bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of cyclin D1 expression by cyclin D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin chemosensitivity
Authors: Zhou Xiaojian , Zhang Zhiyuan , Yang Xiao , Chen Wantao , Zhang Ping 
Published: September 2008

AbstractCyclin D1 is a well‐known cell cycle regulator. Recently, its pro‐survival function has been revealed in several tumors. Because increasing expression of cyclin D1 is a common event in oral squamous cell carcinoma (OSCC) and has been correlated with cisplatin resistance, we investigated if cyclin D1 inhibition could increase cisplatin chemosensitivity of OSCC. Five cyclin D1 shRNAs were prepared and 3 were selected for subsequent experiments. IC50 values for cisplatin were determined by an MTT assay. Cisplatin‐induced apoptosis and cell cycle block were investigated. A tumor transplantation model was generated to examine the cisplatin sensitivity of Tca/cisplatin after in vivo cyclin D1 silencing. The role of nuclear factor‐κB (NF‐κB) and cyclin‐dependent kinase 4 (CDK4) in cyclin D1‐mediated cisplatin resistance was also examined. The most effective shRNA resulted in 84.51% knockdown of the cyclin D1 protein level. After the transfection with the 2 most effective shRNAs, the cisplatin IC50 decreased from 5.88 μg/ml to 1.36 μg/ml and 2.47 μg/ml, although overexpression of cyclin D1 rendered OSCC cells more resistant to cisplatin treatment (IC50 increased from 6.43 μg/ml to 12.24 μg/ml). This decreasing IC50 was correlated with the down‐regulation of cisplatin‐induced NF‐κB activity in cyclin D1 knockdown cells, and was independent of CDK4 function. In vivo tumor transplantation models also confirmed a cisplatin‐sensitizing effect of cyclin D1 shRNA in OSCC. A TUNEL assay validated the increase in apoptosis as induced by cisplatin in cyclin D1 knockdown cells. Cyclin D1 may be an important target for future therapy in patients with OSCC. © 2008 Wiley‐Liss, Inc.
Spatial clustering of childhood cancer in Great Britain during the period 1969–1993
Authors: McNally Richard J.Q. , Alexander Freda E. , Vincent Tim J. , Murphy Michael F.G. 
Published: September 2008

AbstractThe aetiology of childhood cancer is poorly understood. Both genetic and environmental factors are likely to be involved. The presence of spatial clustering is indicative of a very localized environmental component to aetiology. Spatial clustering is present when there are a small number of areas with greatly increased incidence or a large number of areas with moderately increased incidence. To determine whether localized environmental factors may play a part in childhood cancer aetiology, we analyzed for spatial clustering using a large set of national population‐based data from Great Britain diagnosed 1969–1993. The Potthoff‐Whittinghill method was used to test for extra‐Poisson variation (EPV). Thirty‐two thousand three hundred and twenty‐three cases were allocated to 10,444 wards using diagnosis addresses. Analyses showed statistically significant evidence of clustering for acute lymphoblastic leukaemia (ALL) over the whole age range (estimate of EPV = 0.05,p= 0.002) and for ages 1–4 years (estimate of EPV = 0.03,p= 0.015). Soft‐tissue sarcoma (estimate of EPV = 0.03,p= 0.04) and Wilms tumours (estimate of EPV = 0.04,p= 0.007) also showed significant clustering. Clustering tended to persist across different time periods for cases of ALL (estimate of between‐time period EPV = 0.04,p=0.003). In conclusion, we observed low level spatial clustering that is attributable to a limited number of cases. This suggests that environmental factors, which in some locations display localized clustering, may be important aetiological agents in these diseases. For ALL and soft tissue sarcoma, but not Wilms tumour, common infectious agents may be likely candidates. © 2008 Wiley‐Liss, Inc.
Reduction of TIP30 correlates with poor prognosis of gastric cancer patients and its restoration drastically inhibits tumor growth and metastasis
Authors: Li Xiaohua , Zhang Ying , Cao Shanshan , Chen Xiong , Lu Yuanyuan , Jin Haifeng , Sun Shiren , Chen Bei , Liu Jie , Ding Jie , Wu Kaichun , Fan Daiming 
Published: September 2008

