bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma
Authors: Jeng Yung-Ming , Peng Shian-Yang , Lin Chiao-Ying , Hsu Hey-Chi
Published: September 2005

Purpose: Aurora-A/STK15/BTAK, a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation. The purpose of this study was to investigate the expression and amplification of Aurora-A in hepatocellular carcinoma (HCC).

Experimental Design: Aurora-A mRNA levels were measured in 224 HCCs and 199 paired nontumorous liver tissues by reverse transcription-PCR. Aurora-A mRNA and protein levels of 8 were also measured by reverse transcription-PCR and Western blot hybridization in 8 liver cancer cell lines. Amplification of Aurora-A was determined by Southern blot hybridization in 99 cases.

Results: Aurora-A was overexpressed in 137 of 224 (61%) HCCs and all 8 of the cell lines. Overexpression of Aurora-A was associated with high-grade (grade II-IV), and high-stage (stage IIIB-IV) tumors, p53 mutation, infrequent β-catenin mutation, and poor outcome. Aurora-A overexpression and p53 mutation acted synergistically toward poor prognosis. Amplification of Aurora-A was detected only in 3 HCCs.

Conclusion: The results show that Aurora-A is overexpressed frequently in HCC, and correlated with high grade and high stage, indicating that overexpression of Aurora-A plays a role in the development and progression of HCC.
Gene Expression Profiling after Radiation-Induced DNA Damage Is Strongly Predictive ofBRCA1Mutation Carrier Status
Authors: Kote-Jarai Zsofia , Williams Richard D. , Cattini Nicola , Copeland Maria , Giddings Ian , Wooster Richard , tePoele Robert H. , Workman Paul , Gusterson Barry , Peacock John , Gui Gerald , Campbell Colin , Eeles Ros
Published: September 2005

Purpose: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated.

Experimental Design: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones.

Results: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (∼85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51.

Conclusions: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.
Different Molecular Profiles Characterize Well-Differentiated Endocrine Tumors and Poorly Differentiated Endocrine Carcinomas of the Gastroenteropancreatic Tract
Authors: Furlan Daniela , Cerutti Roberta , Uccella Silvia , La Rosa Stefano , Rigoli Elena , Genasetti Anna , Capella Carlo
Published: September 2005

Purpose: The molecular pathogenesis of gastroenteropancreatic endocrine tumors (ETs) is still largely unknown. The purpose of this work was a molecular characterization of 38 gastroenteropancreatic ETs with respect to the primary site and to the morphofunctional profile, pointing out useful diagnostic or prognostic molecular markers.

Experimental Design: Twenty-four well-differentiated ETs or carcinomas (WDET/Cs; 11 pancreatic, 3 gastric, and 10 intestinal) and 14 poorly differentiated endocrine carcinomas (1 pancreatic, 6 gastric, and 7 colorectal) were microallelotyped using 38 polymorphic microsatellite markers covering chromosomes 1, 3, 5q, 6, 11, 17, and 18.

Results: Regardless of the primary site, a significantly higher percentage of allelic imbalances (AIs) was observed in poorly differentiated endocrine carcinomas than in WDET/Cs (P = 0.012), except for 3 of 8 nonfunctioning pancreatic endocrine tumors and 1 colorectal WDEC, exhibiting multiple AIs on chromosomes 1, 3, 6, and 11. A strong positive correlation between AI percentage and Ki-67 proliferation index was detected considering both the whole series of ETs (P = 0.004) and the group of WDET/Cs alone (P = 0.011). The survival analysis showed a positive correlation between low percentage of AI and longer survival (P = 0.01). No recurrent AIs at specific chromosomal regions were identifiable with respect to the primary site.

Conclusions: The malignant progression of endocrine tumors seems to be associated with complex allelotypes and chromosomal instability. Although no specific molecular markers of malignancy can be defined with certainty, the ploidy status and the degree of chromosomal derangements appear to be the most informative genetic factors with prognostic significance.
Usefulness of 99mTc-Sestamibi Scintigraphy in Suggesting the Therapeutic Effect of Chemotherapy against Gastric Cancer
Authors: Kawata Kenji , Kanai Michiyuki , Sasada Tetsuro , Iwata Shingo , Yamamoto Naritaka , Takabayashi Arimichi
Published: September 2005

Purpose: Imaging with 99mTc-sestamibi (99mTc-MIBI) has been used to assess 170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in several types of malignancy, such as breast and lung cancers. The purpose of this study was to evaluate the relationship between 99mTc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients.

Experimental Design: Thirty-six patients with advanced gastric cancer underwent 99mTc-MIBI scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and the expression of P-gp or multidrug resistance-associated protein was analyzed by immunohistochemical staining. The relationship between the accumulation of 99mTc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined.

