bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors
Authors: Vaissière Thomas , Hung Rayjean J. , Zaridze David , Moukeria Anush , Cuenin Cyrille , Fasolo Virginie , Ferro Gilles , Paliwal Anupam , Hainaut Pierre , Brennan Paul , Tost Jörg , Boffetta Paolo , Herceg Zdenko
Published: December 2008

The global increase in lung cancer burden, together with its poor survival and resistance to classical chemotherapy, underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR, and RASSF1A) to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A, and CDKN2A in lung tumors as compared with control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumor-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age, and histologic subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1, and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumor suppression and contribute to lung cancer. [Cancer Res 2009;69(1):243–52]
Inducible Cutaneous Inflammation Reveals a Protumorigenic Role for Keratinocyte CXCR2 in Skin Carcinogenesis
Authors: Cataisson Christophe , Ohman Rebecca , Patel Gopal , Pearson Andrea , Tsien Margaret , Jay Steve , Wright Lisa , Hennings Henry , Yuspa Stuart H.
Published: December 2008

Transgenic mice that overexpress PKCα in the epidermis (K5-PKCα mice) exhibit acute CXCR2-mediated intraepidermal neutrophilic inflammation and a strong epidermal hyperplasia in response to application of 12-O-tetradecanoylphorbol-13-acetate (TPA). We now show that hyperplasia is independent of infiltrating neutrophils. Furthermore, when K5-PKCα mice were initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with a low dose of TPA, 58% of K5-PKCα mice developed skin papillomas that progressed to carcinoma, whereas wild-type mice did not develop tumors. We confirmed that CXCR2 is expressed by keratinocytes and showed that transformation by oncogenic ras (a hallmark of DMBA initiation) or TPA exposure induced all CXCR2 ligands. Ras induction of CXCR2 ligands was mediated by autocrine activation of epidermal growth factor receptor and nuclear factor-κB, and potentiated by PKCα. Oncogenic ras also induced CXCR2 ligands in keratinocytes genetically ablated for CXCR2. However, ras transformed CXCR2 null keratinocytes formed only small skin tumors in orthotopic skin grafts to CXCR2 intact hosts, whereas transformed wild-type keratinocytes produced large tumors. In vitro, CXCR2 was essential for CXCR2 ligand-stimulated migration of ras-transformed keratinocytes and for ligand activation of the extracellular signal-regulated kinase (ERK) and Akt pathways. Both migration and activation of ERK and Akt were restored by CXCR2 reconstitution of CXCR2 null keratinocytes. Thus, activation of CXCR2 on ras-transformed keratinocytes has both promigratory and protumorigenic functions. The up-regulation of CXCR2 ligands after initiation by oncogenic ras and promotion with TPA in the mouse skin model provides a mechanism to stimulate migration by both autocrine and paracrine pathways and contribute to tumor development. [Cancer Res 2009;69(1):319–28]
Role of Cyclin D1 as a Mediator of c-Met– and β-Catenin–Induced Hepatocarcinogenesis
Authors: Patil Mohini A. , Lee Susie A. , Macias Everardo , Lam Ernest T. , Xu Chuanrui , Jones Kirk D. , Ho Coral , Rodriguez-Puebla Marcelo , Chen Xin
Published: December 2008

Activation of c-Met signaling and β-catenin mutations are frequent genetic events observed in liver cancer development. Recently, we demonstrated that activated β-catenin can cooperate with c-Met to induce liver cancer formation in a mouse model. Cyclin D1 (CCND1) is an important cell cycle regulator that is considered to be a downstream target of β-catenin. To determine the importance of CCND1 as a mediator of c-Met– and β-catenin–induced hepatocarcinogenesis, we investigated the genetic interactions between CCND1, β-catenin, and c-Met in liver cancer development using mouse models. We coexpressed CCND1 with c-Met in mice and found CCND1 to cooperate with c-Met to promote liver cancer formation. Tumors induced by CCND1/c-Met had a longer latency period, formed at a lower frequency, and seemed to be more benign compared with those induced by β-catenin/c-Met. In addition, when activated β-catenin and c-Met were coinjected into CCND1-null mice, liver tumors developed despite the absence of CCND1. Intriguingly, we observed a moderate accelerated tumor growth and increased tumor malignancy in these CCND1-null mice. Molecular analysis showed an up-regulation of cyclin D2 (CCND2) expression in CCND1-null tumor samples, indicating that CCND2 may replace CCND1 in hepatic tumorigenesis. Together, our results suggest that CCND1 functions as a mediator of β-catenin during HCC pathogenesis, although other molecules may be required to fully propagate β-catenin signaling. Moreover, our data suggest that CCND1 expression is not essential for liver tumor development induced by c-Met and β-catenin. [Cancer Res 2009;69(1):253–61]
Amyloid Precursor Protein Is a Primary Androgen Target Gene That Promotes Prostate Cancer Growth
Authors: Takayama Ken-ichi , Tsutsumi Shuichi , Suzuki Takashi , Horie-Inoue Kuniko , Ikeda Kazuhiro , Kaneshiro Kiyofumi , Fujimura Tetsuya , Kumagai Jinpei , Urano Tomohiko , Sakaki Yoshiyuki , Shirahige Katsuhiko , Sasano Hironobu , Takahashi Satoru , Kitamura Tadaichi , Ouchi Yasuyoshi , Aburatani Hiroyuki , Inoue Satoshi
Published: December 2008

