bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Associated Macrophages Press the Angiogenic Switch in Breast Cancer
Authors: Lin Elaine Y. , Pollard Jeffrey W. 
Published: June 2007

AbstractThe development of a supportive vasculature is essential for tumor progression. In a mouse model of breast cancer, we found that tumor-associated macrophages that are recruited to the tumor just before malignant conversion are essential for the angiogenic switch. These findings establish a causal linkage to explain well-documented clinical correlations between macrophages, microvessel density, and poor prognosis in breast tumors. [Cancer Res 2007;67(11):5064–3]
Differential Regulation of Estrogen Receptor α Turnover and Transactivation by Mdm2 and Stress-Inducing Agents
Authors: Duong Vanessa , Boulle Nathalie , Daujat Sylvain , Chauvet Jérôme , Bonnet Sandrine , Neel Henry , Cavaillès Vincent 
Published: June 2007

Abstract
In mammalian cells, the level of estrogen receptor α (ERα) is rapidly decreased upon estrogen treatment, and this regulation involves proteasome degradation. Using different approaches, we showed that the Mdm2 oncogenic ubiquitin-ligase directly interacts with ERα in a ternary complex with p53 and is involved in the regulation of ERα turnover (both in the absence or presence of estrogens). Several lines of evidence indicated that this effect of Mdm2 required its ubiquitin-ligase activity and involved the ubiquitin/proteasome pathway. Moreover, in MCF-7 human breast cancer cells, various p53-inducing agents (such as UV irradiation) or treatment with RITA (which inhibits the interaction of p53 with Mdm2) stabilized ERα and abolished its 17β-estradiol–dependent turnover. Interestingly, our data indicated that ligand-dependent receptor turnover was not required for efficient transactivation. Altogether, our results indicate that the Mdm2 oncoprotein and stress-inducing agents complexly and differentially regulate ERα stability and transcriptional activity in human cancer cells. [Cancer Res 2007;67(11):5513–21]
Phase I Trial of BAY 50-4798, an Interleukin-2–Specific Agonist in Advanced Melanoma and Renal Cancer
Authors: Margolin Kim , Atkins Michael B. , Dutcher Janice P. , Ernstoff Marc S. , Smith John W. , Clark Joseph I. , Baar Joseph , Sosman Jeffrey , Weber Jeffrey , Lathia Chetan , Brunetti Janice , Cihon Frank , Schwartz Brian 
Published: June 2007

Abstract
Purpose: BAY 50-4798 is an analogue of interleukin-2 that selectively activates T cells over natural killer cells. This phase I study was designed to determine the maximum tolerated dose (MTD) and safety of BAY 50-4798, screen for tumor response, and assess pharmacokinetics.
Experimental Design: Forty-five patients with metastatic melanoma or renal cancer were enrolled, 31 on escalating doses to determine the MTD, with 20 renal cell carcinoma patients treated at MTD to detect antitumor activity. BAY 50-4798 was delivered i.v. every 8 h, days 1 to 5 and 15 to 19, and could be repeated after 9 weeks if tumor was stable or responding.
Results: The MTD was defined by and reported in terms of doses received. The doses tested ranged from 1.3 to 26.1 μg/kg, and the MTD was defined as 10.4 μg/kg based on toxicities similar to those of aldesleukin. Two patients achieved partial responses, one with melanoma and one with renal cell carcinoma. Among all 45 patients, 53% and 9% experienced a grade 3 and 4 toxicity, respectively. Among the patients treated at the MTD of 10.4 μg/kg, 71% and 10% experienced a grade 3 and 4 toxicity, respectively. Pharmacokinetics showed dose-dependent peak concentrations (Cmax) and area under the curve with a half-life of ∼2 h and no evidence of accumulation. Lymphocyte subset analysis confirmed the preferential expansion of T-cell subsets over natural killer cells.
Conclusions: The antitumor activity of BAY 50-4798 in malignancies that respond to high-dose interleukin-2 was low. BAY 50-4798 might provide advantages over aldesleukin in antigen-specific immunotherapies.
Interaction between Cancer Cells and Stromal Fibroblasts Is Required for Activation of the uPAR-uPA-MMP-2 Cascade in Pancreatic Cancer Metastasis
Authors: He Yu , Liu Xiang-de , Chen Zhi-yu , Zhu Jin , Xiong Yan , Li Kun , Dong Jia-hong , Li Xiaowu 
Published: June 2007