Results: Higher accumulation of 9mTc-MIBI in tumors was observed in 25 and 23 of 36 gastric cancer patients at the early (30 min) and delayed (120 min) images, respectively. Accelerated accumulation of 99mTc-MIBI negatively correlates with increased expression of P-gp, but not of multidrug resistance-associated protein, as determined by immunohistochemistry in gastric cancer tissues. The response rate to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with high 99mTc-MIBI accumulation (15.4%) was much lower than that in patients with low 99mTc-MIBI accumulation (54.5%). In contrast, patients with high 99mTc-MIBI accumulation show a higher response rate (41.7%) to chemotherapy with epirubicin, which is known to be a substrate of P-gp transporter.

Conclusions: 99mTc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.
Telomerase-Specific Replication-Selective Virotherapy for Human Cancer
Authors: Kawashima Takeshi , Kagawa Shunsuke , Kobayashi Naoya , Shirakiya Yoshiko , Umeoka Tatsuo , Teraishi Fuminori , Taki Masaki , Kyo Satoru , Tanaka Noriaki , Fujiwara Toshiyoshi
Published: September 2005

Purpose: Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on human cancer cells.

Experimental Design: We constructed an adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (TRAD)], in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human cancer cells in vitro and in vivo.

Results: TRAD induced selective E1A and E1B expression in human cancer cells, but not in normal cells such as human fibroblasts. TRAD replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human fibroblasts lacking telomerase activity. In nu/nu mice carrying s.c. human lung tumor xenografts, intratumoral injection of TRAD resulted in a significant inhibition of tumor growth. No evidence of TRAD was identified in tissues outside of the tumors, despite the presence of TRAD in the circulation. Moreover, TRAD replication in the distant, noninjected tumors was demonstrated.

Conclusions: Our results suggest that the hTERT promoter confers competence for selective replication of TRAD in human cancer cells, an outcome that has important implications for the treatment of human cancers.
In Vivo
Suppression of Hormone-Refractory Prostate Cancer Growth by Inositol Hexaphosphate
Authors: Singh Rana P. , Sharma Girish , Mallikarjuna G. U. , Dhanalakshmi Sivanandhan , Agarwal Chapla , Agarwal Rajesh
Published: September 2005

Purpose: Diet composition is an important etiologic factor in prostate cancer (PCA) growth and has significant impact on clinical PCA appearance. Because inositol hexaphosphate (IP6) is a dietary phytochemical present in cereals, soy, legumes, and fiber-rich foods, we evaluated efficacy of IP6 against PCA growth and associated molecular events.

Experimental Design: DU145 cells were injected into nude mice, and animals were fed normal drinking water or 1 or 2% IP6 in drinking water for 12 weeks. Body weight, diet, water consumption, and tumor sizes were monitored. Tumors were immunohistochemically analyzed for proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated nick end labeling, and CD31. Tumor-secreted insulin-like growth factor binding protein (IGFBP)-3 and vascular endothelial growth factor (VEGF) were quantified in plasma by ELISA.

Results: IP6 feeding resulted in suppression of hormone-refractory human prostate tumor growth without any adverse effect on body weight gain, diet, and water consumption during entire study. At the end of study, tumor growth inhibition by 1 and 2% IP6 feeding was 47 and 66% (P = 0.049–0.012) in terms of tumor volume/mouse and 40 and 66% (P = 0.08–0.003) in terms of tumor weight/mouse, respectively. Tumor xenografts from IP6-fed mice showed significantly (P < 0.001) decreased proliferating cell nuclear antigen-positive cells but increased apoptotic cells. Tumor-secreted IGFBP-3 levels were also increased up to 1.7-fold in IP6-fed groups. Additionally, IP6 strongly decreased tumor microvessel density and inhibited tumor-secreted VEGF levels.

Conclusions: IP6 suppresses hormone-refractory PCA growth accompanied by inhibition of tumor cell proliferation and angiogenesis and increased apoptosis. IP6-caused increase in IGFBP-3 and decrease in VEGF might have a role in PCA growth control.
Phase I Studies of Interleukin (IL)-2 and Rituximab in B-Cell Non-Hodgkin’s Lymphoma
Authors: Gluck William Larry , Hurst Deborah , Yuen Alan , Levine Alexandra M. , Dayton Mark A. , Gockerman Jon P. , Lucas Jennifer , Denis-Mize Kimberly , Tong Barbara , Navis Dawn , Difrancesco Anita , Milan Sandra , Wilson Susan E. , Wolin Maurice
Published: September 2005

Purpose: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL).

Experimental Design: Thirty-four patients with advanced NHL received rituximab (375 mg/m2 i.v. weekly, weeks 1–4) and escalating doses of s.c. IL-2 [2–7.5 MIU daily (n = 19) or 4.5–14 million international units three times weekly (n = 15), weeks 2–5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated.

Results: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients.

