bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polycyclic Aromatic Hydrocarbon–DNA Adducts in Prostate and Biochemical Recurrence after Prostatectomy
Authors: Rybicki Benjamin A. , Neslund-Dudas Christine , Bock Cathryn H. , Rundle Andrew , Savera Adnan T. , Yang James J. , Nock Nora L. , Tang Deliang 
Published: February 2008

Abstract
Purpose: DNA adduct levels may be influenced by metabolic activity, DNA repair capabilities, and genomic integrity, all of which play a role in cancer progression.
Experimental Design: To determine if elevated DNA adducts are a marker for prostate cancer progression, we measured polycyclic aromatic hydrocarbon–DNA adducts by immunohistochemistry in prostate cells of 368 surgical prostate cancer patients treated at the Henry Ford Hospital in Detroit, Michigan, between September 1999 and July 2004. Patients were followed up to 5 years after surgery with relative risk for biochemical recurrence (BCR) estimated with a Cox proportional hazards model that adjusted for standard clinical risk factors.
Results: At 1 year of follow-up, patients with adduct levels above the median in tumor cells [hazard ratio (HR), 2.40; 95% confidence interval (95% CI), 1.10-5.27] and nontumor cells (HR, 3.22; 95% CI, 1.40-7.39) had significant increased risk of BCR, but these HRs decreased to 1.12 (95% CI, 0.68-1.83) and 1.46 (95% CI, 0.89-2.41) in tumor and nontumor cells at 5 years postsurgery. When we restricted our analysis to patients with advanced-stage (III+) disease, those with high adduct levels in either tumor (53.5% versus 30.2%; P = 0.07) or nontumor (55.2% versus 28.6%; P = 0.02) cells had BCR rates almost 2-fold higher. In race-stratified analyses, the greatest risk of BCR associated with high adduct levels (in nontumor cells) was for African American patients younger than 60 years old (HR, 3.79; 95% CI, 1.01-14.30).
Conclusions: High polycyclic aromatic hydrocarbon–DNA adduct levels in nontumor prostate cells are most strongly associated with BCR between 1 and 2 years after surgery and in patient subsets defined by younger age, advanced tumor stage, and African American race.
Effective Inhibition of the Epidermal Growth Factor/Epidermal Growth Factor Receptor Binding by Anti–Epidermal Growth Factor Antibodies Is Related to Better Survival in Advanced Non–Small-Cell Lung Cancer Patients Treated with the Epidermal Growth Factor Cancer Vaccine
Authors: García Beatriz , Neninger Elia , de la Torre Ana , Leonard Idrissa , Martínez Rocío , Viada Carmen , González Gisela , Mazorra Zaima , Lage Agustín , Crombet Tania 
Published: February 2008

AbstractPurpose: Epidermal growth factor (EGF) might be a suitable immunotherapeutic target in non–small-cell lung cancer (NSCLC). Our approach consists of active immunotherapy with EGF. The aim of the study is to characterize the humoral response and its effects on signal transduction in relation with the clinical outcome.Experimental Design: Eighty NSCLC patients treated with first-line chemotherapy were randomized to receive the EGF vaccine or supportive care. EGF concentration in sera, anti-EGF antibodies and their capacity to inhibit the binding between EGF/EGF receptor (EGFR), and the EGFR phosphorylation were measured.Results: Seventy-three percent of vaccinated patients developed a good antibody response, whereas none of the controls did. In good antibody-responder patients, self EGF in sera was significantly reduced. In 58% of vaccinated patients, the post-immune sera inhibited EGF/EGFR binding; in the control group, no inhibition occurred. Post-immune sera inhibited the EGFR phosphorylation whereas sera from control patients did not have this capacity. Good antibody-responder patients younger than 60 years had a significantly better survival. A high correlation between anti-EGF antibody titers, EGFR phosphorylation inhibition, and EGF/EGFR binding inhibition was found. There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule.Conclusions: Immunization with the EGF vaccine induced neutralizing anti-EGF antibodies capable of inhibiting EGFR phosphorylation. There was a significant positive correlation between antibody titers, EGF/EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients.
Aberrant Expression of Connexin 26 Is Associated with Lung Metastasis of Colorectal Cancer
Authors: Ezumi Koji , Yamamoto Hirofumi , Murata Kohei , Higashiyama Masahiko , Damdinsuren Bazarragchaa , Nakamura Yurika , Kyo Naganori , Okami Jiro , Ngan Chew Yee , Takemasa Ichiro , Ikeda Masataka , Sekimoto Mitsugu , Matsuura Nariaki , Nojima Hiroshi , Monden Morito 
Published: February 2008

