bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I/II Study of LY900003, an Antisense Inhibitor of Protein Kinase C-α, in Combination with Cisplatin and Gemcitabine in Patients with Advanced Non–Small Cell Lung Cancer
Authors: Villalona-Calero Miguel A. , Ritch Paul , Figueroa Jose A. , Otterson Gregory A. , Belt Robert , Dow Edward , George Sebastian , Leonardo James , McCachren Spence , Miller G. Lance , Modiano Manuel , Valdivieso Manuel , Geary Richard , Oliver Jennifer W. , Holmlund Jon 
Published: September 2005

Abstract
Purpose: Protein kinase C-α has been implicated in malignant transformation and proliferation. Based on in vivo superadditive interaction between the protein kinase C-α antisense oligonucleotide LY900003 (Affinitak, ISIS 3521) and cisplatin, we designed this phase I/II trial of LY900003 with cisplatin/gemcitabine
Experimental Design: The safety of the combination, as well as potential pharmacokinetic interactions, was evaluated in the phase I portion of the trial. The phase II portion evaluated the antitumor activity of the combination in previously untreated patients with stage IIIB/IV non–small-cell lung cancer (NSCLC).
Results: Seven patients received 18 cycles of the combination during the phase I portion. Dose-limiting toxicity was only observed in one of six evaluable patients (grade 3 fatigue). However, due to a relatively high frequency of thrombocytopenia, cisplatin 80 (mg/m2) and gemcitabine (1,000 mg/m2) were recommended for the phase II portion. Antitumor activity was observed in two patients (one with NSCLC and one with pancreatic carcinoma), and prolonged stabilization was observed in two others. No pharmacokinetic interactions occurred. In the phase II portion, 55 NSCLC patients received the combination at two gemcitabine doses [1,000 mg/m2, n = 44 (original cohort); 1,250 mg/m2, n = 11 (expanded cohort)]. Fourteen of 39 evaluable patients in the original cohort had a response rate (1 complete response and 13 partial responses; response, 36%), whereas 2 of 9 evaluable patients in the expanded cohort experienced partial response (combined response rate, 33%). The median time to treatment failure was 3.9 months, whereas the median time response to progression for the 48 patients with evaluable response was 4.4 months (confidence interval, 3.5–5.5 months). Intent to treat median survival time was 8.9 months. Forty-eight percent of the patients experienced catheter-related events.
Conclusions: LY900003 can be administered safely in combination with cisplatin and gemcitabine and is associated with antitumor activity in patients with advanced NSCLC. Better characterization of subsets of patients most likely to benefit from this combination therapy is needed.
Proliferation Potential-Related Protein, an Ideal Esophageal Cancer Antigen for Immunotherapy, Identified Using Complementary DNA Microarray Analysis
Authors: Yoshitake Yoshihiro , Nakatsura Tetsuya , Monji Mikio , Senju Satoru , Matsuyoshi Hidetake , Tsukamoto Hirotake , Hosaka Seiji , Komori Hiroyuki , Fukuma Daiki , Ikuta Yoshiaki , Katagiri Toyomasa , Furukawa Yoichi , Ito Hiromi , Shinohara Masanori , Nakamura Yusuke , Nishimura Yasuharu 
Published: September 2005

AbstractPurpose: To establish effective antitumor immunotherapy for esophageal cancer, we tried to identify an useful target antigen of esophageal cancer.Experimental Design: We did cDNA microarray analysis to find a novel candidate antigen, proliferation potential-related protein (PP-RP). We examined cytotoxicity against tumor cells in vitro and in vivo of CTLs specific to PP-RP established from esophageal cancer patients.Results: In 26 esophageal cancer tissues, an average of relative ratio of the expression of the PP-RP mRNA in cancer cells versus adjacent normal esophageal tissues was 396.2. Immunohistochemical analysis revealed that, in 20 of the 22 esophageal cancer tissues, PP-RP protein was strongly expressed only in the cancer cells and not so in normal esophageal epithelial cells. PP-RP protein contains 10 epitopes recognized by HLA-A24–restricted CTLs. These CTLs, generated from HLA-A24–positive esophageal cancer patients, had cytotoxic activity against cancer cell lines positive for both PP-RP and HLA-A24. Furthermore, adoptive transfer of the PP-RP–specific CTL line inhibited the growth of a human esophageal cancer cell line engrafted in nude mice.Conclusions: The expression of PP-RP in esophageal cancer cells was significantly higher than in normal cells, and the CTLs recognizing PP-RP killed tumor cells in vitro and also showed tumor rejection effects in a xenograft model. Therefore, PP-RP may prove to be an ideal tumor antigen useful for diagnosis and immunotherapy for patients with esophageal cancer. cDNA microarray analysis is a useful method to identify ideal tumor-associated antigens.
Enhancement of the Antibody-Dependent Cellular Cytotoxicity of Low-Fucose IgG1 Is Independent of FcγRIIIa Functional Polymorphism
Authors: Niwa Rinpei , Hatanaka Shigeki , Shoji-Hosaka Emi , Sakurada Mikiko , Kobayashi Yukari , Uehara Aya , Yokoi Haruhiko , Nakamura Kazuyasu , Shitara Kenya 
Published: September 2005

