bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia
Authors: Raaijmakers Marc H.G.P. , de Grouw Elke P.L.M. , Heuver Leonie H.H. , van der Reijden Bert A. , Jansen Joop H. , Scheper Rik J. , Scheffer George L. , de Witte Theo J.M. , Raymakers Reinier A.P. 
Published: September 2005

Abstract
Purpose: Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38− stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML.
Experimental Design: BCRP expression (measured flow-cytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38− cells.
Results: BCRP was preferentially expressed in leukemic CD34+38− cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38− cells.
Conclusions: These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broad-spectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.
The Absence of Human Equilibrative Nucleoside Transporter 1 Is Associated with Reduced Survival in Patients With Gemcitabine-Treated Pancreas Adenocarcinoma
Authors: Spratlin Jennifer , Sangha Randeep , Glubrecht Darryl , Dabbagh Laith , Young James D. , Dumontet Charles , Cass Carol , Lai Raymond , Mackey John R. 
Published: September 2005

Abstract
Purpose: Gemcitabine monotherapy is the standard palliative chemotherapy for pancreatic adenocarcinoma. Gemcitabine requires plasma membrane nucleoside transporter proteins to efficiently enter cells and exert it cytotoxicity. In vitro studies have demonstrated that deficiency of human equilibrative nucleoside transporter 1 (hENT1), the most widely abundant and distributed nucleoside transporter in human cells, confers resistance to gemcitabine toxicity, but the distribution and abundance of nucleoside transporters in normal and malignant pancreatic tissue is unknown.
Experimental Design: We studied tumor blocks from normal pancreas and 21 Alberta patients with gemcitabine-treated pancreatic cancer. Immunohistochemistry on the formalin-fixed, paraffin-embedded tissues was performed with specific hENT1 and human Concentrative Nucleoside Transporter 3 monoclonal antibodies and scored by a pathologist blinded to clinical outcomes.
Results: hENT1 was detected in normal Langerhan cells and lymphocytes but not in normal glandular elements. Patients in whom all adenocarcinoma cells had detectable hENT1 had significantly longer median survivals from gemcitabine initiation than those for whom hENT1 was absent in a proportion (10 to 100%) of adenocarcinoma cells (median survival, 13 versus 4 months, P = 0.01). Immunohistochemistry for human Concentrative Nucleoside Transporter 3 revealed moderate to high-intensity staining in all adenocarcinoma tissue samples.
Conclusions: Patients with pancreatic adenocarcinoma with uniformly detectable hENT1 immunostaining have a significantly longer survival after gemcitabine chemotherapy than tumors without detectable hENT1. Immunohistochemistry for hENT1 shows promise as a molecular predictive assay to appropriately select patients for palliative gemcitabine chemotherapy but requires formal validation in prospective, randomized trials.
Molecular Prediction of Response to 5-Fluorouracil and Interferon-α Combination Chemotherapy in Advanced Hepatocellular Carcinoma
Authors: Kurokawa Yukinori , Matoba Ryo , Nagano Hiroaki , Sakon Masato , Takemasa Ichiro , Nakamori Shoji , Dono Keizo , Umeshita Koji , Ueno Noriko , Ishii Shin , Kato Kikuya , Monden Morito 
Published: September 2005