Androgen receptor (AR) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently. Here, we identify amyloid precursor protein (APP) as a primary androgen target through chromatin immunoprecipitation (ChIP) combined with genome tiling array analysis (ChIP-chip). ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies. Ligand-dependent AR binding was further enriched by PCR subtraction. Using chromosome 21/22 arrays, we identified APP as one of the androgen-regulated genes with adjacent functional AR binding sites. APP expression is androgen-inducible in LNCaP cells and APP immunoreactivity was correlated with poor prognosis in patients with prostate cancer. Gain-of-function and loss-of-function studies revealed that APP promotes the tumor growth of prostate cancer. The present study reveals a novel APP-mediated pathway responsible for the androgen-dependent growth of prostate cancer. Our findings will indicate that APP could be a potential molecular target for the diagnosis and treatment of prostate cancer. [Cancer Res 2009;69(1):137–42]
Prevaccination Distribution of Human Papillomavirus Types in Women Attending at Cervical Cancer Screening in Belgium
Authors: Arbyn Marc , Benoy Ina , Simoens Cindy , Bogers Johannes , Beutels Philippe , Depuydt Christophe
Published: January 2009

Introduction: Before the introduction of vaccination against human papillomaviruses (HPV) as a new strategy of combating cervical cancer, it is required to describe the baseline prevalence of HPV infection as well as the distribution of the different HPV types in the population and among women with cervical lesions.

Materials and Methods: Approximately 10,000 liquid cervical cell samples from women, resident of Flanders (North Belgium) and participating in cervical cancer screening, were assessed cytologically and virologically with a multiplex real-time PCR using primers targeting the E6/E7 genes of 16 HPV types. Correlations of HPV infection with age, geographic area, and occurrence of cytologic lesions were assessed.

Results: The prevalence of cytologic abnormalities was atypical squamous cells of undetermined significance (ASC-US), 1.6%; atypical glandular cells (AGC), 0.2%; low-grade squamous intraepithelial lesion (LSIL), 2.6%; atypical squamous cells, HSIL cannot be excluded (ASC-H), 0.3%; and high-grade squamous intraepithelial lesion (HSIL), 1.2%. The frequency of high-risk HPV infections was 11% in women without cytologic abnormalities, 77% in ASC-US, 32% in AGC, 85% in LSIL, and 93% in ASC-H and HSIL. The prevalence of high-risk HPV infection was highest in women of ages 20 to 24 years (29%) and decreased progressively with age. The percentage of women with HSIL in the entire study population attributable to infection with a particular type (ARpop %) was highest for HPV16 (32%), followed by HPV31 (22%), HPV39 (11%), and HPV52 (11%). HPV18 was responsible for 7% of the HSIL lesions. Elimination of HPV16 and HPV18 is expected to reduce the prevalence of ASCUS with 24%, AGC with 19%, LSIL with 29%, ASC-H with 31% and HSIL with 37%.

Discussion: Compared to other West European studies, the prevalence of HPV infection was considerably higher in cytologically negative women but similar in women with cervical lesions. These differences could be due to the use of a PCR with high analytic sensitivity. These data are relevant for estimating the expected and theoretical levels of vaccine protection offered as vaccinated girls gradually age into the groups from which our observations stem. Further periodic laboratory-based surveys, including genotyping of cervical cell samples and linkage with vaccine registries, are an important resource to address pending questions of the effect of HPV vaccination. Research is warranted to disentangle the causal role of individual HPV types in case of multiple infections. (Cancer Epidemiol Biomarkers Prev 2009;18(1):321–30)
A Prospectively Measured Serum Biomarker for a Tobacco-Specific Carcinogen and Lung Cancer in Smokers
Authors: Church Timothy R. , Anderson Kristin E. , Caporaso Neil E. , Geisser Mindy S. , Le Chap T. , Zhang Yan , Benoit Adam R. , Carmella Steven G. , Hecht Stephen S.
Published: January 2009

Background: No prior studies have related a tobacco-specific carcinogen to the risk of lung cancer in smokers. Of the over 60 known carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is specific to tobacco and causes lung cancer in laboratory animals. Its metabolites, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), have been studied as biomarkers of exposure to NNK. We studied the relation of prospectively measured NNK biomarkers to lung cancer risk.