Abstract
Purpose: The most common polymorphic variant of Fcγ receptor type IIIa (FcγRIIIa), FcγRIIIa-158F, has been associated with inferior clinical responses to anti-CD20 chimeric IgG1 rituximab compared with FcγRIIIa-158V. As we previously found that removal of fucose residues from the oligosaccharides of human IgG1 results in enhanced antibody-dependent cellular cytotoxicity, we compared the effects of the FcγRIIIa gene (FCGR3A) polymorphism on normal and low-fucose versions of rituximab on antibody-dependent cellular cytotoxicity.
Experimental Design: The polymorphism at position 158 of FcγRIIIa was determined for the peripheral blood mononuclear cells (PBMCs) of 20 healthy donors. The PBMCs were then used as effector cells to compare the antibody-dependent cellular cytotoxicity of rituximab and a low-fucose version, KM3065. The contributions of the different cell types within the PBMC to antibody-dependent cellular cytotoxicity were examined.
Results: We found KM3065-mediated antibody-dependent cellular cytotoxicity was increased 10 to 100-fold compared with rituximab for each of the 20 donors. In contrast to rituximab, KM3065 antibody-dependent cellular cytotoxicity enhancement was similar for both FCGR3A alleles and thus independent of genotype. In addition, antibody-dependent cellular cytotoxicity of both KM3065 and rituximab requires natural killer cells but not monocytes nor polymorphonuclear cells. The antibody-dependent cellular cytotoxicity (ADCC) of each of the 20 donors correlated with the natural killer cell numbers present in the PBMCs. Importantly, using KM3065, the ADCC mediated by effector cells bearing the lower affinity variant FcγRIIIa-158F was significantly increased compared with rituximab-mediated ADCC using effector cells bearing the higher affinity FcγRIIIa-158V receptors.
Conclusions: The use of low-fucose antibodies might improve the therapeutic effects of anti-CD20 therapy for all patients independent of FcγRIIIa phenotype beyond that currently seen with even the most responsive patients.
Prognostic Significance of Tissue Factor in Pancreatic Ductal Adenocarcinoma
Authors: Nitori Nobuhiro , Ino Yoshinori , Nakanishi Yukihiro , Yamada Tesshi , Honda Kazufumi , Yanagihara Kazuyoshi , Kosuge Tomoo , Kanai Yae , Kitajima Masaki , Hirohashi Setsuo 
Published: September 2005

Abstract
Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into “negative TF” (0%), “weak TF” (&lt;25%), or “high TF” (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0.0043), lymphatic distant metastasis (P = 0.0039), advanced tumor-node-metastasis stage (P = 0.0002), and high tumor grade (P = 0.0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P &lt; 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.
Troglitazone Acts on Cellular pH and DNA Synthesis through a Peroxisome Proliferator-Activated Receptor γ-Independent Mechanism in Breast Cancer-Derived Cell Lines
Authors: Turturro Francesco , Friday Ellen , Fowler Rocky , Surie Diya , Welbourne Tomas 
Published: September 2005

