bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strong Convergence Theorems of Common Fixed Points for a Family of Quasi-"Equation missing" -Nonexpansive Mappings
Authors: Qin Xiaolong , Cho YeolJe , Cho SunYoung , Kang ShinMin 
Published: December 2009

AbstractWe consider a modified Halpern type iterative algorithm for a family of quasi-"Equation missing"-nonexpansive mappings in the framework of Banach spaces. Strong convergence theorems of the purposed iterative algorithms are established.
Potentiation of Temozolomide Cytotoxicity by Inhibition of DNA Polymerase β Is Accentuated by BRCA2 Mutation
Authors: Stachelek Gregory C. , Dalal Shibani , Donigan Katherine A. , Campisi Hegan Denise , Sweasy Joann B. , Glazer Peter M. 
Published: December 2009

Abstract
Base excision repair (BER) plays a critical role in the repair of bases damaged by oxidative metabolism or alkylating agents, such as those commonly used in cancer therapy. Incomplete BER generates intermediates that require activation of homology-dependent DNA repair to resolve. We investigated the effects of lithocholic acid (LCA), an inhibitor of the key BER enzyme DNA polymerase β (pol β), in cells deficient in expression of the homology-dependent repair factor BRCA2. In vitro studies show that LCA suppresses the DNA polymerase and 5′-deoxyribose phosphate lyase activities of DNA pol β by preventing the formation of a stable pol β–DNA complex, reducing BER effectiveness. Cytotoxicity assays based on colony formation revealed that LCA exhibits synergism with the alkylating agent temozolomide, which engages BER through DNA methylation, and that the degree of synergism is increased in cells lacking functional BRCA2. BRCA2-deficient cells also showed heightened susceptibility to both LCA and temozolomide individually. The potentiation of temozolomide cytotoxicity by LCA owes to the conversion of single-stranded DNA breaks generated through incomplete BER of methylated nucleotides into double-stranded breaks during DNA replication, as indicated by γH2AX immunofluorescence. Death seems to be induced in cotreated cells through an accumulation of persistent double-stranded DNA breaks. Mutations of the BRCA2 gene have been extensively characterized and are present in various cancers, implying that inhibition of BER may offer a means to augment tumor selectivity in the use of conventional cancer therapies. Cancer Res; 70(1); 409–17
CCL2 Blockade Augments Cancer Immunotherapy
Authors: Fridlender Zvi G. , Buchlis George , Kapoor Veena , Cheng Guanjun , Sun Jing , Singhal Sunil , Crisanti M. Cecilia , Wang Liang-Chuan S. , Heitjan Daniel , Snyder Linda A. , Albelda Steven M. 
Published: December 2009

Abstract
Altering the immunosuppressive microenvironment that exists within a tumor will likely be necessary for cancer vaccines to trigger an effective antitumor response. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immunoinhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the human papillomavirus E7 antigen expressed by a non–small cell lung cancer (NSCLC) line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus-expressing IFN-α to treat a nonimmunogenic NSCLC line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intratumoral CD8+ T cells that were more activated and more antitumor antigen–specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T regulatory cells. CCL2 seems to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T-cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials. Cancer Res; 70(1); 109–18
OTX2 Is Critical for the Maintenance and Progression of Shh-Independent Medulloblastomas
Authors: Adamson David C. , Shi Qun , Wortham Matthew , Northcott Paul A. , Di Chunhui , Duncan Christopher G. , Li Jianjun , McLendon Roger E. , Bigner Darell D. , Taylor Michael D. , Yan Hai 
Published: December 2009

Abstract
OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma. Cancer Res; 70(1); 181–91
Evaluation of MicroRNA Expression Profiles That May Predict Recurrence of Localized Stage I Non–Small Cell Lung Cancer after Surgical Resection
Authors: Patnaik Santosh K. , Kannisto Eric , Knudsen Steen , Yendamuri Sai 
Published: December 2009

