confers broad-spectrum cancer treatment resistance, and its targeted inhibitor (OGX-011) is currently in phase II trials for prostate, lung, and breast cancer. However, the molecular mechanisms by which sCLU inhibits treatment-induced apoptosis in prostate cancer remain incompletely defined. We report that sCLU increases NF-κB nuclear translocation and transcriptional activity by serving as a ubiquitin-binding protein that enhances COMMD1 and I-κB proteasomal degradation by interacting with members of the SCF-βTrCP E3 ligase family. Knockdown of sCLU in prostate cancer cells stabilizes COMMD1 and I-κB, thereby sequestrating NF-κB in the cytoplasm and decreasing NF-κB transcriptional activity. Comparative microarray profiling of sCLU-overexpressing and sCLU-knockdown prostate cancer cells confirmed that the expression of many NF-κB–regulated genes positively correlates with sCLU levels. We propose that elevated levels of sCLU promote prostate cancer cell survival by facilitating degradation of COMMD1 and I-κB, thereby activating the canonical NF-κB pathway. Mol Cancer Res; 8(1); 119–30
Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells
Authors: Lyakhovich Alex , Surrallés Jordi 
Published: January 2010

Abstract
Fanconi anemia (FA) is a rare syndrome characterized by developmental abnormalities, progressive bone marrow failure, and cancer predisposition. Cells from FA patients exhibit hypersensitivity to DNA cross-linking agents and oxidative stress that may trigger apoptosis. Damage-induced activation of caspases and poly ADP ribose polymerase (PARP) enzymes have been described for some of the FA complementation groups. Here, we show the constitutive activation of caspase-3 and PARP cleavage in the FA cells without exposure to exogenous DNA-damaging factors. These effects can be reversed in the presence of reactive oxygen species scavenger N-acetylcystein. We also show the accumulation of oxidized proteins in FA cells, which is accompanied by the tumor necrosis factor (TNF)-α oversecretion and the upregulation of early stress response kinases pERK1/2 and p-P38. Suppression of TNF-α secretion by the extracellular signal-regulated kinase inhibitor PD98059 results in reduction of caspase-3 cleavage, suggesting a possible mechanism of caspases-3 activation in FA cells. Thus, the current study is the first evidence demonstrating the damage-independent activation of caspase-3 and PARP in FA cells, which seems to occur through mitogen-activated protein kinase activation and TNF-α oversecretion.Mol Cancer Res; 8(1); 46–56