bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Significance of Sphingosine Kinase-1 Expression in Human Astrocytomas Progression and Overall Patient Survival
Authors: Li Jun , Guan Hong-Yu , Gong Li-Yun , Song Li-Bing , Zhang Nu , Wu Jueheng , Yuan Jie , Zheng Yi-Jie , Huang Zheng-Song , Li Mengfeng 
Published: November 2008

Abstract
Purpose: To characterize the expression of sphingosine kinase-1 (SPHK1) in human astrocytomas and to investigate the association between SPHK1 expression and progression of astrocytomas.
Experimental Design: The expression of SPHK1 in normal human astrocytes, astrocytoma cell lines, and four pairs of matched astrocytoma tissues and their adjacent normal brain tissues were detected by quantitative reverse transcription-PCR and Western blot. In addition, SPHK1 protein expression was examined in 243 cases of histologically characterized astrocytomas by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations.
Results: SPHK1 in astrocytoma cell lines was elevated at both mRNA and protein levels, and the SPHK1 mRNA and protein were significantly up-regulated by up to 6.8- and 40-fold, respectively, in primary astrocytomas compared with those in the adjacent noncancerous brain tissues. Immunohistochemical analysis showed that 100 of 243 (41.2%) paraffin-embedded archival astrocytoma biopsies exhibited high expression of SPHK1. Statistical analysis suggested that the up-regulation of SPHK1 was significantly correlated with the histologic grade of astrocytoma (P = 0.000) and that patients with high SPHK1 level exhibited shorter survival time (P &lt; 0.001). Multivariate analysis revealed that SPHK1 up-regulation might be an independent prognostic indicator for the survival of patients with astrocytoma.
Conclusions: SPHK1 might represent a novel and useful prognostic marker for astrocytoma and play a role during the development and progression of the disease.
Claudin-1 Protein Expression is a Prognostic Marker of Patient Survival in Renal Cell Carcinomas
Authors: Fritzsche Florian R. , Oelrich Beibei , Johannsen Manfred , Kristiansen Ilka , Moch Holger , Jung Klaus , Kristiansen Glen 
Published: November 2008

Abstract
Purpose: Claudin-1 is a tight junction protein described in normal tissues as well as in malignancies. We aimed to assess the diagnostic or prognostic significance of claudin-1 expression in renal cell carcinoma and to correlate the expression of claudin-1 with clinical, histopathologic, and prognostic parameters in renal cell carcinoma.
Experimental Design: A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissue from renal cell carcinomas and corresponding normal renal tissue from 318 patients. The protein expression of claudin-1 was assessed and correlated to clinicopathologic tumor parameters including patient survival. A separate cohort of 44 papillary renal cell carcinoma was used for validation of results.
Results: Claudin-1 was expressed in 29.9% of renal cell cancer cases. Whereas the vast majority of clear cell carcinomas were negative for claudin-1, most papillary tumors (76-86%) were positive. Claudin-1 expression was associated with markers of unfavorable tumor biology in clear cell renal cell carcinoma, whereas the opposite was valid for papillary renal cell carcinoma. In clear cell renal cell carcinoma claudin-1 positivity was a prognosticator of shortened disease-specific patient survival in univariate analysis (P = 0.008), which also remained significant in multivariate analyses in the clinically important subgroups of nonmetastasized or asymptomatic patients.
Conclusions: Claudin-1 is expressed in the majority of papillary renal cell carcinomas, suggesting a diagnostic value of this marker. Its expression is an independent prognosticator of shortened disease-specific patient survival in clinically relevant subgroups of clear cell renal cell carcinoma. Further functional studies are needed to clarify the different biological roles of claudin-1 expression in these histologic subtypes of renal cell carcinoma.
Sulforaphane Enhances the Therapeutic Potential of TRAIL in Prostate Cancer Orthotopic Model through Regulation of Apoptosis, Metastasis, and Angiogenesis
Authors: Shankar Sharmila , Ganapathy Suthakar , Srivastava Rakesh K. 
Published: November 2008

AbstractPurpose: The purpose of this study was to examine the molecular mechanisms by which sulforaphane enhances the therapeutic potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer.Experimental Design: Cell viability and apoptosis assays were done by XTT and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. Tumor-bearing mice were treated with vehicle, sulforaphane, TRAIL, and sulforaphane plus TRAIL. Markers of apoptosis, angiogenesis, and metastasis were measured by immunohistochemistry.Results: Sulforaphane enhanced the therapeutic potential of TRAIL in PC-3 cells and sensitized TRAIL-resistant LNCaP cells. Sulforaphane-induced apoptosis in PC-3 cells correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspase-3 and caspase-9, and up-regulation of DR4 and DR5. Sulforaphane induced the expression of Bax, Bak, Bim, and Noxa and inhibited the expression of Bcl-2, Bcl-XL, and Mcl-1. The quenching of ROS generation with antioxidant N-acetyl-l-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis. Sulforaphane inhibited growth of orthotopically implanted PC-3 tumors by inducing apoptosis and inhibiting proliferation and also enhanced the antitumor activity of TRAIL. Sulforaphane up-regulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and Bak and inhibited the activation of nuclear factor-κB P13K/AKT and MEK/ERK pathways in tumor tissues. The combination of sulforaphane and TRAIL was more effective in inhibiting markers of angiogenesis and metastasis and activating FOXO3a transcription factor than single agent alone.Conclusions: The ability of sulforaphane to inhibit tumor growth, metastasis, and angiogenesis and to enhance the therapeutic potential of TRAIL suggests that sulforaphane alone or in combination with TRAIL can be used for the management of prostate cancer.
Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults
Authors: Petain Aurélie , Kattygnarath Darouna , Azard Julie , Chatelut Etienne , Delbaldo Catherine , Geoerger Birgit , Barrois Michel , Séronie-Vivien Sophie , LeCesne Axel , Vassal Gilles ,   On behalf of the Innovative Therapies with Children with Cancer European consortium
Published: November 2008