Abstract
Prognostic markers that can predict the relapse of localized non–small cell lung cancer (NSCLC) have yet to be defined. We surveyed expression profiles of microRNA (miRNA) in stage I NSCLC to identify patterns that might predict recurrence after surgical resection of this common deadly cancer. Small RNAs extracted from formalin-fixed and paraffin-embedded tissues were hybridized to locked nucleic acid probes against 752 human miRNAs (representing 82% of the miRNAs in the miRBase 13.0 database) to obtain expression profiles for 37 cases with recurrence and 40 cases without recurrence (with clinical follow-up for at least 32 months). Differential expression between the two case groups was detected for 49% of the miRNAs (Wilcoxon rank sum test; P &lt; 0.01). The performance of expression profiles at differentiating the two case groups was assessed by leave-one-out and Monte Carlo cross-validations. In leave-one-out cross-validation using support vector machines- or top-scoring gene pair classifier methods, which looked for six- or two-miRNA-based classifiers, the identified miRNA expression pattern predicted recurrence with an accuracy of 70% and 83%, and hazard ratio of 3.6 [95% confidence interval (95% CI), 1.8–7.1] and 9.0 (95% CI, 4.4–18.2), respectively. Mean accuracy in Monte Carlo cross-validation using 1,000 random 60–17 splits was 69% (95% CI, 68–70) and 72% (95% CI, 71–72), respectively. The specific miRNAs mir-200b*, mir-30c-1*, mir-510, mir-630, mir-657, and mir-146b-3p and mir-124*, mir-585, and mir-708, respectively, represented most commonly among the 1,000 classifiers identified in Monte Carlo cross-validation by the two methods. MiRNAs mir-488, mir-503, and mir-647 were identified as potential reference miRNAs for future studies, based on the stability of their expression patterns across the 77 cases and the two case-groups. Our findings reinforce efforts to profile miRNA expression patterns for better prognostication of stage I NSCLC. Cancer Res; 70(1); 36–45
Changes in the Mouse Estrus Cycle in Response to Brca1 Inactivation Suggest a Potential Link between Risk Factors for Familial and Sporadic Ovarian Cancer
Authors: Hong Hao , Yen Hai-Yun , Brockmeyer Amy , Liu Ying , Chodankar Rajas , Pike Malcolm C. , Stanczyk Frank Z. , Maxson Robert , Dubeau Louis 
Published: December 2009

Abstract
Menstrual cycle activity is the most important risk factor for sporadic serous ovarian carcinoma, whereas a germ-line mutation in BRCA1 is the most important risk factor for the familial form. Given the rarity of BRCA1 mutations in sporadic ovarian cancers, we hypothesized that BRCA1 influences the menstrual cycle in a way that mimics the factors underlying sporadic ovarian cancer predisposition, making BRCA1 mutations redundant in such cancers. We compared the length of each phase of the estrus cycle (equivalent to the human menstrual cycle) and of circulating levels of estradiol in control mice and in mice carrying a Brca1 mutation in their ovarian granulosa cells, two thirds of which develop ovarian or uterine epithelial tumors. We also compared the length of the different phases of the cycle in mutants that subsequently developed tumors with those in mutants that remained tumor-free. Mutant mice as well as oophorectomized wild-type mice harboring mutant ovarian grafts showed a relative increase in the average length of the proestrus phase of the estrus cycle, which corresponds to the estrogen-dominated follicular phase of the human menstrual cycle. Total circulating levels of estradiol were also increased in mutant mice injected with pregnant mare serum gonadotropins. The relative increase in proestrus length was highest in mutant mice that subsequently developed reproductive epithelial tumors. We conclude that loss of a functional Brca1 increases murine ovarian epithelial tumor predisposition by increasing estrogen stimulation in the absence of progesterone, recapitulating conditions associated with sporadic ovarian cancer predisposition in humans. Cancer Res; 70(1); 221–8
P-glycoprotein (P-gp/Abcb1), Abcc2, and Abcc3 Determine the Pharmacokinetics of Etoposide
Authors: Lagas Jurjen S. , Fan Lin , Wagenaar Els , Vlaming Maria L.H. , van Tellingen Olaf , Beijnen Jos H. , Schinkel Alfred H. 
Published: December 2009

