bluuebunny/crossref_metadata_2025 huggingface dataset:
HER2-Specific T Cells Target Primary Glioblastoma Stem Cells and Induce Regression of Autologous Experimental Tumors
Authors: Ahmed Nabil , Salsman Vita S. , Kew Yvonne , Shaffer Donald , Powell Suzanne , Zhang Yi J. , Grossman Robert G. , Heslop Helen E. , Gottschalk Stephen
Published: January 2010

Purpose: Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment.

Experimental Design: HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor. The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model.

Results: Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-γ and interleukin-2 in a HER2-dependent manner. Patients' HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of autologous GBM xenografts established in the brain of severe combined immunodeficient mice.

Conclusions: Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T cells may be a promising immunotherapeutic approach for GBM. Clin Cancer Res; 16(2); 474–85
The Cross-Validated Adaptive Signature Design
Authors: Freidlin Boris , Jiang Wenyu , Simon Richard
Published: January 2010

Purpose: Many anticancer therapies benefit only a subset of treated patients and may be overlooked by the traditional broad eligibility approach to design phase III clinical trials. New biotechnologies such as microarrays can be used to identify the patients that are most likely to benefit from anticancer therapies. However, due to the high-dimensional nature of the genomic data, developing a reliable classifier by the time the definitive phase III trail is designed may not be feasible.

Experimental Design: Previously, Freidlin and Simon (Clinical Cancer Research, 2005) introduced the adaptive signature design that combines a prospective development of a sensitive patient classifier and a properly powered test for overall effect in a single pivotal trial. In this article, we propose a cross-validation extension of the adaptive signature design that optimizes the efficiency of both the classifier development and the validation components of the design.

Results: The new design is evaluated through simulations and is applied to data from a randomized breast cancer trial.

Conclusion: The cross-validation approach is shown to considerably improve the performance of the adaptive signature design. We also describe approaches to the estimation of the treatment effect for the identified sensitive subpopulation. Clin Cancer Res; 16(2); 691–8
Safety, Pharmacokinetics, and Pharmacodynamics of AMG 102, a Fully Human Hepatocyte Growth Factor–Neutralizing Monoclonal Antibody, in a First-in-Human Study of Patients with Advanced Solid Tumors
Authors: Gordon Michael S. , Sweeney Christopher J. , Mendelson David S. , Eckhardt S. Gail , Anderson Abraham , Beaupre Darrin M. , Branstetter Daniel , Burgess Teresa L. , Coxon Angela , Deng Hongjie , Kaplan-Lefko Paula , Leitch Ian M. , Oliner Kelly S. , Yan Lucy , Zhu Min , Gore Lia
Published: January 2010

Purpose: The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)–neutralizing monoclonal antibody, in patients with solid tumors.

Experimental Design: Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti–AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed.

Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti–AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses.

Conclusions: AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents. Clin Cancer Res; 16(2); 699–710
Activity of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Models of Breast Cancer
Authors: Purcell James W. , Davis Jefferson , Reddy Mamatha , Martin Shamra , Samayoa Kimberly , Vo Hung , Thomsen Karen , Bean Peter , Kuo Wen Lin , Ziyad Safiyyah , Billig Jessica , Feiler Heidi S. , Gray Joe W. , Wood Kenneth W. , Cases Sylvaine
Published: January 2010

Purpose: Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.

Experimental Design: We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.

Results: In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.