Abstract
Purpose: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children.
Experimental Design: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m2 and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma α1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients).
Results: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C&gt;A (P &lt; 0.05).
Conclusions: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.
Histone Deacetylase Inhibitor Romidepsin Has Differential Activity in Core Binding Factor Acute Myeloid Leukemia
Authors: Odenike Olatoyosi M. , Alkan Serhan , Sher Dorie , Godwin John E. , Huo Dezheng , Brandt Stephen J. , Green Margaret , Xie Jingping , Zhang Yanming , Vesole David H. , Stiff Patrick , Wright John , Larson Richard A. , Stock Wendy 
Published: November 2008

AbstractPurpose: Recruitment of histone deacetylases (HDAC) is a mechanism of transcriptional repression implicated in the differentiation block in acute myeloid leukemia (AML). We hypothesized that the HDAC inhibitor romidepsin could cause transcriptional derepression, up-regulation of specific target genes in AML, and differentiation of the leukemic clone. The primary objectives of the study were to evaluate the safety and efficacy of romidepsin in advanced AML.Experimental Design: Twenty patients were stratified into cohort A or B based on the absence or presence of chromosomal abnormalities known to recruit HDACs, including those involving core binding factor (CBF). Romidepsin was administered i.v. at 13 mg/m2/d on days 1, 8, and 15 of a 28-day cycle. Pharmacodynamic endpoints were evaluated at serial time points.Results: Common adverse effects noted were grade 1 to 2 nausea, anorexia, and fatigue. No objective evidence of antileukemic activity was seen in cohort A. In cohort B, although there were no clinical responses by standard criteria, antileukemic activity was observed in 5 of 7 patients. Two patients had clearance of bone marrow blasts and 3 patients had a &gt;50% decrease in bone marrow blasts. Furthermore, in cohort B, at 24 h, there was a significant increase in MDR1 (P = 0.005), p15 (P = 0.01), and p14 (P &lt; 0.0001) expression. In cohort A, although there was a trend toward up-regulation of MDR1, p15, and p14 expression, these changes were not statistically significant.Conclusion: Romidepsin has differential antileukemic and molecular activity in CBF AML. Development of this agent in CBF AML should focus on combinations that target related mechanisms of gene silencing such as DNA methylation.
Regulation of Pancreatic Tumor Cell Proliferation and Chemoresistance by the Histone Methyltransferase Enhancer of Zeste Homologue 2
Authors: Ougolkov Andrei V. , Bilim Vladimir N. , Billadeau Daniel D. 
Published: November 2008

Abstract
Purpose: Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells.
Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival.
Results: We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P &lt; 0.001). We found that genetic depletion of EZH2 results in reexpression of p27Kip1 and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer.
Conclusions: Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27Kip1 as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.
A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin in Previously Untreated Patients with Metastatic Colorectal Cancer
Authors: Fisher George A. , Kuo Timothy , Ramsey Meghan , Schwartz Erich , Rouse Robert V. , Cho Cheryl D. , Halsey Joanne , Sikic Branimir I. 
Published: November 2008

AbstractPurpose: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer.Experimental Design: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle.Results: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response. Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients.Conclusions: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.
CD44 is of Functional Importance for Colorectal Cancer Stem Cells
Authors: Du Lei , Wang Hongyi , He Leya , Zhang Jingyu , Ni Biyun , Wang Xiaohui , Jin Haijing , Cahuzac Nathalie , Mehrpour Maryam , Lu Youyong , Chen Quan 
Published: November 2008

