bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the Envelope Genetic Context in the Development of Enfuvirtide Resistance in Human Immunodeficiency Virus Type 1-Infected Patients
Authors: Labrosse Béatrice , Morand-Joubert Laurence , Goubard Armelle , Rochas Séverine , Labernardière Jean-Louis , Pacanowski Jerôme , Meynard Jean-Luc , Hance Allan J. , Clavel François , Mammano Fabrizio 
Published: August 2006

ABSTRACTAcquired human immunodeficiency virus type 1(HIV-1) resistance to the fusion inhibitor enfuvirtide (ENF) is primarily associated with mutations within the highly conserved first heptad repeat (HR1) region of gp41. Viralenvsequences, however, are remarkably variable, and the envelope genetic background could have an important impact on optimal expression of HR1 mutations. We have examined the genetic evolution ofenvsequences, ENF susceptibility, and Env replicative capacity in patients failing ENF treatment. Sequential plasma-derived virus populations, obtained from six patients initiating ENF treatment as part of a salvage therapy, were studied using a recombinant phenotypic assay evaluating the entire gp120 and the gp41 ectodomains. Regardless of major differences in the baseline ENF susceptibilities, viral populations with similar phenotypic ENF resistance (50% inhibitory concentration, >3,000 ng/ml) were selected under treatment in four of six patients. As expected, in all patients ENF-resistant viruses harbored one or more HR1 mutations (positions 36, 38, and 43). Interestingly, in five patients the emergence of resistance mutations was not associated with reduced Env replicative capacity. Phylogenetic analysis ofenvsequences in sequential samples from two patients showed that the HR1 mutations had emerged in the context ofenvquasi-species that were different from those prevalent at baseline. Thus, the envelope genetic context appears to play a critical role in the selection of HR1 mutations and the expression of ENF resistance, thereby conditioning the evolution of HIV-1 under fusion inhibitor selective pressure.
TWO-COMPONENT EXTREME VALUE DISTRIBUTION FOR ASIA-PACIFIC STOCK INDEX RETURNS
Authors: ANÉ THIERRY 
Published: August 2006

Financial risk management typically deals with low-probability events in the tails of asset return distributions. To better capture the behavior of these tails, several studies have clearly highlighted that one should rely on a methodology that directly focuses on the tails of the distribution rather than getting the tails as an outcome of modelling the entire density function. Traditional Extreme Value Theory (EVT) distributions, however, provide a good fit for the bulk of the extreme data but usually underestimate a small amount of observations considered as "outliers".Since the main objective of risk management analysis is to estimate the size and probability of very large price movements, these "outliers" are by definition the very events we need to investigate. In this paper we suggest the use of a Two-Component Extreme Value (TCEV) distribution where a 'basic distribution' generates ordinary extremes (more frequent and less severe in the mean) while an "outlying distribution" generates rarer but severe extremes.Goodness-of-fit tests show the superiority of this distribution to capture the extremes of eleven MSCI Indices of the Pacific-Basin region relative to traditional EVT densities. Measures of accuracy and efficiency used to assess the performance of VaR forecasts also indicate that the additional flexibility brought by the TCEV model provides strong improvements for risk management.
WEIGHTED THRESHOLD-BASED CLUSTERING FOR INTRUSION DETECTION SYSTEMS
Authors: NIKULIN VLADIMIR 
Published: August 2006

Signature-based intrusion detection systems look for known, suspicious patterns in the input data. In this paper we explore compression of labeled empirical data using threshold-based clustering with regularization. The main target of clustering is to compress training dataset to the limited number of signatures, and to minimize the number of comparisons that are necessary to determine the status of the input event as a result. Essentially, the process of clustering includes merging of the clusters which are close enough. As a consequence, we will reduce original dataset to the limited number of labeled centroids. In a complex with k-nearest-neighbor (kNN) method, this set of centroids may be used as a multi-class classifier. Clearly, different attributes have different importance depending on the particular training database and given cost matrix. This importance may be regulated in the definition of the distance using linear weight coefficients. The paper introduces special procedure to estimate above weight coefficients. The experiments on the KDD-99 intrusion detection dataset have confirmed the effectiveness of the proposed methods.
Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells
Authors: Wang Maria Y. , Lu Kan V. , Zhu Shaojun , Dia Ederlyn Q. , Vivanco Igor , Shackleford Gregory M. , Cavenee Webster K. , Mellinghoff Ingo K. , Cloughesy Timothy F. , Sawyers Charles L. , Mischel Paul S. 
Published: August 2006