Conclusions: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.
Plasma Level of Transforming Growth Factor β1 Measured from the Azygos Vein Predicts Prognosis in Patients with Esophageal Cancer
Authors: Fukuchi Minoru , Miyazaki Tatsuya , Fukai Yasuyuki , Nakajima Masanobu , Sohda Makoto , Masuda Norihiro , Manda Ryokuhei , Tsukada Katsuhiko , Kato Hiroyuki , Kuwano Hiroyuki
Published: September 2005

Purpose: Transforming growth factor (TGF)-β regulates cell growth inhibition. When tumor cells lose their sensitivity to TGF-β growth inhibition, the excess TGF-β that results may act on tumor cells to facilitate tumor development. Previously, we have shown that an elevated systemic TGF-β1 level is not related to tumor progression in esophageal cancer (Y. Fukai et al., Int J Cancer 2003;104:161–6). We considered that systemic inflammation or chronic disease, in addition to the tumor, may influence the plasma TGF-β level. Therefore, we examined the hypothesis that the plasma TGF-β level measured from the azygos vein would independently predict tumor progression and prognosis in patients with esophageal cancer.

Experimental Design: Fifty-seven plasma samples were obtained intraoperatively from the azygos vein in patients with esophageal cancer. ELISA was used to quantify the plasma TGF-β1 levels, which were correlated with pathological features and patient survival.

Results: The mean plasma TGF-β1 level measured from the azygos vein of esophageal cancer patients was 5.09 ± 0.48 ng/ml (mean ± SE). The survival rates of patients with a high TGF-β1 level (defined as a level above the 4.6 ng/ml level of normal controls) in the azygos vein were significantly lower than those of patients with a low TGF-β1 level (P = 0.0317). Moreover, the TGF-β1 level in the azygos vein was an independent prognostic factor for overall survival (P = 0.0474).

Conclusions: The level of plasma TGF-β1 measured from the azygos vein is an independent predictor in patients with esophageal cancer and may reflect tumor progression more specifically because the azygos vein is responsible for venous return from the esophagus.
Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma
Authors: Lee Hye Seung , Chang Mee Soo , Yang Han-Kwang , Lee Byung Lan , Kim Woo Ho
Published: September 2005

Purpose: EBV has been detected in 2–16% of gastric carcinomas. However, there is little information available about the gene expression profile of EBV-positive gastric carcinomas.

Experimental Design: EBV infection was examined using EBV-encoded small RNAs (EBERs) in situ hybridization, and 63 (5.6%) of 1127 consecutive gastric carcinomas were found to be EBV-positive. The expressions of 27 tumor-associated proteins were evaluated immunohistochemically in 63 EBV-positive gastric carcinomas and 287 EBV-negative carcinomas using the tissue array method. In addition, the genotype of EBV was investigated by PCR amplification of LMP1 (latent membrane protein 1), Epstein-Barr nuclear antigen 2 (EBNA2), and EBNA3B genes.

Results: EBV-positive gastric carcinomas are characterized by the presence of lymphoid stroma, proximal location, and predominance in males. In comparison with EBV-negative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7. Using hierarchical cluster analysis, we divided EBV-positive gastric carcinomas into two clusters. Those patients with cluster 1 (42 cases) carcinomas had a better prognosis than those with cluster 2 (12 cases; P = 0.0002) or those with EBV-negative carcinomas (280 cases; P = 0.0251). Fifty-one (92.7%) of 55 EBV-positive carcinomas demonstrated the 30-bp deletion in LMP1 gene, and 53 (96.4%) of 55 cases were type 1 for EBNA2 and EBNA3B genes.

Conclusion: EBV-positive gastric carcinomas have a distinct protein expression profile as well as distinct clinicopathological features, as compared with EBV-negative carcinomas. The subclassification of EBV-positive carcinomas, by hierarchical cluster analysis, is significantly associated with patient survival.
Molecular Pathology Shows p16 Methylation in Nonadenomatous Pituitaries from Patients with Cushing’s Disease
Authors: Simpson David J. , McNicol Anne M. , Murray David C. , Bahar Adil , Turner Helen E. , Wass John A. H. , Esiri Margaret M. , Clayton Richard N. , Farrell William E.
Published: September 2005

Purpose: The majority of cases of Cushing’s disease are due to the presence of a corticotroph microadenoma. Less frequently no adenoma is found and histology shows either corticotroph hyperplasia, or apparently normal pituitary. In this study we have used molecular pathology to determine whether the tissue labeled histologically as “normal” is indeed abnormal.

Experimental Design: Tissue from 31 corticotroph adenomas and 16 nonadenomatous pituitaries were subject to methylation-sensitive PCR to determine the methylation status of the p16 gene CpG island. The proportion of methylated versus unmethylated CpG island was determined using combined bisulphite restriction analysis. Methylation status was correlated with immunohistochemical detection of p16.

