bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recognition of Six-Transmembrane Epithelial Antigen of the Prostate–Expressing Tumor Cells by Peptide Antigen–Induced Cytotoxic T Lymphocytes
Authors: Rodeberg David A. , Nuss Rebecca A. , Elsawa Sherine F. , Celis Esteban 
Published: September 2005

AbstractThe identification of novel markers and therapeutic targets in advanced cancer is critical for improving diagnosis and therapy. Six-transmembrane epithelial antigen of the prostate (STEAP) is expressed predominantly in human prostate tissue and in other common malignancies including prostate, bladder, colon, and ovarian carcinomas, and in Ewing's sarcoma, suggesting that it could function as an almost universal tumor antigen. We have used MHC peptide binding algorithms to predict potential STEAP sequences capable of stimulating in vitro naïve HLA-A2–restricted CTLs. Four of six peptides predicted by these algorithms were able to induce antigen-specific CTLs that killed peptide-pulsed HLA-A2 target cells. Two of these peptides, STEAP-292 (MIAVFLPIV) and a modification of this peptide STEAP-292.2L (MLAVFLPIV), were the most efficient in the induction of primary CTL responses. More importantly, these CTLs were able to respond to tumor cells that express HLA-A2 and STEAP (colon, bladder, prostate, Ewing's sarcoma, and melanoma). Our results provide strong evidence that STEAP-292 is naturally processed by many tumor types and is presented in the context of HLA-A2 in sufficient amounts to allow recognition by CTLs. Also because STEAP-292.2L is a more immunogenic peptide able to induce CTL recognition of these STEAP-containing tumors and may have potential as an antitumor peptide vaccine.
Recognition of Prostate and Breast Tumor Cells by Helper T Lymphocytes Specific for a Prostate and Breast Tumor-Associated Antigen, TARP
Authors: Kobayashi Hiroya , Nagato Toshihiro , Oikawa Kensuke , Sato Keisuke , Kimura Shoji , Aoki Naoko , Omiya Ryusuke , Tateno Masatoshi , Celis Esteban 
Published: September 2005

AbstractPurpose: T cell–based immunotherapy via the in vitro or in vivo expansion of prostate tumor-associated antigen (TAA)–specific T lymphocytes is one of the most promising therapeutic approaches to treat prostate cancer. T-cell alternate reading frame protein (TARP) is a mitochondrial protein that is specifically expressed in prostate epithelial cells. We have done experiments aimed at identifying helper T lymphocyte (HTL) epitopes for TARP for the design of T cell–based immunotherapy for prostate cancer.Experimental Design: Dendritic cells from normal donors were pulsed with synthetic peptides derived from TARP, which were predicted to serve as HTL epitopes. These dendritic cells were used to stimulate CD4+ T cells in vitro to trigger HTL responses against TARP. T-cell responses to these peptides were also studied with lymphocytes from prostate cancer patients.Results: The two peptides, TARP1-14 and TARP14-27, were shown to elicit effective in vitro HTL responses using lymphocytes from both normal volunteers and prostate cancer patients. Peptide TARP1-14-reactive HTLs were found restricted by HLA-DR53 and could recognize naturally processed protein antigen derived from tumor cells, which was presented by autologous dendritic cells. Most significantly, stimulation with peptide TARP14-27 generated four HTL lines restricted by HLA-DR1, HLA-DR9, HLA-DR13, and HLA-DR15, some of which capable of recognizing naturally processed antigens presented by dendritic cell or directly by TARP-positive tumor cells.Conclusions: Our results show that TARP constitutes a TAA that can be recognized by tumor-reactive HTL. The newly described TARP epitopes could be used to optimize and improve T-cell epitope–based immunotherapy against prostate and other tumors expressing TARP.
Polysomy 17 in HER-2/neu Status Elaboration in Breast Cancer: Effect on Daily Practice
Authors: Ma Yan , Lespagnard Laurence , Durbecq Virginie , Paesmans Marianne , Desmedt Christine , Gomez-Galdon Maria , Veys Isabelle , Cardoso Fatima , Sotiriou Christos , Di Leo Angelo , Piccart Martine J. , Larsimont Denis 
Published: September 2005

