bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodality Imaging of IL-18–Binding Protein-Fc Therapy of Experimental Lung Metastasis
Authors: Cao Qizhen , Cai Weibo , Niu Gang , He Lina , Chen Xiaoyuan 
Published: October 2008

Abstract
Purpose: Interleukin (IL)-18 plays important roles in cancer progression and metastasis. The goal of this study is to identify cell lines that are most sensitive to stand alone IL-18–binding protein (IL-18bp)-Fc treatment, to study the pharmacokinetics and tumor targeting efficiency of IL-18bp-Fc, and to evaluate the efficacy of IL-18bp-Fc in treating breast cancer experimental lung metastasis by multimodality imaging.
Experimental Design: Reverse transcription-PCR, ELISA, and other cell-based assays were done on murine 4T1, CT-26, and B16F10 cells. The most IL-18bp-Fc–sensitive 4T1 cells were stably transfected with firefly luciferase (fLuc) and injected i.v. into female BALB/C mice to establish the experimental lung metastasis model. Tumor targeting efficiency and pharmacokinetics of IL-18bp-Fc was assessed by 64Cu-DOTA-IL-18bp-Fc positron emission tomography (PET) and biodistribution studies. Two groups of fLuc-4T1 experimental lung metastasis tumor-bearing mice were each given saline or IL-18bp-Fc (1 mg/kg) daily i.p. Bioluminescence imaging, 18F-FDG PET, and computed tomography scans were done to evaluate the treatment efficacy. Ex vivo experiments were also carried out to validate the imaging results.
Results: IL-18bp-Fc had high and specific accumulation in the fLuc-4T1 lung metastasis tumor as evidenced by both PET and biodistribution studies. Bioluminescence imaging, 18F-FDG PET, and computed tomography scans all revealed that IL-18bp-Fc treatment was effective in inhibiting the lung metastasis tumor progression, validated by ex vivo examination of the lung.
Conclusions: IL-18bp-Fc therapy can inhibit 4T1 breast cancer experimental lung metastasis. Noninvasive multimodality molecular imaging is a powerful tool for evaluating the tumor targeting efficiency/pharmacokinetics of the drug and effective monitoring of the therapeutic response.
Immunohistochemical Expression of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptors 1 and 2 in the Pathogenesis of Lung Cancer
Authors: Behrens Carmen , Lin Heather Y. , Lee J. Jack , Raso Maria Gabriela , Hong Waun Ki , Wistuba Ignacio I. , Lotan Reuben 
Published: October 2008

Abstract
Purpose: To identify the patterns of protein expression of basic fibroblast growth factor (bFGF) and FGF receptors 1 and 2 in non-small cell lung carcinoma (NSCLC) and their role in the early pathogenesis of squamous cell carcinoma (SCC) of the lung.
Experimental Design: Archived tissue from NSCLC (adenocarcinoma and SCC; n = 321) and adjacent bronchial epithelial specimens (n = 426) were analyzed for the immunohistochemical expression of bFGF, FGFR1, and FGFR2, and the findings were correlated with clinicopathologic features of the patients.
Results: High expression of bFGF, FGFR1, and FGFR2 was shown in most NSCLC tumors. The pattern of expression for all markers varied according to tumor histologic type and cellular localization. Cytoplasmic expression scores were significantly higher in tumors than in normal epithelia. Nuclear bFGF (P = 0.03) and FGFR1 (P = 0.02) levels were significantly higher in women than in men. Although cytoplasmic FGFR1 expression was significantly higher (P = 0.002) in ever smokers than in never smokers, nuclear FGFR1 (P = 0.0001) and FGFR2 (P = 0.003) expression was significantly higher in never smokers. Different prognostic patterns for the expression of these markers were detected for both NSCLC histologic types. Dysplastic changes showed significantly higher expression of all markers compared with squamous metaplasia.
Conclusions: bFGF, FGFR1, and FGFR2 are frequently overexpressed in SCC and adenocarcinoma of the lung. bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of SCC and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies.
CpG Island Methylator Phenotype Associates with Low-Degree Chromosomal Abnormalities in Colorectal Cancer
Authors: Cheng Yu-Wei , Pincas Hanna , Bacolod Manny D. , Schemmann Gunter , Giardina Sarah F. , Huang Jianmin , Barral Sandra , Idrees Kamran , Khan Sajid A. , Zeng Zhaoshi , Rosenberg Shoshana , Notterman Daniel A. , Ott Jurg , Paty Philip , Barany Francis 
Published: October 2008