AbstractGastric cancer is an aggressive cancer with poor prognosis. Identification of precise prognostic marker and effective therapeutic target is important in the treatment of gastric cancer. TIP30, a newly identified tumor suppressor, appears to be involved in multiple functions including tumorigenic suppression, apoptosis induction and diminishing angiogenic properties. Here, the level of TIP30 expression was determined in gastric cancer, and the impact of its alteration on cancer biology and clinical outcome was investigated. We found that TIP30 protein was absent or reduced in gastric cancer cell lines. There was also a loss or substantial decrease of TIP30 expression in 106 cases of gastric tumors as compared with that in normal gastric mucosa (p < 0.05), which was significantly associated with inferior survival duration. In a Cox proportional hazards model, TIP30 expression independently predicted better survival (p < 0.05). We also restored TIP30 protein expression in human gastric cancer‐derived cells AGS and MKN28 lacking endogenous TIP30 protein to study the effects of TIP30 expression on cell proliferation, cell kinetics, tumorigenicity and metastasis in BALB/c nude mice and found that adenoviral‐mediated restoration of TIP30 expression led to downregulation of cyclin D1, Bcl‐2, Bcl‐xl, but to upregulation of p27, Bax, p53, caspase 3 and 9 expression, cell cycle G0/G1 arrest and apoptosis in vitro, and dramatic attenuation of tumor growth and abrogation of metastasis in animal models. Taken together, the present work revealed a novel function of TIP30, which can possibly be used as an independent prognostic factor and a potential therapeutic target for gastric cancer. © 2008 Wiley‐Liss, Inc.
TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance
Authors: Wong Nathalie , Yeo Winnie , Wong Wai‐Lap , Wong Navy L.‐Y. , Chan Kathy Y.‐Y. , Mo Frankie K.‐F. , Koh Jane , Chan Stephan Lam , Chan Anthony T.‐C. , Lai Paul B.‐S. , Ching Arthur K.‐K. , Tong Joanna H.‐M. , Ng Ho‐Keung , Johnson Philip J. , To Ka‐Fai 
Published: September 2008

AbstractGenomic gain represents an important mechanism in the activation of proto‐oncogenes. In many instances, induced oncogenes hold clinical implications both as prognostic markers and targets for therapeutic design. In hepatocellular carcinoma (HCC), although chromosomal gains are common, information on underlying oncogenes induced remains minimal. Here, we examined 7 causal sites of HCC for overexpressed genes by array‐based transcriptional mapping. In 22 HCC cell lines and early passages of cultures studied, clusters of up‐regulated genes were indicated, where TOP2A expression ranked the highest. Distinct TOP2A transcriptions were confirmed in an independent series of HCC tumors relative to adjacent non‐tumoral liver (p = 0.0018). By tissue microarray analysis of 172 HCC, we found TOP2A expressions correlated with advance histological grading (p < 0.001), microvascular invasion (p = 0.004) and an early age onset of the malignancy (≤40 years; p = 0.007). In conjunction with P‐gp and MRP1, TOP2A were further assessed for its association with chemotherapy responsiveness and survival in 148 patients who entered our recently reported Phase III prospective randomized study. In 73 chemoresistant and 75 nonresistant patients, only TOP2A positivity correlated with chemoresistance (p = 0.029) and shorter patients survival (p < 0.0001). The potential therapeutic value in targeting TOP2A by Etoposide, as a single agent, and in combination with Doxorubicin was also explored. In vitro cytotoxic studies suggested Etoposide at IC20 readily reduced IC50 values of Doxorubicin by a magnitude of ∼3.5 to 10‐fold compared to Doxorubicin alone (p < 0.028). Our study highlighted for the first time the prognostic value of TOP2A in HCC and the potential use of TOP2A reactive agents in therapy. © 2008 Wiley‐Liss, Inc.
Grading the severity of cervical neoplasia based on combined histopathology, cytopathology, and HPV genotype distribution among 1,700 women referred to colposcopy in Oklahoma
Authors: Wentzensen Nicolas , Schiffman Mark , Dunn S. Terence , Zuna Rosemary E. , Walker Joan , Allen Richard A. , Zhang Roy , Sherman Mark E. , Wacholder Sholom , Jeronimo Jose , Gold Michael A. , Wang Sophia S. 
Published: September 2008