Abstract
Purpose: To assess the effect of chromosome 17 copy number on HER-2/neu status determination in breast cancers.
Experimental Design: HER-2/neu gene copy and chromosome 17 centromere numbers were evaluated on 893 breast carcinomas using double color fluorescence in situ hybridization (FISH). The net and chromosome 17 corrected (ratio) HER-2/neu copy numbers were compared and related to immunohistochemistry done according to the Food and Drug Administration (FDA)–approved scoring system (0, 1+, 2+, and 3+) as a first screening step in 584 cases.
Results: When a ratio ≥2 was considered as criterion for FISH positivity, 49.3% (440 of 893) of cases showed amplification versus 56.2% (502 of 893) by using a net HER-2/neu gene copy number &gt;4 as a alternative criterion; 14.8% (67 of 453) of cases having a ratio &lt;2 had a net HER-2/neu gene copy number &gt;4 and 1.1% (5 of 440) with a ratio ≥2 had a net HER-2/neu gene copy number &lt;4. Among discordant cases, 88.8% (64 of 72) were polysomic (&gt;2.25 chromosomes 17/cell) and among polysomic cases, 12.8% (40 of 312) of the low polysomic (2.26-3.75 chromosomes 17/cell) and 36.9% (24 of 65) of the highly polysomic (&gt;3.75 chromosomes 17/cell) cases showed discordance. In cases with a ratio &lt;2, polysomy 17 incidences were 85.7% (6 of 7) in IHC 3+, 42.4% (79 of 186) in IHC 2+, 33.3% (15 of 45) in IHC 1+, and 29.1% (16 of 55) in IHC 0.
Conclusion: A net increase in HER-2/neu gene copy number consecutive to polysomy 17 in the absence of specific gene amplification might lead to a strong protein overexpression in a small subset of breast carcinomas. HER-2/neu status determination by FISH is dependent on the criterion considered for positivity in clinical practice.
Stronger Association between Obesity and Biochemical Progression after Radical Prostatectomy among Men Treated in the Last 10 Years
Authors: Freedland Stephen J. , Isaacs William B. , Mangold Leslie A. , Yiu Sindy K. , Grubb Kelly A. , Partin Alan W. , Epstein Jonathan I. , Walsh Patrick C. , Platz Elizabeth A. 
Published: September 2005

Abstract
Background: Prior prospective cohort studies found that obesity was associated with increased risk of prostate cancer death. However, in the last 20 years dramatic changes in both the extent of obesity and prostate cancer screening and treatment have occurred. Whether the association between obesity and aggressive disease has changed as a result of these temporal changes is unclear.
Methods: The study population consisted of 2,832 men treated by anatomic radical retropubic prostatectomy between 1985 and 2004 by a single surgeon. We evaluated the associations of obesity (body mass index ≥30 kg/m2)with tumor stage and grade using logistic regression and with biochemical progression using Cox proportional hazards regression. We examined whether these associations have changed over the last 20 years.
Results: On multivariable analysis, the strength of the positive association between obesity and high-grade disease increased over time whereas the strength of the positive association between obesity and positive surgical margins decreased over time. The strength of the positive association between obesity and extraprostatic extension fluctuated over time, although the strongest and only statistically significant association was among men treated since 2000. The association between obesity and biochemical progression was strongest among men treated since 1995 (relative risk, 1.90; 95% confidence interval, 1.09-3.30; P = 0.02).
Conclusions: In the current study, with the exception of positive surgical margins, the positive association between obesity and high-grade disease, advanced stage, and biochemical progression after radical retropubic prostatectomy was in general strongest among men treated in the last 10 years. The reasons for these findings are not clear, although factors possibly related to prostate-specific antigen–based screening and/or other temporal changes in prostate cancer diagnosis and treatment may play a role.
In vitro and In vivo Pharmacokinetic-Pharmacodynamic Relationships for the Trisubstituted Aminopurine Cyclin-Dependent Kinase Inhibitors Olomoucine, Bohemine and CYC202
Authors: Raynaud Florence I. , Whittaker Steven R. , Fischer Peter M. , McClue Steven , Walton Michael I. , Barrie S. Elaine , Garrett Michelle D. , Rogers Paul , Clarke Simon J. , Kelland Lloyd R. , Valenti Melanie , Brunton Lisa , Eccles Suzanne , Lane David P. , Workman Paul 
Published: September 2005