Methods: In a case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we randomly selected 100 lung cancer cases and 100 controls who smoked at baseline and analyzed their baseline serum for total NNAL, cotinine, and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbon exposure and metabolic activation. To examine the association of the biomarkers with all lung cancers and for histologic subtypes, we computed odds ratios for total NNAL, PheT, and cotinine using logistic regression to adjust for potential confounders.

Findings: Individual associations of age, smoking duration, and total NNAL with lung cancer risk were statistically significant. After adjustment, total NNAL was the only biomarker significantly associated with risk (odds ratio, 1.57 per unit SD increase; 95% confidence interval, 1.08-2.28). A similar statistically significant result was obtained for adenocarcinoma risk, but not for nonadenocarcinoma.

Conclusions: This first reporting of the effect of the prospectively measured tobacco-specific biomarker total NNAL, on risk of lung cancer in smokers provides insight into the etiology of smoking-related lung cancer and reinforces targeting NNK for cancer prevention. (Cancer Epidemiol Biomarkers Prev 2009;18(1):260–6)
Tea Consumption and Risk of Breast Cancer
Authors: Kumar Nagi , Titus-Ernstoff Linda , Newcomb Polly A. , Trentham-Dietz Amy , Anic Gabriella , Egan Kathleen M.
Published: January 2009

Objective: The purpose of our study was to examine the association of regular tea consumption with the risk of breast cancer in a large population-based case-control study from the United States.

Methods: Five thousand and eighty-two women with incident breast cancer between the ages of 20 and 74 years old from population-based cancer registries in Wisconsin, Massachusetts, and New Hampshire and 4,501 age-matched controls from lists of licensed drivers and Medicare beneficiaries completed a structured telephone interview that included information on usual tea consumption 5 years prior to the interview and other breast cancer risk factors. Logistic regression was used to obtain covariate-adjusted odds ratios and 95% confidence intervals associated with quantities of tea consumed.

Results: Tea consumption was not related to breast cancer risk overall (P for trend = 0.18). However, when stratified by age, an inverse association was observed among women less than 50 years: those consuming three or more cups per day had a 37% reduced breast cancer risk when compared with women reporting no tea consumption (age and study site–adjusted odds ratios, 0.63; 95% confidence intervals, 0.44-0.89; P = 0.01) with a significant test for trend (P = 0.01). The inverse association noted among younger women was consistent for in situ and invasive breast cancer, and for ductal and lobular breast cancer. All results were unchanged after adjustment for established risk factors.

Conclusion: We observed evidence to support a potential beneficial influence for breast cancer associated with moderate levels of tea consumption (three or more cups per day) among younger women. Further research is needed to confirm this association. (Cancer Epidemiol Biomarkers Prev 2009;18(1):341–5)
Heat Shock Protein 90 as a Drug Target: Some Like It Hot
Authors: Banerji Udai
Published: December 2008

Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH2-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.
Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention
Authors: Ondrey Frank
Published: December 2008

The peroxisome proliferator-activated receptor (PPAR) γ is one member of the nuclear receptor superfamily that contains in excess of 80 described receptors. PPARγ activators are a diverse group of agents that range from endogenous fatty acids or derivatives (linolenic, linoleic, and 15-deoxy-Δ12,14-prostaglandin J2) to Food and Drug Administration-approved thiazolidinedione drugs [pioglitazone (Actos) and rosiglitazone (Avandia)] for the treatment of diabetes. Once activated, PPARγ will preferentially bind with retinoid X receptor α and signal antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for down-regulation of carcinogenesis. Although PPAR-γ activators show many anticancer effects on cell lines, their advancement into human advanced cancer clinical trials has met with limited success. This article will review translational findings in PPARγ activation and targeting in carcinogenesis prevention as they relate to the potential use of PPARγ activators clinically as cancer chemoprevention strategies.
Validation of a Standardized Method for Enumerating Circulating Endothelial Cells and Progenitors: Flow Cytometry and Molecular and Ultrastructural Analyses
Authors: Mancuso Patrizia , Antoniotti Pierluigi , Quarna Jessica , Calleri Angelica , Rabascio Cristina , Tacchetti Carlo , Braidotti Paola , Wu Hua-Kang , Zurita Amado J. , Saronni Luca , Cheng John B. , Shalinsky David R. , Heymach John V. , Bertolini Francesco
Published: December 2008

Purpose: Antigenic overlap among circulating endothelial cells (CEC) and progenitors (CEP), platelets, and other blood cells led to the need to develop a reliable standardized method for CEC and CEP quantification. These cells are emerging as promising preclinical/clinical tools to define optimal biological doses of antiangiogenic therapies and to help stratify patients in clinical trials.