Abstract
Purpose: The prognosis of hepatocellular carcinoma (HCC) is very poor, particularly in patients with tumors that have invaded the major branches of the portal vein. Combination chemotherapy with intra-arterial 5-fluorouracil and subcutaneous interferon-α has shown promising results for such advanced HCC, but it is important to develop the ability to accurately predict chemotherapeutic responses.
Experimental Design: We analyzed the expression of 3,080 genes using a polymerase chain reaction-based array in 20 HCC patients who were treated with combination chemotherapy after reduction surgery. After unsupervised analyses, a supervised classification method for predicting chemotherapeutic responses was constructed. To minimize the number of predictive genes, we used a random permutation test to select only significant (P &lt; 0.01) genes. A leave-one-out cross-validation confirmed the gene selection. We also prepared an additional 11 cases for validation of predictive performance.
Results: Hierarchical clustering analysis and principal component analysis with all 3,080 genes revealed distinct gene expression patterns in responders (those with complete response or partial response) and nonresponders (those with stable disease or progressive disease) to the combination chemotherapy. Using a weighted-voting classification method with either all genes or only significant genes as assessed by permutation testing, the objective responses to treatment were correctly predicted in 17 of 20 cases (accuracy, 85%; positive predictive value, 100%; negative predictive value, 80%). Moreover, patients in the validation dataset could be classified into two distinct prognostic groups using 63 predictive genes.
Conclusions: Molecular analysis of 63 genes can predict the response of patients with advanced HCC and major portal vein tumor thrombi to combination chemotherapy with 5-fluorouracil and interferon-α.
Prognostic Significance of
TP53
Tumor Suppressor Gene Expression and Mutations in Human Osteosarcoma
Authors: Pakos Emilios E. , Kyzas Panayiotis A. , Ioannidis John P. A. 
Published: September 2005

Abstract
Purpose: Various studies examining the relationship between tumor suppressor protein TP53 overexpression and/or TP53 gene mutations and the response to chemotherapy and clinical outcome in patients with osteosarcoma have yielded inconclusive results. The purpose of the current study was to evaluate the relation of TP53 status with response to chemotherapy and/or clinical outcome in osteosarcoma.
Experimental Design: We conducted a meta-analysis of 16 studies (n = 499 patients) that evaluated the correlation between TP53 status and histologic response to chemotherapy and 2-year survival. Data were synthesized in summary receiver operating characteristic curves and with summary likelihood ratios (LRs) and risk ratios.
Results: The quantitative synthesis showed that TP53 status is not a prognostic factor for the response to chemotherapy. The positive LR was 1.21 (95% confidence interval, 0.86–1.71), and the negative LR was 0.91 (95% confidence interval, 0.77–1.07). There was no significant between-study heterogeneity. TP53-positive status tended to be associated with a worse 2-year survival, but the overall results were not formally statistically significant. The association was formally significant in studies that clearly stated that measurements were blinded to outcomes (risk ratio, 2.05; 95% confidence interval, 1.23–3.44), and in studies using reverse transcription-PCR for evaluating TP53 alterations (risk ratio, 1.76; 95% confidence interval, 1.07–2.91).
Conclusions: TP53 status is not associated with the histologic response to chemotherapy in patients with osteosarcoma, whereas TP53 gene alterations may be associated with decreased survival.
Effects of the Antiestrogen Tamoxifen and the Aromatase Inhibitor Letrozole on Serum Hormones and Bone Characteristics in a Preclinical Tumor Model for Breast Cancer
Authors: Núñez Nomelí P. , Jelovac Danijela , Macedo Luciana , Berrigan David , Perkins Susan N. , Hursting Stephen D. , Barrett J. Carl , Brodie Angela 
Published: September 2005

Abstract
Purpose: The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice.
Experimental Design: Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks.
Results: As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 μg/day) and letrozole (10 μg/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment.
Conclusions: Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer.
Epratuzumab, a Humanized Anti-CD22 Antibody, in Aggressive Non-Hodgkin’s Lymphoma
Authors: Leonard John P. , Coleman Morton , Ketas Jamie C. , Chadburn Amy , Furman Richard , Schuster Michael W. , Feldman Eric J. , Ashe Michelle , Schuster Stephen J. , Wegener William A. , Hansen Hans J. , Ziccardi Heather , Eschenberg Michael , Gayko Urte , Fields Scott Z. , Cesano Alessandra , Goldenberg David M. 
Published: September 2005