Abstract
Purpose: To investigate pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine, and CYC202 (R-roscovitine; seliciclib) in the HCT116 human colon carcinoma model.
Experimental Design: The in vitro activity of the agents was determined in a human tumor panel using the sulforhodamine B assay. The concentration and time dependence was established in HCT116 cells. Molecular biomarkers, including RB phosphorylation and cyclin expression, were assessed by Western blotting. Pharmacokinetic properties were characterized in mice following analysis by liquid chromatography-tandem mass spectrometry. Based on these studies, a dosing regimen was developed for CYC202 that allowed therapeutic exposures in the HCT116 tumor xenograft.
Results: The antitumor potency of the agents in vitro was in the order olomoucine (IC50, 56 μmol/L) &lt; bohemine (IC50, 27 μmol/L) &lt; CYC202 (IC50, 15 μmol/L), corresponding to their activities as cyclin-dependent kinase inhibitors. Antitumor activity increased with exposure time up to 16 hours. The agents caused inhibition of RB and RNA polymerase II phosphorylation and depletion of cyclins. They exhibited relatively rapid clearance following administration to mice. CYC202 displayed the slowest clearance from plasma and the highest tumor uptake, with oral bioavailability of 86%. Oral dosing of CYC202 gave active concentrations in the tumor, modulation of pharmacodynamic markers, and inhibition of tumor growth.
Conclusions: CYC202 showed therapeutic activity on human cancer cell lines in vitro and on xenografts. Pharmacodynamic markers are altered in vitro and in vivo, consistent with the inhibition of cyclin-dependent kinases. Such markers may be potentially useful in the clinical development of CYC202 and other cyclin-dependent kinase inhibitors.
N
1,N12-Diacetylspermine as a Sensitive and Specific Novel Marker for Early- and Late-Stage Colorectal and Breast Cancers
Authors: Hiramatsu Kyoko , Takahashi Keiichi , Yamaguchi Taturo , Matsumoto Hiroshi , Miyamoto Hidenori , Tanaka Souichi , Tanaka Chikako , Tamamori Yoshiko , Imajo Mari , Kawaguchi Masashi , Toi Masakazu , Mori Takeo , Kawakita Masao 
Published: September 2005

Abstract
Purpose: N 1,N12-diacetylspermine (DiAcSpm) in the urine of colorectal and breast cancer patients was examined to establish its usefulness as a novel diagnostic tool for detecting these cancers at clinically early stages.
Experimental Design: Urine samples from 248 colon cancer patients and 83 breast cancer patients as well as 51 patients with benign gastrointestinal diseases treated in Tokyo Metropolitan Komagome Hospital during the period of August 1999 to January 2004 were collected. DiAcSpm was analyzed by ELISA and its sensitivity for malignant conditions was compared with that of serum carcinoembryonic antigen (CEA), CA19-9, and CA15-3.
Results: The sensitivity of urinary DiAcSpm for colon cancer patients (n = 248) was 75.8% (mean ± 2 SD for 52 healthy controls as a cutoff value), which was markedly higher than the sensitivities of serum CEA (39.5%, P &lt; 0.0001) and CA19-9 (14.1%, P &lt; 0.0001). DiAcSpm was elevated in 60% of tumor-node-metastasis cancer stage 0 + I patients, whereas only 10% (P &lt; 0.0001) and 5% (P &lt; 0.0001) of these patients were CEA- and CA19-9–positive, respectively. The sensitivity of urinary DiAcSpm for 83 cases of breast cancer (60.2%) was higher than the sensitivities of CEA (37.3%, P = 0.0032) and CA15-3 (37.3%, P = 0.0032). DiAcSpm was elevated in 28% of tumor-node-metastasis stage I + II patients, whereas only 3% (P = 0.0064) and 0% (P = 0.001) of these patients were CEA- and CA15-3–positive, respectively.
Conclusion: The observations indicate that urinary DiAcSpm is a more sensitive marker than CEA, CA19-9, and CA15-3 and that it can efficiently detect colorectal and breast cancers at early stages.
A Bispecific Recombinant Immunotoxin, DT2219, Targeting Human CD19 and CD22 Receptors in a Mouse Xenograft Model of B-Cell Leukemia/Lymphoma
Authors: Vallera Daniel A. , Todhunter Deborah A. , Kuroki David W. , Shu Yanqun , Sicheneder Andy , Chen Hua 
Published: September 2005