Conclusions: These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer. Clin Cancer Res; 16(2); 566–76
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

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

Purpose: 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 < 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

Purpose: 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

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

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

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

Purpose: 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 < 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 < 0.05). Orthotopic tumors treated with NK012 showed decreased tumor cellularity and lower Ki-67 index (P < 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

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

Purpose: 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

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

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
What Determines the Later Clinical Course of Patients Who Do Not Undergo Colectomy at the First Attack A Japanese Cohort Study on Ulcerative Colitis
Authors: Shiga Hisashi , Takagi Sho , Inoue Ryusuke , Kinouchi Yoshitaka , Ohkubo Takayoshi , Takahashi Seiichi , Negoro Kenichi , Yokoyama Hiroshi , Kato Seiichi , Fukushima Kouhei , Hiwatashi Nobuo , Shimosegawa Tooru
Published: January 2010

Background/Aims: Several earlier studies on factors predicting the long-term outcome of ulcerative colitis only encompassed treatment failure for one severe episode, or suffered from a lack of multivariate analyses. We aimed to identify factors assessable at diagnosis or after the first induction therapy which predicted relapse or later colectomy in patients with mild to severe ulcerative colitis. Methods: Clinical parameters (age, sex, disease extent, and disease activity at diagnosis) and laboratory data (hemoglobin, albumin, C-reactive protein, and erythrocyte sedimentation rate at diagnosis and 4 weeks after the first induction therapy) were evaluated in 296 patients (median follow-up 87 months). Factors predicting relapse and later colectomy were sought using the Cox proportional hazard model. Results: The presence of moderate or severe disease at diagnosis were significant predictors of relapse [adjusted hazard ratio (95% CI) 2.07 (1.48–2.89) and 1.70 (1.06–2.72), respectively] and later colectomy [3.40 (1.09–10.54) and 6.77 (1.92–23.86)]. After the first induction therapy, hemoglobin and albumin were associated with relapse [0.87 (0.76–0.99) and 0.58 (0.41–0.83)] and later colectomy [0.60 (0.47–0.77) and 0.11 (0.06–0.22)]. Conclusion: Relapse and later colectomy were associated with (1) disease activity at diagnosis and (2) lower levels of hemoglobin and albumin after the first induction therapy.
Do Macromorphological Features of the Human Placenta Influence Somatic and Psychomotor Development of the Newborn and Early Infant? A Historic Question Revisited
Authors: Westhof Gregor , Deerberg Jost C. , Schad Wolfgang , Zimmermann Ralf C. , Hatzmann Hendrike
Published: January 2010

Objective: We examined the meaning of placental weight, form (massive and thick or extended and flat) and circumference for early somatic and psychomotor childhood development. Methods:In this prospective study, fresh placentas (n = 265) were measured for weight and circumference and correlated with neonatal data. A subset of placentas statistically defined as ‘massive’ (circumference <10th percentile) and ‘extended’ (circumference >90th percentile) was correlated with somatic and basic psychomotor variables during the first 4 years of life. A ‘medium’ category (circumference 45–55th percentile) served as control. Results: Placental weight correlated with birth weight (r = 0.53, p < 0.0005) and mean infantile weight until month 48 (r = 0.29, p = 0.016). Placental circumference weakly correlated with birth weight (r = 0.17, p = 0.011) but not with mean infantile weight. Placental extremes (massive, medium, extended) demonstrated significant influences only on very early somatic growth (day 1 to month 4): Massive placentas were associated with heavier and taller children (p = 0.02–0.033). Markers of early psychomotor development (first sitting, crawling, running, one- and two-word sentences) were not related with placental weight or circumference nor with extremes of placental morphology. Conclusion: Placental weight and circumference seem to influence very early somatic but not psychomotor development.
Estimation of Short-Term Effects of Air Pollution on Stroke Hospital Admissions in Southern Sweden
Authors: Oudin Anna , Strömberg Ulf , Jakobsson Kristina , Stroh Emilie , Björk Jonas
Published: January 2010