Results: Seventeen of 31 adenomas (54.8%), 4 of 6 cases of corticotroph hyperplasia, and 7 of 10 apparently normal pituitaries showed p16 methylation. Ten of 14 (71%; P = 0.01) adenomas and 2 of 3 cases of corticotroph hyperplasia, which were methylated, failed to express p16 protein. However, only 2 of 7 apparently normal pituitaries that were methylated failed to express p16 protein. Quantitative analysis of methylation using combined bisulphite restriction analysis showed only unmethylated CpG islands in postmortem normal pituitaries; however, in adenomas 80–90% of the cells within a specimen were methylated. The reverse was true for corticotroph hyperplasia and apparently normal pituitaries where only 10–20% of the cells were methylated. Thus, the decreased proportion of cells that were methylated, particularly in those cases of apparently normal pituitary, is the most likely explanation for the lack of association between this change and loss of cognate protein in these cases.

Conclusions: To our knowledge this is the first report that describes an intrinsic molecular change, namely methylation of the p16 gene CpG island, common to all three histological patterns associated with Cushing’s disease. Thus, the use of molecular pathology reveals abnormalities undetected by routine pathological investigation. In cases of “apparently” normal pituitaries it is not possible to determine whether the change is associated with adenoma cells “scattered” throughout the gland, albeit few in number, or with the ancestor-clonal origin of these tumor cells.
Epithelial Cell Adhesion Molecule (KSA) Expression
Authors: Seligson David B. , Pantuck Allan J. , Liu Xueli , Huang Yunda , Horvath Steven , Bui Matthew H. T. , Han Ken-ryu , Correa Adrian J. L. , Eeva Mervi , Tze Sheila , Belldegrun Arie S. , Figlin Robert A.
Published: September 2005

Purpose: Epithelial cell adhesion molecule (EpCAM) is a widely expressed adhesion molecule in epithelial cancers. The purpose of this study is to determine the protein expression patterns of EpCAM in renal cell carcinoma (RCC) using tissue arrays linked to a clinicopathological database to evaluate both its predictive power in patient stratification and its suitability as a potential target for immunotherapeutic treatment strategies.

Experimental Design: The University of California, Los Angeles kidney cancer tissue microarray contains specimens from 417 patients treated with nephrectomy. EpCAM protein expression in tumors and matched morphologically normal renal tissues was evaluated using anti-EpCAM immunohistochemistry. The resultant expression reactivity was correlated with clinicopathological variables.

Results: EpCAM is consistently expressed in the distal nephron on normal renal epithelium. Clear cell RCCs show minimal and infrequent EpCAM expression, whereas chromophobe and collecting duct RCCs both demonstrate intense and frequent expression. Of 318 clear cell carcinomas used in the analysis, 10% were EpCAM positive in ≥50% of cells, and 8% of patients would be considered candidates for EpCAM-based therapy, based on high expression [≥moderate intensity and frequent (≥50%) expression] and the need for systemic treatment. EpCAM expression was an independent prognostic factor for improved disease-specific survival, with a multivariate hazard ratio of 0.63 (P = 0.017; 95% confidence interval, 0.43–0.92).

Conclusions: EpCAM is a novel prognostic molecular marker in RCC patients, and its positive expression is an independent predictor associated with improved survival. However, high expression in morphologically normal renal tissues and minimal or absent expression in clear cell carcinomas will likely limit the utility of this epithelial marker in targeted treatments of this most common RCC type.
Targeting the Platelet-Derived Growth Factor Receptor in Antivascular Therapy for Human Ovarian Carcinoma
Authors: Apte Sachin M. , Fan Dominic , Killion Jerald J. , Fidler Isaiah J.
Published: September 2005

Purpose: We sought to determine whether blockade of platelet-derived growth factor receptor (PDGF-R) activation by oral administration of a PDGF-R tyrosine kinase inhibitor (STI571) alone or in combination with i.p. paclitaxel can inhibit the progression of tumors caused by human ovarian carcinoma cells growing in the peritoneal cavity of female nude mice.

Experimental Design: In several different experiments, paclitaxel-sensitive and paclitaxel-resistant metastatic human ovarian carcinoma cells were injected into the peritoneal cavity of nude mice. Seven days later, groups (n = 10) of mice began receiving a control treatment, STI571 alone, paclitaxel alone, or a combination of STI571 and paclitaxel. The mice were necropsied after 45 days of treatment.

Results: Treatment with combination therapy significantly reduced tumor weight (relative to control or single-agent therapy) in all three human ovarian cancer cell lines. Immunohistochemical analyses revealed that PDGF-R activation was blocked by STI571 administered alone or in combination with paclitaxel. Tumor-associated endothelial cells expressed both PDGF-R and phosphorylated PDGF-R. In mice receiving combination therapy, tumor-associated endothelial cells underwent apoptosis, leading to decreases in microvessel density and tumor cell proliferation relative to control and single-agent therapy.