Abstract
Purpose: Aberrant promoter methylation and genomic instability occur frequently during colorectal cancer development. CpG island methylator phenotype (CIMP) has been shown to associate with microsatellite instability, and BRAF mutation and is often found in the right-side colon. Nevertheless, the relative importance of CIMP and chromosomal instability (CIN) for tumorigenesis has yet to be thoroughly investigated in sporadic colorectal cancers.
Experimental Design: We determined CIMP in 161 primary colorectal cancers and 66 matched normal mucosae using a quantitative bisulfite/PCR/ligase detection reaction (LDR)/Universal Array assay. The validity of CIMP was confirmed in a subset of 60 primary tumors using MethyLight assay and five independent markers. In parallel, CIN was analyzed in the same study cohort using Affymetrix 50K Human Mapping arrays.
Results: The identified CIMP-positive cancers correlate with microsatellite instability (P = 0.075) and the BRAF mutation V600E (P = 0.00005). The array-based high-resolution analysis of chromosomal aberrations indicated that the degree of aneuploidy is spread over a wide spectrum among analyzed colorectal cancers. Whether CIN was defined by copy number variations in selected microsatellite loci (criterion 1) or considered as a continuous variable (criterion 2), CIMP-positive samples showed a strong correlation with low-degree chromosomal aberrations (P = 0.075 and P = 0.012, respectively). Similar correlations were observed when CIMP was determined by MethyLight assay (P = 0.001 and P = 0.013, respectively).
Conclusion: CIMP-positive tumors generally possess lower chromosomal aberrations, which may only be revealed using a genome-wide approach. The significant difference in the degree of chromosomal aberrations between CIMP-positive and the remainder of samples suggests that epigenetic (CIMP) and genetic (CIN) abnormalities may arise from independent molecular mechanisms of tumor progression.
Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia
Authors: Sitkovsky Michail V. , Kjaergaard Jorgen , Lukashev Dmitriy , Ohta Akio 
Published: October 2008

AbstractCancerous tissue protection from tumor-recognizing CD8+ and CD4+ T cells (antitumor T cells) limits the therapeutic potential of immunotherapies. We propose that tumor protection is to a large extent due to (a) inhibition of antitumor T cells by hypoxia-driven accumulation of extracellular adenosine in local tumor microenvironment and due to (b) T regulatory cell-produced extracellular adenosine. The adenosine triggers the immunosuppressive signaling via intracellular cyclic AMP–elevating A2A adenosine receptors (A2AR) on antitumor T cells. In addition, the activated antitumor T cells in hypoxic tumor microenvironment could be inhibited by elevated levels of immunosuppressive hypoxia-inducible factor-1α. Complete rejection or tumor growth retardation was observed when A2AR has been genetically eliminated or antagonized with synthetic drug or with natural A2AR antagonist 1,3,7-trimethylxanthine (caffeine). The promising strategy may be in combining the anti-hypoxia-adenosinergic treatment that prevents inhibition of antitumor T cells by tumor-produced and T regulatory cell-produced adenosine with targeting of other negative regulators, such as CTL antigen-4 blockade. Observations of tumor rejection in mice and massive prospective epidemiologic studies support the feasibility of anti-hypoxia-adenosinergic combined immunotherapy.
Immunohistochemical and Biogenetic Features of Diffuse-Type Tenosynovial Giant Cell Tumors: The Potential Roles of Cyclin A, P53, and Deletion of 15q in Sarcomatous Transformation
Authors: Huang Hsuan-Ying , West Robert B. , Tzeng Ching-Cherng , van de Rijn Matt , Wang Jun-Wen , Chou Shih-Cheng , Huang Wen-Wei , Eng Hock-Liew , Lin Ching-Nan , Yu Shih-Chen , Wu Jing-Mei , Lu Chiu-Chin , Li Chien-Feng 
Published: October 2008