Abstract
Purpose: Connexin 26 (Cx26) is one of the gap junction–forming family members classically considered to be tumor suppressors. However, recent studies show association of elevated expression of Cx26 with poor prognosis in several human malignancies. Furthermore, Cx26 has been observed to be indispensable to spontaneous metastasis of melanoma cells. Here, we assessed Cx26 expression in primary colorectal cancer (CRC) and the metastatic lesions to elucidate its role in metastasis.
Experimental Design: Cx26 expression was assessed in 25 adenomas, 167 CRCs, and normal mucosa, together with the metastatic lesions.
Results: Normal mucosa and adenomatous tissue expressed Cx26 mainly in the plasma membrane, whereas cancer cells mostly contained Cx26 in the cytoplasm. The incidence of aberrant Cx26 expression varied widely in CRC (mean, 49.5 ± 35.5%), and the expression levels were confirmed by Western blot and quantitative reverse transcription–PCR. Clinicopathologic survey revealed association of high expression with less differentiated histology and venous invasion (P = 0.0053 and P = 0.0084, respectively). Notably, high Cx26 expression was associated with shorter disease-free survival and shorter lung metastasis–free survival in 154 curatively resected CRC sets (P = 0.041 and P = 0.028, respectively). Survey of metastatic lesions revealed that lung metastasis, but not liver and lymph nodes metastases, expressed higher Cx26 than the CRC series or corresponding primary CRCs (P &lt; 0.0001 and P = 0.0001, respectively).
Conclusions: These findings suggest that aberrant expression of Cx26 plays an essential role in lung metastasis. Thus, Cx26 is a promising therapeutic target, particularly for CRC patients who develop lung metastasis.
Follistatin Suppresses the Production of Experimental Multiple-Organ Metastasis by Small Cell Lung Cancer Cells in Natural Killer Cell–Depleted SCID Mice
Authors: Ogino Hirokazu , Yano Seiji , Kakiuchi Soji , Muguruma Hiroaki , Ikuta Kenji , Hanibuchi Masaki , Uehara Hisanori , Tsuchida Kunihiro , Sugino Hiromu , Sone Saburo 
Published: February 2008

Abstract
Purpose: Follistatin (FST), an inhibitor of activin, regulates a variety of biological functions, including cell proliferation, differentiation, and apoptosis. However, the role of FST in cancer metastasis is still unknown. Previous research established a multiple-organ metastasis model of human small cell lung cancer in natural killer cell–depleted SCID mice. In this model, i.v. inoculated tumor cells produced metastatic colonies in multiple organs including the lung, liver, and bone. The purpose of this study is to determine the role of FST in multiple-organ metastasis using this model.
Experimental Design: A human FST gene was transfected into the small cell lung cancer cell lines SBC-3 and SBC-5 and established transfectants secreting biologically active FST. The metastatic potential of the transfectants was evaluated using the metastasis model.
Results: FST-gene transfection did not affect the cell proliferation, motility, invasion, or adhesion to endothelial cells in vitro. I.v. inoculated SBC-3 or SBC-5 cells produced metastatic colonies into multiple organs, including the lung, liver, and bone in the natural killer cell–depleted SCID mice. FST transfectants produced significantly fewer metastatic colonies in these organs when compared with their parental cells or vector control clones. Immunohistochemical analyses of the liver metastases revealed that the number of proliferating tumor cells and the tumor-associated microvessel density were significantly less in the lesions produced by FST transfectants.
Conclusions: These results suggest that FST plays a critical role in the production of multiple-organ metastasis, predominantly by inhibiting the angiogenesis. This is the first report to show the role of FST in metastases.
Effective Treatment of Established Human Breast Tumor Xenografts in Immunodeficient Mice with a Single Dose of the α-Emitting Radioisotope Astatine-211 Conjugated to Anti-HER2/neu Diabodies
Authors: Robinson Matthew K. , Shaller Calvin , Garmestani Kayhan , Plascjak Paul S. , Hodge Kathryn M. , Yuan Qing-An , Marks James D. , Waldmann Thomas A. , Brechbiel Martin W. , Adams Gregory P. 
Published: February 2008