Abstract
The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTEN-deficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors. (Cancer Res 2006; 66(16): 7864-9)
Sequence Variants in Cell Cycle Control Pathway, X-ray Exposure, and Lung Cancer Risk: A Multicenter Case-Control Study in Central Europe
Authors: Hung Rayjean J. , Boffetta Paolo , Canzian Federico , Moullan Norman , Szeszenia-Dabrowska Neonila , Zaridze David , Lissowska Jolanta , Rudnai Peter , Fabianova Eleonora , Mates Dana , Foretova Lenka , Janout Vladimir , Bencko Vladimir , Chabrier Amelie , Landi Stefano , Gemignani Federica , Hall Janet , Brennan Paul 
Published: August 2006

Abstract
Exposure to ionizing radiation (IR) results in various types of DNA damage and is a suspected cause of lung cancer. An essential cellular machinery against DNA damage is cell cycle control, which is regulated by several genes, including TP53, CCND1, and CDKN2A. Therefore, we hypothesized that the genetic variants in these three genes influence the predisposition of lung cancer (i.e., CCND1 G870A, CDKN2A Ala148Thr, TP53 Arg72Pro, and 16-bp repeat in intron 3) and that the effect of X-ray on lung cancer risk can be modified by the presence of these genetic variations. The study was conducted in 15 centers in 6 countries of Central Europe between 1998 and 2002. A total of 2,238 cases and 2,289 controls were recruited and provided DNA samples. Cases with positive family history were analyzed separately. The joint effect of X-ray and previous risk genotypes was assessed, and modification by sequence variants on X-ray dose-response relationship with lung cancer risk was evaluated. We found an overall effect of TP53 intron 3 16-bp repeats [odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.27-3.13], which was stronger among cases with family history of lung cancer (OR, 2.98; 95% CI, 1.29-6.87). In addition, our results suggested an interaction that was greater than multiplicativity between TP53 intron 3 16-bp repeats and multiple X-ray exposures (interaction OR, 5.69; 95% CI, 1.33-24.3). We did not observe a main effect of CCND1 G870A polymorphism; however, the dose-response relationship between lung cancer risk and X-ray exposures was modified by CCND1 genotype with no risk from X-ray exposures among subjects who carried G/G genotype, intermediate risk [trend OR for X-ray, 1.16; 95% CI, 1.05-1.27) among subjects with G/A genotype, and highest risk [trend OR for X-ray, 1.29; 95% CI, 1.12-1.49) among subjects with A/A genotype. Sequence variants in cell cycle control pathway may increase the risk of lung cancer and modify the risk conferred by multiple X-ray exposures. However, a definite conclusion can only be drawn on replication by different studies among individuals who are highly exposed to IR. (Cancer Res 2006; 66(16): 8280-6)
Transforming Growth Factor-β Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells
Authors: Ao Mingfang , Williams Karin , Bhowmick Neil A. , Hayward Simon W. 
Published: August 2006

Abstract
Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-β can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-β generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-β expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-β on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1CAFTD1, BPH1CAFTD3, and BPH1CAFTD5. The data show that TGF-β has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-β. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-β. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-β by blocking Smad3 and p21 nuclear translocation. On TGF-β stimulation of the tumorigenic sublines, the activated Akt allows the cell to escape cell cycle arrest. The phosphatidylinositol 3-kinase/Akt pathway is also involved in TGF-β-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-β signaling show increased invasion with EMT, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-β can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo. (Cancer Res 2006; 66(16): 8007-16)
Inhibition of 7,12-Dimethylbenz(a)anthracene-Induced Skin Tumorigenesis in C57BL/6 Mice by Sulforaphane Is Mediated by Nuclear Factor E2–Related Factor 2
Authors: Xu Changjiang , Huang Mou-Tuan , Shen Guoxiang , Yuan Xiaoling , Lin Wen , Khor Tin Oo , Conney Allan H. , Kong Ah-Ng Tony 
Published: August 2006

Abstract
Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2–related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (−/−) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(−/−) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(−/−) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(−/−) mice group. Taken together, our results show for the first time that Nrf2(−/−) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2. (Cancer Res 2006; 66(16): 8293-6)
Targeting Mitogen-Activated Protein Kinase/Extracellular Signal–Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases
Authors: Sharma Arati , Tran Melissa A. , Liang Shile , Sharma Arun K. , Amin Shantu , Smith Charles D. , Dong Cheng , Robertson Gavin P. 
Published: August 2006