Experimental Design: We report the experimental validation of a novel flow cytometry method that precisely dissects CEC/CEP from platelets and other cell populations and provides information about CEC/CEP viability.

Results: Sorted DNA/Syto16+CD45−CD31+CD146+ CECs, investigated by electron microscopy, were found to be bona fide endothelial cells by the presence of Weibel-Palade bodies. More than 75% of the circulating mRNAs of the endothelial-specific gene, VE-cadherin, found in the blood were present in the sorted population. CECs were 140 ± 171/mL in healthy subjects (n = 37) and 951 ± 1,876/mL in cancer patients (n = 78; P < 0.0001). The fraction of apoptotic/necrotic CECs was 77 ± 14% in healthy subjects and 43 ± 23% in cancer patients (P < 0.0001). CEPs were 181 ± 167/mL in healthy donors and 429 ± 507/mL in patients (P = 0.00019). Coefficients of variation were 4 ± 4% (intrareader), 17 ± 4% (interreader), and 17 ± 7% (variability over 0-72 h), respectively. Parallel samples were frozen by a standardized protocol. After thawing, coefficients of variation were 12 ± 8% (intrareader), 16 ± 10% (interreader), and 26 ± 16% (variability over 0-14 days of frozen storage), respectively.

Conclusions: This procedure enumerates a truly endothelial cell population with limited intrareader and interreader variability. It appears possible to freeze samples for large-scale CEC enumeration during clinical trials. This approach could be enlarged to investigate other angiogenic cell populations as well.
Proapoptotic Function of Integrin β3 in Human Hepatocellular Carcinoma Cells
Authors: Wu Yanhua , Zuo Jie , Ji Guoqing , Saiyin Hexige , Liu Xing , Yin Feiyu , Cao Ning , Wen Yunfei , Li Jian Jian , Yu Long
Published: December 2008

Purpose: This study evaluates the proapoptotic function of integrin β3 in human hepatocellular carcinoma (HCC).

Experimental Design: The expression of integrin β3 in 67 HCC specimens paired with corresponding neighboring nontumorous tissue was studied by quantitative real-time PCR and Western blot. The proapoptotic function of integrin β3 in SMMC-7721 human hepatoma cells overexpressing ITGB3 (gene coding integrin β3) was determined through colony formation, serum starvation, and anoikis assay.

Results: Compared with neighboring pathologically normal liver tissue, ∼60% of the HCC specimens showed a significant down-regulated level of integrin β3 expression. Transient expression of integrin β3 in SMMC-7721 resulted in an enhanced level of apoptosis and suppression of colony formation. Cell growth inhibition on serum/ligand deprivation and incidences of anoikis were remarkably increased in SMMC-7721 with stable expression of integrin β3 in comparison with vector control transfectants. In addition, expression of fibrinogen and vitronectin, two native ligands for integrin αvβ3 in liver, was inhibited, which was correlated with the decreased integrin β3 expression. Replenishing these ligands to the starved SMMC-7721 stable transfectants effectively restored the proapoptotic function of integrin β3.

Conclusions: Down-regulation of integrin β3 and its ligands in liver is related to the aggressive growth of HCC. Thus, reconstitution of integrin β3 in HCC may be a potential therapeutic approach to inhibit aggressive growth of liver cancer.
Broad Antitumor Activity in Breast Cancer Xenografts by Motesanib, a Highly Selective, Oral Inhibitor of Vascular Endothelial Growth Factor, Platelet-Derived Growth Factor, and Kit Receptors
Authors: Coxon Angela , Bush Tammy , Saffran Douglas , Kaufman Stephen , Belmontes Brian , Rex Karen , Hughes Paul , Caenepeel Sean , Rottman James B. , Tasker Andrew , Patel Vinod , Kendall Richard , Radinsky Robert , Polverino Anthony
Published: December 2008

Purpose: Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes.

Experimental Design: Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen).

Results: Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors).

Conclusions: Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.
SCG3 Transcript in Peripheral Blood Is a Prognostic Biomarker for REST-Deficient Small Cell Lung Cancer
Authors: Moss Adrian C. , Jacobson Gregory M. , Walker Lauren E. , Blake Neil W. , Marshall Ernie , Coulson Judy M.
Published: December 2008

Purpose: Specific markers of circulating tumor cells may be informative in managing lung cancer. Because the RE-1 silencing transcription factor (REST/NRSF) is a transcriptional repressor that is inactivated in neuroendocrine lung cancer, we identified REST-regulated transcripts (CHGA, CHGB, SCG3, VGF, and PCSK1) for evaluation as biomarkers in peripheral blood.