Abstract
Purpose: Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived α-emitting radioisotope 211At.
Experimental Design: Immunodeficient nude mice bearing established HER2/neu–positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[211At]astatophenethyl)succinamate (211At-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with 211At-SAPS T84.66 diabody targeting the carcinoembryonic antigen or 211At-SAPS on a diabody specific for the Müllerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line.
Results: A single i.v. injection of 211At-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 μCi dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 μCi dose was used. Treatment of mice bearing the same tumors with 211At-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 μCi of 211At-SAPS on the anti–Müllerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect.
Conclusions: These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived α-emitting radioisotopes.
Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment
Authors: Huston Alissa , Leleu Xavier , Jia Xiaoying , Moreau Anne-Sophie , Ngo Hai T. , Runnels Judith , Anderson Judy , Alsayed Yazan , Roccaro Aldo , Vallet Sonia , Hatjiharissi Evdoxia , Tai Yu-Tsu , Sportelli Peter , Munshi Nikhil , Richardson Paul , Hideshima Teru , Roodman David G. , Anderson Kenneth C. , Ghobrial Irene M. 
Published: February 2008

Abstract
Purpose: We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells.
Experimental Design: MM cell lines were incubated with perifosine (5 and 10 μmol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination.
Results: The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin.
Conclusions: This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.
A Phase I Study of OGX-011, a 2′-Methoxyethyl Phosphorothioate Antisense to Clusterin, in Combination with Docetaxel in Patients with Advanced Cancer
Authors: Chi Kim N. , Siu Lillian L. , Hirte Hal , Hotte Sebastien J. , Knox Jennifer , Kollmansberger Christian , Gleave Martin , Guns Emma , Powers Jean , Walsh Wendy , Tu Dongsheng , Eisenhauer Elizabeth 
Published: February 2008

AbstractPurpose: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2′-methoxyethyl–modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA, has a prolonged tissue half life, enhances drug efficacy in xenograft models, and reduces clusterin expression in humans with a biologically effective dose of 640 mg. The objective of this study was to determine a recommended phase II dose of OGX-011 in combination with docetaxel.Experimental Design: Patients with cancers known from the literature to express clusterin were eligible. OGX-011 was given by 2-h i.v. infusion starting at 40 mg weekly after loading doses on days 1, 3, and 5. Docetaxel was given i.v. 30 mg/m2 weekly for 5 of 6 weeks (schedule A) or 75 mg/m2 every 3 weeks (schedule B). All patients had serial samples of peripheral blood mononuclear cells and serum assessed for clusterin expression.Results: Forty patients were enrolled to eight cohorts. OGX-011 could be given at the full biologically effective single-agent dose of 640 mg with both docetaxel schedules. Toxic effects were primarily myelosuppression, fatigue, hair loss, gastrointestinal effects (expected docetaxel effects), as well as dose-related chills and fever (expected OGX-011 effects). OGX-011 AUC and Cmax increased proportionally with no apparent effect on docetaxel pharmacokinetics. At the end of cycle 1, serum clusterin showed mean decreases of 34% and 38% (range, 15-99%) at the 640-mg dose levels.Conclusions: OGX-011 can be given at a biologically effective dose with standard doses of docetaxel. Phase II trials of combined OGX-011 and chemotherapy are ongoing in patients with prostate, breast, and lung cancers.
Higher Expression of the Androgen-Regulated Gene PSA/HK3 mRNA in Prostate Cancer Tissues Predicts Biochemical Recurrence-Free Survival
Authors: Sterbis Joseph R. , Gao Chunling , Furusato Bungo , Chen Yongmei , Shaheduzzaman Syed , Ravindranath Lakshmi , Osborn David J. , Rosner Inger L. , Dobi Albert , McLeod David G. , Sesterhenn Isabell A. , Srivastava Shiv , Cullen Jennifer , Petrovics Gyorgy 
Published: February 2008

