bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative Regulation of the Osteoblast Function in Multiple Myeloma through the Repressor Gene E4BP4 Activated by Malignant Plasma Cells
Authors: Silvestris Franco , Cafforio Paola , De Matteo Monica , Calvani Nicola , Frassanito Maria A. , Dammacco Franco 
Published: October 2008

Abstract
Purpose: To explore the pathogenetic mechanisms that suppress the osteoblast function in multiple myeloma because osteogenesis results in defective new bone formation and repair.
Experimental Design: Microarray gene analysis revealed the overexpression of E4BP4, a transcriptional repressor gene, in normal osteoblasts cocultured with myeloma cells that were releasing the parathyroid hormone-related protein (PTHrP). Thus, the effect of E4BP4 was assessed in PTHrP-stimulated osteoblasts by measuring the RNA levels of both Runx2 and Osterix as major osteoblast transcriptional activators. Because E4BP4 is a negative regulator of the cyclooxygenase-2 (COX-2) pathway that drives the expression of both Runx2 and Osterix, these factors were investigated after prostaglandin E2 treatment to overcome the COX-2 defect as well as in E4BP4-silenced osteoblasts. Finally, E4BP4, PTHrP, Osterix, and osteocalcin levels were measured in vivo in patients with bone disease together with the E4BP4 protein in bone biopsies.
Results: E4BP4 was specifically induced by PTHrP and inhibited both Runx2 and Osterix, whereas E4BP4-silenced osteoblasts expressed functional levels of both factors. The prostaglandin E2 treatment of E4BP4-up-regulated osteoblasts promptly restored Runx2 and Osterix activities, suggesting that integrity of COX-2 pathway is essential for their transcription. Down-regulation of Osterix by E4BP4 was confirmed in vivo by its inverse levels in osteoblasts from myeloma patients with increased serum PTHrP, whose bone biopsies expressed the E4BP4 protein.
Conclusions: Our data support the role of E4BP4 as osteoblast transcriptional repressor in inhibiting both Runx2 and Osterix in myeloma bone disease and correlate its effect with the increased PTHrP activity.
Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer
Authors: Bailey Jennifer M. , Swanson Benjamin J. , Hamada Tomofumi , Eggers John P. , Singh Pankaj K. , Caffery Thomas , Ouellette Michel M. , Hollingsworth Michael A. 
Published: October 2008

Abstract
Purpose: We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression.
Experimental Design: We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth. We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice.
Results: Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts.
Conclusions: These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.
Deletions of CDKN2C in Multiple Myeloma: Biological and Clinical Implications
Authors: Leone Paola E. , Walker Brian A. , Jenner Matthew W. , Chiecchio Laura , Dagrada GianPaolo , Protheroe Rebecca K.M. , Johnson David C. , Dickens Nicholas J. , Brito Jose Luis , Else Monica , Gonzalez David , Ross Fiona M. , Chen-Kiang Selina , Davies Faith E. , Morgan Gareth J. 
Published: October 2008

Abstract
Purpose: Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.
Experimental Design: We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.
Results: By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.
Conclusions: Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.
Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells
Authors: Okabe Seiichi , Tauchi Tetsuzo , Ohyashiki Kazuma 
Published: October 2008

AbstractPurpose: Although dual src-family kinase/BCR/ABL inhibitor, dasatinib (BMS-354825), provides therapeutic advantages to imatinib-resistant cells, the mechanism of dasatinib resistance was not fully known.Experimental Design: We used TF-1 BCR/ABL cells, by introducing the BCR/ABL gene into a leukemia cell line, TF-1 and K562, and established dasatinib- (BMS-R) and imatinib-resistant (IM-R) cells. We characterized chronic myelogenous leukemia drug-resistant cells and examined intracellular signaling.Results: The IC50 of dasatinib was 0.75 nmol/L (TF-1 BCR/ABL), 1 nmol/L (K562), 7.5 nmol/L (TF-1 BCR/ABL IM-R), 10 nmol/L (K562 IM-R), 15 μmol/L (TF-1 BCR/ABL BMS-R), and 25 μmol/L (K562 BMS-R). The number of BCR/ABL copies in resistant cell lines was the same as the parental cell line by fluorescence in situ hybridization analysis. There was no mutation in Abl kinase. We found that protein levels of BCR/ABL were reduced in dasatinib-resistant cell lines. BCR/ABL protein was increased by treatment of an ubiquitin inhibitor. The Src kinase, Lck, as well as mitogen-activated protein kinase and Akt were activated, but p21WAF, phosphatase and tensin homologue was reduced in K562 BMS-R cells. Removal of dasatinib from the culture medium of K562 BMS-R cells led to apoptosis, and activated caspase 3 and poly (ADP-ribose) polymerase.Conclusion: These results suggest that the expression and protein activation signatures identified in this study provide insight into the mechanism of resistance to dasatinib and imatinib and may be of therapeutic chronic myelogenous leukemia value clinically.
Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma
Authors: Huynh Hung , Ngo Van Chanh , Fargnoli Joseph , Ayers Mark , Soo Khee Chee , Koong Heng Nung , Thng Choon Hua , Ong Hock Soo , Chung Alexander , Chow Pierce , Pollock Pamela , Byron Sara , Tran Evelyn 
Published: October 2008