Abstract
Purpose: Interaction between tumor cells and surrounding stromal fibroblast (SF) plays a critical role in tumor growth and invasion. The aim of the study is to determine the role of SF in regulating the invasive behaviors of pancreatic cancer by evaluating the mode of SF activating the urokinase plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP)-2 cascade.
Experimental Design: The expression patterns of uPA, MMP-2, and uPA receptor (uPAR) in human metastatic pancreatic cancer were analyzed by immunohistochemistry and the roles of SF in activation of the uPA-plasmin-MMP-2 cascade were evaluated by coculturing pancreatic cancer cell lines with SF.
Results: uPA expression and fibroblastic uPAR expression were correlated with liver metastasis of human pancreatic cancer. MMP-2 rather than MMP-9 was activated in the metastatic pancreatic cancer. In the in vitro culture system, the coculture of peritumor fibroblasts with metastatic pancreatic cancer BxPc3 cells resulted in activation of MMP-2 and up-regulation of uPAR expression. In this coculture system, the uPA-plasminogen cascade was involved in MMP-2 activation. This activation required a direct interaction between SF and cancer cells. In the coculture system, intergrin α6β1 expression was increased in BxPc3 cells, and blocking the function of integrin α6β1 decreased the activation of uPA and MMP-2. This suggests that interaction between integrins of cancer cells and the uPARs of the SF might be involved in the activation of the uPAR-uPA-MMP-2 cascade.
Conclusion: Our results suggest that SF plays a role in promoting pancreatic cancer metastasis via activation of the uPA-plasminogen-MMP-2 cascade.
In vivo Therapeutic Synergism of Anti–Epidermal Growth Factor Receptor and Anti-HER2 Monoclonal Antibodies against Pancreatic Carcinomas
Authors: Larbouret Christel , Robert Bruno , Navarro-Teulon Isabelle , Thèzenas Simon , Ladjemi Maha-Zohra , Morisseau Sébastien , Campigna Emmanuelle , Bibeau Frédéric , Mach Jean-Pierre , Pèlegrin André , Azria David 
Published: June 2007

Abstract
Purpose: Pancreatic carcinoma is highly resistant to therapy. Epidermal growth factor receptor (EGFR) and HER2 have been reported to be both dysregulated in this cancer. To evaluate the in vivo effect of binding both EGFR and HER2 with two therapeutic humanized monoclonal antibodies (mAb), we treated human pancreatic carcinoma xenografts, expressing high EGFR and low HER2 levels.
Experimental Design: Nude mice, bearing xenografts of BxPC-3 or MiaPaCa-2 human pancreatic carcinoma cell lines, were injected twice weekly for 4 weeks with different doses of anti-EGFR (matuzumab) and anti-HER2 (trastuzumab) mAbs either alone or in combination. The effect of the two mAbs, on HER receptor phosphorylation, was also studied in vitro by Western blot analysis.
Results: The combined mAb treatment significantly inhibited tumor progression of the BxPC-3 xenografts compared with single mAb injection (P = 0.006) or no treatment (P = 0.0004) and specifically induced some complete remissions. The two mAbs had more antitumor effect than 4-fold greater doses of each mAb. The significant synergistic effect of the two mAbs was confirmed on the MiaPaCa-2 xenograft and on another type of carcinoma, SK-OV-3 ovarian carcinoma xenografts. In vitro, the cooperative effect of the two mAbs was associated with a decrease in EGFR and HER2 receptor phosphorylation.
Conclusions: Anti-HER2 mAb has a synergistic therapeutic effect when combined with an anti-EGFR mAb on pancreatic carcinomas with low HER2 expression. These observations may open the way to the use of these two mAbs in a large panel of carcinomas expressing different levels of the two HER receptors.
Effect of Positive Bone Marrow EBV In situ Hybridization in Staging and Survival of Localized Extranodal Natural Killer/T-Cell Lymphoma, Nasal-Type
Authors: Lee Jeeyun , Suh Cheolwon , Huh Jooryung , Jun Hyun Jung , Kim Kihyun , Jung Chulwon , Park Keunchil , Park Yeon Hee , Ko Young Hyeh , Kim Won Seog 
Published: June 2007

