bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice
Authors: Wallner Lauren , Dai Jinlu , Escara-Wilke June , Zhang Jian , Yao Zhi , Lu Yi , Trikha Mohit , Nemeth Jeffrey A. , Zaki Mohamed H. , Keller Evan T. 
Published: March 2006

AbstractInitially, prostate cancer is androgen dependent. However, most cases progress to an androgen-independent state through unknown mechanisms. Interleukin-6 (IL-6) has been associated with prostate cancer progression including activation of the androgen receptor (AR). To determine if IL-6 plays a role in the conversion of prostate cancer from androgen dependent to androgen independent, we established androgen-dependent LuCaP 35 human prostate cancer xenografts in nude mice, castrated the mice, and blocked IL-6 activity using a neutralizing antibody (CNT0328) for a period of 18 weeks. IL-6 inhibition increased survival of mice and inhibited tumor growth, as reflected by decreased tumor volume and prostate-specific antigen levels, compared with that in mice receiving isotype control antibody. To test the effect of IL-6 inhibition on the conversion from androgen dependent to androgen independent, tumor cells from the treated mice were assessed for their androgen dependence both in vitro and by implanting them into sham-operated or orchiectomized mice. Tumor cells derived from the isotype-treated animals converted to androgen-independent state, whereas tumor cells from the anti-IL-6 antibody-treated mice were still androgen dependent in vitro and in vivo. Although there was no difference in AR levels between the androgen-independent and androgen-dependent tumors, IL-6 inhibition promoted both apoptosis and inhibited cell proliferation in tumors and blocked the orchiectomy-induced expression of histone acetylases, p300 and CBP, which are AR cofactors. These data show that IL-6 contributes to the development of androgen independence in prostate cancer and suggest that it mediates this effect, in part, through modulation of p300 and CBP. (Cancer Res 2006; 66(6): 3087-95)
Intrapulmonary Administration of CCL21 Gene-Modified Dendritic Cells Reduces Tumor Burden in Spontaneous Murine Bronchoalveolar Cell Carcinoma
Authors: Yang Seok-Chul , Batra Raj K. , Hillinger Sven , Reckamp Karen L. , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven 
Published: March 2006

AbstractThe antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing secondary lymphoid chemokine (CCL21) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. The transgenic mice (CC-10 TAg) express the SV40 large T antigen (TAg) under the Clara cell promoter, develop bilateral, multifocal, and pulmonary adenocarcinomas, and die at 4 months as a result of progressive pulmonary tumor burden. A single intratracheal administration of CCL21 gene-modified dendritic cells (DC-AdCCL21) led to a marked reduction in tumor burden with extensive mononuclear cell infiltration of the tumors. The reduction in tumor burden was accompanied by the enhanced elaboration of type 1 cytokines [IFN-γ, interleukin (IL)-12, and granulocyte macrophage colony-stimulating factor] and antiangiogenic chemokines (CXCL9 and CXCL10) but a concomitant decrease in the immunosuppressive molecules (IL-10, transforming growth factor-β, prostaglandin E2) in the tumor microenvironment. The DC-AdCCL21 therapy group revealed a significantly greater frequency of tumor-specific T cells releasing IFN-γ compared with the controls. Continuous therapy with weekly intranasal delivery of DC-AdCCL21 significantly prolonged median survival by &gt;7 weeks in CC-10 TAg mice. Both innate natural killer and specific T-cell antitumor responses significantly increased following DC-AdCCL21 therapy. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of intrapulmonary-administered DC-AdCCL21 in regulation of tumor immunity and genetic immunotherapy for lung cancer.(Cancer Res 2006; 66(6): 3205-13)
Galectin-3 Regulates Mitochondrial Stability and Antiapoptotic Function in Response to Anticancer Drug in Prostate Cancer
Authors: Fukumori Tomoharu , Oka Natsuo , Takenaka Yukinori , Nangia-Makker Pratima , Elsamman Essam , Kasai Toshinori , Shono Masayuki , Kanayama Hiro-omi , Ellerhorst Julie , Lotan Reuben , Raz Avraham 
Published: March 2006

AbstractProstate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug–induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 μmol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 μmol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser112 of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug–induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer. (Cancer Res 2006; 66(6): 3114-9)
Signal Transducer and Activator of Transcription 3 Is Required for the Oncogenic Effects of Non–Small-Cell Lung Cancer–Associated Mutations of the Epidermal Growth Factor Receptor
Authors: Alvarez James V. , Greulich Heidi , Sellers William R. , Meyerson Matthew , Frank David A. 
Published: March 2006