AbstractPurpose: Despite the extensive use of etoposide for the treatment of different malignant neoplasms, its main pharmacokinetic determinants are not completely defined. We aimed to study the impact of P-glycoprotein (P-gp/ABCB1) and the multidrug resistance proteins ABCC2 (MRP2) and ABCC3 (MRP3) on the pharmacokinetics of etoposide.Experimental Design: Abcb1a/1b−/−, Abcc2−/−, Abcc3−/−, Abcb1a/1b;Abcc2−/−, and Abcc2;Abcc3−/− mice were used to investigate the separate and combined impact of P-gp, Abcc2, and Abcc3 on the in vivo behavior of etoposide.Results: P-gp restricted the oral (re)uptake of unchanged etoposide, and mediated its excretion across the gut wall. In contrast, hepatobiliary excretion was almost entirely dependent on Abcc2. Yet, complete loss of Abcc2 did not result in elevated liver or plasma concentrations of etoposide. Instead, Abcc2−/− mice displayed an increased hepatic formation of etoposide glucuronide, which was secreted via Abcc3 from the liver to the blood circulation and eliminated with the urine. Combination Abcc2;Abcc3−/− mice had highly increased accumulation of etoposide glucuronide in their livers, whereas both single knockouts did not, indicating that Abcc2 and Abcc3 provide alternative pathways for the hepatic elimination of etoposide glucuronide.Conclusions: P-gp, ABCC2, and ABCC3 significantly affect the pharmacokinetics of etoposide and/or etoposide glucuronide. Variation in transporter expression or activity may explain the high variation in oral availability of etoposide (25-80%) among cancer patients. However, despite the fact that substantial variations in transporter activity can occur, we believe that cancer patients are often relatively protected from etoposide toxicity due to overlapping functions of these transporters in the elimination of etoposide. Clin Cancer Res; 16(1); 130–40
Activation of WD Repeat and High-Mobility Group Box DNA Binding Protein 1 in Pulmonary and Esophageal Carcinogenesis
Authors: Sato Nagato , Koinuma Junkichi , Fujita Masahiro , Hosokawa Masao , Ito Tomoo , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro 
Published: December 2009

Abstract
Purpose: We attempted to identify novel biomarkers and therapeutic targets for lung and esophageal cancers.
Experimental Design: We screened for genes that were overexpressed in a large proportion of lung and esophageal carcinomas using a cDNA microarray representing 27,648 genes or expressed sequence tags. A gene encoding WDHD1, a WD repeat and high-mobility group box DNA binding protein 1, was selected as a candidate. Tumor tissue microarray containing 267 archival non–small cell lung cancers and 283 esophageal squamous cell carcinomas (ESCC) was used to investigate the clinicopathologic significance of WDHD1 expression. The role of WDHD1 in cancer cell growth and/or survival was examined by small interfering RNA experiments and cell growth assays. The mechanism of WDHD1 activation through its phosphorylation in cancer cells was examined by immunoprecipitation and kinase assays.
Results: Positive WDHD1 immunostaining was associated with a poor prognosis for patients with non–small cell lung cancer (P = 0.0403) as well as ESCC (P = 0.0426). Multivariate analysis indicated it to be an independent prognostic factor for ESCC (P = 0.0104). Suppression of WDHD1 expression with small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induction of the exogenous expression of WDHD1 promoted the growth of mammalian cells. AKT1 kinase seemed to phosphorylate and stabilize the WDHD1 protein in cancer cells.
Conclusions: WDHD1 expression is likely to play an important role in lung and esophageal carcinogenesis as a cell cycle regulator and a downstream molecule in the phosphoinositide 3-kinase/AKT pathway, and that WDHD1 is a candidate biomarker and a promising therapeutic target for cancer. Clin Cancer Res; 16(1); 226–39
Microarray-Based Response Prediction in Esophageal Adenocarcinoma
Authors: Schauer Matthias , Janssen Klaus-Peter , Rimkus Caroline , Raggi Matthias , Feith Marcus , Friess Helmut , Theisen Joerg 
Published: December 2009

Abstract
Purpose: In locally advanced (uT3, N+) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis.
Experimental Design: Biopsies of 47 patients with locally advanced (uT3, N+) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was &gt;70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67.
Results: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown.
Conclusions: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis. Clin Cancer Res; 16(1); 330–7
Immunotherapy for Human Renal Cell Carcinoma by Adoptive Transfer of Autologous Transforming Growth Factor β–Insensitive CD8+ T Cells
Authors: Wang Longxin , Wen Weihong , Yuan Jianlin , Helfand Brian , Li Yu , Shi Changhong , Tian Feng , Zheng Jia , Wang Fuli , Chen Lin , Liang Lili , Zhou Liqun , Lee Chung , Chen Zhinan , Guo Yinglu , Wang He , Zhang Qiang , Qin Weijun 
Published: December 2009