AbstractDiagnosis and treatment of cervical cancer precursors rely on colposcopic biopsy, which is sometimes hampered by incorrect biopsy placement and the unclear prognostic value of poorly reproducible diagnoses such as cervical intraepithelial neoplasia (CIN) Grade 1 and 2. Searching for discrete disease categories that incorporate the value of cytology and that reflect the causal role of particular HPV types, we analyzed histology, cytology and HPV genotype distributions in the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED). This cross‐sectional study comprises ∼1,700 women referred to colposcopy or treatment for the spectrum of cervical disease, including 439 women with <CIN1, 429 CIN1, 322 CIN2, 297 CIN3 and 107 with cancer. Using hierarchical clustering of histology‐cytology groups based on HPV genotype distributions, we could plainly distinguish in this referral population 5 increasingly severe diagnostic groups of HPV‐positive women: (i) HPV‐positive women with <CIN2 histology and normal cytology, (ii) HPV positive women with <CIN2 histology and ASC or LSIL cytology; (iii) CIN2, including histologic CIN2 and HSIL cytology with any histology <CIN2; (iv) CIN3; and (v) invasive cervical cancer. The grouping of women with HSIL cytology, but without histological abnormalities to women with CIN2 suggests that in these cases the worst lesion was missed during colposcopy‐biopsy. We are now using these sharpened diagnostic categories to search for novel biomarkers predicting the risk of progression and invasion. © 2008 Wiley‐Liss, Inc.
High expression of 90K (Mac‐2 BP) is associated with poor survival in node‐negative breast cancer patients not receiving adjuvant systemic therapies
Authors: Tinari Nicola , Lattanzio Rossano , Querzoli Patrizia , Natoli Clara , Grassadonia Antonino , Alberti Saverio , Hubalek Michael , Reimer Daniel , Nenci Italo , Bruzzi Paolo , Piantelli Mauro , Iacobelli Stefano ,   on behalf of the Consorzio Interuniversitario Nazionale per la Bio‐Oncologia (CINBO)
Published: September 2008

Abstract90K (Mac‐2 BP) expression was evaluated by immunohistochemistry in paraffin‐embedded tissue from a consecutive series of lymph‐node negative breast cancer patients who did not receive adjuvant systemic treatment. An independent series of patients served as validation set. The association of 90K expression with risk of recurrence and death was examined in survival analyses together with known prognostic factors. High levels of 90K expression (IHC score > 8) were observed in 43 (25.3%) of 170 tumors examined. We found elevated risks of distant recurrence and overall mortality in patients with high 90K expression compared with patients with low 90K expression in their tumors. This increase persisted after adjusting for other prognostic factors in multivariate analysis (hazard ratio = 4.084; p < 0.001 for recurrence; hazard ratio = 4.298; p < 0.001 for death). These findings were confirmed in the validation set. Therefore, evaluation of 90K expression may be beneficial to identify lymph‐node negative breast cancer patients at lower risk of disease recurrence and death. © 2008 Wiley‐Liss, Inc.
Risk of cancer in first‐ and second‐degree relatives of testicular germ cell tumor cases and controls
Authors: Chia Victoria M. , Li Yan , Goldin Lynn R. , Graubard Barry I. , Greene Mark H. , Korde Larissa , Rubertone Mark V. , Erickson Ralph L. , McGlynn Katherine A. 
Published: September 2008

