bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of Imatinib Mesylate with Autologous Leukocyte-Derived Heat Shock Protein and Chronic Myelogenous Leukemia
Authors: Li Zihai , Qiao Yi , Liu Bei , Laska Elizabeth J. , Chakravarthi Priyamvadha , Kulko Judith M. , Bona Robert D. , Fang Min , Hegde Upendra , Moyo Victor , Tannenbaum Susan H. , Ménoret Antoine , Gaffney Judy , Glynn Laura , Runowicz Carolyn D. , Srivastava Pramod K. 
Published: September 2005

Abstract
Purpose: To test the feasibility, safety, immunogenicity, and clinical efficacy of an autologous vaccine of leukocyte-derived heat shock protein 70-peptide complexes (Hsp70PC), in conjunction with imatinib mesylate, in patients with chronic myeloid leukemia (CML) in chronic phase.
Experimental Design: Patients had cytogenetic or molecular evidence of disease, despite treatment with imatinib mesylate for all except one patient, at the beginning of study. Hsp70PCs were purified from the leukopheresed peripheral blood mononuclear cells and were administered in eight weekly intradermal injections at 50 μg/dose without adjuvant. Clinical responses were assessed by bone marrow analysis before and after vaccinations. An IFN-γ enzyme-linked immunospot assay was used to estimate the effect of treatment on natural killer cells and T cells against CML.
Results: Twenty patients were treated. The manufacturing of Hsp70PCs was successful and the administration was safe for all patients. Minimal or no side effects were reported. Clinical responses were seen in 13 of 20 patients as measured by cytogenetic analysis of bone marrow Philadelphia chromosome–positive cells in metaphases and/or, when possible, the level of Bcr/Abl transcript by PCR. Immunologic responses were observed in 9 of 16 patients analyzed, characterized by an increase in the frequency of CML-specific IFN-γ-producing cells and IFN-γ-secreting natural killer cells in the blood. A significant correlation between clinical responses and immunologic responses was observed.
Conclusions: Autologous Hsp70PC vaccination is feasible and safe. When combined with imatinib mesylate, it is associated with immunologic and possible clinical responses against CML in chronic phase.
Pulmonary Squamous Cell Carcinoma following Head and Neck Squamous Cell Carcinoma: Metastasis or Second Primary?
Authors: Geurts Tom W. , Nederlof Petra M. , van den Brekel Michiel W.M. , van't Veer Laura J. , de Jong Daphne , Hart August A.M. , van Zandwijk Nico , Klomp Houke , Balm Alfons J.M. , van Velthuysen Marie-Louise F. 
Published: September 2005

Abstract
Purpose: To distinguish a metastasis from a second primary tumor in patients with a history of head and neck squamous cell carcinoma and subsequent pulmonary squamous cell carcinoma.
Experimental Design: For 44 patients with a primary squamous cell carcinoma of the head and neck followed by a squamous cell carcinoma of the lung, clinical data, histology, and analysis of loss of heterozygosity (LOH) were used to differentiate metastases from second primary tumors.
Results: Clinical evaluation suggested 38 patients with metastases and 6 with second primaries. We developed a novel interpretation strategy based on biological insight and on our observation that multiple LOH on different chromosome arms are not independent. LOH analysis indicated metastatic disease in 19 cases and second primary squamous cell carcinoma in 24 cases. In one case, LOH analysis was inconclusive. For 25 patients, LOH supported the clinical scoring, and in 18 cases, it did not. These 18 discordant cases were all considered to be second primary tumors by LOH analysis.
Conclusions: A considerable number of squamous cell lung lesions (50% in this study), clinically interpreted as metastases, are suggested to be second primaries by LOH analysis. For these patients, a surgical approach with curative intent may be justified.
Targeting Matrilysin and Its Impact on Tumor Growth In vivo: The Potential Implications in Breast Cancer Therapy
Authors: Jiang Wen G. , Davies Gaynor , Martin Tracey A. , Parr Christian , Watkins Gareth , Mason Malcolm D. , Mokbel Kefah , Mansel Robert E. 
Published: September 2005