Abstract
Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways.
Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines.
Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib–induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr1054/1059, increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation.
Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.
N-(2,6-Dimethoxypyridine-3-yl)-9-Methylcarbazole-3-Sulfonamide as a Novel Tubulin Ligand against Human Cancer
Authors: Wang Yue-Ming , Hu Lai-Xing , Liu Zhen-Ming , You Xue-Fu , Zhang Sheng-Hua , Qu Jing-Rong , Li Zhuo-Rong , Li Yan , Kong Wei-Jia , He Hong-Wei , Shao Rong-Guang , Zhang Liang-Ren , Peng Zong-Gen , Boykin David W. , Jiang Jian-Dong 
Published: October 2008

Abstract
Purpose: We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105). This work investigates its anticancer effect and mechanism.
Experimental Design: Anticancer efficacy was evaluated at the molecular target, cancer cells and nude mice. The mechanism was explored at submolecular, molecular, and cellular levels.
Results: IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC50 values between 0.012 and 0.298 μmol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. It inhibited microtubule assembly followed by M-phase arrest, Bcl-2 inactivation, and then apoptosis through caspase pathways. The colchicine pocket on tubulin is the binding site of IG-105. Nude mice experiments showed that IG-105 monotherapy at 100 mg/kg i.p. (q2d) yielded 81% inhibition of Bel-7402 hepatoma growth and at 275 mg/kg i.p. (q2d) completely inhibited the tumor growth. MCF-7 breast cancer in nude mice showed a similar therapeutic response to IG-105. Acute toxicity of IG-105 was not found even at 1,000 mg/kg i.p. In combination with oxaliplatin or doxorubicin, IG-105 converted each of these subcurative compounds into a curative treatment with complete inhibition for tumor growth in the hepatoma-bearing nude mice. The combination was more active than either drug. In no experiment was toxicity increased by combination chemotherapy.
Conclusions: IG-105 inhibits microtubule assembly by binding at colchicine pocket. It shows a potent anticancer activity in vitro and in vivo and has good safety in mice. We consider IG-105 merits further investigation.
Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer
Authors: de Bono Johann S. , Scher Howard I. , Montgomery R. Bruce , Parker Christopher , Miller M. Craig , Tissing Henk , Doyle Gerald V. , Terstappen Leon W.W.M. , Pienta Kenneth J. , Raghavan Derek 
Published: October 2008

Abstract
Purpose: A method for enumerating circulating tumor cells (CTC) has received regulatory clearance. The primary objective of this prospective study was to establish the relationship between posttreatment CTC count and overall survival (OS) in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points.
Experimental Design: Blood was drawn from CRPC patients with progressive disease starting a new line of chemotherapy before treatment and monthly thereafter. Patients were stratified into predetermined Favorable or Unfavorable groups (&lt;5 and ≥5 CTC/7.5mL).
Results: Two hundred thirty-one of 276 enrolled patients (84%) were evaluable. Patients with Unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P &lt; 0.0001). Unfavorable posttreatment CTC counts also predicted shorter OS at 2 to 5, 6 to 8, 9 to 12, and 13 to 20 weeks (median OS, 6.7-9.5 versus 19.6-20.7 months; Cox hazard ratio, 3.6-6.5; P &lt; 0.0001). CTC counts predicted OS better than PSA decrement algorithms at all time points; area under the receiver operator curve for CTC was 81% to 87% and 58% to 68% for 30% PSA reduction (P = 0.0218). Prognosis for patients with (a) Unfavorable baseline CTC who converted to Favorable CTC improved (6.8 to 21.3 months); (b) Favorable baseline CTC who converted to Unfavorable worsened (&gt;26 to 9.3 months).
Conclusions: CTC are the most accurate and independent predictor of OS in CRPC. These data led to Food and Drug Administration clearance of this assay for the evaluation of CRPC.
Dissociation of Its Opposing Immunologic Effects Is Critical for the Optimization of Antitumor CD8+ T-Cell Responses Induced by Interleukin 21
Authors: Ansén Sascha , Butler Marcus O. , Berezovskaya Alla , Murray Andrew P. , Stevenson Kristen , Nadler Lee M. , Hirano Naoto 
Published: October 2008