AbstractPurpose: We conducted a single-center, dose-escalation study evaluating the safety, pharmacokinetics, and efficacy of epratuzumab, an anti-CD22 humanized monoclonal antibody, in patients with aggressive non-Hodgkin’s lymphoma.Experimental Design: Epratuzumab was administered once weekly for 4 weeks at 120-1000-mg/m2 doses to 56 patients [most (n = 35) with diffuse large B-cell lymphoma].Results: Patients were heavily pretreated (median, 4 prior therapies), 25% received prior high-dose chemotherapy with stem cell transplant, and 84% had bulky disease (≥5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Most (95%) infusions were completed within 1 h. The mean serum half-life was 23.9 days. Across all dose levels and histologies, objective responses (ORs) were observed in five patients (10%; 95% confidence interval, 3–21%), including three complete responses. In patients with diffuse large B-cell lymphoma, 15% had ORs. Overall, 11 (20%) patients experienced some tumor mass reduction. Median duration of OR was 26.3 weeks, and median time to progression for responders was 35 weeks. Two responses are ongoing at ≥34 months, including one rituximab-refractory patient.Conclusions: These data demonstrate that epratuzumab has a good safety profile and exerts antitumor activity in aggressive non-Hodgkin’s lymphoma at doses of ≥240 mg/m2, thus warranting further evaluation in this clinical setting.
Proteomic Analysis of Human Acute Leukemia Cells
Authors: Cui Jiu-Wei , Wang Jie , He Kun , Jin Bao-Feng , Wang Hong-Xia , Li Wei , Kang Li-Hua , Hu Mei-Ru , Li Hui-Yan , Yu Ming , Shen Bei-fen , Wang Guan-Jun , Zhang Xue-Min 
Published: September 2005

Abstract
Purpose: French-American-British (FAB) classification of acute leukemia with genetic heterogeneity is important for treatment and prognosis. However, the distinct protein profiles that contribute to the subtypes and facilitate molecular definition of acute leukemia classification are still unclear.
Experimental Design: The proteins of leukemic cells from 61 cases of acute leukemia characterized by FAB classification were separated by two-dimensional electrophoresis, and the differentially expressed protein spots were identified by both matrix-assisted laser desorption/ionization–time-of-flight–mass spectrometry (MALDI-TOF-MS) and tandem electrospray ionization MS (ESI-MS/MS).
Results: The distinct protein profiles of acute leukemia FAB types or subtypes were successfully explored, including acute myeloid leukemia (AML), its subtypes (M2, M3, and M5) and acute lymphoid leukemia (ALL), which were homogeneous within substantial samples of the respective subgroups but clearly differed from all other subgroups. We found a group of proteins that were highly expressed in M2 and M3, rather than other subtypes. Among them, myeloid-related proteins 8 and 14 were first reported to mark AML differentiation and to differentiate AML from ALL. Heat shock 27 kDa protein 1 and other proteins that are highly expressed in ALL may play important roles in clinically distinguishing AML from ALL. Another set of proteins up-regulated was restricted to granulocytic lineage leukemia. High-level expression of NM23-H1 was found in all but the M3a subtype, with favorable prognosis.
Conclusions: These data have implications in delineating the pathways of aberrant gene expression underlying the pathogenesis of acute leukemia and could facilitate molecular definition of FAB classification. The extension of the present analysis to currently less well-defined acute leukemias will identify additional subgroups.
Nitric Oxide Accelerates Interleukin-13 Cytotoxin-Mediated Regression in Head and Neck Cancer Animal Model
Authors: Kawakami Koji , Kawakami Mariko , Puri Raj K. 
Published: September 2005

AbstractReceptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi’s sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter Nω-monomethyl-l-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with Nω-monomethyl-l-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent.
Immunization of Patients with the hTERT:540-548 Peptide Induces Peptide-Reactive T Lymphocytes That Do Not Recognize Tumors Endogenously Expressing Telomerase
Authors: Parkhurst Maria R. , Riley John P. , Igarashi Takehito , Li Yong , Robbins Paul F. , Rosenberg Steven A. 
Published: September 2005