Abstract
Introduction: Matrilysin (MMP-7) is a metalloproteinase that is involved in the degradation of extracellular matrix, invasion, and tumor progression. The current study examined if targeting matrilysin using retroviral ribozyme transgenes may have an impact on breast cancer cells and may have clinical implications.
Experimental Design: Retroviral hammerhead ribozyme transgenes were designed to specifically target human matrilysin mRNA. The breast cancer cell MDA-MB-231 was transfected with either a retroviral matrilysin transgene or a control retroviral transgene. Stably transfected cells were tested for their invasiveness and migratory properties in vitro. The cells were also used in creating a tumor model in athymic nude mice in which the growth of tumors and levels of matrilysin were assessed. In addition, levels of both protein and mRNA of matrilysin were investigated in a cohort of human breast tumors.
Results: Expression of matrilysin in MDA-MB-231 was successfully eliminated by the retroviral hammerhead ribozyme transgene for matrilysin as revealed by reverse transcription-PCR. Matrilysin transgene–transduced cancer cells (MDA-MB-231ΔMatrilysin) exhibited a significantly lower degree of invasion (number of invading cells 16.0 ± 2.5) compared with wild type (MDA-MB-231WT; 26.2 ± 6.2, P &lt; 0.05) or control transgene-transduced cancer cells (MDA-MB-231pRevTRE; 25.3 ± 4.2, P &lt; 0.01). However, the rate of growth of the cells in vitro was not significantly affected. In the in vivo tumor model, MDA-MB-231ΔMatrilysin tumors, which had very low levels of immunoreactive matrilysin, grew at a significantly lower rate (0.24 ± 0.03 cm3, 4 weeks after inoculation) compared with the wild-type MDA-MB-231WT (1.46 ± 0.04 cm3) and MDA-MB-231pRevTRE (1.12 ± 1.0 cm3) tumors. In human breast tumors, breast cancer cells stained matrilysin at a significantly higher density, compared with normal mammary epithelium. The highest level of matrilysin was seen in high-grade tumors and that from patients with moderate and poor prognosis. Finally, high levels of matrilysin were significantly linked with a poor long-term survival (P = 0.0143).
Conclusion: Matrilysin, which is aberrantly expressed in human breast tumors, can be effectively eliminated from breast cancer cells by way of hammerhead ribozyme transgene. Elimination of matrilysin is associated with low invasiveness and slow tumor growth. Taken together, the study suggests that targeting matrilysin may have important therapeutic implications.
Enhanced Production of Interleukin 6 in Peripheral Blood Monocytes Stimulated with Mucins Secreted into the Bloodstream
Authors: Yokoigawa Norio , Takeuchi Noriko , Toda Munetoyo , Inoue Mizue , Kaibori Masaki , Yanagida Hidesuke , Tanaka Hironori , Ogura Tokuhiro , Takada Hideho , Okumura Tadayoshi , Kwon A-H , Kamiyama Yasuo , Nakada Hiroshi 
Published: September 2005