Abstract
Purpose: Interleukin 21 (IL-21) is a promising new cytokine, which is undergoing clinical testing as an anticancer agent. Although IL-21 provides potent stimulation of CD8+ T cells, it has also been suggested that IL-21 is immunosuppressive by counteracting the maturation of dendritic cells. The dissociation of these two opposing effects may enhance the utility of IL-21 as an immunotherapeutic. In this study, we used a cell-based artificial antigen-presenting cell (aAPC) lacking a functional IL-21 receptor (IL-21R) to investigate the immunostimulatory properties of IL-21.
Experimental Design: The immunosuppressive activity of IL-21 was studied using human IL-21R+ dendritic cells. Antigen-specific CD8+ T cells stimulated with human cell–based IL-21R-aAPC were used to isolate the T-cell immunostimulatory effects of IL-21. The functional outcomes, including phenotype, cytokine production, proliferation, and cytotoxicity were evaluated.
Results: IL-21 limits the immune response by maintaining immunologically immature dendritic cells. However, stimulation of CD8+ T cells with IL-21R- aAPC, which secrete IL-21, results in significant expansion. Although priming in the presence of IL-21 temporarily modulated the T-cell phenotype, chronic stimulation abrogated these differences. Importantly, exposure to IL-21 during restimulation promoted the enrichment and expansion of antigen-specific CD8+ T cells that maintained IL-2 secretion and gained enhanced IFN-γ secretion. Tumor antigen-specific CTL generated in the presence of IL-21 recognized tumor cells efficiently, demonstrating potent effector functions.
Conclusions: IL-21 induces opposing effects on antigen-presenting cells and CD8+ T cells. Strategic application of IL-21 is required to induce optimal clinical effects and may enable the generation of large numbers of highly avid tumor-specific CTL for adoptive immunotherapy.
IntroductionRethinking the Forms of Autonomy at the Dawn of the 21st Century
Authors: Légaré André , Suksi Markku 
Published: September 2008

AbstractArguably, other forms of autonomy also exist than territorial autonomy with law-making powers, such as personal autonomy, cultural autonomy and functional autonomy as well as autonomies with administrative or regulatory powers. The existence of such diff erent forms of autonomy should be kept in mind when the term ‘autonomy’ is used and the context of the usage of the term should be made clear. In addition, the interface between territorial autonomy with law-making powers on the one hand, and federal organization on the other is explored, the point being that a more coherent theoretical approach to territorial autonomy on the one hand and federalism on the other should be developed.
Meta-analysis of Quality of Life Outcomes Following Diabetes Self-management Training
Authors: Cochran Jane , Conn Vicki S. 
Published: October 2008

Purpose The purpose of this meta-analysis was to meet the need to quantify the influence of diabetes self-management training on quality of life (QOL) of adult diabetes patients. Methods Extensive literature searching located published and unpublished diabetes self-management intervention studies that measured QOL outcomes among at least 5 subjects with type 1 or 2 diabetes. Data were extracted from primary study reports which included interventions designed to improve diabetes self-management and adequate data to calculate effect sizes. Random-effects meta-analytic procedures were used to estimate overall effects between treatment and control groups at outcome assessment and between baseline and outcome data for both treatment subjects and control subjects. Results Exhaustive searching yielded 20 comparisons across 1892 subjects. The comparisons between treatment and control group outcomes following interventions yielded an effect size of 0.281. The comparisons between treatment group at baseline and outcome measurement yielded an effect size of 0.312 to 0.313. Each of these effect sizes were statistically significant, meaning that the hypothesis that interventions to improve diabetes self-management results in increased QOL was supported. Control subjects did not experience improved QOL while participating in studies. Conclusions These findings document that people with diabetes experience improved QOL from participation in diabetes self-management training programs. Future diabetes self-management intervention studies should include quality of life outcomes so that this important outcome can be further studied. After more primary studies are available, future meta-analyses can explore important moderator analyses.
Caffeic acid phenethyl ester modulates methotrexate-induced oxidative stress in testes of rat
Authors: Armagan A , Uzar E , Uz E , Yilmaz HR , Kutluhan S , Koyuncuoglu HR , Soyupek S , Cam H , Serel TA 
Published: October 2008