Abstract
Purpose: The aim of the study was to determine the effect of EBV-encoded RNA-1 in situ hybridization (EBER-1 ISH) in bone marrow specimens on survival outcome in patients with clinical stage I/II natural killer/T-cell lymphoma.
Experimental Design: We systematically did EBER-1 ISH on 182 archival bone marrow tissues from 91 patients who were diagnosed of stage I/II natural killer/T-cell lymphoma and analyzed the correlation between bone marrow EBER-1 ISH status and survival. We defined minimal bone marrow involvement and definite bone marrow involvement to distinguish the subgroups who revealed EBV-positive cells from normal marrow by EBER-1 ISH from those who showed typical neoplastic cells in bone marrow biopsies.
Results: In total, 17 of the 91 (18.7%) patients showed positivity for EBER-1 ISH at least in one of the bilateral bone marrow biopsies with 14 minimal bone marrow involvements and 3 definite bone marrow involvements. Patients with positive bone marrow EBER-1 ISH showed significantly poorer overall survival than those who were negative for bone marrow EBER-1 ISH (median survival, 16.1 months versus not reached; P = 0.045).
Conclusion: Considering a high proportion of stage I/II patients (15.4%) with minimal in bone marrow specimens, bone marrow EBER-1 ISH should be routinely done in all patients with localized disease for more accurate staging.
Phase I and Pharmacokinetic Study of AI-850, A Novel Microparticle Hydrophobic Drug Delivery System for Paclitaxel
Authors: Mita Alain C. , Olszanski Anthony J. , Walovitch Richard C. , Perez Raymond P. , MacKay Kathleen , Tuck David P. , Simmons Cecilia , Hammond Susan , Mita Monica M. , Beeram Muralidhar , Stone Anne J. , Rowinsky Eric K. , Lewis Lionel D. 
Published: June 2007

AbstractPurpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of administering AI-850 as a &lt;30-min i.v. infusion without premedication every 3 weeks, determine the maximum tolerated dose and the phase II recommended dose of AI-850, study the pharmacokinetics of paclitaxel in this new formulation, and seek evidence of anticancer activity.Experimental Design: This was an open-label phase I dose escalation study of AI-850 in patients with advanced solid malignancies. AI-850 doses were escalated according to a modified Fibonacci scheme. Clinical and laboratory toxicity was monitored, and paclitaxel plasma concentrations were measured by liquid chromatography-tandem mass spectrometry.Results: Twenty-two patients received 56 courses of AI-850 at five dose cohorts ranging from 36 to 250 mg/m2. Grade 4 neutropenia, either exceeding 5 days or complicated by fever, was dose limiting in two of six patients at 250 mg/m2 AI-850. Three patients experienced grade 2 to 4 infusion-related adverse reactions. Toxicities, including fatigue, alopecia, nausea and vomiting, neuropathy, anorexia, and myalgia, were mild to moderate, reversible, and not dose related. Pharmacokinetics of free and total paclitaxel showed biexponential plasma decay and dose proportionality for maximum plasma paclitaxel concentration and area under the concentration versus time curve. Antitumor activity was documented in two patients with endometrial and tongue carcinomas.Conclusions: The administration of AI-850 as a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m2. The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.
Association between the Estrogen Receptor α A908G Mutation and Outcomes in Invasive Breast Cancer
Authors: Herynk Matthew H. , Parra Irma , Cui Yukun , Beyer Amanda , Wu Meng-Fen , Hilsenbeck Susan G. , Fuqua Suzanne A.W. 
Published: June 2007

Abstract
Purpose: Estrogen receptor α (ERα) predicts the natural history of breast cancer without intervening therapy. Here, we have optimized the detection of a somatic mutation, an A908G transition of ERα, and examined its association with clinical and biological features of invasive breast cancer.
Experimental Design: We compared two methods of sequencing to detect the A908G ERα mutation. We then used primer extension sequencing with genomic DNA isolated from invasive breast tumors to determine whether the mutation was associated with clinical outcome in 267 axillary node–negative and axillary node–positive breast tumors. The presence of the mutation and clinical variables were analyzed for association with recurrence-free survival and overall survival by Cox proportional hazards regression models.
Results: We determined that dye-labeled terminator sequencing was not adequate for detection of the A908G ERα mutation. The mutation was detected at a high frequency (50%) in invasive breast tumors using primer extension sequencing, and was found to be associated with clinical measures of poor outcome, including larger tumor size and axillary lymph node positivity. Although the mutation was associated with recurrence-free survival in univariate analysis, it was not an independent predictor of outcomes in multivariate analysis.
Conclusions: Consistent with our previous finding of this somatic ERα mutation in breast ductal hyperplasias, we now present evidence that the A908G mutation is present in invasive breast tumors using an optimized sequencing method. We find that the mutation is significantly associated with aggressive biological tumor features, and with an unfavorable prognosis, but was not an independent prognostic marker in untreated patients.
Cross-Linking of Signal Transducer and Activator of Transcription 3—A Molecular Marker for the Photodynamic Reaction in Cells and Tumors
Authors: Henderson Barbara W. , Daroqui Cecilia , Tracy Erin , Vaughan Lurine A. , Loewen Gregory M. , Cooper Michele T. , Baumann Heinz 
Published: June 2007