AbstractRisk factors for testicular germ cell tumors (TGCT) have not been well identified; however, data suggest that risks of cancer in family members of men with TGCT is elevated. Using family history data from 738 cases and 904 controls enrolled in the U.S. Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) Study from 2002 to 2005, the risk of cancer in first‐ and second‐degree family members of these men was examined. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusting for reference age of case or control, race/ethnicity of case or control, sex of family member and lineage (maternal vs. paternal). An increased risk of all cancer among first‐degree relatives of cases compared to controls was observed (RR = 1.17, 95% CI: 1.01–1.35). There were suggestions of differences in risk when stratifying all relatives by lineage. For maternal relatives, there was a statistically significant increased risk of all cancer (RR = 1.16, 95% CI: 1.04–1.30), digestive tract (RR = 1.52, 95% CI: 1.15–2.00) and male genital organ cancer (RR = 1.70, 95% CI: 1.15–2.51); there was also a suggestion of increased risks of hematopoetic cancers, cancers in the female genital organs and nonmelanoma skin cancer. For paternal relatives, there was a statistically significant association only with decreased risk of lung cancer (RR = 0.69, 95% CI: 0.51–0.94). Thus, this study suggests that there may be aggregation of cancer among families of men diagnosed with TGCT. Published 2008 Wiley‐Liss, Inc.
Genetic and epigenetic inactivation of LPL gene in human prostate cancer
Authors: Kim Jin Woo , Cheng Yu , Liu Wennuan , Li Tao , Yegnasubramanian Srinivasan , Zheng Siqun L. , Xu Jianfeng , Isaacs William B. , Chang Bao‐Li 
Published: September 2008

AbstractLipoprotein lipase (LPL) is in chromosome 8p22, site of one of the most common somatic deletions in prostate tumors. Additionally, a CpG island (CGI) was identified in the LPL promoter region. To test the hypothesis that LPL is a tumor suppressor gene, which is inactivated by somatic deletion and hypermethylation in prostate cancer, we evaluated somatic DNA deletion and methylation status at LPL in 56 pairs of DNA samples isolated from prostate cancer tissues and matching normal controls and 11 prostate cell lines. We found that the DNA in 21 of 56 primary cancers (38%) was methylated in the LPL promoter CGI, whereas no methylation was detected in any normal samples. In addition, we found a hemizygous deletion at LPL in 38 of the 56 tumors (68%). When the results of deletion and methylation were considered together, we found LPL promoter CGI methylation occurred in 45% of LPL deleted tumors and in 22% of LPL retained tumors. Within several clinical characteristics tested, the preoperative PSA levels were found to be significantly higher in subjects with LPL promoter CGI methylation compared with subjects without LPL promoter methylation (p = 0.0012). Additionally, demethylation of the LPL promoter CGI was accompanied by transcriptional reactivation of LPL in the prostate cancer cell lines DU145 and PC3. In summary, we report a novel finding that the LPL gene is commonly methylated in prostate tumors, and our results suggest that biallelic inactivation of LPL by chromosomal deletion and promoter hypermethylation may play a role in human prostate cancer. © 2008 Wiley‐Liss, Inc.
Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin‐6 expression
Authors: Karst Alison M. , Gao Kai , Nelson Colleen C. , Li Gang 
Published: September 2008