Background: Short-term exposure to high levels of air pollution can increase stroke risk. In this study we investigated the short-term effects of air pollution on hospital admissions for stroke in a setting where pollutant levels are rather low. We also addressed methodological issues in evaluating the short-term effects of air pollution. Methods: Daily admissions of ischemic (n = 11,267) and hemorrhagic (n = 1,681) stroke were obtained from a Swedish quality register for stroke, Riks-Stroke. We used two types of exposure data: (1) daily measured background levels of ozone, temperature and particles with a diameter <10 µm (PM10) and (2) modeled levels of a mixture of NO and NO2 (NOx) at the residential address of each individual. Results: We estimated a 13% (95% confidence interval, 4–22%) increased risk for hospital admissions for ischemic stroke for levels of PM10 above 30 µg/m3 compared to <15 µg/m3, whereas temperature above 16°C decreased the risk. No consistent associations were found for hemorrhagic stroke or for ischemic stroke and ozone or NOx. Conclusion: Particulate air pollution and temperature seemed to be associated with ischemic stroke hospital admissions. Individual exposure modeling facilitates a detailed exposure assessment but may also be more prone to misclassification errors. The time series and case crossover approaches yielded similar effect estimates.
Whole-Genome Sequence Analysis of Human Papillomavirus Type 18 from Infected Thai Women
Authors: Lurchachaiwong Woradee , Junyangdikul Pairoj , Termrungruanglert Wichai , Payungporn Sunchai , Sampatanukul Pichet , Tresukosol Damrong , Niruthisard Somchai , Trivijitsilp Prasert , Karalak Anant , Swangvaree Sukumarn , Poovorawan Yong
Published: January 2010

Objective: The aim of this study was to attain molecular knowledge of human papillomavirus type 18 (HPV18) by sequencing the whole genome of HPV18 isolated from Thai women at various clinical stages of disease progression. Method: Our group analyzed 9 samples of whole-genome HPV18 in infected women ranging from normal to cervical cancer by PCR, a sequencing method and bioinformatics programs. Results: Phylogenetic analysis based on the whole genome showed that HPV18 samples were more closely related to the European and Asian-American type than the African type. The vaccine strain’s L1 nucleotide (US patent 5820870) showed a close relationship to the African type. However, our data cannot indicate the correlation between cytological data and nucleotide or amino acid variation. Conclusion: Our group cannot draw any inference between the clinical stage of disease progression and amino acid alterations as there were only 1 or 2 samples available for each clinical trial. However, we hope that these new data on the HPV genome, which are representative of the entire genome of HPV in Southeast Asia, can serve as basis data for future research on the pathogenesis of cervical cancer. Additionally, the second-generation HPV18 vaccines should be tested on both HPV18-L1 and HPV18-L2 for increasing potential protection.
Resuscitation of Severely Asphyctic Newborn Pigs with Cardiac Arrest by Using 21% or 100% Oxygen
Authors: Solevåg Anne L. , Dannevig Ingrid , Nakstad Britt , Saugstad Ola D.
Published: January 2010

Background: In spite of evidence suggesting that resuscitation with 100% O2 is detrimental, international guidelines still recommend its use. Clinical studies comparing 21% and 100% O2 included many infants with only mild and moderate asphyxia. Objectives: We aimed to investigate the effect of these oxygen fractions on haemodynamic parameters, arterial blood gases, oxygen saturation indices and markers of inflammation and hypoxic damage when resuscitating asystolic newborn pigs following asphyxia. Methods: Newborn swine (n = 32, age 12–36 h, weight 2.0–2.7 kg) were progressively asphyxiated until asystole occurred. Cardiopulmonary resuscitation was initiated with ventilation with either 21% (n = 16) or 100% O2 (n = 16). Return of spontaneous circulation (ROSC) was defined as a heart rate ≧100 min–1. Results: Mean time of hypoxia, pH, base excess and pCO2 at asystole were comparable between the groups. All animals except 2 in the 100% group achieved ROSC. One animal in the 21% group suffered bradycardia at baseline and was excluded. For the remaining 15 animals resuscitated with 21% O2, median time to ROSC (interquartile range) was 150 s (115–180), whereas animals in the 100% group achieved ROSC after 135 s (113–168); p = 0.80. There were no differences in the temporal changes in mean arterial blood pressure, heart rate, pH, pCO2, interleukin-1β or lactate/pyruvate ratios. However, systemic and regional cerebral oxygen saturations were higher in the animals resuscitated with 100% oxygen. Conclusion: In this animal model of severe perinatal asphyxia, resuscitation with room air seemed to be as safe and effective as the use of 100% oxygen.
Investigation of the Use of Antioxidants to Diminish the Adverse Effects of Postnatal Glucocorticoid Treatment on Mortality and Cardiac Development
Authors: Adler Alexandra , Camm Emily J. , Hansell Jeremy A. , Richter Hans G. , Giussani Dino A.
Published: January 2010