Abstract
Somatic mutations in the epidermal growth factor receptor (EGFR) occur frequently in lung cancer and confer sensitivity to EGFR kinase inhibitors gefitinib and erlotinib. These mutations, which occur in the kinase domain of the protein, also render EGFR constitutively active and transforming. Signal transducers and activators of transcription 3 (STAT3) transduces signals from a number of oncogenic tyrosine kinases and contributes to a wide spectrum of human malignancies. Here, we show that STAT3 is activated by mutant EGFRs and is necessary for its downstream phenotypic effects. Inhibiting STAT3 function in fibroblasts abrogates transformation by mutant EGFR. In non–small-cell lung cancer cells, STAT3 activity is regulated by EGFR through modulation of STAT3 serine phosphorylation. Inhibiting STAT3 function increases apoptosis of these cells, suggesting that STAT3 is necessary for their survival. Finally, a group of genes constituting a STAT3 signature is enriched in lung tumors with EGFR mutations. Thus, STAT3 is a critical mediator of the oncogenic effects of somatic EGFR mutations and targeting STAT3 may be an effective strategy for treating tumors characterized by these mutations. (Cancer Res 2006; 66(6): 3162-8)
Identification of 14-3-3σ as a Contributor to Drug Resistance in Human Breast Cancer Cells Using Functional Proteomic Analysis
Authors: Liu Yang , Liu Hailan , Han Baoguang , Zhang Jian-Ting 
Published: March 2006

Abstract
Multidrug resistance (MDR) is a major obstacle to successful cancer treatment. To understand the mechanism of MDR, many cancer cell lines have been established, and various mechanisms of resistance, such as ATP-binding cassette (ABC) transporter–mediated drug efflux, have been discovered. Previously, a MDR cell line MCF7/AdVp3000 was selected from breast cancer cell line MCF7 against Adriamycin, and overexpression of ABCG2 was thought to cause MDR in this derivative cell line. However, ectopic overexpression of ABCG2 in MCF7 cells could not explain the extremely high drug resistance level of the selected MCF7/AdVp3000 cells. We hypothesized that MCF7/AdVp3000 cells must have other resistance mechanisms selected by Adriamycin. To test this hypothesis, we compared the global protein profiles between MCF7 and MCF7/AdVp3000 cells. Following two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry analysis, 17 protein spots with differential levels between the two cell lines were identified. Although 14-3-3σ, keratin 18, keratin 19, ATP synthase β, protein disulfide isomerase, heat shock protein 27, cathepsin D, triose-phosphate isomerase, peroxiredoxin 6, and electron transfer flavoprotein were increased, nm23/H1, peroxiredoxin 2, nucleophosmin 1/B23, and inorganic pyrophosphatase were decreased in MCF7/AdVp3000 cells. The differential levels of these proteins were validated using Western blot. Furthermore, functional validation showed that the elevated 14-3-3σ expression contributes considerably to the observed drug resistance in MCF7/AdVp3000 cells. We, thus, conclude that these proteins likely contribute to the resistance selected in the MCF7/AdVp3000 cells, and their altered expression in tumors may cause clinical resistance to chemotherapy. (Cancer Res 2006; 66(6): 3248-55)
Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells
Authors: Pourroy Bertrand , Honoré Stéphane , Pasquier Eddy , Bourgarel-Rey Véronique , Kruczynski Anna , Briand Claudette , Braguer Diane 
Published: March 2006

AbstractAngiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis. (Cancer Res 2006; 66(6): 3256-63)
Development of a Highly Active Nanoliposomal Irinotecan Using a Novel Intraliposomal Stabilization Strategy
Authors: Drummond Daryl C. , Noble Charles O. , Guo Zexiong , Hong Keelung , Park John W. , Kirpotin Dmitri B. 
Published: March 2006

AbstractLiposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with unprecedented drug loading efficiency and in vivo drug retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, either polymeric (polyphosphate) or nonpolymeric (sucrose octasulfate), liposomes were capable of entrapping CPT-11 at extremely high drug-to-lipid ratios (&gt;800 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release in the circulation of 56.8 hours. CPT-11 was also protected from hydrolysis to the inactive carboxylate form and from metabolic conversion to SN-38 while circulating. The maximum tolerated dose in normal mice was determined to be 80 mg/kg for free CPT-11 and &gt;320 mg/kg for nanoliposomal CPT-11. Nanoliposomal CPT-11 showed markedly superior efficacy when compared with free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models. This study shows that intraliposomal stabilization of CPT-11 using a polymeric or highly charged, nonpolymeric polyanionic trapping agent results in a markedly active antitumor agent with low toxicity. (Cancer Res 2006; 66(6): 3271-7)
αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity
Authors: van der Veken Lars T. , Hagedoorn Renate S. , van Loenen Marleen M. , Willemze Roel , Falkenburg J.H. Frederik , Heemskerk Mirjam H.M. 
Published: March 2006