Abstract
Purpose: It has been reported that tumor progression is correlated with the serum level of interleukin 6 (IL-6). The purpose of this study was to investigate by what mechanism, other than production from tumor cell, the serum level of IL-6 is elevated in the tumor-bearing state.
Experimental Design: Monocytes from healthy donors were cultured in the presence of sera from colon cancer patients, and the activity to elevate IL-6 production was estimated. This activity of serum was also examined after various biochemical treatments.
Results: When monocytes from healthy donors were cultured in the presence of sera from patients with colon cancer, secretion of IL-6 from the cells was markedly elevated. Serum proteins were fractionated on Sepharose 4B and the activity to elevate IL-6 production was found in the excluded fractions. Sialyl Tn antigen was detected in these same fractions. By excluding some mucins from the serum, the inducing activity was reduced to 40% of the original level. Furthermore, we purified mucins from the conditioned medium of colon cancer cells. Production of IL-6 was effectively elevated by a small amount of purified mucins in a dose-dependent manner. When the inducing activity was examined in the presence of binding or competitive inhibitors to the scavenger receptor, the effect was remarkably reduced.
Conclusions: Mucins secreted from colon cancer cells into the bloodstream induce production of IL-6 in peripheral blood monocytes through the scavenger receptor, which may be responsible for the high level of serum IL-6 in colon cancer patients.
Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features
Authors: Shibata Tatsuhiro , Uryu Satomi , Kokubu Akiko , Hosoda Fumie , Ohki Misao , Sakiyama Tokuki , Matsuno Yoshihiro , Tsuchiya Ryosuke , Kanai Yae , Kondo Tadashi , Imoto Issei , Inazawa Johji , Hirohashi Setsuo 
Published: September 2005

AbstractThe array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes. We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13, 12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.
Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis
Authors: Fraser Scott P. , Diss James K.J. , Chioni Athina-Myrto , Mycielska Maria E. , Pan Huiyan , Yamaci Rezan F. , Pani Filippo , Siwy Zuzanna , Krasowska Monika , Grzywna Zbigniew , Brackenbury William J. , Theodorou Dimis , Koyutürk Meral , Kaya Handan , Battaloglu Esra , De Bella Manuela Tamburo , Slade Martin J. , Tolhurst Robert , Palmieri Carlo , Jiang Jie , Latchman David S. , Coombes R. Charles , Djamgoz Mustafa B.A. 
Published: September 2005

Abstract
Purpose: Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na+ channel (VGSC) expression and its possible role in human breast cancer.
Experimental Design: Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC α-subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSCα expression and its association with metastasis in vivo.
Results: VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Nav1.5, in its newly identified “neonatal” splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo. An antibody specific for this form confirmed up-regulation of neonatal Nav1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Nav1.5 expression and clinically assessed lymph node metastasis.
Conclusions: Up-regulation of neonatal Nav1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.
Inhibition of Tumor Growth by RGD Peptide–Directed Delivery of Truncated Tissue Factor to the Tumor Vasculature
Authors: Kessler Torsten , Bieker Ralf , Padró Teresa , Schwöppe Christian , Persigehl Thorsten , Bremer Christoph , Kreuter Michael , Berdel Wolfgang E. , Mesters Rolf M. 
Published: September 2005

Abstract
Selective activation of blood coagulation in tumor vessels with subsequent tumor infarction is a promising anticancer strategy. To this end, a fusion protein consisting of the extracellular domain of tissue factor [truncated tissue factor (tTF)] was fused to the peptide GRGDSP selectively targeting αv-integrins on tumor endothelial cells. tTF-RGD retained its thrombogenic and integrin-binding activity in vitro. In vivo studies in mice bearing human adenocarcinomas (CCL185), melanoma (M21), and fibrosarcoma (HT1080) revealed that i.v. administration of tTF-RGD induced thrombotic occlusion of tumor vessels resulting in tumor growth retardation or regression in all three types of solid tumors. No apparent side effects, such as thrombosis, in other organs or other treatment-related toxicities were observed. Reduced tumor blood flow in tTF-RGD–treated animals as determined by contrast-enhanced magnetic resonance imaging underlines the proposed mechanism. In conclusion, we consider RGD peptide–directed delivery of tTF as alternative to previously used antibody fusion proteins. Small peptide-directed delivery of coaguligands does not cause immunologic side effects and those caused by accumulation in the reticuloendothelial system. This is the first report to describe the induction of selective thrombosis in tumor vessels by RGD peptide–directed delivery of tTF, which may be a promising strategy for the treatment of cancer.
Enhancement of Cisplatin Sensitivity of Cisplatin-Resistant Human Cervical Carcinoma Cells by Bryostatin 1
Authors: Mohanty Sanghamitra , Huang Jie , Basu Alakananda 
Published: September 2005