Abstract
Purpose: The purpose of this study was to assess whether troglitazone (TRO) would induce cellular acidosis by inhibiting Na+/H+ exchanger (NHE) 1 in breast carcinoma-derived cell lines and, if so, whether cellular acidosis would be associated with a reduction in proliferation.
Experimental Design: Intracellular pH (pHi) and acid extrusion capacity after an exogenous acid load were assayed using (2, 7)-biscarboxyethyl-5(6)-carboxyfluorescein in MCF-7 and MDA-MB-231 cells treated with TRO. Radiolabeled thymidine incorporation was used to assess DNA synthesis. Peroxisome proliferator-activated receptor (PPAR) γ involvement was assessed using an antagonist and PPARγ−/− NIH3T3 cells.
Results: TRO induced a prompt (&lt;4 minute) and severe cellular acidosis in both MCF-7 (7.54 ± 0.23 to 6.77 ± 0.06; P &lt; 0.001) and MDA-MB-231 cells (7.38 ± 0.18 to 6.89 ± 0.25; P &lt; 0.05) after 12 minutes, without increasing acid production. Acid extrusion as assessed by the response to an exogenous acid load (NH4Cl pulse) was markedly blunted (MDA-MB-231, P &lt; 0.01) or eliminated (MCF-7, P &lt; 0.001). Chronic exposure to TRO resulted in NHE1 activity reduction (P &lt; 0.05) and a dose-dependent decrease in DNA synthesis (&lt;75% inhibition at 100 μmol/L; P &lt; 0.001 and P &lt; 0.01 for MCF-7 and MDA-MB-231, respectively) associated with a decreased number of viable cells. TRO-mediated inhibition of proliferation was not reversed by the presence of the PPARγ inhibitor GW9662 and was demonstrable in PPARγ−/− NIH3T3 cells, consistent with a PPARγ-independent mechanism.
Conclusions: TRO induces marked cellular acidosis in MCF-7 and MDA-MD-231 cells. Sustained acidosis is consonant with decreased proliferation and growth that is not reversed by a PPARγ antagonist. Our results support a NHE-mediated action of TRO that exerts its effect independent of PPARγ.
Modulation of Pulmonary Leukotriene B4 Production by Cyclooxygenase-2 Inhibitors and Lipopolysaccharide
Authors: Mao Jenny T. , Tsu I-Hsien , Dubinett Steven M. , Adams Bradley , Sarafian Theodore , Baratelli Felicita , Roth Michael D. , Serio Kenneth J. 
Published: September 2005

AbstractPurpose: Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B4 synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.Experimental Design: Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.Results: Treatment with oral celecoxib only modestly increased LTB4 levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB4 production from smokers’ AMs was markedly increased by 10.6-fold. In addition, smokers’ AMs were twice as responsive in producing LTB4 when exposed to lipopolysaccharide compared with ex-smokers’ AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB4 in a dose-responsive manner. Finally, cycloheximide increased the production of LTB4 under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors.Conclusions: Our findings suggest that whereas oral celecoxib is capable of modulating LTB4 production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.
Enhanced Sensitivity to the HER1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Hydrochloride in Chemotherapy-Resistant Tumor Cell Lines
Authors: Dai Qun , Ling Yi-He , Lia Marie , Zou Yi-Yu , Kroog Glenn , Iwata Kenneth K. , Perez-Soler Roman 
Published: September 2005

Abstract
Purpose: Erlotinib (Tarceva, OSI-774) is a potent and specific inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. In phase II clinical studies, oral erlotinib monotherapy has shown antitumor activity in patients with advanced non–small cell lung cancer, head and neck cancer, and ovarian cancer after the failure of standard chemotherapy. We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the HER1/EGFR signaling pathways for survival.
Experimental Design: The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive, parental, and chemoresistant tumor cell lines.
Results: Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180. The IC50 values of erlotinib in the resistant cell lines were 2- to 20-fold lower than those in the corresponding parental cell lines. This enhanced sensitivity to erlotinib correlated with higher HER1/EGFR and phospho-HER1/EGFR expression when compared with the corresponding parental cell lines. Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib. AE-ME180/CDDP-resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did.
Conclusions: Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to HER1/EGFR inhibitors, which correlates with increased HER1/EGFR expression. These data may explain some of the observed clinical activity of HER1/EGFR inhibitors in patients previously treated with multiple therapies. HER1/EGFR tyrosine kinase inhibitors may be more effective as second- or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens.
Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth
Authors: Gregory Christopher W. , Whang Young E. , McCall Wesley , Fei Xiaoyin , Liu Yuanbo , Ponguta Liliana A. , French Frank S. , Wilson Elizabeth M. , Earp H. Shelton 
Published: September 2005

AbstractPurpose: The androgen receptor (AR) is a ligand-dependent transcription factor that mediates gene expression and growth of normal and malignant prostate cells. In prostate tumors that recur after androgen withdrawal, the AR is highly expressed and transcriptionally active in the absence of testicular androgens. In these “androgen-independent” tumors, alternative means of AR activation have been invoked, including regulation by growth factors and their receptors in prostate cancer recurrence.Experimental Design and Results: In this report, we show that HER receptor tyrosine kinases 1 through 4 are expressed in the CWR-R1 recurrent prostate cancer cell line; their stimulation by epidermal growth factor (EGF) and heregulin activates downstream signaling, including mitogen-activated protein kinase and phosphatidylinositol-3 kinase and Akt pathways. We show that heregulin activates HER2 and HER3 and increases androgen-dependent AR transactivation of reporter genes in CWR-R1 cells. Tyrosine phosphorylation of HER2 and HER3, AR transactivation, and cell proliferation induced by heregulin were more potently inhibited by the EGFR/HER2 dual tyrosine kinase inhibitor GW572016 (lapatinib) than the EGFR-specific inhibitor ZD1839 (gefitinib). Basal proliferation in the absence of growth factors was also inhibited by GW572016 to a greater extent than ZD1839, suggesting that low level HER2/HER3 activation perhaps by an autocrine pathway contributes to the proliferation signal.Conclusions: These data indicate that heregulin signaling through HER2 and HER3 increases AR transactivation and alters growth in a recurrent prostate cancer cell line. Therefore, inhibition of low-level HER2 signaling may be a potential novel therapeutic strategy in prostate cancer.
Elevated Expression of Wnt Antagonists Is a Common Event in Hepatoblastomas
Authors: Koch Arend , Waha Andreas , Hartmann Wolfgang , Hrychyk Aksana , Schüller Ulrich , Waha Anke , Wharton Keith A. , Fuchs Serge Y. , Schweinitz Dietrich von , Pietsch Torsten 
Published: September 2005