Experimental Design: Transcripts were screened across lung cancer and normal cell lines. Candidates were assessed by reverse transcription-PCR and hybridization of RNA extracted from the peripheral blood of 111 lung cancer patients obtained at clinical presentation and from 27 cancer-free individuals.

Results: Expression profiling revealed multiple chromogranin transcripts were readily induced on REST depletion, most notably SCG3 was induced >500-fold. The SCG3 transcript was also overexpressed by 12,000-fold in neuroendocrine compared with nonneuroendocrine lung cancer cells. In peripheral blood of lung cancer patients and cancer-free individuals, we found that SCG3 was more tumor-specific and more sensitive than other chromogranin transcripts as a biomarker of circulating tumor cells. Overall, 36% of small cell lung cancer (SCLC) and 16% of non-SCLC patients scored positively for normalized SCG3 transcript. This correlated with worse survival among SCLC patients with limited disease (n = 33; P = 0.022) but not extensive disease (n = 29; P = 0.459). Interestingly, the subcohort of 6 SCLC patients with resistance to platinum/etoposide chemotherapy all scored positively for peripheral blood SCG3 transcript (P = 0.022).

Conclusions: SCG3 mRNA, a component of the REST-dependent neurosecretory transcriptional profile, provides a sensitive prognostic biomarker for noninvasive monitoring of neuroendocrine lung cancer.
In vivo Knockdown of the Androgen Receptor Results in Growth Inhibition and Regression of Well-Established, Castration-Resistant Prostate Tumors
Authors: Snoek Robert , Cheng Helen , Margiotti Katia , Wafa Latif A. , Wong Charmaine A. , Wong Erica Chan , Fazli Ladan , Nelson Colleen C. , Gleave Martin E. , Rennie Paul S.
Published: December 2008

Purpose: Progression to the castration-resistant state is the incurable and lethal end stage of prostate cancer, and there is strong evidence that androgen receptor (AR) still plays a central role in this process. We hypothesize that knocking down AR will have a major effect on inhibiting growth of castration-resistant tumors.

Experimental Design: Castration-resistant C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) were generated to directly test the effects of AR knockdown in C4-2 human prostate cancer cells and tumors.

Results: In vitro expression of AR shRNA resulted in decreased levels of AR mRNA and protein, decreased expression of prostate-specific antigen (PSA), reduced activation of the PSA-luciferase reporter, and growth inhibition of C4-2 cells. Gene microarray analyses revealed that AR knockdown under hormone-deprived conditions resulted in activation of genes involved in apoptosis, cell cycle regulation, protein synthesis, and tumorigenesis. To ensure that tumors were truly castration-resistant in vivo, inducible AR shRNA expressing C4-2 tumors were grown in castrated mice to an average volume of 450 mm3. In all of the animals, serum PSA decreased, and in 50% of them, there was complete tumor regression and disappearance of serum PSA.

Conclusions: Whereas castration is ineffective in castration-resistant prostate tumors, knockdown of AR can decrease serum PSA, inhibit tumor growth, and frequently cause tumor regression. This study is the first direct evidence that knockdown of AR is a viable therapeutic strategy for treatment of prostate tumors that have already progressed to the castration-resistant state.
Intracellular Clusterin Inhibits Mitochondrial Apoptosis by Suppressing p53-Activating Stress Signals and Stabilizing the Cytosolic Ku70-Bax Protein Complex
Authors: Trougakos Ioannis P. , Lourda Magda , Antonelou Marianna H. , Kletsas Dimitris , Gorgoulis Vassilis G. , Papassideri Issidora S. , Zou Yonglong , Margaritis Lukas H. , Boothman David A. , Gonos Efstathios S.
Published: December 2008

Purpose: Secretory clusterin (sCLU)/apolipoprotein J is an extracellular chaperone that has been functionally implicated in DNA repair, cell cycle regulation, apoptotic cell death, and tumorigenesis. It exerts a prosurvival function against most therapeutic treatments for cancer and is currently an antisense target in clinical trials for tumor therapy. However, the molecular mechanisms underlying its function remained largely unknown.

Experimental Design: The molecular effects of small interfering RNA-mediated sCLU depletion in nonstressed human cancer cells were examined by focusing entirely on the endogenously expressed sCLU protein molecules and combining molecular, biochemical, and microscopic approaches.

Results: We report here that sCLU depletion in nonstressed human cancer cells signals stress that induces p53-dependent growth retardation and high rates of endogenous apoptosis. We discovered that increased apoptosis in sCLU-depleted cells correlates to altered ratios of proapoptotic to antiapoptotic Bcl-2 protein family members, is amplified by p53, and is executed by mitochondrial dysfunction. sCLU depletion-related stress signals originate from several sites, because sCLU is an integral component of not only the secretory pathway but also the nucleocytosolic continuum and mitochondria. In the cytoplasm, sCLU depletion disrupts the Ku70-Bax complex and triggers Bax activation and relocation to mitochondria. We show that sCLU binds and thereby stabilizes the Ku70-Bax protein complex serving as a cytosol retention factor for Bax.