AbstractA novel bispecific single-chain fusion protein, DT2219, was assembled consisting of the catalytic and translocation domains of diphtheria toxin (DT390) fused to two repeating sFv subunits recognizing CD19 and CD22 and expressed in Escherichia coli. Problems with yield, purity, and aggregation in the refolding step were solved by incorporating a segment of human muscle aldolase and by using a sodium N-lauroyl-sarcosine detergent-based refolding procedure. Problems with reduced efficacy were addressed by combining the anti-CD19 and anti-CD22 on the same single-chain molecule. DT2219 had greater anticancer activity than monomeric or bivalent immunotoxins made with anti-CD19 and anti-CD22 sFv alone and it showed a higher level of binding to patient leukemia cells and to CD19+CD22+ Daudi or Raji cells than did anti-CD19 and anti-CD22 parental monoclonal antibodies. The resulting DT2219, mutated to enhance its avidity, was cytotoxic to Daudi cells in vitro (IC50 = 0.3 nmol/L). In vivo, DT2219 was effective in a flank tumor therapy model in which it significantly inhibited tumor growth (P &lt; 0.05) and in a systemic model in which it significantly prolonged survival of severe combined immunodeficient mice with established Daudi (P &lt; 0.008) compared with controls. DT2219 has broader reactivity in recognizing B-cell malignancies, has more killing power, and requires less toxin than using individual immunotoxin, which warrants further investigation as a new drug for treating B leukemia/lymphoma.
Detection of Micrometastases in Pelvic Lymph Nodes in Patients Undergoing Radical Cystectomy for Focally Invasive Bladder Cancer by Real-time Reverse Transcriptase-PCR for Cytokeratin 19 and Uroplakin II
Authors: Kurahashi Toshifumi , Hara Isao , Oka Nobutoshi , Kamidono Sadao , Eto Hiroshi , Miyake Hideaki 
Published: September 2005

Abstract
Purpose: The objective of this study was to clarify the significance of micrometastases in pelvic lymph nodes in patients who underwent radical cystectomy for bladder cancer.
Experimental Design: We included 40 patients with locally invasive bladder cancer who underwent radical cystectomy and pelvic lymphadenectomy. Expression of cytokeratin 19 (CK19), uroplakin II (UP II), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in 760 lymph nodes were assessed by a fully quantitative real-time reverse transcription-PCR (RT-PCR) assay. The quantification value of CK19 or UP II mRNA was described as each value relative to GAPDH mRNA. In this study, we regarded specimen in which either CK19 or UP II mRNA was positive as “presence of micrometastasis.”
Results: Routine pathologic examinations detected tumor cells in 29 lymph nodes from six patients. Real-time RT-PCR identified positive expression of CK19 and UP II mRNAs in 49 lymph nodes from 10 patients and 98 lymph nodes from 16 patients, respectively. Of 633 lymph nodes from 34 patients with no pathologic evidence of nodal involvement, 13 nodes from five patients and 58 nodes from 10 patients were diagnosed as positive for CK19 and UP II mRNAs expression, respectively, by real-time RT-PCR. Presence of micrometastases was significantly associated with other conventional prognostic variables, including pathologic stage and microvascular invasion. Disease recurrence was occurred in eight patients, among whom four patients were negative for lymph node metastasis by routine pathologic examination and diagnosed as having micrometastasis by real-time RT-PCR assay. Furthermore, cause-specific survival rate in patients without micrometastasis was significantly higher than that in those with micrometastasis, irrespective of the presence of pathologic-positive nodes.
Conclusions: Approximately 30% of locally invasive bladder cancer shed cancer cells to pelvic lymph nodes, and disease recurrence after radical cystectomy could be explained, at least in part, by micrometastases in pelvic lymph nodes.
Phase I Combining a P-Glycoprotein Inhibitor, MS209, in Combination with Docetaxel in Patients with Advanced Malignancies
Authors: Diéras Véronique , Bonneterre Jacques , Laurence Valérie , Degardin Marian , Pierga Jean-Yves , Bonneterre Marie-Edith , Marreaud Sandrine , Lacombe Denis , Fumoleau Pierre 
Published: September 2005