Conclusions: These results show that administration of a PDGF-R tyrosine kinase inhibitor in combination with paclitaxel impairs the progression of ovarian cancer in the peritoneal cavity of nude mice, in part, by blockade of PDGF, an endothelial cell survival factor, which results in the increased apoptosis of tumor-associated endothelial cells.
Down Regulation of High in Normal-1 (
HIN-1
) is a Frequent Event in Stage I Non-Small Cell Lung Cancer and Correlates with Poor Clinical Outcome
Authors: Marchetti Antonio , Barassi Fabio , Martella Carla , Chella Antonio , Salvatore Simona , Castrataro Antonio , Mucilli Felice , Sacco Rocco , Buttitta Fiamma
Published: September 2005

Purpose: The aim of this study was to evaluate the prevalence and the clinical significance of HIN-1 mRNA expression in early stage non-small cell lung carcinomas (NSCLCs).

Experimental Design: A series of 91 NSCLC patients with stage I neoplastic disease was studied. HIN-1 expression was investigated by quantitative real-time reverse transcription-PCR on tumor specimens and matching normal lung tissues. Variables were analyzed by χ2 test and Fisher’s exact tests. Survival was evaluated with the method of Kaplan-Meier. Multivariate analysis was performed with Cox’s proportional hazards model.

Results: Seventy one (78%) tumors showed a reduction of HIN-1 mRNA compared with the normal counterpart. The range of reduction varied greatly, from −2-fold to −3350-fold. Setting a cutoff at −46-fold (median value of HIN-1 mRNA reduction), 46 cases (51%) had a markedly reduced expression, and 45 cases (49%) showed a normal or slightly reduced expression. A statistically significant association between low HIN-1 mRNA levels and T status was observed (P = 0.036). Univariate survival curves, estimated using the method of Kaplan-Meier, defined a significant association between HIN-1 expression and both overall survival (P = 0.0095) and disease-free survival (P = 0.0122). A multivariate analysis, performed by Cox’s proportional hazards regression model, confirmed that a low HIN-1 expression was the only significant factor to predict poor prognosis.

Conclusions: Our data indicate that HIN-1 expression, measured by real-time reverse transcription-PCR, is a possible prognostic factor in patients with stage I NSCLC. Additional studies are required to further validate this potential prognostic marker.
UDP-Glucuronosyltransferase 1A7 Genetic Polymorphisms Are Associated with Hepatocellular Carcinoma in Japanese Patients with Hepatitis C Virus Infection
Authors: Wang Yue , Kato Naoya , Hoshida Yujin , Otsuka Motoyuki , Taniguchi Hiroyoshi , Moriyama Masaru , Shiina Shuichiro , Kawabe Takao , Ito Yoichi M. , Omata Masao
Published: September 2005

Purpose: Genetic polymorphisms of UDP-glucuronosyltransferase 1A7 (UGT1A7), which detoxifies endogenous and environmental carcinogens, have been reported to be associated with hepatocellular carcinoma (HCC) in German populations. On the other hand, we reported that interleukin-1β (IL-1β) gene polymorphisms were associated with hepatitis C virus (HCV)-related HCC. In this study, we evaluated the association of both genes with the risk of HCC in Japanese HCV-infected patients.

Experimental Design: Genetic polymorphisms of UGT1A7 and IL-1β were investigated in 280 Japanese patients (122 with HCC and 158 without HCC) with chronic HCV infections, by use of standard PCR-based genotyping techniques.

Results: We designated the UGT1A7*1 allele (a haplotype conferring higher activity) as H and the *2, *3, and *4 alleles (haplotypes conferring lower activity) as L. The proportions of UGT1A7 L/L and H/L alleles (genotypes) in patients with HCC (25% and 45%, respectively) were higher than those in patients without HCC (15% and 39%, respectively) with odds ratios of 2.73 (95% confidence interval, 1.40–5.35) and 1.80 (95% confidence interval, 1.05–3.09), respectively, compared with the UGT1A7 H/H alleles. Multivariate analyses revealed that UGT1A7 L/L and IL-1β/−31T/T−511C/C genotypes, the presence of cirrhosis, age >60 years, male sex, and α-fetoprotein >20 μg/ml were associated with the presence of HCC (odds ratios, 2.33, 2.67, 4.20, 3.12, 3.09, and 2.90, respectively).

Conclusion: The UGT1A7 polymorphisms together with IL-1β were associated with the presence of HCC in Japanese HCV-infected patients.
Safety and Biological Activity of Repeated Doses of Recombinant Human Flt3 Ligand in Patients with Bone Scan-Negative Hormone-Refractory Prostate Cancer
Authors: Higano Celestia S. , Vogelzang Nicholas J. , Sosman Jeffrey A. , Feng Anyang , Caron Dania , Small Eric J
Published: September 2005

Purpose: The purpose of this study was to evaluate the safety, biological activity, and feasibility of repeated doses of the dendritic cell (DC)-stimulating agent Flt3 ligand (FL) in patients with bone scan-negative hormone-refractory prostate cancer.

Experimental Design: Thirty-one patients with hormone-refractory prostate cancer who had elevated prostate-specific antigen (PSA) levels and negative bone scans were enrolled. Six cycles (28 days each) were planned. In the first cycle, patients were randomized to FL or placebo. All patients received open-label FL during the next five courses. DC, anti-FL antibody, and PSA levels were measured every 15 days to assess biological activity.