Abstract
Purpose: Bryostatin 1, a unique protein kinase C (PKC) activator, is already in the clinical trials. An understanding of complex regulation of PKC by bryostatin 1 is essential for effective use of bryostatin 1 in the clinic. We have previously shown that the ability of bryostatin 1 to enhance cisplatin sensitivity correlated with its ability to down-regulate PKCδ in HeLa cells. We have investigated how bryostatin 1 influences PKCδ regulation in cisplatin-resistant HeLa (HeLa/CP) cells, and if bryostatin 1 could be used to reverse cisplatin resistance.
Experimental Design: Phorbol 12,13-dibutyrate (PDBu), bryostatin 1, and small interfering RNA were used to manipulate PKC level/activation status. Cell death was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Annexin V dye-binding assay, and analysis of hypodiploid peak in a flow cytometer.
Results: Bryostatin 1 elicited a biphasic concentration response on PKCδ down-regulation and cisplatin-induced cell death in HeLa/CP cells; the maximum effect was achieved with 1 nmol/L bryostatin 1. Down-regulation of PKCα increased with increasing concentrations of bryostatin 1. PDBu induced down-regulation of PKCα in HeLa and HeLa/CP cells but it had little effect on PKCδ down-regulation in HeLa/CP cells. However, both PDBu and bryostatin 1 enhanced the sensitivity of HeLa/CP cells to cisplatin. Knockdown of PKCδ by small interfering RNA inhibited cisplatin-induced apoptosis but knockdown of PKCα enhanced cisplatin-induced cell death.
Conclusions: These results suggest that although PKCδ acts as a proapoptotic protein, full-length PKCδ may inhibit cisplatin-induced cell death. Thus, persistent activation/down-regulation of PKCδ by bryostatin 1 was associated with cisplatin sensitization. Furthermore, PKCα acts as an antiapoptotic protein and down-regulation of PKCα by PDBu was associated with cellular sensitization to cisplatin.
Glioblastoma Patients Exhibit Circulating Tumor-Specific CD8+ T Cells
Authors: Tang Jie , Flomenberg Phyllis , Harshyne Larry , Kenyon Lawrence , Andrews David W. 
Published: September 2005

AbstractPurpose: There is growing interest in developing cellular immune therapies for glioblastoma multiforme, but little is known about tumor-specific T-cell responses. A glioblastoma multiforme–specific T-cell assay was developed using monocyte-derived dendritic cells to present tumor antigens from the established glioblastoma multiforme cell line U118.Experimental Design: Peripheral blood mononuclear cells (PBMC) and tumor cells were obtained from nine patients with newly diagnosed brain tumors: five glioblastoma multiforme, two oligodendroglioma, one ependymoma, and one astrocytoma. PBMCs were incubated overnight with autologous tumor cells or autologous dendritic cells loaded with a U118 cell lysate, and responses were detected by IFN-γ ELISPOT and cytokine flow cytometry assays.Results: PBMCs from all glioblastoma multiforme patients exhibited IFN-γ responses to autologous tumor but not to HLA-mismatched U118 cells. Glioblastoma multiforme–specific IFN-γ responses were primarily mediated by CD8+ T cells and represented ∼2% of total CD8+ T cells. Additionally, all glioblastoma multiforme patients responded to autologous dendritic cells loaded with U118 lysate but not with low-grade astrocytoma cell lysates. PBMCs from four patients with other brain tumor types and one normal donor failed to respond to U118 lysate–loaded autologous dendritic cells. These data indicate that the IFN-γ responses to U118 lysate–loaded autologous dendritic cells are glioblastoma multiforme specific. Moreover, PBMCs stimulated 1 to 2 weeks with U118 lysate–loaded dendritic cells exhibited MHC class I–restricted cytotoxicity against autologous tumor cells.Conclusions: Glioblastoma multiforme patients exhibit circulating tumor-specific CD8+ T cells that recognize shared tumor antigens from the glioblastoma multiforme cell line U118. These data show that glioblastoma multiformes are immunogenic and support the development of immunotherapy trials.
Generation of Rituximab Polymer May Cause Hyper-Cross-linking–Induced Apoptosis in Non-Hodgkin's Lymphomas
Authors: Zhang Nan , Khawli Leslie A. , Hu Peisheng , Epstein Alan L. 
Published: September 2005