AbstractRetroviral transfer of T-cell receptors (TCR) to peripheral blood–derived T cells generates large numbers of T cells with the same antigen specificity, potentially useful for adoptive immunotherapy. One drawback of this procedure is the formation of mixed TCR dimers with unknown specificities due to pairing of endogenous and introduced TCR chains. We investigated whether γδ T cells can be an alternative effector population for TCR gene transfer because the γδTCR is not able to form dimers with the αβTCR. Peripheral blood–derived γδ T cells were transduced with human leukocyte antigen (HLA) class I– or HLA class II–restricted minor histocompatibility antigen (mHag) or virus-specific TCRs. Because most γδ T cells do not express CD4 and CD8, we subsequently transferred these coreceptors. The TCR-transduced γδ T cells exerted high levels of antigen-specific cytotoxicity and produced IFN-γ and IL-4, particularly in the presence of the relevant coreceptor. γδ T cells transferred with a TCR specific for the hematopoiesis-specific mHag HA-2 in combination with CD8 displayed high antileukemic reactivity against HA-2–expressing leukemic cells. These data show that transfer of αβTCRs to γδ T cells generated potent effector cells for immunotherapy of leukemia, without the expression of potentially hazardous mixed TCR dimers. (Cancer Res 2006; 66(6): 3331-7)
Nucleophosmin Mutations in De novo Acute Myeloid Leukemia: The Age-Dependent Incidences and the Stability during Disease Evolution
Authors: Chou Wen-Chien , Tang Jih-Luh , Lin Liang-In , Yao Ming , Tsay Woei , Chen Chien-Yuan , Wu Shang-Ju , Huang Chi-Fei , Chiou Rong-Jing , Tseng Mei-Hsuan , Lin Dong-Tsamn , Lin Kai-Hsin , Chen Yao-Chang , Tien Hwei-Fang 
Published: March 2006

Abstract
Nucleophosmin (NPM) mutations have been found in a significant proportion of adults with de novo acute myeloid leukemia (AML), especially in those of a normal karyotype. These results provide a basis for studies of the pathogenesis in this specific subgroup of AML. In this study, NPM mutations were analyzed in 173 Chinese patients of de novo AML, including adults and children. We found that NPM mutations were present in 19.1% of the overall population and 40.3% of those with a normal karyotype. Adults had a significantly higher incidence of NPM mutations than children [32 of 126 (25.4%) versus 1 of 47 (2.1%), P &lt; 0.001]. NPM mutations were closely associated with normal karyotype (P &lt; 0.001) and internal tandem duplication of FLT3 (P = 0.002), but negatively associated with CEBPA mutations (P = 0.032) and expression of CD34 (P &lt; 0.001) and HLA-DR (P = 0.003). Serial analyses of NPM mutations showed the mutation disappeared at complete remission, but the same mutation reappeared at relapse, except for one who lost the mutation at the second relapse, when new cytogenetic abnormalities emerged. None acquired novel mutations during the follow-up period. In conclusion, NPM mutations occur in an age-dependent fashion. Moreover, the findings that NPM mutations are stable during disease evolution and closely associated with disease status make it a potential marker for monitoring minimal residual disease. (Cancer Res 2006; 66(6): 3310-6)
The Phosphoinositide 3-Kinase/Akt1/Par-4 Axis: A Cancer-Selective Therapeutic Target
Authors: Goswami Anindya , Ranganathan Padhma , Rangnekar Vivek M. 
Published: March 2006

Abstract
Activation of the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway in many cancers makes it an appealing target for therapeutic development. However, because this pathway also has an important role in the survival of normal cells, tactics to achieve cancer selectivity may prove important. We recently showed that the cancer-selective proapoptotic protein Par-4 is a key target for inactivation by PI3K/Akt signaling. Additionally, we found that Par-4 participates in mediating apoptosis by PTEN, the tumor suppressor responsible for blocking PI3K/Akt signaling. As a central player in cancer cell survival, Par-4 may provide a useful focus for the development of cancer-selective therapeutics. (Cancer Res 2006; 66(6): 2889-92)
Babylonian Royal Land Grants, Memorials of Financial Interest, and Invocation of the Divine
Authors:   Brinkman
Published: March 2006