Results: DCs increased markedly in FL-treated patients from precycle to day 15, and the increase was consistent in each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% precycle and from 10.1% to 13.9% on day 15, and after the first cycle, absolute counts on day 15 were approximately 29-fold higher than precycle levels. Natural killer cell counts (CD56+) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22). Twenty-two of 27 patients tested developed nonneutralizing anti-FL antibody. The most frequently experienced toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007).

Conclusions: FL was well tolerated. FL consistently produced an increase in DC count without any evidence of decreasing response with continued exposure. The expansion of DCs and the slowing of PSA velocity after administration of FL suggest potential clinical applications in the immunotherapy of prostate cancer.
Debulking Nephrectomy in Metastatic Renal Cancer
Authors: Flanigan Robert C.
Published: September 2005

Up to one third of patients with renal cell carcinoma will present with metastatic disease, and 20 to 40% of those with clinically localized disease will eventually be found to have metastatic involvement. Prognosis continues to be guarded for this population, with a 2-year survival of only 10 to 30%. Although advances are being made in the medical management of renal cell carcinoma, the role of surgery in the treatment algorithm is also being additionally refined. Palliative surgery either via nephrectomy or metastasectomy has a role in certain well-selected patients. There are also data to support total metastasectomy at the time of either nephrectomy or recurrence in a small subset of patients with minimal, resectable metastases. More controversial is the idea of cytoreductive nephrectomy as an adjunct to immunotherapy. Recent phase III trials indicate that nephrectomy may play an important role in management of metastatic renal cell carcinoma in conjunction with cytokine-based immunotherapy. Nephrectomy is also an essential component of tumor-based vaccine and adoptive immunotherapy protocols and may play a role in other novel therapies.
Tissue Array-Based Predictions of Pathobiology, Prognosis, and Response to Treatment for Renal Cell Carcinoma Therapy
Authors: Lam John S. , Belldegrun Arie S. , Figlin Robert A.
Published: September 2005

Renal cell carcinoma is the most lethal of the common urologic malignancies, with ∼40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Historically, clinical factors have been used as prognostic markers for patients with renal cell carcinoma. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for renal cell carcinoma patients. Furthermore, reliable predictive factors are essential for the stratification of patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities, and determine eligibility for clinical trials. This has led to the creation of integrated staging systems that predict outcome by combining pathological and clinical variables. Although staging has been improved with the development of integrated systems, molecular tumor markers are expected to revolutionize the staging of renal cell carcinoma in the future. The development of methods based on gene and tissue arrays has created a powerful tool for evaluating hundreds to thousands of tumors simultaneously with histologic, immunohistochemical, and chromosomal analyses. Gene array analysis permits rapid molecular profiling, and tissue arrays enable the analysis of protein expression profiles on specimens to determine their potential clinical significance and role in renal cell carcinoma biology. This article reviews the tissue array-based predictors of pathobiology, prognosis, response to treatment, and potential molecular targets for therapy of renal cell carcinoma.
Hierarchical Organization in Smooth Dynamical Systems
Authors: Jacobi Martin N.
Published: September 2005

This article is concerned with defining and characterizing hierarchical structures in smooth dynamical systems. We define transitions between levels in a dynamical hierarchy by smooth projective maps from a phase space on a lower level, with high dimensionality, to a phase space on a higher level, with lower dimensionality. It is required that each level describe a self-contained deterministic dynamical system. We show that a necessary and sufficient condition for a projective map to be a transition between levels in the hierarchy is that the kernel of the differential of the map is tangent to an invariant manifold with respect to the flow. The implications of this condition are discussed in detail. We demonstrate two different causal dependences between degrees of freedom, and how these relations are revealed when the dynamical system is transformed into global Jordan form. Finally these results are used to define functional components on different levels, interaction networks, and dynamical hierarchies.
Evolvability Suppression to Stabilize Far-Sighted Adaptations
Authors: Altenberg Lee
Published: September 2005

The opportunistic character of adaptation through natural selection can lead to evolutionary pathologies —situations in which traits evolve that promote the extinction of the population. Such pathologies include imprudent predation and other forms of habitat overexploitation, or the tragedy of the commons, adaptation to temporally unreliable resources, cheating and other antisocial behavior, infectious pathogen carrier states, parthenogenesis, and cancer, an intraorganismal evolutionary pathology. It is known that hierarchical population dynamics can protect a population from invasion by pathological genes. Can it also alter the genotype so as to prevent the generation of such genes in the first place, that is, suppress the evolvability of evolutionary pathologies? A model is constructed in which one locus controls the expression of the pathological trait, and a series of modifier loci exist that can prevent the expression of this trait. It is found that multiple evolvability checkpoint genes can evolve to prevent the generation of variants that cause evolutionary pathologies. The consequences of this finding are discussed.
Cultural Perceptions of Africans in Diaspora and in Africa on Atlantic Slave Trade and Reparations
Authors: Dibie Robert , Njoku Johnston
Published: September 2005