Abstract
Purpose: Diffuse-type tenosynovial giant cell tumor (D-TSGCT) is an aggressive proliferation of synovial-like mononuclear cells with inflammatory infiltrates. Despite the COL6A3-CSF1 gene fusion discovered in benign lesions, molecular aberrations of malignant D-TSGCTs remain unidentified.
Experimental Design: We used fluorescent in situ hybridization and in situ hybridization to evaluate CSF1 translocation and mRNA expression in six malignant D-TSGCTs, which were further immunohistochemically compared with 24 benign cases for cell cycle regulators involving G1 phase and G1-S transition. Comparative genomic hybridization, real-time reverse transcription-PCR, and a combination of laser microdissection and sequencing were adopted to assess chromosomal imbalances, cyclin A expression, and TP53 gene, respectively.
Results: Five of six malignant D-TSGCTs displayed CSF1 mRNA expression by in situ hybridization, despite only one having CSF1 translocation. Cyclin A (P = 0.008) and P53 (P &lt; 0.001) could distinguish malignant from benign lesions without overlaps in labeling indices. Cyclin A transcripts were more abundant in malignant D-TSGCTs (P &lt; 0.001). All malignant cases revealed a wild-type TP53 gene, which was validated by an antibody specifically against wild-type P53 protein. Chromosomal imbalances were only detected in malignant D-TSGCTs, with DNA losses predominating over gains. Notably, −15q was recurrently identified in five malignant D-TSGCTs, four of which showed a minimal overlapping deletion at 15q22-24.
Conclusions: Deregulated CFS1 overexpression is frequent in malignant D-TSGCTs. The sarcomatous transformation involves aberrations of cyclin A, P53, and chromosome arm 15q. Cyclin A mRNA is up-regulated in malignant D-TSGCTs. Non–random losses at 15q22-24 suggest candidate tumor suppressor gene(s) in this region. However, P53 overexpression is likely caused by alternative mechanisms rather than mutations in hotspot exons.
Differentiation of Human Embryonic Stem Cells into Immunostimulatory Dendritic Cells under Feeder-Free Culture Conditions
Authors: Su Zhen , Frye Carole , Bae Kyung-Mi , Kelley Vicky , Vieweg Johannes 
Published: October 2008

Abstract
Purpose: The objective of this study was to develop a scalable and broadly applicable active immunotherapy approach against cancer, circumventing the limitations typically encountered with autologous vaccination strategies. We hypothesized that human embryonic stem cells (hESC) can serve as a virtually unlimited source for generating dendritic cells (DC) with potent antigen-presenting function. Here, we investigated the developmental processes and requirements for generating large numbers of mature, antigen-presenting DC from pluripotent hESC.
Experimental Design: A feeder cell-free culture system was developed to differentiate hESC into mature DC sequentially through hematopoietic and myeloid precursor stages.
Results: Using this method, we were able to yield large numbers of mature immunostimulatory DC from hESC to enable clinical investigation. Upon activation, the hESC-derived DC secreted interleukin-12p70, migrated in response to MIP-3β, and exhibited allostimulatory capacity. Most importantly, antigen-loaded, hESC-derived DC were capable of stimulating potent antigen-specific CD8+ T-cell responses in an HLA class I–matched semiallogeneic assay system. Moreover, HLA class II–mismatched hESC-derived DC induced a potent Th1-type cytokine response without expanding FOXP3+ regulatory T cells in vitro.
Conclusions: These data suggest the development of a novel active immunotherapy platform to stimulate potent T-cell immunity in patients with intractable diseases, such as cancer or viral infection.
Epidermal Growth Factor Receptor Mutations in Small Cell Lung Cancer
Authors: Tatematsu Akiko , Shimizu Junichi , Murakami Yoshiko , Horio Yoshitsugu , Nakamura Shigeo , Hida Toyoaki , Mitsudomi Tetsuya , Yatabe Yasushi 
Published: October 2008

Abstract
Purpose: The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis.
Experimental Design: The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined.
Results: EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib.
Conclusions: Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.
A Phase I Trial of Pemetrexed Plus Gemcitabine Given Biweekly with B-Vitamin Support in Solid Tumor Malignancies or Advanced Epithelial Ovarian Cancer
Authors: Hensley Martee L. , Larkin Joseph , Fury Matthew , Gerst Scott , Tai D. Fritz , Sabbatini Paul , Konner Jason , Orlando Mauro , Goss Tiana L. , Aghajanian Carol A. 
Published: October 2008