Abstract
Purpose: Alterations of the androgen receptor (AR)-mediated signaling through numerous mechanisms are increasingly recognized in prostate cancer (CaP) progression. We hypothesized that the assessment of well-defined AR transcriptional targets (e.g., PSA/HK3 mRNA) in CaP tissues will provide in vivo readout of AR dysfunctions. Moreover, quantitative expression features of PSA/HK3 mRNA in prostate tumor cells may serve as a prognostic indicator of disease progression.
Experimental Design: Paired benign and malignant epithelial cells (242 specimens) were obtained from laser capture microdissection of frozen OCT-embedded tissue sections prepared from radical prostatectomy specimens of 121 patients. Quantitative expression of PSA/HK3 mRNA in the matched malignant and benign cells was analyzed by real-time reverse transcription-PCR.
Results: CaP cells express significantly lower PSA/HK3 mRNA levels than matched benign cells (P = 0.0133). Moreover, low PSA/HK3 mRNA expression in malignant cells was associated with increased risk of biochemical recurrence (P = 0.0217), as well as with time to recurrence (P = 0.0371), in patients with intermediate preoperative serum prostate-specific antigen levels (2-10 ng/mL). The expression of androgen-dependent genes in clinical samples correlates with each other in patients with higher expression of PSA/HK3 mRNA but not in patients with lower expression of PSA/HK3 mRNA reflecting AR pathway dysfunction.
Conclusions: Our study has unraveled a novel prognostic utility of quantitative measurements of PSA/HK3 mRNA reflecting AR transcriptional activity in CaP cells, which is independent of serum prostate-specific antigen. It also has potential in stratifying subsets of patients exhibiting progressive disease associated with dampened AR transcriptional functions who may be targeted by tailored therapeutic strategies.
Enhanced In vitro and In vivo Cytotoxicity of Combined Reovirus and Radiotherapy
Authors: Twigger Katie , Vidal Laura , White Christine L. , De Bono Johann S. , Bhide Shreerang , Coffey Matt , Thompson Brad , Vile Richard G. , Heinemann Lucy , Pandha Hardev S. , Errington Fiona , Melcher Alan A. , Harrington Kevin J. 
Published: February 2008