This study examines the cultural perceptions of Africans in Diaspora on the Atlantic slave trade and reparations. It uses a cultural centered model to analyze the perception of Africans in Diaspora about the issue of slavery and reparations. The paper also uses a survey method to explore the perceptions of African-Americans in the United States, Africans living in Europe, and Africans living in the African continent about reparations. It argues that the environmental, religious, occupational, social and political conditions that Africans in Diaspora currently live in will determine their perception of slavery and reparations. Despite this argument, the paper stresses that it is a violation of the established precedence in law that is based on the principle of unjust enrichment to not pay some reparations to the present generation of Africans. This principle stipulates that if a person, a corporation or a country profit from the criminal treatment of a group of people, such a person, corporation or country is subject to the payment of reparations on the basis of unjust enrichment. The study further attempts to explain why it has been difficult for the western industrial world to agree to pay reparations to the children of over 25,000,000 Africans who were wrenched out of Africa as slaves. The concluding section of the paper suggests different reparation methods that would help create a permanent solution that might be acceptable to all.
A Critical Examination of the State versus Non-Governmental Organizations (NGOs) in the Policy Sphere in the Global South: Will the State Die as the NGOs Thrive in Sub-Saharan Africa and Asia?
Authors: Obiyan A. Sat
Published: September 2005

This paper examines the role of non-governmental organizations (NGOs) in service provision with a special focus on Sub-Saharan Africa and Asia. First, it reviews the conceptual and taxonomic issues in NGOs. It then proceeds to examine the performance of NGOs in some countries. The paper notes the increased relevance of NGOs in many countries. It, however, argues that any expectation that the NGOs will supplant the state in service provision is likely to be utopian. It contends that just as we have government failure and market failure, we can also have third sector failure. The paper argues for an appropriate balance between the state and NGOs in meeting the needs of the poor. It concludes that while it may be necessary to continue to strengthen the private sector and the third sector, it would be useful to continue to inquire into how the state can be effective.
Venting of Heat and Carbon Dioxide from Urban Canyons at Night
Authors: Salmond J. A. , Oke T. R. , Grimmond C. S. B. , Roberts S. , Offerle B.
Published: September 2005

Turbulent fluxes of carbon dioxide and sensible heat were observed in the surface layer of the weakly convective nocturnal boundary layer over the center of the city of Marseille, France, during the Expérience sur Sites pour Contraindre les Modèles de Pollution Atmosphérique et de Transport d’Emission (ESCOMPTE) field experiment in the summer of 2001. The data reveal intermittent events or bursts in the time series of carbon dioxide (CO2) concentration and air temperature that are superimposed upon the background values. These features relate to intermittent structures in the fluxes of CO2 and sensible heat. In Marseille, CO2 is primarily emitted into the atmosphere at street level from vehicle exhausts. In a similar way, nocturnal sensible heat fluxes are most likely to originate in the deep street canyons that are warmer than adjacent roof surfaces. Wavelet analysis is used to examine the hypothesis that CO2 concentrations can be used as a tracer to identify characteristics of the venting of pollutants and heat from street canyons into the above-roof nocturnal urban boundary layer. Wavelet analysis is shown to be effective in the identification and analysis of significant events and coherent structures within the turbulent time series. Late in the evening, there is a strong correlation between the burst structures observed in the air temperature and CO2 time series. Evidence suggests that the localized increases of temperature and CO2 observed above roof level in the urban boundary layer (UBL) are related to intermittent venting of sensible heat from the warmer urban canopy layer (UCL). However, later in the night, local advection of CO2 in the UBL, combined with reduced traffic emissions in the UCL, limit the value of CO2 as a tracer of convective plumes in the UBL.
Optical Properties of Aerosol Particles over the Northeast Pacific
Authors: Marshall Julia , Lohmann Ulrike , Leaitch W. Richard , Shantz Nicole , Phinney Lisa , Toom-Sauntry Desiree , Sharma Sangeeta
Published: September 2005

In July 2002, atmospheric aerosol measurements were conducted over the northeast Pacific Ocean as part of the Subarctic Ecosystem Response to Iron Enhancement Study (SERIES). The following aerosol quantities were measured: particle number size distribution, particle scattering and backscattering coefficients at three wavelengths, particle absorption coefficient at one wavelength, and size-segregated particle chemical composition. Using Mie theory to calculate the aerosol particle scattering and absorption coefficients from the size distribution and chemical measurements, closure with the measured optical coefficients is not attained. Discrepancies between the calculated and measured scattering and backscattering coefficients are largely a result of the fact that the nephelometer measures scattering only between 7° and 170°. Over 90% of the total scattering and 50% of the backscattering in this study was not measured by the nephelometer because of the missing forward-scattering (0°–7°) and backscattering (170°–180°) segments of the phase function. During this study the majority of the total scattering and backscattering in the marine boundary layer of this region was a result of coarse particles consisting almost entirely of sea salt.
Cloud-Base-Height Estimation from Paired Ground-Based Hemispherical Observations
Authors: Kassianov Evgueni , Long Charles N. , Christy Jason
Published: September 2005