AbstractPurpose: Although Rituximab has produced significant tumor regressions in lymphoma patients, only 50% respond. Clinically, it has been shown that the major mechanism of action of Rituximab is antibody-dependent cytotoxicity requiring presentation by Fc-bearing cells. To improve the clinical efficacy of Rituximab for the treatment of CD20+ lymphomas, we now describe a new formulation of Rituximab, which, on direct binding to target, can induce apoptosis.Methods: In this report, enhanced apoptosis was observed by treating CD20+ lymphoma cells with a new polymer formulation of Rituximab. The polymer was produced by formation of a peptide bond using the sugar moiety of dextran (MW 6,000) to generate a clinically relevant reagent for use in vivo.Results: Comparison of Rituximab with a previously described dimer and the newly generated polymer shows that the polymer induced apoptosis more effectively in CD20+ cells as shown by the terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling assay (Rituximab, 3%; dimer, 3%; polymer, 58%). Consistent with these results, the polymer produced marked regression in CD20+ lymphoma xenografts, whereas the dimer and monomer reagents showed little effect. In addition, we were able to show that the level of apoptosis induced in human lymphoma cell lines was in accordance with the extent of both surface CD20 clustering and caspase-3 activation.Conclusions: These data suggest that hyper-cross-linking–induced apoptosis can be simulated by the use of a dextran polymer of Rituximab, which, when used in vivo, can directly kill CD20+ lymphoma cells and improve the clinical efficacy of this important therapeutic for human B-cell lymphomas.
New Monoclonal Antibodies to Mesothelin Useful for Immunohistochemistry, Fluorescence-Activated Cell Sorting, Western Blotting, and ELISA
Authors: Onda Masanori , Willingham Mark , Nagata Satoshi , Bera Tapan K. , Beers Richard , Ho Mitchell , Hassan Raffit , Kreitman Robert J. , Pastan Ira 
Published: September 2005

Abstract
Purpose: Mesothelin is a cell surface protein that is highly expressed in some malignant tumors, and is a promising target for immunotherapy. Recent data suggests that mesothelin is an adhesive protein and may have a role in the metastases of ovarian cancer. Although a few monoclonal antibodies (MAb) to mesothelin have been produced, they have limitations for the study of expression of native mesothelin because of their low affinity or reactivity only with denatured mesothelin protein. We have produced novel MAbs to mesothelin to help study mesothelin function and to develop improved diagnosis and immunotherapy of mesothelin-expressing tumors.
Experimental Design: Mesothelin-deficient mice were immunized with plasmid cDNA encoding mesothelin, and boosted with a mesothelin-rabbit IgG Fc fusion protein prior to cell fusion. Hybridomas were screened by an ELISA using plates coated with mesothelin-Fc protein.
Results: Seventeen hybridomas producing anti-mesothelin antibodies were established and shown to react with two epitopes on mesothelin. One group reacts with the same epitope as the low affinity antibody K1 that was originally used to identify mesothelin. The other is a new group that reacts with a new epitope. One antibody from each group was chosen for further study and shown to react strongly on ELISA, on immunohistochemistry, and by fluorescence-activated cell sorting on living cells.
Conclusion: Our two newly established MAbs, MN and MB, have different and useful properties compared with current antibodies used for the detection of mesothelin by immunohistochemistry, fluorescence-activated cell sorting, ELISA, and Western blotting.