AbstractFrom the fourteenth to the seventh centuries B.C., Babylonian royal land grants and related documents were often engraved on stone stelae, which were decorated with divine symbols, inscribed with elaborate curses against offenders, and placed in a temple. These stone memorials (traditionally called kudurrus) throw light on contemporary legal and economic practices with individual cases involving property rights, royal patronage, family disputes, overzealous functionaries, temple offices and income, and taxation woes. This article assesses a new book which discusses the form and function of these stelae. Du XIVe au VIIe s. av. J.-C., les textes d'attribution de terrain par les rois babyloniens et certains documents similaires étaient gravés sur des stèles en pierre, décorées de symboles divins, munies de malédictions contre ceux qui ne les respecteraient pas, et installées dans un temple. Ces mémoriaux en pierre (appelés traditionellement kudurrus) éclairent les systèmes juridiques et économiques contemporains en citant des cas particuliers: ceux-ci documentent le droit de la propriété foncière, la faveur royale, les fonctionnaires trop exigeants, les disputes familiales, les bénéfices et revenus du temple, et les problèmes fiscaux. Dans cet article, on rend compte d'un livre récemment publié concernant la forme et la fonction de ces stèles.
G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells
Authors: Kim Hyun Kyung , De La Luz Sierra Maria , Williams Cassin Kimmel , Gulino A. Virginia , Tosato Giovanna 
Published: March 2006

AbstractCXCR4 receptor expression is required for the retention of granulocyte precursors and mature neutrophils within the bone marrow, and disruption of the SDF-1/CXCR4 axis in the bone marrow results in the mobilization of myeloid lineage cells to the peripheral circulation. We report that G-CSF down-regulates CXCR4 expression in bone marrow–derived murine and human myeloid lineage cells. When exposed to G-CSF, murine Gr1+ bone marrow myeloid cells display a time-dependent reduction of cell-surface CXCR4 and respond poorly to SDF-1 in attachment and migration assays. Bone marrow–derived cells of nonmyeloid lineage display no change in surface CXCR4 expression upon exposure to G-CSF. Compared with controls, mice treated with G-CSF for mobilization of hematopoietic progenitor cells display reduced levels of CXCR4 selectively in bone marrow Gr1+ myeloid cells. Since bone marrow myeloid cells express G-CSF receptors and G-CSF rapidly reduces CXCR4 expression in purified Gr1+ cells populations, these results provide evidence that G-CSF acts directly on myeloid lineage cells to reduce CXCR4 expression. By down-regulating CXCR4 expression in bone marrow myeloid cells and attenuating their responsiveness to SDF-1, G-CSF promotes their mobilization from the bone marrow to the peripheral blood.
Simvastatin–Amiodarone Interaction Resulting in Rhabdomyolysis, Azotemia, and Possible Hepatotoxicity
Authors: Ricaurte Basma , Guirguis Amir , Taylor Harris C , Zabriskie Don 
Published: March 2006

Objective: To describe the fifth reported instance, as of February 15, 2006, of a severe interaction between simvastatin and amiodarone and hypothesize inhibition of CYP3A4 as the major mechanism. Case Summary: A 72-year-old white man (178 cm, 77.2 kg) with diabetes mellitus, hyperlipidemia, hypertension, and mild azotemia was hospitalized on September 21, 2004, with thigh weakness, achiness, and dark urine for 7 days. Coronary artery bypass had been performed on July 7, 2004. Amiodarone 200 mg/day was started on July 10, and simvastatin 80 mg/day was initiated on August 13. Laboratory testing on the present admission included creatine kinase (CK) 19 620 U/L (reference range 60–224), blood urea nitrogen 50 mg/dL, creatinine 2.6 mg/dL, aspartate aminotransferase (AST) 912 U/L (30–60), alanine aminotransferase (ALT) 748 U/L (30–60), urine myoglobin 71100 μg/L (<50), and serum myoglobin 13 877 μg/L (<110). Simvastatin and amiodarone were discontinued, and the patient was hydrated with forced alkaline diuresis. Thirteen days later, his CK was 323 U/L, creatinine 1.7 mg/dL, ALT 145 U/L, and AST 37 U/L. Discussion: Simvastatin is metabolized primarily by CYP3A4, and amiodarone is a recognized inhibitor of this enzyme. This may, therefore, account for the presumed drug interaction. Conclusions: An objective causal assessment suggests that rhabdomyolysis, renal failure, and possibly hepatotoxicity were probably related to an amiodarone–simvastatin interaction.