Abstract
Malignant melanoma has a high propensity for metastatic spread, making it the most deadly form of skin cancer. B-RAF has been identified as the most mutated gene in these invasive cells and therefore an attractive therapeutic target. However, for uncertain reasons, chemotherapy inhibiting B-Raf has not been clinically effective. This has raised questions whether this pathway is important in melanoma metastasis or whether targeting a protein other than B-Raf in the signaling cascade could more effectively inhibit this pathway to reduce lung metastases. Here, we investigated the role played by V600EB-Raf in melanoma metastasis and showed that targeting this signaling cascade significantly reduces lung metastases. Small interfering RNA (siRNA)–mediated inhibition was used in mice to reduce expression (activity) of each member of the signaling cascade and effects on metastasis development were measured. Targeting any member of the signaling cascade reduced metastasis but inhibition of mitogen-activated protein kinase/extracellular signal–regulated kinase kinase (Mek) 1 and Mek 2 almost completely prevented lung tumor development. Mechanistically, metastatic inhibition was mediated through reduction of melanoma cell extravasation through the endothelium and decreased proliferative capacity. Targeting B-Raf with the pharmacologic inhibitor BAY 43-9006, which was found ineffective in clinical trials and seems to act primarily as an angiogenesis inhibitor, did not decrease metastasis, whereas inhibition of Mek using U0126 decreased cellular proliferative capacity, thereby effectively reducing number and size of lung metastases. In summary, this study provides a mechanistic basis for targeting Mek and not B-Raf in the mutant V600EB-Raf signaling cascade to inhibit melanoma metastases. (Cancer Res 2006; 66(16): 8200-9)
Autocrine/Paracrine Platelet-Derived Growth Factor Regulates Proliferation of Neural Progenitor Cells
Authors: Erlandsson Anna , Brännvall Karin , Gustafsdottir Sigrun , Westermark Bengt , Forsberg-Nilsson Karin 
Published: August 2006

Abstract
Growth factors play an important role in regulating neural stem cell proliferation and differentiation. This study shows that platelet-derived growth factor (PDGF) induces a partial differentiation of neural stem/progenitor cells (NSPCs) in the absence of other mitogens in vitro. NSPCs thus acquire an immature morphology and display markers for both neurons and glia. In addition, these cells do not readily mature in the absence of further stimuli. When NSPC cultures treated with PDGF were exposed to additional differentiation factors, however, the differentiation proceeded into neurons, astrocytes, and oligodendrocytes. We find that NSPC cultures are endowed with an endogenous PDGF-BB production. The PDGF-BB expression peaks during early differentiation and is present both in cell lysates and in conditioned medium, allowing for autocrine as well as paracrine signaling. When the NSPC-derived PDGF was inhibited, progenitor cell numbers decreased, showing that PDGF is involved in NSPC expansion. Addition of a PDGF receptor (PDGFR) inhibitor resulted in a more rapid differentiation. Neurons and oligodendrocytes appeared earlier and had more elaborate processes than in control cultures where endogenous PDGFR signaling was not blocked. Our observations point to PDGF as an inducer of partial differentiation of NSPC that also sustains progenitor cell division. Such an intermediate stage in stem cell differentiation is of relevance for the understanding of brain tumor development because autocrine PDGF stimulation is believed to drive malignant conversion of central nervous system progenitor cells. (Cancer Res 2006; 66(16): 8042-8)
Quantitative Detection of p53 Mutations in Plasma DNA from Tobacco Smokers
Authors: Hagiwara Nobutoshi , Mechanic Leah E. , Trivers Glenwood E. , Cawley Helen L. , Taga Masataka , Bowman Elise D. , Kumamoto Kensuke , He Peijun , Bernard Mark , Doja Saira , Miyashita Masao , Tajiri Takashi , Sasajima Koji , Nomura Tsutomu , Makino Hiroshi , Takahashi Ken , Hussain S. Perwez , Harris Curtis C. 
Published: August 2006