Abstract
Purpose: Photodynamic therapy (PDT) depends on the delivery of a photosensitizer to the target tissue that, under light exposure, produces singlet oxygen and other reactive oxygen species, which in turn cause the death of the treated cell. This study establishes a quantitative marker for the photoreaction that will predict the outcome of PDT.
Experimental Design: Cells in tissue culture, murine s.c. tumors, and endobronchial carcinomas in patients were treated with PDT, and the noncleavable cross-linking of the latent signal transducer and activator of transcription 3 (STAT3) was determined.
Results: Murine and human cancer cell lines reacted to PDT by an immediate covalent cross-linking of STAT3 to homodimeric and other complexes. The magnitude of this effect was strictly a function of the PDT reaction that is determined by the photosensitizer concentration and light dose. The cross-link reaction of STAT3 was proportional to the subsequent cytotoxic outcome of PDT. An equivalent photoreaction as detected in vitro occurred in tumors treated in situ with PDT. The light dose-dependent STAT3 cross-linking indicated the relative effectiveness of PDT as a function of the distance of the tissue to the treating laser light source. Absence of cross-links correlated with treatment failure.
Conclusions: The data suggest that the relative amount of cross-linked STAT3 predicts the probability for beneficial outcome, whereas absence of cross-links predicts treatment failure. Determination of STAT3 cross-links after PDT might be clinically useful for early assessment of PDT response.
Cytokeratin-18 Is a Useful Serum Biomarker for Early Determination of Response of Breast Carcinomas to Chemotherapy
Authors: Olofsson Maria Hägg , Ueno Takayuki , Pan Yang , Xu Ren , Cai Feng , van der Kuip Heiko , Muerdter Thomas E. , Sonnenberg Maike , Aulitzky Walter E. , Schwarz Stephan , Andersson Elina , Shoshan Maria C. , Havelka Aleksandra Mandic , Toi Masakazu , Linder Stig 
Published: June 2007

AbstractPurpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer.Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/epirubicin/5-fluorouracil (CEF) therapy.Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P &lt; 0.0001).Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracycline-based therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.
Mifepristone Inhibits Ovarian Cancer Cell GrowthIn vitroandIn vivo
Authors: Goyeneche Alicia A. , Carón Rubén W. , Telleria Carlos M. 
Published: June 2007

AbstractPurpose: These studies were designed to determine whether the synthetic steroid mifepristone inhibits ovarian cancer growth in vitro and in vivo and the molecular mechanisms involved.Experimental Design: The effect of mifepristone on ovarian cancer cell growth in vitro was studied in ovarian cancer cell lines of different genetic backgrounds (SK-OV-3, Caov-3, OV2008, and IGROV-1). In addition, the growth inhibition capacity of mifepristone on ovarian carcinoma xenografts was tested in nude mice.Results: Mifepristone inhibited ovarian cancer cell proliferation in a dose- and time-dependent manner. The cytostatic effect of mifepristone was confirmed in a clonogenic survival assay and was not linked to loss of viability. Mifepristone blocked DNA synthesis, arrested the cell cycle at the G1-S transition, up-regulated cyclin-dependent kinase (cdk) inhibitors p21cip1and p27kip1, down-regulated transcription factor E2F1, decreased expression of the E2F1-regulated genes cdk1 (cdc2) and cyclin A, and modestly decreased cdk2 and cyclin E levels. The abrupt arrest in cell growth induced by mifepristone correlated with reduced cdk2 activity, increased association of cdk2 with p21cip1 and p27kip1, increased nuclear localization of the cdk inhibitors, and reduced nuclear abundance of cdk2 and cyclin E. In vivo, mifepristone significantly delayed the growth of ovarian carcinoma xenografts in a dose-dependent manner and without apparent toxic effects for the animals.Conclusions: These preclinical studies show that mifepristone is effective as a single agent in vitro and in vivo, inhibiting the growth of human epithelial ovarian cancer cells. Mifepristone markedly reduces cdk2 activity likely due to increased association of cdk2 with the cdk inhibitors p21cip1 and p27kip1 and reduced nuclear cdk2/cyclin E complex availability. Acting as a cytostatic agent, mifepristone promises to be of translational significance in ovarian cancer therapeutics.
Identification ofNTN4, TRA1, andSTC2as Prognostic Markers in Breast Cancer in a Screen for Signal Sequence Encoding Proteins
Authors: Esseghir Selma , Kennedy Alan , Seedhar Pooja , Nerurkar Ashutosh , Poulsom Richard , Reis-Filho Jorge S. , Isacke Clare M. 
Published: June 2007