Conclusions: We suggest that elevated sCLU levels may enhance tumorigenesis by interfering with Bax proapoptotic activities and contribute to one of the major characteristics of cancer cells, that is, resistance to apoptosis.
Reoxygenation of Hypoxic Glioblastoma Multiforme Cells Potentiates the Killing Effect of an Interleukin-13-Based Cytotoxin
Authors: Liu Tie Fu , Cai Jiaozhong , Gibo Denise M. , Debinski Waldemar
Published: December 2008

Purpose: Hypoxia is a cause for resistance to cancer therapies. Molecularly targeted recombinant cytotoxins have shown clinical efficacy in the treatment of patients with primary brain tumors, glioblastoma multiforme, but it is not known whether hypoxia influences their antitumor effect.

Experimental Design: We have exposed glioblastoma multiforme cells, such as U-251 MG, U-373 MG, SNB-19, and A-172 MG, to either anoxia or hypoxia and then reoxygenated them while treating with an interleukin (IL)-13-based diphtheria toxin (DT)-containing cytotoxin, DT-IL13QM. We measured the levels of immunoreactive IL-13Rα2, a receptor that mediates IL-13-cytotoxin cell killing, and the levels of active form of furin, a protease that activates the bacterial toxin portion in a cytotoxin.

Results: We found that anoxia/hypoxia significantly alters the responsiveness of glioblastoma multiforme cells to DT-IL13QM. Interestingly, bringing these cells back to normoxia caused them to become even more susceptible to the cytotoxin than the cells maintained under normoxia. Anoxia/hypoxia caused a highly prominent decrease in the immunoreactive levels of both IL-13R and active forms of furin, and reoxygenation not only restored their levels but also became higher than that in normoxic glioblastoma multiforme cells.

Conclusions: Our results show that a recombinant cytotoxin directed against glioblastoma multiforme cells kills these cells much less efficiently under anoxic/hypoxic conditions. The reoxygenation brings unexpected additional benefit of making glioblastoma multiforme cells even more responsive to the killing effect of a cytotoxin.
Developmental Basis for Electrophysiological Heterogeneity in the Ventricular and Outflow Tract Myocardium As a Substrate for Life-Threatening Ventricular Arrhythmias
Authors: Boukens Bastiaan J.D. , Christoffels Vincent M. , Coronel Ruben , Moorman Antoon F.M.
Published: December 2008

Reentry is the main mechanism of life-threatening ventricular arrhythmias, including ventricular fibrillation and tachycardia. Its occurrence depends on the simultaneous presence of an arrhythmogenic substrate (a preexisting condition) and a “trigger,” and is favored by electrophysiological heterogeneities. In the adult heart, electrophysiological heterogeneities of the ventricle exist along the apicobasal, left–right, and transmural axes. Also, conduction is preferentially slowed in the right ventricular outflow tract, especially during pharmacological sodium channel blockade. We propose that the origin of electrophysiological heterogeneities of the adult heart lies in early heart development. The heart is formed from several progenitor regions: the first heart field predominantly forms the left ventricle, whereas the second heart field forms the right ventricle and outflow tract. Furthermore, the embryonic outflow tract consists of slowly conducting tissue until it is incorporated into the ventricles and develops rapidly conducting properties. The subepicardial myocytes and subendocardial myocytes run distinctive gene programs from their formation onwards. This review discusses the hypothesis that electrophysiological heterogeneities in the adult heart result from persisting patterns in gene expression and function along the craniocaudal and epicardial–endocardial axes of the developing heart. Understanding the developmental origins of electrophysiological heterogeneity contributing to ventricular arrhythmias may give rise to new therapies.
Prototype Classification: Insights from Machine Learning
Authors: Graf Arnulf B. A. , Bousquet Olivier , Rätsch Gunnar , Schölkopf Bernhard
Published: December 2008

We shed light on the discrimination between patterns belonging to two different classes by casting this decoding problem into a generalized prototype framework. The discrimination process is then separated into two stages: a projection stage that reduces the dimensionality of the data by projecting it on a line and a threshold stage where the distributions of the projected patterns of both classes are separated. For this, we extend the popular mean-of-class prototype classification using algorithms from machine learning that satisfy a set of invariance properties. We report a simple yet general approach to express different types of linear classification algorithms in an identical and easy-to-visualize formal framework using generalized prototypes where these prototypes are used to express the normal vector and offset of the hyperplane. We investigate non-margin classifiers such as the classical prototype classifier, the Fisher classifier, and the relevance vector machine. We then study hard and soft margin classifiers such as the support vector machine and a boosted version of the prototype classifier. Subsequently, we relate mean-of-class prototype classification to other classification algorithms by showing that the prototype classifier is a limit of any soft margin classifier and that boosting a prototype classifier yields the support vector machine. While giving novel insights into classification per se by presenting a common and unified formalism, our generalized prototype framework also provides an efficient visualization and a principled comparison of machine learning classification.
A New Approach for Estimating the Attraction Domain for Hopfield-Type Neural Networks
Authors: Jin Dequan , Peng Jigen
Published: December 2008