Abstract
Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating β-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of β-catenin leads to an increased formation of nuclear β-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes. In this study, we analyzed the mRNA expression levels of nine Wnt genes, including c-JUN, c-MYC, CYCLIN D1, FRA-1, NKD-1, ITF-2, MMP-7, uPAR, and β-TRCP, by competitive reverse transcription-PCR. We analyzed 23 hepatoblastoma biopsies for which matching liver tissue was available, 6 hepatoblastoma cell lines, and 3 human fetal liver samples. β-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the β-catenin mutational status, in comparison with their nontumorous counterparts. β-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear β-TrCP protein. In human liver tumor cells without β-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with β-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of β-TrCP and Nkd-1 on the Wnt signaling pathway in a manner analogous to Conductin (AXIN2) and Dkk-1, inhibitors shown previously to be up-regulated in hepatoblastomas. Our findings indicate that overexpression of the Wnt antagonists Nkd-1 and β-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and β-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.
Morphology of Tumor Cell Nuclei Is Significantly Related with Survival Time of Patients with Glioblastomas
Authors: Nafe Reinhold , Franz Kea , Schlote Wolfgang , Schneider Berthold 
Published: September 2005

Abstract
Purpose: To investigate whether histomorphology of tumor cell nuclei has a significant and independent relation to survival time of patients with glioblastomas.
Experimental Design: Seventy-two tumors from 72 patients were investigated by means of digital image analysis. Proliferating and nonproliferating nuclei were separately measured and parameters of nuclear size, shape, texture, and spatial relationships (topometric parameters) were detected. Survival analysis was done regarding morphometric data together with the patients' age, the amount of resection (total or subtotal), and the classification of the tumor as a “primary” (de novo) or “secondary” glioblastoma.
Results: The overall relation of all morphometric data to the time of survival was highly significant (Cox analysis, P &lt; 0.0001). Apart from the extent of surgical resection, parameters of nuclear shape and topometric variables, such as the distance between two nuclei lying nearest to each other, showed an independent and significant relation to survival time. The patients' age had also a significant but comparably slight relation to survival time.
Conclusions: The morphology of tumor cell nuclei, as represented by morphometric data, shows a significant relation to survival time of patients with glioblastomas. This relation is statistically independent from the amount of surgical resection, from the patients' age and from the classification of the glioblastoma as being primary or secondary. The results support the view that histomorphometry of tumor cell nuclei is a valuable prognostic marker for patients with glioblastomas. We believe that such a marker ought to be incorporated into the formation of individual therapeutic decisions.
Prospective Study of Quantitation of Plasma DNA Levels in the Diagnosis of Malignant versus Benign Prostate Disease
Authors: Boddy Jane L. , Gal Shira , Malone Peter R. , Harris Adrian L. , Wainscoat Jim S. 
Published: September 2005

Abstract
Purpose: The aim of this study was to determine the potential of cell-free DNA levels as a diagnostic marker for prostate cancer, having first established the effect that blood sample processing has on this measurement.
Experimental Design: A total of 152 blood samples were collected prospectively from patients before their prostate biopsy and 25 from men in two distinct control groups. Blood was processed to yield three components: one-spin plasma (n = 68), two-spin plasma (n = 152), and serum (n = 56) samples.
Results: Having established the effect of sample preparation on the measured DNA level, the more reliable two-spin plasma sample was used to determine the relationship between DNA and the presence of prostate cancer. Those patients with cancer (n = 78) had a significantly higher level of DNA compared with the control groups (P &lt; 0.0001 and P &lt; 0.0001). However, DNA levels in patients with a benign biopsy (n = 74) were significantly higher than the 78 patients confirmed to have cancer (P = 0.02).
Conclusions: We conclude that the sample type used in the quantitation of cell-free DNA has an effect on the level reported. Elevated levels are present in the two-spin plasma samples of patients with prostate cancer compared with healthy controls but are not of diagnostic value during the management of prostate cancer.