Background: In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on growth and the cardiovascular system. Glucocorticoid excess promotes free radical overproduction and vascular dysfunction. Objectives: We hypothesized that the adverse effects of postnatal glucocorticoid therapy are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Methods: Male rat pups received a clinically relevant course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1–6 (P1–6). Controls received saline (Ctrl) or saline with vitamins (CtrlCE). Results: At P21, Dex reduced survival (Ctrl: 96 vs. Dex: 70%) and promoted asymmetric growth restriction (ponderal index, Ctrl: 6.3 ± 0.1 g · mm–3 × 10–5 vs. Dex: 7.4 ± 0.2 g · mm–3 × 10–5), both p < 0.05. Dex increased cardiac oxidative stress (protein expression: 4-HNE +20%, Hsp90 –42% and eNOS –54%), induced left ventricle (LV) wall thinning (LV wall volume: Ctrl: 47.2 ± 1.2 mm3 vs. Dex: 38.9 ± 1.7 mm3) and decreased the ratio of the aortic lumen:total vessel area (Ctrl: 0.74 ± 0.01 vs. Dex: 0.66 ± 0.02), all p < 0.05. DexCE restored towards control values survival, growth symmetry the aortic lumen:total vessel area, and increased the cardiac expression of Hsp90 relative to Dex. In addition, relative to controls, the decrease in the cardiac expression of eNOS was no longer significant in DexCE animals (–20.3 ± 14.4%, p > 0.05). However, DexCE did not prevent growth retardation, cardiac 4-HNE upregulation (DexCE: +29%) or LV thinning (DexCE: 40.1 ± 1.1 mm3). Treatment of neonates with vitamins alone affected somatic growth and promoted thinner LV walls (CtrlCE: 39.9 ± 0.5 mm3, p < 0.05). Conclusions: Combined glucocorticoid and antioxidant therapy in premature infants may be safer than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.
New-Onset Diabetes after Hemodialysis Initiation: Impact on Survival
Authors: Salifu Moro O. , Abbott Kevin C. , Aytug Serhat , Hayat Amir , Haria Dhiren M. , Shah Syed , Friedman Eli A. , Delano Barbara G. , McFarlane Samy I. , Hurst Frank P. , Flom Peter L. , Jindal Rahul M.
Published: January 2010

Background: The incidence of new-onset diabetes after initiation of hemodialysis (NODAD) and its impact on survival is not known. Methods: We used data from the United States Renal Data System (USRDS) from January 2000 to December 2001, with at least 3 years of follow-up for this study. Patients aged 18–80 years were included. NODAD was defined as two Medicare institutional claims for diabetes in patients with no history of diabetes prior to starting hemodialysis (HD). Incidence (per 1,000 patient-years), prevalence (%) and hazard ratios for mortality in patients with NODAD were calculated. Results: There were 59,340 incident patients with no history of diabetes prior to starting HD, of which 3,853 met criteria for NODAD. The overall incidence and prevalence of NODAD were 20 per 1,000 patient-years and 7.6%, respectively. In a cohort of 444 patients without diabetes and documented glycosylated hemoglobin A1c, <6% prior to starting HD (from January 2005 and March 2006), at a mean follow-up of 4.7 ± 2.6 months, 6.8% developed NODAD defined by two Medicare claims for diabetes after initiation of HD. NODAD was associated with a significantly increased risk of death as compared to non-diabetes patients (hazard ratio 1.20, 95% confidence interval 1.14–1.25). Conclusion: The USRDS showed a high incidence of NODAD, associated with significantly higher mortality compared to those who did not develop NODAD. The mechanism of NODAD needs to be explored further in experimental and clinical studies.
Grouping patterns in warthogs, Phacochoerus africanus: is communal care of young enough to explain sociality?
Authors: Peacock Mary , White Angela , Cameron Elissa
Published: January 2010