Total-sky imager (TSI) and hemispheric-sky imager (HSI) each have a hemispherical field of view, and many TSIs are now deployed. These instruments have been used routinely to provide a time series of the fractional sky cover only. In this study, the possible retrieval of cloud-base height (CBH) from TSI surface observations is examined. This paper presents a validation analysis of a new retrieval using both a model-output inverse problem and independent, ground-based micropulse lidar data. The obtained results suggest that, at least for single-layer cloud fields, moderately accurate (within ∼0.35 km) CBH retrieval is possible.
The way it really happened: Competing narratives in the political process of technological change
Authors: Dawson Patrick , Buchanan David
Published: September 2005

Corporate narratives concerning technological change are often constructed around a linear event sequence that presents the organization in a positive light to internal and external observers. These narratives often sanitize the change process, and present data from which commentators can formulate neat linear prescriptions on how to implement new technology. In contrast, this article draws on processual-contextual theoretical perspectives to argue that technological change is a more complex political process represented by multiple versions of events which compete with each other for dominance as definitive change accounts. It also calls for an analysis of narratives over time (before, during and after change) in seeking to demonstrate the analytical significance of identifying and unpacking the multiple interpretive frameworks that are utilized in organizational struggles over technology and change at work. These struggles draw attention to the ways in which power is exercised through the construction and management of compelling stories that shape change. It is the contribution of these stories (competing narratives) to understanding the political process of technological change, that is the focus of this article.
Explaining Trends in Hospitalizations for Pneumonia and Influenza in the Elderly
Authors: Hebert Paul L. , McBean A. Marshall , Kane Robert L.
Published: September 2005

From 1987–99, influenza and pneumococcal vaccination rates among elderly Medicare beneficiaries increased by 300 percent and 500 percent, respectively. Despite these gains, annual rates of hospitalizations for pneumonia and influenza (P&I) have not decreased; rather, they have increased steadily. The authors investigate whether this paradoxical increase in hospitalization rates reflects an increasing burden of P&I or the effects of a changing healthcare environment. They find that from 1987–99, P&I hospitalizations per one thousand beneficiaries increased from 15.1 to 23.4. Of this increase, 23 percent was due to an aging Medicare population, 2.4 percent was due to increased rates of rehospitalization, and at most 5 percent was due to upcoding. There was no evidence that physicians were increasingly admitting patients with less complicated cases of P&I. The changing healthcare environment only partially explained the paradoxical increase in P&I hospitalizations. P&I appears to be an increasing burden to the elderly, despite increased vaccination rates.
Mung-bean Protein Hydrolysates Obtained with Alcalase Exhibit Angiotensin I-converting Enzyme Inhibitory Activity
Authors: Li Guan Hong , Le Guo Wei , Liu Huan , Shi Yong Hui
Published: September 2005

Mung-bean protein isolates were hydrolysed by two proteases alcalase and neutrase commercially available for food industry use, and the angiotensin I-converting enzyme (ACE) inhibitory activities of the enzymatic hydrolysates were measured at different hydrolysis times. The non-hydrolysed protein showed no inhibitory activity. Hydrolysates generated with neutrase displayed very low ACE inhibitory activity, while those obtained with alcalase exhibited high inhibitory activity. The highest ACE inhibitory activity with the IC50 value of 0.64 mg protein/mL was found in the hydrolysate obtained with alcalase at 2h of hydrolysis time. These results indicated that mung-bean protein is a good protein source of ACE inhibitory peptides when hydrolysed with the protease alcalase. The mung-bean protein hydrolysates prepared with alcalase might be utilised for physiologically functional foods with antihypertensive activity.
Taking the Biscuit? A Discursive Approach to Managing Diet in Type 2 Diabetes
Authors: Peel Elizabeth , Parry Odette , Douglas Margaret , Lawton Julia
Published: September 2005

Adopting and maintaining a healthy diet is pivotal to diabetic regimens. Behavioural research has focused on strategies to modify/maintain healthy behaviours; thus ‘compliance’ and ‘ noncompliance’ are operationalized by researchers. In contrast, discursive psychology focuses on the actions different accounts accomplish—in this case regarding diets. Using thematic discourse analysis, we examine dietary management talk in repeat-interviews with 40 newly diagnosed type 2 diabetes patients. Women in our study tended to construct dietary practices as an individual concern, while men presented food consumption as a family matter. Participants accounted for ‘cheating’ in complex ways that aim to accomplish, for instance, a compliant identity. Discursive psychology may facilitate fluidity in our understandings of dietary management, and challenge fixed notions of ‘compliant’ and ‘non-compliant’ diabetes patients.