Abstract
Purpose: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics.
Experimental design: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body).
Results: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209.
Conclusion: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.
Dietary Flaxseed Alters Tumor Biological Markers in Postmenopausal Breast Cancer
Authors: Thompson Lilian U. , Chen Jian Min , Li Tong , Strasser-Weippl Kathrin , Goss Paul E. 
Published: September 2005

AbstractPurpose: Flaxseed, the richest source of mammalian lignan precursors, has previously been shown to reduce the growth of tumors in rats. This study examined, in a randomized double-blind placebo-controlled clinical trial, the effects of dietary flaxseed on tumor biological markers and urinary lignan excretion in postmenopausal patients with newly diagnosed breast cancer.Experimental Design: Patients were randomized to daily intake of either a 25 g flaxseed-containing muffin (n = 19) or a control (placebo) muffin (n = 13). At the time of diagnosis and again at definitive surgery, tumor tissue was analyzed for the rate of tumor cell proliferation (Ki-67 labeling index, primary end point), apoptosis, c-erbB2 expression, and estrogen and progesterone receptor levels. Twenty-four–hour urine samples were analyzed for lignans, and 3-day diet records were evaluated for macronutrient and caloric intake. Mean treatment times were 39 and 32 days in the placebo and flaxseed groups, respectively.Results: Reductions in Ki-67 labeling index (34.2%; P = 0.001) and in c-erbB2 expression (71.0%; P = 0.003) and an increase in apoptosis (30.7%; P = 0.007) were observed in the flaxseed, but not in the placebo group. No significant differences in caloric and macronutrient intake were seen between groups and between pre- and posttreatment periods. A significant increase in mean urinary lignan excretion was observed in the flaxseed group (1,300%; P &lt; 0.01) compared with placebo controls. The total intake of flaxseed was correlated with changes in c-erbB2 score (r = −0.373; P = 0.036) and apoptotic index (r = 0.495; P &lt; 0.004).Conclusion: Dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.
The Farnesyltransferase Inhibitor L744832 Potentiates UCN-01–Induced Apoptosis in Human Multiple Myeloma Cells
Authors: Pei Xin-Yan , Dai Yun , Rahmani Mohamed , Li Weiqun , Dent Paul , Grant Steven 
Published: September 2005

Abstract
Purpose: The purpose of this study was to characterize interactions between the farnesyltransferase inhibitor L744832 and the checkpoint abrogator UCN-01 in drug-sensitive and drug-resistant human myeloma cell lines and primary CD138+ multiple myeloma cells.
Experimental Design: Wild-type and drug-resistant myeloma cell lines were exposed to UCN-01 ± L744832 for 24 hours, after which mitochondrial injury, caspase activation, apoptosis, and various perturbations in signaling and survival pathways were monitored.
Results: Simultaneous exposure of myeloma cells to marginally toxic concentrations of L744832 and UCN-01 resulted in a synergistic induction of mitochondrial damage, caspase activation, and apoptosis, associated with activation of p34cdc2 and c-Jun-NH2-kinase and inactivation of extracellular signal-regulated kinase, Akt, GSK-3, p70S6K, and signal transducers and activators of transcription 3 (STAT3). Enhanced lethality for the combination was also observed in primary CD138+ myeloma cells, but not in their CD138− counterparts. L744832/UCN-01–mediated lethality was not attenuated by conventional resistance mechanisms to cytotoxic drugs (e.g., melphalan or dexamethasone), addition of exogenous interleukin-6 or insulin-like growth factor-I, or the presence of stromal cells. In contrast, enforced activation of STAT3 significantly protected myeloma cells from L744832/UCN-01–induced apoptosis.
Conclusions: Coadministration of the farnesyltransferase inhibitor L744832 promotes UCN-01–induced apoptosis in human multiple myeloma cells through a process that may involve perturbations in various survival signaling pathways, including extracellular signal-regulated kinase, Akt, and STAT3, and through a process capable of circumventing conventional modes of myeloma cell resistance, including growth factor– and stromal cell–related mechanisms. They also raise the possibility that combined treatment with farnesyltransferase inhibitors and UCN-01 could represent a novel therapeutic strategy in multiple myeloma.