In this letter, using methods proposed by E. Kaslik, St. Balint, and their colleagues, we develop a new method, expansion approach, for estimating the attraction domain of asymptotically stable equilibrium points of Hopfield-type neural networks. We prove theoretically and demonstrate numerically that the proposed approach is feasible and efficient. The numerical results that obtained in the application examples, including the network system considered by E. Kaslik, L. Brăescu, and St. Balint, indicate that the proposed approach is able to achieve better attraction domain estimation.
Density-Weighted Nyström Method for Computing Large Kernel Eigensystems
Authors: Zhang Kai , Kwok James T.
Published: December 2008

The Nyström method is a well-known sampling-based technique for approximating the eigensystem of large kernel matrices. However, the chosen samples in the Nyström method are all assumed to be of equal importance, which deviates from the integral equation that defines the kernel eigenfunctions. Motivated by this observation, we extend the Nyström method to a more general, density-weighted version. We show that by introducing the probability density function as a natural weighting scheme, the approximation of the eigensystem can be greatly improved. An efficient algorithm is proposed to enforce such weighting in practice, which has the same complexity as the original Nyström method and hence is notably cheaper than several other alternatives. Experiments on kernel principal component analysis, spectral clustering, and image segmentation demonstrate the encouraging performance of our algorithm.
Generation of Correlated Spike Trains
Authors: Brette Romain
Published: December 2008

Neuronal spike trains display correlations at diverse timescales throughout the nervous system. The functional significance of these correlations is largely unknown, and computational investigations can help us understand their role. In order to generate correlated spike trains with given statistics, several case-specific methods have been described in the litterature. This letter presents two general methods to generate sets of spike trains with given firing rates and pairwise correlation functions, along with efficient simulation algorithms.
How to attract and retain the best in government
Authors: Pan Suk Kim
Published: December 2008

The purpose of this article is to discuss challenges and strategies of attracting and retaining the best in government, particularly from the perspective of government in developing countries or transitional economies. This article will first touch briefly on the technical and practical issues of how to attract and retain the best, followed by an elaboration of current trends in human resource management (HRM). It will also look at a case of the Korean experience on HRM, followed by discussion of the theoretical and policy implications on HRM. Various kinds of best practices and new ideas are available through diverse venues around the world, but it is difficult to determine what really works for whom and how. It is not feasible to apply the same reform strategy to all countries. The challenge is, therefore, to find out what is applicable to the specific country; and how things can be applied while minimizing negative consequences.

Points for the practitioners Under rapidly changing circumstances around the world with increasing pressure on performance and innovation in government, old-fashioned personnel management must be significantly transformed, in order to attract and retain the best in government as well as to win the war for talent. Thus HR managers should initiate far-reaching, much needed change in talent management in terms of how they source, attract, select, train, develop, retain, promote, and move employees through the organization. In order to make government the model employer of choice, HR managers need to make a new Copernican transition in finding a new way of human resource management.
Tsunami engulfs Sri Lankan governance
Authors: Samaratunge Ramanie , Coghill Ken , Herath H.M.A.
Published: December 2008

The features of governance during the provision of relief immediately following the 2004 tsunami, the restoration of key services and facilities, and the longer term rebuilding of damaged/destroyed infrastructure, in the Galle District of Sri Lanka, are investigated in this case study. Interview data revealed that recovery attempts were significantly weakened by the lack of collaboration among key players at the central and the district level. In particular, at the district level, interactions among key stakeholders have lacked focus and were ad hoc. We argue that despite the growing recognition of the advantages of the integration of the actions of various state and non-state actors in such governance, government appears to be reluctant to move away from the existing `command and control mode' of governance. As a result, transaction costs of governance were excessive, and the resources allocated for reconstruction were either misused or left underutilized.