AbstractNuclear factor kappa B (NF‐κB) signaling is deregulated in many tumor types, resulting in aberrant expression and/or activation of NF‐κB transcriptional complexes. We have previously reported that nuclear expression of the NF‐κB subunit p50 is strongly correlated with melanoma progression and poor 5‐year patient survival. In this study, we used cDNA microarray to analyze the gene expression profiles of melanoma cells overexpressing NF‐κB p50. We found that NF‐κB p50 expression strongly induced interleukin‐6 (IL‐6) upregulation in melanoma cells at both the transcriptional and translational levels and that IL‐6 production by melanoma cells enhanced the growth of endothelial cells in vitro. Expression of activating transcription factor 3 (ATF3), a negative regulator of IL‐6 gene transcription, inhibited p50‐mediated IL‐6 upregulation. Knockdown of p50 expression using lentiviral‐based shRNA abrogated IL‐6 induction in melanoma cells and inhibited its effects on endothelial cell growth. Finally, we used an in vivo matrigel plug assay to show that NF‐κB p50 overexpression promotes angiogenesis, while silencing NF‐κB p50 inhibits blood vessel formation. Our results demonstrate for the first time that the NF‐κB p50 subunit mediates melanoma angiogenesis by specifically upregulating IL‐6, highlighting a novel and important role for the NF‐κB p50/IL‐6 signaling axis in melanoma progression. © 2008 Wiley‐Liss, Inc.
UV‐induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines
Authors: Singh Bhuminder , Schneider Matthias , Knyazev Pjotr , Ullrich Axel 
Published: September 2008

AbstractExposure to extensive ultraviolet (UV) rays is a major cause of skin cancer, which is thought to be initiated by DNA mutations. Members of the epidermal growth factor receptor (EGFR) family are important in various pathophysiologic processes like cancer and are shown to be phosphorylated upon UV exposure. Here we show that EGFR phosphorylation by modest UV doses is dependent on metalloprotease activity and resultant epidermal growth factor (EGF) family proligand shedding. This proligand cleavage releases the mature ligand, which then binds to and activates EGFR. We show that UV induced EGFR phosphorylation in transformed cell lines of melanocyte and keratinocyte origin, which was reduced upon preincubation with a broad‐spectrum metalloprotease inhibitor, BB94. UV also activated EGFR downstream signaling via Erk and Akt pathways in a BB94‐sensitive manner. Furthermore, using neutralizing antibodies we found that proligand amphiregulin was required for UV‐induced EGFR activation in SCC‐9 cells. Using RNAi this EGFR activation was further shown to depend on the metalloproteases ADAM9 and ADAM17 in SCC‐9 cells. cDNA array hybridization and RT‐PCR analysis showed overexpression of a Disintegrin and a Metalloproteases (ADAMs) and EGF family proligands in melanoma cell lines. Additionally, blocking EGFR signal transactivation by BB94 led to increased apoptosis in UV‐irradiated cells. EGFR signal transactivation also led to increased stability of the DNA repair protein, PARP, under UV stress. Thus, both antiapoptotic and DNA repair pathways are activated simultaneously by EGFR signal transactivation. Together, our data provide novel insights into the mechanism of UV‐induced EGFR activation, suggesting broad relevance of the UV‐ADAM‐proligand‐EGFR‐Erk/Akt pathway and its significance in skin cancer. © 2008 Wiley‐Liss, Inc.
p53 and p73 in suppression of Myc‐driven lymphomagenesis
Authors: Griesmann Heidi , Schlereth Katharina , Krause Michael , Samans Birgit , Stiewe Thorsten 
Published: September 2008