AbstractPurpose: To determine the maximally tolerated dose (MTD) of biweekly pemetrexed with gemcitabine plus B12 and folate supplementation in patients with advanced solid tumors and ovarian cancer.Experimental Design: Patients with no prior pemetrexed or gemcitabine therapy enrolled in cohorts of three, expanding to six if dose-limiting toxicity (DLT) was observed. Pemetrexed, escalated from to 700 mg/m2, was given before gemcitabine 1,500 mg/m2 every 14 days. DLTs were grade 4 neutropenia lasting &gt;7 days or febrile neutropenia, grade 4 or 3 thrombocytopenia (with bleeding), grade ≥3 nonhematologic toxicity, or treatment delay of ≥1 week due to unresolved toxicity.Results: The ovarian cancer cohort enrolled 24 patients with unlimited prior cytotoxic chemotherapies. MTD was observed at pemetrexed 600 mg/m2, with 2 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (83%), leukopenia (67%), lymphopenia (73%), and febrile neutropenia (12%). Median cycle per patient was 8 (range, 1-16). Six of 21 (28%) patients had confirmed partial responses. Study protocol was modified for the solid tumor cohort (n = 30) to enroll patients with two or more prior cytotoxic regimens. MTD was observed at pemetrexed 500 mg/m2, with 1 of 9 patients experiencing DLT. Most common grade 3 to 4 toxicities per patient were neutropenia (63%), lymphopenia (43%), leukopenia (70%) and febrile neutropenia (6.6%). Median cycle per patient was 4 (range, 1-20). Three of 29 (10.3%) response-evaluable patients had confirmed partial responses: 2 squamous cell carcinomas of head and neck and 1 nasopharyngeal cancer.Conclusion: MTDs for the solid tumor and ovarian cancer cohorts were reached at pemetrexed 500 and 600 mg/m2, respectively, given biweekly with gemcitabine 1,500 mg/m2.
Therapy of Advanced B-Lymphoma Xenografts with a Combination of 90Y-anti-CD22 IgG (Epratuzumab) and Unlabeled Anti-CD20 IgG (Veltuzumab)
Authors: Mattes M. Jules , Sharkey Robert M. , Karacay Habibe , Czuczman Myron S. , Goldenberg David M. 
Published: October 2008

AbstractPurpose: Antibodies are effective therapeutic agents in cancer, but cures are rarely if ever obtained. Combination therapies are likely to be more effective than a single agent. In this study, the combination of a new unconjugated humanized anti-CD20 IgG, veltuzumab, with a 90Y-conjugated humanized antibody to CD22 (epratuzumab) was evaluated for the treatment of B-cell lymphoma in a nude mouse model system.Experimental Design: Nude mice were grafted with the Ramos human B-lymphoma and treatment initiated when tumors were &gt;0.1 cm3. In most experiments, mice were injected first with unconjugated anti-CD20, then with 90Y-anti-CD22 1 day later. Additional weekly injections of the unconjugated veltuzumab were administered for 3 weeks. Controls included a single agent only and a nonreactive control radiolabeled antibody.Results: Unconjugated anti-CD20 veltuzumab alone did not have a significant therapeutic effect, even at a total dose of 2.5 mg per mouse. The 90Y-anti-CD22 epratuzumab alone induced marked regressions of all tumors, but they regrew in a few weeks. The combination of these agents cured ∼80% of the mice. A nonreactive control antibody labeled with 90Y, used without veltuzumab, had no therapeutic effect. The therapeutic effect of 90Y-epratuzumab required the maximum tolerated dose of radioactivity, which was 160 μCi per mouse.Conclusions: These studies illustrate how combinations of unconjugated and radioconjugated antibodies against different B-cell markers can improve therapeutic outcome, and offer a new therapeutic paradigm for the treatment of B-cell lymphomas.
Therapeutic Potential of Replication-Selective Oncolytic Adenoviruses on Cells from Familial and Sporadic Desmoid Tumors
Authors: Peerlinck Inge , Amini-Nik Saeid , Phillips Robin K. , Iggo Richard , Lemoine Nicholas R. , Tejpar Sabine , Vassaux Georges 
Published: October 2008

AbstractPurpose: Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers and has been associated with familial and sporadic desmoid tumors. The aim of the present study is to assess the therapeutic potential of oncolytic adenoviruses selectively replicating in cells in which the Wnt signaling pathway is active on primary cells from desmoid tumors.Experimental Design: Primary cells extracted from familial (n = 3) or sporadic (n = 3) desmoid tumors were cultured short term. Cancer cell survival and viral replication were measured in vitro upon infection with two different oncolytic adenoviruses targeting a constitutive activation of the Wnt signaling pathway. Adenoviral infectivity was also assessed.Results: Although cells extracted from one sporadic desmoid tumor responded very well to the oncolytic action of the adenoviruses (&lt;20% of viable cells upon infection at a multiplicity of infection of 10), cells from two tumor samples were totally resistant to the viral action. Cells from the remaining samples showed intermediate sensitivity to the oncolytic viruses. These effects were correlated to the level of infectivity of the cells. Finally, in responder cells, evidences of viral replication was observed.Conclusions: Our experimental data suggest that the response of desmoid tumor cells to oncolytic adenovirus is neither correlated to the type of mutation activating the Wnt signaling pathway nor to the familial or sporadic nature of the tumor. In addition, they highlight the variability of infectivity of individual tumors and predict a great variability in the response to oncolytic adenoviruses.
Fluorescence In situ Hybridization Subgroup Analysis of TRIBUTE, a Phase III Trial of Erlotinib Plus Carboplatin and Paclitaxel in Non–Small Cell Lung Cancer
Authors: Hirsch Fred R. , Varella-Garcia Marileila , Dziadziuszko Rafal , Xiao Yun , Gajapathy Sujatha , Skokan Margaret , Lin Ming , O'Neill Vincent , Bunn Paul A. 
Published: October 2008