Abstract
Purpose: To test combination treatment schedules of reovirus and radiation in human and murine tumor cells in vitro and in vivo.
Experimental Design: In vitro cytotoxicity and cell cycle effects of reovirus given alone and combined with radiotherapy were assessed by colorimetric, tissue culture infectious dose 50, and fluorescence-activated cell sorting–based assays. Interactions between the agents were evaluated using combination index analysis. The effect of different schedules of reovirus and radiotherapy on viral replication and cytotoxicity was tested in vitro and the combination was assessed in three tumor models in vivo.
Results: Characterization of reovirus cytotoxicity in a panel of cell lines yielded a range of sensitivities. Combined reovirus and radiotherapy yielded statistically significantly increased cytotoxicity, particularly in cell lines with moderate susceptibility to reovirus alone. The enhanced cytotoxicity of the combination occurred independently of treatment sequence or schedule. Radiation did not affect viral replication and only reduced reoviral cytotoxicity after clinically irrelevant single doses (&gt;50 Gy). Combination index analysis revealed synergy between radiation (3-10 Gy) and reovirus at multiplicities of infection between 0.001 and 1. Combination treatment significantly increased apoptosis in tumor cells relative to either single-agent treatment. In vivo studies using xenograft and syngeneic tumors showed enhanced activity of the combination relative to reovirus or radiation alone (P &lt; 0.001).
Conclusions: Combining reovirus and radiotherapy synergistically enhances cytotoxicity in a variety of tumor cells in vitro and in vivo. These results offer strong support for translational clinical trials of reovirus plus radiotherapy that have been initiated in the clinic.
Combined Clinical Trial Results of a HER2/neu(E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02
Authors: Peoples George E. , Holmes Jarrod P. , Hueman Matthew T. , Mittendorf Elizabeth A. , Amin Asna , Khoo Steven , Dehqanzada Zia A. , Gurney Jennifer M. , Woll Michael M. , Ryan Gayle B. , Storrer Catherine E. , Craig Dianna , Ioannides Constantin G. , Ponniah Sathibalan 
Published: February 2008

AbstractPurpose: E75 is an immunogenic peptide from the HER2/neu protein, which is overexpressed in many breast cancer patients. We have conducted two overlapping E75 vaccine trials to prevent recurrence in node-positive (NP) and node-negative (NN) breast cancer patients.Experimental Design: E75 (HER2/neu 369-377) + granulocyte macrophage colony-stimulating factor was given intradermally to previously treated, disease-free NP breast cancer patients in a dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented.Results: One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91). Human leucocyte antigen A2 (HLA-A2) and HLA-A3 patients were vaccinated (n = 101), whereas all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a dose-dependent immunologic response to the vaccine was shown. Planned primary analysis revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls (P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus 14.8%); however, a significant difference in the pattern of recurrence persisted.Conclusions: E75 is safe and effective in raising a dose-dependent HER2/neu immunity in HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These findings warrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster to prevent breast cancer recurrences.
Effect of Melanoma on Immune Function in the Regional Lymph Node Basin
Authors: Negin Benjamin , Panka David , Wang Wei , Siddiqui Mustaqueem , Tawa Nicholas , Mullen John , Tahan Steven , Mandato Lucy , Polivy Adam , Mier James , Atkins Michael 
Published: February 2008

AbstractPurpose: To determine if melanoma within the tumor microenvironment will result in immunosuppression within the draining lymph node as measured by down-regulation of T-cell receptor ζ (TCR ζ) expression.Experimental Design: Patients with clinical stage I to III melanoma undergoing wide local excision and sentinel lymph node biopsy or therapeutic lymph node dissection were consented to have a portion of their lymph node sampled. Lymph nodes were classified as macroscopically involved (TI), microscopically involved (MI), noninvolved with positive wide excision (NI+), or noninvolved with negative wide excision (NI−). Lymphocytes were stained using antibodies to TCR ζ and other immune cells and analyzed via flow cytometer. Reverse transcription-PCR was used to assess for mediators of immunosuppression.Results: Fifty patient lymph node samples (15 TI, 7 MI, 9 NI+, and 19 NI−) were evaluated. Increasing involvement of tumor in the lymph node was associated with decreasing TCR ζ chain expression (TI 56%, MI 76%, and NI− 89%). Differences between TI and MI (P = 0.005), TI and NI− (P = 0.0001), and MI and NI− (P = 0.019) were statistically significant. There was also a significant difference between TCR ζ chain expression of NI+ and NI− (73% versus 89%; P = 0.0016). A trend toward increased arginase expression in tumor-involved lymph nodes was detected by reverse transcription-PCR.Conclusions: Melanoma involvement of regional nodes is associated with loss of TCR ζ expression that is inversely related to tumor burden. Residual melanoma within the wide local excision specimen is associated with TCR ζ loss in noninvolved sentinel lymph nodes, suggesting that immune modulation precedes tumor spread.