Abstract
In lung tumors, the p53 tumor suppressor gene is commonly mutated with a characteristic mutation spectrum. The amount of and alterations in plasma DNA, such as mutations in p53, were associated with several cancers. Few studies used quantitative methods of high sensitivity. Previously, we observed p53 mutations in the noncancerous tissue that differed from those in lung tumors using the highly sensitive p53 mutation load assay. Based on our observation of an increased p53 mutation load in nontumorous lung tissue in smokers, we hypothesized that plasma DNA may contain mutant p53 indicative of tobacco smoke exposure and will be an effective biomarker of lung cancer or smoking exposure. We modified the p53 mutation load assay to detect mutations at p53 codons 248 and 249, common mutations in lung cancer, in plasma DNA samples with a sensitivity of 1:5,000. The assay was applied to a set of lung cancer cases (n = 39), hospital controls (n = 21), and population controls (n = 20) from a larger study. Controls were selected to consist of equal numbers of both ever and never smokers. The p53 mutation load (mutated p53 copies per total number of p53 copies) was associated with smoking (P = 0.06), but not with lung cancer (P = 0.59). Most of the individuals with p53 mutations observed in plasma DNA were ever smokers and the p53 mutation load was higher in those who smoked for longer durations (P = 0.04). In summary, we were able to detect p53 mutations in plasma DNA from healthy individuals and our data suggest that p53 mutations in plasma DNA may be a marker of carcinogen exposure from tobacco smoke. (Cancer Res 2006; 66(16): 8309-17)
Assessment of Endostatin Gene Therapy for Familial Adenomatous Polyposis–Related Desmoid Tumors
Authors: Martinico Sandra C.M. , Jezzard Sarah , Sturt N. Julian H. , Michils Genevieve , Tejpar Sabine , Phillips Robin K. , Vassaux Georges 
Published: August 2006

Abstract
Constitutive activation of the Wnt signaling pathway is a hallmark of many cancers, including familial adenomatous polyposis (FAP)–related desmoid tumors. Endostatin is a well-known antiangiogenic protein that has been described recently as a potential inhibitor of this signaling pathway. Here, we show that endostatin directly induces apoptosis and inhibits the Wnt signaling pathway in colorectal cancer cell lines bearing mutations on the adenomatous polyposis coli (APC) gene as a model of FAP-related malignant cells. We then explore the relationship between apoptosis and inhibition of this pathway and show that they are not correlated. These results seem to contradict a well-recognized study, showing that reintroduction of the APC cDNA in APC-deficient cells leads to apoptosis. To reconcile our conclusions with the literature, we further show that a truncated fragment of APC capable of inhibiting the Wnt signaling pathway in SW480 cells is incapable of inducing apoptosis in these cells, confirming that APC-mediated apoptosis is uncoupled to the inhibition of the Wnt signaling pathway. Finally, we show that endostatin directly induces cell death on primary FAP-related desmoid tumor cells in culture. This phenomenon is also independent of the inhibition of the Wnt signaling pathway. Considering the current lack of effective treatment against desmoid tumors, we advocate that endostatin gene therapy represents an attractive new therapeutic approach for this disease. (Cancer Res 2006; 66(16): 8233-40)
Tyrosine Kinase Etk/BMX Is Up-regulated in Human Prostate Cancer and Its Overexpression Induces Prostate Intraepithelial Neoplasia in Mouse
Authors: Dai Bojie , Kim Oekyung , Xie Yingqiu , Guo Zhiyong , Xu Kexin , Wang Bin , Kong Xiangtian , Melamed Jonathan , Chen Hegang , Bieberich Charles J. , Borowsky Alexander D. , Kung Hsing-Jien , Wei Guo , Ostrowski Michael C. , Brodie Angela , Qiu Yun 
Published: August 2006

Abstract
The nonreceptor tyrosine kinase Etk/BMX was originally identified from the human prostate xenograft CWR22. Here, we report that Etk is up-regulated in human prostate tumor specimens surveyed. Knocking down Etk expression by a specific small interfering RNA (siRNA) in prostate cancer cells attenuates cell proliferation, suggesting an essential role of Etk for prostate cancer cell survival and growth. Targeted expression of Etk in mouse prostate epithelium results in pathologic changes resembling human prostatic intraepithelial neoplasia, indicating that up-regulation of Etk may contribute to prostate cancer development. A marked increase of luminal epithelial cell proliferation was observed in the Etk transgenic prostate, which may be attributed in part to the elevated activity of Akt and signal transducers and activators of transcription 3 (STAT3). More interestingly, the expression level of acetyltransferase cyclic AMP–responsive element binding protein–binding protein (CBP) is also increased in the Etk transgenic prostate as well as in a prostate cancer cell line overexpressing Etk, concomitant with elevated histone 3 acetylation at lysine 18 (H3K18Ac). Down-modulation of Etk expression by a specific siRNA leads to a decrease of H3 acetylation in prostate cancer cell lines. Our data suggest that Etk may also modulate chromatin remodeling by regulating the activity of acetyltransferases, such as CBP. Given that Etk may exert its effects in prostate through modulation of multiple signaling pathways altered in human prostate cancer, the Etk transgenic mouse model may be a useful tool for studying the functions of Etk and identification of new molecular markers and drug targets relevant to human diseases. (Cancer Res 2006; 66(16): 8058-64)