Abstract
Purpose: Both CD44 and CD133 were reported as putative markers for isolating colorectal cancer stem cells (CSC). It remains to be resolved if both of these markers are of functional importance for colorectal CSC.
Experimental Design: The expression of CD44 and CD133 in normal colonic tissues and primary colorectal cancer was assessed by immunohistochemistry in a series of 60 patients on tissue microarray sections. Both in vitro clonogenic and in vivo tumorigenic assay were applied to measure CSC activities from the cells isolated from patients. Lentiviral RNA interference was used to stably knock down CD44 or CD133 in colorectal cancer cells from patients.
Results: We found that CD44+ cells displayed clustered growth and they did not colocalize with CD133+ cells within colorectal cancer. As few as 100 CD44+ cells from a patients' tumor initiated a xenograft tumor in vivo. A single CD44+ cell from a tumor could form a sphere in vitro which has characteristic stem cell properties and was able to generate a xenograft tumor resembling the properties of the primary tumor. Knockdown of CD44, but not CD133, strongly prevented clonal formation and inhibited tumorigenicity in xenograft model.
Conclusions: These results indicate that CD44 is a robust marker and is of functional importance for colorectal CSC for cancer initiation.
Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage
Authors: Koyama Kenichi , Kagamu Hiroshi , Miura Satoru , Hiura Toru , Miyabayashi Takahiro , Itoh Ryo , Kuriyama Hideyuki , Tanaka Hiroshi , Tanaka Junta , Yoshizawa Hirohisa , Nakata Koh , Gejyo Fumitake 
Published: November 2008

AbstractPurpose: Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. Cumulative evidence regulates that a balance between immune and regulatory T (Treg) cells determines the magnitude of immune responses to not only self-antigens but also tumor-associated antigens. The purpose of this study was to elucidate the immunologic balance induced in SCLC patients.Experimental Design: We analyzed T cells in the peripheral blood of 35 consecutive SCLC patients, 8 long-term survivors, and 19 healthy volunteers.Results: Purified CD4+ T cells with down-regulated expression of CD62L (CD62Llow) produced IFN-γ, interleukin (IL)-4, and IL-17, thus considered to be immune effector T cells (Teff). Significantly more Teff cell numbers were detected in LD-SCLC patients than that of extended-stage SCLC (ED-SCLC). By contrast, induction of CD62LhighCD25+ CD4+ Treg cells was significantly higher in ED-SCLC patients. Long-term survivors of SCLC maintained a high Teff to Treg cell ratio, whereas patients with recurrent disease exhibited a low Teff to Treg cell ratio. Teff cells in LD-SCLC patients included more IL-17–producing CD4+ T cells (Th17). Moreover, dendritic cells derived from CD14+ cells of LD-SCLC patients secreted more IL-23.Conclusion: These results show that CD4+ T-cell balance may be a biomarker that distinguishes ED-SCLC from LD-SCLC and predicts recurrence. This study also suggests the importance of inducing Teff cells, particularly Th17 cells, while eliminating Treg cells to control systemic dissemination of SCLC.
Systematic Review and Meta-analysis of Ovarian Cancers: Estimation of Microsatellite-High Frequency and Characterization of Mismatch Repair Deficient Tumor Histology
Authors: Pal Tuya , Permuth-Wey Jenny , Kumar Ambuj , Sellers Thomas A. 
Published: November 2008

Abstract
Purpose: A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various histologic subtypes of mismatch repair (MMR)-deficient epithelial ovarian cancers.
Methods: A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966, and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample size, MSI-H frequency, and histology of MMR-deficient ovarian tumors.
Results: The pooled proportion of MSI-H ovarian cancers was 0.12 [95% confidence interval (CI), 0.08-0.17] from 18 studies with 977 cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95% CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI, 0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies.
Conclusions: The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications for medical management.
Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib
Authors: Costa Daniel B. , Nguyen Kim-Son H. , Cho Byoung C. , Sequist Lecia V. , Jackman David M. , Riely Gregory J. , Yeap Beow Y. , Halmos Balázs , Kim Joo H. , Jänne Pasi A. , Huberman Mark S. , Pao William , Tenen Daniel G. , Kobayashi Susumu 
Published: November 2008

Abstract
Purpose: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib.
Experimental Design: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification.
Results: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib.
Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
Prenegotiation and Mediation: Anglo-Argentine Diplomacy After the Falklands/Malvinas War, 1983–1989
Authors: Corbacho Alejandro Luis 
Published: November 2008

AbstractThis paper studies the process of prenegotiation and the role of mediators between the Argentine and British governments concerning the sovereignty dispute of the Falkland/Malvinas Islands between 1982 and 1990. During this period, the relationship between both governments evolved from rupture and norelations to an agreement on the conditions to negotiate the renewal of full diplomatic relations which was concluded in early 1990. In a preliminary process of prenegotiation, the governments of Switzerland, initially, and the United States played a role in helping to reach an agreement. The former failed when the talks ended abruptly in July 1984. The latter succeeded in getting both parties to the table and keeping them there, thus avoiding a potential rupture until the two parties reached an agreement in principle. During the prenegotiation stage, the principal parties were able to reduce the risks of escalation; they defined and narrowed the boundaries of the dispute, clearly identified the trade-offs, and structured the agenda of formal negotiations. Consequently, the likelihood of successful negotiation improves significantly when the parties reach an agreement during prenegotiation on what will be discussed later. This case also illustrate that sometimes, when negotiations reach a point of stalemate, a mediator can help to find a “zone of agreement.” When this situation occurs, the degree of involvement and the resources of the mediator are particularly important. Finally, this case confirms the assertions that effective mediation is more a matter of leverage and influence than a matter of impartiality.