Group-living will evolve when individuals increase their lifetime reproductive success by joining with other individuals. In cooperatively breeding societies, individuals living in a group will participate in the communal rearing of young. Several factors can influence the evolutionary trade-offs of grouping and it is often unclear whether cooperative breeding is advantageous or is simply a by-product of selection acting on grouping behaviour. We used sightings of 1318 warthogs in 711 groups to investigate whether the advantages of sociality in the warthog differ depending on an individual's age, sex, reproductive state, or the time of year. Adult males only formed temporary associations with other individuals indicating that participation in a group was not advantageous. In contrast, yearlings were almost inevitably found in groups, regardless of their sex or time of year, suggesting any costs to sociality were outweighed by the benefits. Grouping in adult female warthogs was complex; adult females were more likely to form groups in the presence of juveniles and when juveniles were at their most vulnerable stage indicating that sociality in females could be partially explained by the benefits of communal care of young. However, other factors influenced female cooperation including group composition and the time of year.
Clutch variation and egg rejection in three hosts of the pallid cuckoo, Cuculus pallidus
Authors: Langmore Naomi , Landstrom Michelle , Heinsohn Robert
Published: January 2010

In theory, hosts of avian brood parasites would benefit by modifying their egg appearance in two ways to help identify mimetic foreign eggs: (i) by laying clutches that are more uniform in appearance and (ii) by laying clutches that differ from those of other females in the population. Support for these theories is inconsistent, and few studies have used objective measures of clutch variation. Here we used reflectance spectrophotometry to quantify within-clutch and between-clutch variation of three host species of an Australian brood parasite, the pallid cuckoo (Cuculus pallidus). We used egg-swapping experiments in which subjects were presented with either a conspecific egg or a heterospecific egg to compare the egg rejection responses of a frequently parasitised host, the white-plumed honeyeater (Lichenostomus penicillatus), with two less frequently parasitised hosts, dusky woodswallows (Artamus cyanopterus) and willie wagtails (Rhipidura leucophrys). As predicted, rejection rate increased as contrast between foreign egg and host clutch increased. Further, the major host showed greater between-clutch variation than the occasional hosts, and also rejected more similar-looking eggs. Contrary to predictions however, within-clutch variation was not lower in the major host, nor was it important in predicting the rejection rate of foreign eggs by the three host species.
Effect of predation on male mating behaviour in a unisexual-bisexual mating system
Authors: Gabor Caitlin , Coyle Julia , Aspbury Andrea
Published: January 2010

Mate choice for conspecifics is beneficial when closely related species live in sympatry, but mate choice can be costly in the presence of predators. Male sailfin mollies are sexually parasitized by gynogenetic Amazon mollies. Amazon mollies must mate with male sailfin mollies to initiate embryogenesis, but inheritance is maternal. We tested if male sailfin molly mate choice for conspecific females is affected by predation risk. Male mate choice was tested in one of four treatments: (1) predation/no refuge, (2) predation/refuge, (3) no predation/refuge and (4) no predation/no refuge. Predation consisted of dipping the beak of a great blue heron decoy in the aquarium prior to a mating trial. Refuge was provided by java-moss. For each trial the number of mating attempts toward each female was recorded. There was a significant interaction between predation and refuge on strength of preference (SOP) for conspecific females. The highest SOP was in the no predator/no refuge treatment, and the lowest SOP was in the predator/no refuge treatment. These results suggest that the cost of predation is higher than the cost of mating with heterospecifics, and that the presence of a refuge may reduce this cost. This could explain the continued maintenance of Amazon mollies.