Points for practitioners Following a major disaster there is enormous goodwill, with willingness to overlook previous divisions and partisan interests. However, this is fragile and easily dissipated. It must be deliberately preserved and built on. Practitioners should seize the opportunity to build collaborative relationships and to reform administrative processes to facilitate the delivery of supplies and services, giving priority according to need. Advice to the political executive must emphasize the urgency and public interest in drawing on all available human, financial and physical resources through collaborative arrangements involving all sources, including the public service at each level of government, business and non-government organizations.
Tricks of the Trade in Community Mental Health Research: Working With Mental Health Services and Clients
Authors: Dadich Ann , Muir Kristy
Published: December 2008

The complexities of research in the community mental health sector are seldom acknowledged in existing literature; this article attempts to address this void. It presents the methodological challenges experienced in the longitudinal evaluation of the Housing and Accommodation Support Initiative—a program that supports people with chronic mental illness toward long-term recovery. The evaluation provides a case study for understanding methodological problems in community mental health research, which include working with organizations that experience high staff turnover; staff members who have large caseloads; and clients who have chronic mental illness. Although not applicable to all research designs, the suggested strategies highlight the importance of innovation, flexibility, and balance between research theory and practical limitations when conducting community mental health research.
Taxes, Wages, and the Labor Supply of Older Americans
Authors: Schmidt Lucie , Sevak Purvi
Published: December 2008

Given the aging of the U.S. population and the greater contributions of older workers to the labor force, understanding how policy levers can affect elderly labor supply has become increasingly important. The authors use data from the Health and Retirement Study linked to state identifiers to estimate the responsiveness of the labor supply of older workers to the wage and features of the tax code, both on the probability of participating in the labor market and on hours of work for those who choose to work. The authors find that a 10% increase in the wage is associated with a 5% increase in participation, and they estimate slightly larger responses to marginal tax rates. These results suggest that government policies could increase the labor supply of older individuals by changing the returns to work through the tax code.
Beyond Affirmation
Authors: Gonzalez Rosemary
Published: December 2008

Identity development is a dynamic process which involves reconciling multiple messages. While ethnic minority adolescents' development is affected profoundly by discrimination, positive racial/ethnic encounters can also transform one's identity. Questionnaire data were gathered from 122 tenth-grade Mexican Americans in a low-performing school that had over 60% “Hispanic” students. Based on the data, 12 second-generation youth were selected for interviews based on their level of academic engagement and experiences with negative racial/ethnic encounters in school. Interviewees' descriptions of positive encounter experiences revealed ways in which schools can reinforce equal status and integrate Mexican American youth. Youth felt a renewed commitment to their ethnic selves when they participated in events that they perceived as dispelling stereotypes and when they had concrete experiences in which their bilingual competence was perceived as an asset. This qualitative study identifies avenues for future research on positive racial/ethnic encounters and academic engagement.
South Texas Mexican American Use of Traditional Folk and Mainstream Alternative Therapies
Authors: Martinez Leslie N.
Published: December 2008

A telephone survey was conducted with a large sample of Mexican Americans from border ( n = 1,001) and nonborder ( n = 1,030) regions in Texas. Patterns of traditional folk and mainstream complementary and alternative medicine (CAM) use were analyzed with two binary logistic regressions, using gender, self-rated health, confidence in medical doctors, income, education, and acculturation as predictors. Approximately 45% of respondents were CAM users within the last 12 months. Users of both types of CAM were likely to be women and to have a high education level. Compared to nonusers, traditional folk CAM users were found to have lower self-rated health, less confidence in medical doctors, and lower acculturation. Mainstream CAM users had higher income and self-rated health than nonusers.
Hispanic Acculturation in a Predominately Black High School
Authors: Hughes Carolyn , Hollander Matthew J. , Martinez Amber W.
Published: December 2008

The authors applied an adaptation of prior models of acculturation to all 16 Hispanic students attending a predominately Black, high-poverty, urban high school ( n = 1,267 students) identified by No Child Left Behind standards as failing. No published study to date has investigated Hispanic acculturation within such a setting. Findings reveal that students were identified across all four acculturation modes of the model and that only half ( n = 8) of students demonstrated substantial affiliation with a dominant U.S. culture. Of these, five students identified more strongly with the dominant Black culture of the school versus the prevailing White U.S. culture. Findings are discussed with respect to future research and practice designed to improve educational experiences for Hispanic youth.
Investigating Queer Future Meanings
Authors: Goltz Dustin
Published: December 2008

This study interrogates the meanings that gay youth attach to the future, using discussion, creative engagement, and embodied performance to explore the possibility of queer fantasy as a resistant and generative site of future making. The project explores the creative potentials of focus group research as a method for education, exploration, and collaborative generation. The research identifies a strong gender divide in the narratives gay men and lesbians create about the future. Gay men associate primarily negative and gloomy meanings to future, strongly influenced by cultural myths of “the miserable, bitter, old man.” Lesbian women associate more positive meanings to future, and their perceived future relies much more on heteronormative models of family and children. This article examines how access to heteronormative meanings of future affect overall perceptions of the future, problematizing an antinormative positioning of queer theory.