The aim of this study was to investigate the possible protective role of caffeic acid phenethyl ester on testicular toxicity of methotrexate in rats. Nineteen male rats were divided into three groups as follows: group I, control; group II, methotrexate-treated; group III, methotrexate + caffeic acid phenethyl ester-treated. In the second day of experiment, a single dose of methotrexate was intraperitoneally administered to groups II and III, although a daily single dose of caffeic acid phenethyl ester was intraperitoneally administered to group III for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. In the tissue, the level of lipid peroxidation as malondialdehyde and activities of superoxide dismutase were higher in the methotrexate group than in the control group. Lipid peroxidation levels and superoxide dismutase activities were decreased in caffeic acid phenethyl ester + methotrexate group compared with methotrexate group. The activities of catalase in the methotrexate group decreased insignificantly although its activities were significantly increased by caffeic acid phenethyl ester administration. The activity of glutathione peroxidase did not change in the groups. There was significant difference in body weight between control and methotrexate-induced groups. In conclusion, the administration of methotrexate causes elevation of oxidative stress although treatment with caffeic acid phenethyl ester has protective effects on the oxidative stress in testes.
Influence of plasma electrolytic oxidation on mechanical characteristics of NiTi alloy
Authors: Sinebryukhov S. L. , Gnedenkov A. S. , Khrisanfova O. A. , Gnedenkov S. V. 
Published: September 2008

The aim of the present work was to examine the effect of the plasma electrolytic oxidation (PEO) process on the mechanical properties of nitinol. The comparative evaluation of the microhardness and elastic modulus of the nitinol alloy and the PEO coating was carried out. The analysis of the obtained data confirmed closeness of the microhardness and elastic modulus with the respective values for nitinol layers adjacent to the coating. The reason for such a transformation on the boundary with the coating layers of nitinol could consist in the alloy amorphism as a result of the microsecond high temperature plasma influence occurring under PEO conditions and followed by sharp material cooling after attenuation of the plasma microdischarge. Unlike the thermal air oxidation (as a result, the hardness and fragility of the titanium alloy surface layers increase sharply), the changes described above facilitate increase of the mechanical and corrosion mechanical strength of the processed sample.
Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients
Authors: Sekeres Mikkael A. , Elson Paul , Kalaycio Matt E. , Advani Anjali S. , Copelan Edward A. , Faderl Stefan , Kantarjian Hagop M. , Estey Elihu 
Published: October 2008

Abstract
Acute myeloid leukemia (AML) is considered an oncologic emergency. Delaying induction chemotherapy until molecular testing results return, may benefit some patients but harm others. We examined the effect of time from AML diagnosis to treatment (TDT) on complete remission (CR) and overall survival (OS), using patient characteristics available at diagnosis. Regression models were applied to older (≥ 60 years) and younger (< 60 years) adults, controlling for age, baseline white blood cell count, secondary AML (sAML), and performance status. Median patient age was 60 years (range, 17-87 years), TDT 4 days (range, 1-78 days), and 45% had sAML. Cytogenetic risk distribution was: favorable, 8%; intermediate, 66%; unfavorable, 26%. CR rate was 67% and median OS was 68 weeks in patients younger than 60 years; 55% and 33 weeks in older patients, respectively. In univariate and multivariate analyses, longer TDT was associated with worse CR and OS in younger (univariate: P < .001 in both; multivariate: P < .001 and P = .001, respectively), but not older patients (univariate: P = .45, P = .19; multivariate: P = .63, P = .30, respectively). Results did not change with inclusion of cytogenetic data or in risk group subsets. AML therapy should be initiated immediately in younger patients. Delaying treatment does not seem harmful in older patients, allowing individualized approaches.