Abstract
Purpose: Transforming growth factor-β (TGF-β) is a potent immunosuppressor that has been associated with tumor evasion from the host immune surveillance and, thus, tumor progression. We tested a novel immunotherapy for human renal cell cancer (RCC) using a technique that involves the adoptive transfer of autologous tumor–reactive, TGF-β–insensitive CD8+ T cells into human RCC–challenged immunodeficient mice to identify its potent antitumor responses.
Experimental Design: The present study was conducted using a one-to-one adoptive transfer strategy to treat tumor-bearing severe combined immunodeficient (SCID/beige) mouse. The SCID/beige mice were humanized with peripheral blood mononuclear cells from patients with RCC (Hu-PBMC-SCID) before adoptive transfer. Autologous CD8+ T cells were expanded ex vivo using autologous patient's dendritic cells pulsed with the tumor lysate and rendered TGF-β insensitive by dominant-negative TGF-β type II receptor. In addition, human RCC cell lines were generated using patients' tumor cells injected into SCID/beige mice.
Results: Using flow cytometry analysis, we confirmed the expression of the tumor-reactive, TGF-β–insensitive CD8+ T cells were the effector CD8+ cells (CD27−CDRA+). Adoptive transfer of autologous TGF-β–insensitive CD8+ T cells into tumor-bearing Hu-PBMC-SCID mice induced robust tumor-specific CTL responses in vitro, were associated with tumor apoptosis, suppressed lung metastasis, and prolonged survival times in vivo.
Conclusion: The one-to-one adoptive transfer strategy is an ideal in vivo murine model for studying the relationship between TGF-β and immunosurveillance in RCC in vivo. Furthermore, this technique may offer the promise of a novel therapeutic option for the treatment of human patients with RCC. Clin Cancer Res; 16(1); 164–73
Phase 1 Study of Aflibercept Administered Subcutaneously to Patients with Advanced Solid Tumors
Authors: Tew William P. , Gordon Michael , Murren John , Dupont Jakob , Pezzulli Sandra , Aghajanian Carol , Sabbatini Paul , Mendelson David , Schwartz Lawrence , Gettinger Scott , Psyrri Amanda , Cedarbaum Jesse M. , Spriggs David R. 
Published: December 2009

Abstract
Purpose: To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent.
Experimental Design: In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.
Results: Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 μg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t1/2 of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for &gt;1 year.
Conclusion: Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. Clin Cancer Res; 16(1); 358–366
Evaluating a Marker's Contribution to a Nomogram: The GEMCaP Example
Authors: Kattan Michael W. 
Published: December 2009

Abstract
A postoperative nomogram developed in 1999 by Kattan et al. has been externally validated, but needs improvement. This tool predicts well but not perfectly. The Genomic Evaluators of Metastatic Prostate Cancer (GEMCaP) biomarkers hold promise for improving this tool; however, a larger data set that permits more involved analyses is needed. Clin Cancer Res; 16(1); 1–3
Revision Ulnar Collateral Ligament Reconstruction Using a Suspension Button Fixation Technique
Authors: Lee Gregory H. , Limpisvasti Orr , Park Maxwell C. , McGarry Michelle H. , Yocum Lewis A. , Lee Thay Q. 
Published: December 2009

Background Revision ulnar collateral ligament reconstruction remains a challenging problem. The objective of this study was to biomechanically evaluate an ulnar collateral ligament reconstruction technique using a suspension button fixation technique that can be used even in the case of ulnar cortical bone loss. Hypothesis An ulnar suspension fixation technique for ulnar collateral ligament reconstruction can restore elbow kinematics and demonstrate failure strength comparable to that of currently available techniques. Study Design Controlled laboratory study. Methods Nine pairs of cadaveric elbows were dissected free of soft tissue and potted. After simulating ulnar cortical bone loss, ulnar collateral ligament reconstruction was performed in 1 elbow of each pair using palmaris longus autograft and a 30-mm RetroButton suspended from the far (lateralmost) ulnar cortex. A docking technique was used for humeral fixation of the graft. Elbow valgus angle was quantified using a Microscribe 3DLX digitizer at multiple elbow flexion angles. Valgus angle was measured with the ulnar collateral ligament intact, transected, and reconstructed. In addition, load-to-failure testing was performed in 1 elbow of each pair. Results Release of the ulnar collateral ligament caused a significant increase in valgus angle at each flexion angle tested (P < .002). Reconstructed elbows demonstrated no significant differences in valgus angle from the intact elbow at all flexion angles tested. Load-to-failure tests showed that reconstructed elbows had an ultimate torque (10.3 ± 5.7 N·m) significantly less than intact elbows (26.4 ± 10.6 N·m) (P = .001). Conclusion Ulnar collateral ligament reconstruction using a suspension button fixation technique reliably restored elbow kinematics to the intact state. Load-to-failure testing demonstrated comparable fixation strength to several historic controls of primary reconstruction techniques despite the simulated ulnar cortical bone loss. Clinical Relevance Ulnar collateral ligament reconstruction using a suspension button fixation technique can be considered in the case of ulnar cortical bone loss in a primary or revision setting.