AbstractPurpose: Telomerase is an attractive target antigen for cancer immunotherapies because it is expressed in &gt;85% of human tumors but is rarely found in normal tissues. A HLA-A*0201-restricted T-cell epitope was previously identified within telomerase reverse transcriptase hTERT:540-548. This peptide was reported to induce CTL that recognized tumor cells and transfectants that endogenously expressed telomerase. Therefore, we initiated a clinical protocol to evaluate the therapeutic and immunological efficacy of this peptide.Experimental Design: Fourteen patients with metastatic cancers were vaccinated with hTERT:540-548 emulsified in incomplete Freund’s adjuvant.Results: In 7 patients, peripheral blood mononuclear cells collected after immunization recognized hTERT:540-548, whereas those collected before vaccination did not. However, none of these CTLs recognized tumors that endogenously expressed telomerase, and none of the patients had an objective clinical response. Several highly avid T-cell clones were generated that recognized T2 cells pulsed with ≤1 nm hTERT:540-548, but none of these recognized HLA-A*0201+ hTERT+ tumors or cells transduced with the human telomerase reverse transcriptase (hTERT) gene. Also, an antibody specific for hTERT:540-548/HLA-A*0201 complexes stained peptide-pulsed cells but not telomerase+ tumors.Conclusions: Our results are discordant with previous studies and those of a clinical trial that claimed peripheral blood mononuclear cells from patients vaccinated with peptide-pulsed dendritic cells lysed hTERT+ tumors. However, our findings are consistent with a previous study that demonstrated that the hTERT:540-548 peptide is cleaved in the proteasome. These results suggest that hTERT:540-548 is not presented on the surfaces of tumor cells in the context of HLA-A*0201 and will not be useful for the immunotherapy of patients with cancer.
Identification of Glypican-3 as a Novel Tumor Marker for Melanoma
Authors: Nakatsura Tetsuya , Kageshita Toshiro , Ito Shosuke , Wakamatsu Kazumasa , Monji Mikio , Ikuta Yoshiaki , Senju Satoru , Ono Tomomichi , Nishimura Yasuharu 
Published: September 2005

AbstractPurpose: We reported recently the novel tumor marker glypican-3 (GPC3) for hepatocellular carcinoma. In the present study, we investigated the expression of GPC3 in human melanoma cell lines and tissues and asked whether GPC3 could be a novel tumor marker for melanoma.Experimental Design: Expression of GPC3 mRNA and protein was investigated in human melanoma cell lines and tissues using reverse transcription-PCR and immunohistochemical analysis. Secreted GPC3 protein was quantified using ELISA in culture supernatants of melanoma cell lines and in sera from 91 patients with melanoma and 28 disease-free patients after surgical removal of primary melanoma. All of the subjects were Japanese nationals.Results: In &gt;80% of melanoma and melanocytic nevus, there was evident expression of GPC3 mRNA and protein. Furthermore, GPC3 protein was evidenced in sera of 39.6% (36 of 91) of melanoma patients but not in sera from subjects with large congenital melanocytic nevus (0 of 5) and from healthy donors (0 of 60). Twenty-seven of 36 serum GPC3-positive patients were negative for both serum 5-S-cysteinyldopa and melanoma-inhibitory activity, well-known tumor markers for melanoma. The positive rate of serum GPC3 (39.6%) was significantly higher than that of 5-S-cysteinyldopa (26.7%) and of melanoma-inhibitory activity (20.9%). Surprisingly, we detected serum GPC3 even in patients with stage 0 in situ melanoma. The positive rate of serum GPC3 at stage 0, I, and II (44.4%, 40.0%, and 47.6%) was significantly higher than that of 5-S-cysteinyldopa (0.0%, 8.0%, and 10.0%). Also observed was the disappearance of GPC3 protein in sera from 11 patients after surgical removal of the melanoma.Conclusions: GPC3 is apparently a novel tumor marker useful for the diagnosis of melanoma, especially in early stages of the disorder.
Hypoxia and Photofrin Uptake in the Intraperitoneal Carcinomatosis and Sarcomatosis of Photodynamic Therapy Patients
Authors: Busch Theresa M. , Hahn Stephen M. , Wileyto E. Paul , Koch Cameron J. , Fraker Douglas L. , Zhang Paul , Putt Mary , Gleason Kristen , Shin Daniel B. , Emanuele Michael J. , Jenkins Kevin , Glatstein Eli , Evans Sydney M. 
Published: September 2005

Abstract
Purpose: Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis.
Experimental Design: Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization.
Results: Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as ∼2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 ± 0.4 to 3.9 ± 0.5 ng/mg (mean ± SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean ± SE drug uptake among these patients ranged from 0.6 ± 0.8 to 5.8 ± 0.5 ng/mg.
Conclusions: Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of ∼10× among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.