AbstractPurpose: In a previous screen using a signal-trap library, we identified a number of secreted proteins up-regulated in primary tumor cells isolated from invasive breast cancers. The purpose of this study was to assess the expression of these genes in human invasive breast tumors and to determine the significance of their expression for prognosis in breast cancer.Experimental Design: A tissue microarray containing 245 invasive breast tumors from women treated with curative surgery followed by anthracycline-based chemotherapy and hormone therapy for the estrogen receptor (ER)–positive tumors was screened by in situ hybridization with probes against thrombospondin 3 (TSP3), insulin-like growth factor binding protein 7 (IGFBP7), tumor rejection antigen 1 (TRA1), stanniocalcin 2 (STC2), and netrin 4 (NTN4). Correlations between categorical variables were done using the χ2 test and Fisher's exact test. Cumulative survival probabilities were calculated using the Kaplan-Meier method and multivariate survival analysis was done with Cox hazard model. A series of breast cancers were also stained with NTN4 antibodies.Results: All five genes examined were expressed in invasive breast tumor cells. NTN4 protein expression was also confirmed by immunohistochemistry. Together, these data validate the design and screening of the signal-trap library. Univariate survival analysis revealed that expressions of TRA1, STC2, and NTN4 are correlated with longer disease-free survival and that TRA1 and NTN4 are associated with longer overall survival. Multivariate analysis showed that NTN4 is an independent prognostic factor of overall survival.Conclusions: This article describes the identification of three secreted proteins, NTN4, TRA1, and STC2, as potential novel prognostic markers in breast cancer.
Suppression of lung cancer tumor growth in a nude mouse model by the Ras inhibitor salirasib (farnesylthiosalicylic acid)
Authors: Zundelevich Adi , Elad-Sfadia Galit , Haklai Ronit , Kloog Yoel 
Published: June 2007

AbstractAberrant Ras pathway functions contribute to the malignant phenotype of lung cancers. Inhibitors of Ras might therefore be considered as potential drugs for lung cancer therapy. Here, we show that the Ras inhibitor farnesylthiosalicylic acid (salirasib) inhibits proliferation of human lung cancer cells harboring a mutated K-ras gene (A549, H23, or HTB54) or overexpressing a growth factor receptor (H1299 or HTB58) and enhances the cytotoxic effect of the chemotherapeutic drug gemcitabine. Salirasib inhibited active K-Ras in A549 cells, reversed their transformed morphology, and inhibited their anchorage-independent growth in vitro. Tumor growth in A549 and HTB58 cell nude mouse models was inhibited by i.p. administration of salirasib. P.o. formulated salirasib also inhibited A549 cell tumor growth. Our results suggest that p.o. salirasib may be considered as a potential treatment for lung cancer therapy. [Mol Cancer Ther 2007;6(6):1765–1773]
Structure of Art, Structure of Mind
Authors: Anati Emmanuel 
Published: June 2007

AbstractThis paper sketches a comprehensive methodology to analyse the elementary structures of prehistoric art. A formal analysis of art is proposed through the distinction between pictograms, ideograms and psychograms. The dynamic between these elements and the thematic contents of the represented scenes is related to the four main types of social organization: early hunters, early gatherers, late hunters, pastoralists and complex economy societies. Cultural patterns of these societies and formal elements of art may appear as sharing the same elementary structures.