AbstractInduction of apoptosis by the tumor suppressor p53 is known to protect from Myc‐driven lymphomagenesis. The p53 family member p73 is also a proapoptotic protein, which is activated in response to oncogenes like Myc. Here, we have investigated whether p73 provides a similar protection from Myc‐driven lymphomas as p53. Confirming previous studies, the inactivation of a single p53 allele (p53+/−) strongly reduced the median survival of Eμ‐Myc transgenic mice from 103 to 39 days and was invariably associated with a loss of the wild‐type p53 allele. In contrast, mutational inactivation of a p73 allele (p73+/−) reduced the median survival by only 12 days. Lymphomas that developed in the p73+/− background showed no loss of heterozygosity (LOH). Furthermore, gene expression profiling of p73+/+, p73+/− and p73−/− lymphomas indicated that p73+/− lymphomas retained p73 transcriptional activity. Subtle gene expression differences between p73+/+ and p73+/− lymphomas, however, suggest a haploinsufficient phenotype on some p73 target genes. This might help to explain why p73+/− animals succumbed to disease slightly earlier than their p73+/+ littermates (log‐rank test p < 0.0395) and why p73 often shows monoallelic inactivation in human lymphomas. Together these data demonstrate that in Myc‐driven lymphomagenesis p73 has weak tumor suppressor activity compared with p53. © 2008 Wiley‐Liss, Inc.
Joining the loops: β‐Globin gene regulation
Authors: Noordermeer Daan , de Laat Wouter 
Published: September 2008

AbstractThe mammalian β‐globin locus is a multigene locus containing several globin genes and a number of regulatory elements. During development, the expression of the genes changes in a process called “switching.” The most important regulatory element in the locus is the locus control region (LCR) upstream of the globin genes that is essential for high‐level expression of these genes. The discovery of the LCR initially raised the question how this element could exert its effect on the downstream globin genes. The question was solved by the finding that the LCR and activate globin genes are in physical contact, forming a chromatin structure named the active chromatin hub (ACH). Here we discuss the significance of ACH formation, provide an overview of the proteins implicated in chromatin looping at the β‐globin locus, and evaluate the relationship between nuclear organization and β‐globin gene expression. © 2008 IUBMB IUBMB Life, 60(12): 824–833, 2008
Expression of Concern: Laccase treatment impairs bisphenol A‐induced cancer cell proliferation affecting estrogen receptor α‐dependent rapid signals
Authors: Bolli Alessandro , Galluzzo Paola , Ascenzi Paolo , Del Pozzo Giovanna , Manco Immacolata , Vietri Maria Teresa , Mita Luigi , Altucci Lucia , Mita Damiano Gustavo , Marino Maria 
Published: September 2008

AbstractA wide variety of environmental contaminants exert estrogenic actions in wildlife, laboratory animals, and in human beings through binding to nuclear estrogen receptors (ERs). Here, the mechanism(s) of bisphenol A (BPA) to induce cell proliferation and the occurrence of its bioremediation by treatment with laccase are reported. BPA, highly present in natural world and considered as a model of environmental estrogen action complexity, promotes human cancer cell proliferation via ERα‐dependent signal transduction pathways. Similar to 17β‐estradiol, BPA increases the phosphorylation of both extracellular regulated kinase and AKT. Specific inhibitors of these kinase completely block the BPA effect on cancer cell proliferation. Notably, high BPA concentrations (i.e., 0.1 and 1 mM) are cytotoxic even in ERα‐devoid cancer cells, indicating that an ERα‐independent mechanism participates to BPA‐induced cytotoxicity. On the other hand, BPA oxidation by laccase impairs the binding of this environmental estrogen to ERα loosing at all ERα‐dependent effect on cancer cell proliferation. Moreover, the laccase‐catalyzed oxidation of BPA reduces the BPA cytotoxic effect. Thus, laccase appears to impair BPA action(s), representing an invaluable bioremediation enzyme. © 2008 IUBMB IUBMB Life, 60(12): 843–852, 2008
R&D and subsidies at the firm level: an application of parametric and semiparametric two‐step selection models
Authors: Hussinger Katrin 
Published: September 2008

AbstractThis paper analyzes the effect of public R&D subsidies on firms' private R&D investment per employee and new product sales in German manufacturing. Parametric and semiparametric two‐step selection models are applied to this evaluation problem. The results show that the average treatment effect on the treated firms' R&D intensity is positive. The estimated effects are robust with respect to the different selection models. Further results show that publicly induced R&D spending is as productive as private R&D investment in generating new product sales. Copyright © 2008 John Wiley & Sons, Ltd.