Abstract
Purpose: TRIBUTE was a phase III trial evaluating the addition of erlotinib to carboplatin and paclitaxel as a first-line treatment for advanced non–small cell lung cancer that did not meet its primary end point of improving overall survival. Here, we assess the value of using epidermal growth factor receptor (EGFR) gene copy number in tumor biopsy samples, as determined by fluorescence in situ hybridization (FISH), as a predictor of treatment outcome.
Methods: EGFR FISH analysis was done using LSI EGFR SpectrumOrange/CEP7 SpectrumGreen probe.
Results: Of 275 samples, 245 (89.1%) were successfully analyzed by FISH. One hundred (40.8%) of patients were EGFR FISH(+). Median overall survival was not different between FISH(+) and FISH(−) patients in either the chemotherapy+erlotinib arm or the chemotherapy+placebo arm. In FISH(+) patients, median time to progression (TTP) was 6.3 months in the erlotinib arm versus 5.8 months in the placebo arm (hazard ratio, 0.59; 95% confidence interval, 0.35-0.99; P = 0.0430); in FISH(−) patients, median TTP was 4.6 months versus 6.0 months (hazard ratio, 1.42; 95% confidence interval, 0.95-2.14; P = 0.0895; treatment interaction test, P = 0.007). After 6 months of treatment, a notable separation of the TTP curves in favor of erlotinib emerged. Objective response rates were 11.6% versus 29.8% in FISH(+) patients (chemotherapy+erlotinib arm versus chemotherapy+placebo arm; P = 0.0495) and 21.8% versus 25.4%, respectively, for FISH(−) patients (P = 0.6954).
Conclusions: EGFR gene copy number by FISH did not predict survival benefit. However, among EGFR FISH(+) patients, TTP was longer in patients who received erlotinib and continued to receive it after completing first-line therapy.
Effects of Manganese Superoxide Dismutase Silencing on Androgen Receptor Function and Gene Regulation: Implications for Castration-Resistant Prostate Cancer
Authors: Sharifi Nima , Hurt Elaine M. , Thomas Suneetha B. , Farrar William L. 
Published: October 2008

Abstract
Purpose: Advanced prostate cancer is first treated with androgen deprivation therapy. However, tumors become resistant to and grow despite castrate levels of testosterone. Growth and proliferation of CRPC is mediated by gain-of-function changes in the AR and AR reactivation. Expression of manganese superoxide dismutase (SOD2), which regulates cellular ROS, is markedly down-regulated in CRPC when compared with hormone-responsive tumors.
Experimental Design: Here, we knocked down SOD2 expression in AR-expressing LNCaP prostate cancer cells and determined gene expression changes, transcription factor binding, and AR transcription activity in SOD2 knockdown cells.
Results: SOD2 knockdown results in an increase in ROS. Gene expression changes induced by SOD2 knockdown results in the up-regulation of genes that are also androgen responsive and 46% of genes up-regulated 2-fold by the androgen ligand R1881 are also up-regulated to the same extent with SOD2 knockdown. The induction of many of these genes with SOD2 knockdown, such as VEGFA and FKBP5, is reversible with the antioxidant N-acetylcysteine, suggesting that this mechanism is directly linked to ROS. Furthermore, an array for transcription factor DNA-binding activity shows that SOD2 knockdown induces DNA binding by several transcription factors, including AR. SOD2 knockdown-induced AR activation was confirmed by electrophoretic mobility shift assay and luciferase activity, and both were readily reversible with N-acetylcysteine.
Conclusions: These findings show that down-regulation of SOD2 induces AR activity in a ROS-dependent manner, and suggest that there may be a role for antioxidant therapy in CRPC.