bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects on tree swallows exposed to dioxin-like compounds associated with the Tittabawassee River and floodplain near Midland, Michigan, USA
Authors: Fredricks Timothy B , Zwiernik Matthew J , Seston Rita M , Coefield Sarah J , Tazelaar Dustin L , Roark Shaun A , Kay Denise P , Newsted John L , Giesy John P
Published: February 2011

Concentrations of dioxin-like compounds, primarily polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-p-dioxins (PCDDs), in soils and sediments downstream of Midland, Michigan (USA) were greater than upstream sites and prompted a site-specific hazard assessment of tree swallows breeding in the associated floodplains. Potential for adverse population-level effects from site-specific contaminant exposures were evaluated at study areas (SAs) along the Tittabawassee and Saginaw rivers downstream of Midland. The site-specific multiple lines of evidence approach to hazard assessment included endpoints for dietary- and tissue-based exposures, and population productivity measurements for tree swallows ([TS]; Tachycineta bicolor) measured during the 2005, 2006, and 2007 breeding seasons. Exposure to dioxin-like compounds in TS eggs were some of the greatest recorded and were similar among all upstream and downstream study sites. Conversely, concentrations in nestlings from SAs were significantly greater compared to reference areas (RAs). The pattern of relative concentrations of PCDD/DFs in eggs and nestlings at RAs was dominated by dioxin congeners, whereas at SAs it was dominated by furan congeners. No statistically significant differences were noted in exposure to PCDD/DFs or in population-level responses when compared among locations, and total clutch failures were rare. Hatching success and fledging success were weakly negatively correlated with concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TEQs) in individual eggs and nestlings, respectively. On-site concentrations of TEQs in floodplain soils were some of the greatest ever reported in the environment, and several lines of evidence indicate potential population-level effects on TS overall reproductive productivity. Environ. Toxicol. Chem. 2011; 30:1354–1365. © 2011 SETAC
A short life-cycle test with the epibenthic copepod Nitocra spinipes for sediment toxicity assessment
Authors: Perez-Landa Victor , Simpson Stuart L
Published: February 2011

A new short life-cycle test methodology is presented to evaluate sublethal effects of contaminated sediments to the harpacticoid copepod species Nitocra spinipes. The method combines a 4-d survival-gravidity test with a 7-d development test. For water-only Cu exposures, the sensitivity of the development test endpoints were compared with tests using nonexposed gravid females to initiate the 7-d development test phase, and also with a multiple generation test comprising three successive phases: 9-d development; 21-d survival-gravidity; second-generation 9-d development. The results indicated that the development endpoints were the most sensitive, with median effective concentration (EC50) values of 95 µg Cu/L for nauplii/gravid female and 101 µg Cu/L copepodites/gravid female endpoints, followed by the gravidity (144 µg Cu/L) and survival (347 µg Cu/L). The sensitivity of the short life-cycle test endpoints was similar to the multiple-generation test endpoints, and the shorter test had less variability in controls. The multiple-generation test showed a large amount of stimulation of reproduction and development at Cu concentrations of 50 to 100 µg/L. The suitability of the short life-cycle test for assessing sediment toxicity was demonstrated using Cu-spiked and naturally contaminated whole sediments. Although the small nauplii were more difficult to isolate from sediments, the small amounts of sediments used for the tests and the large effects of the contaminated sediments on nauplii and copepodite numbers resulted in significant differences to controls. For sediment exposures, the sensitivity of the endpoints was in the order development > gravidity > survival. The short life-cycle test was demonstrated to detect, within 11 d of exposure, similar levels of effects on reproduction and development to those detected using a 39-d multiple-generation exposure. Environ. Toxicol. Chem. 2011; 30:1430–1439. © 2011 SETAC
Forecasting Stock Market Volatility in Central and Eastern European Countries
Authors: Harrison Barry , Moore Winston
Published: February 2011

In recent years, considerable attention has focused on modelling and forecasting stock market volatility. Stock market volatility matters because stock markets are an integral part of the financial architecture in market economies and play a key role in channelling funds from savers to investors. The focus of this paper is on forecasting stock market volatility in Central and East European (CEE) countries. The obvious question to pose, therefore, is how volatility can be forecast and whether one technique consistently outperforms other techniques. Over the years a variety of techniques have been developed, ranging from the relatively simple to the more complex conditional heteroscedastic models of the GARCH family. In this paper we test the predictive power of 12 models to forecast volatility in the CEE countries. Our results confirm that models which allow for asymmetric volatility consistently outperform all other models considered. Copyright © 2011 John Wiley & Sons, Ltd.
Influence of Pressurisation on SOFC Performance and Durability: A Theoretical Study
Authors: Henke M. , Kallo J. , Friedrich K. A. , Bessler W. G.
Published: February 2011

Hybrid power plants consisting of a solid oxide fuel cell (SOFC) and a gas turbine show high electrical efficiencies, however require pressurisation of the SOFC to several bar. This paper presents a theoretical investigation of the pressure influence on SOFC performance and durability. A two‐dimensional elementary kinetic model is used to predict the performance of a single cell in the pressure range of 1–20 bar. The influence of pressure on thermodynamics, reaction kinetics, porous electrode diffusion, channel transport and efficiency is assessed. It was found that polarisation resistance decreases with increasing pressure due to increased diffusion through porous electrodes and a higher electrode surface coverage with reactant species. Furthermore, open‐circuit voltage increases slightly with pressure. As a consequence, power density and efficiency increase upon pressurisation with the strongest increase at low pressures between 1 and 5 bar. The influence of pressure on two typical degradation mechanisms, nickel oxidation and carbon deposition, is assessed using thermodynamic simulations. Pressurisation facilitates nickel oxidation whereas its effect on carbon deposition strongly depends on temperature.
Preparation of BaZr0.1Ce0.7Y0.2O3–δ Based Solid Oxide Fuel Cells with Anode Functional Layers by Tape Casting
Authors: Nien S. H. , Hsu C. S. , Chang C. L. , Hwang B. H.
Published: February 2011

Solid oxide fuel cells (SOFCs) based on the proton conducting BaZr0.1Ce0.7Y0.2O3–δ (BZCY) electrolyte were prepared and tested in 500–700 °C using humidified H2 as fuel (100 cm3 min–1 with 3% H2O) and dry O2 (50 cm3 min–1) as oxidant. Thin NiO‐BZCY anode functional layers (AFL) with 0, 5, 10 and 15 wt.% carbon pore former were inserted between the NiO‐BZCY anode and BZCY electrolyte to enhance the cell performance. The anode/AFL/BZCY half cells were prepared by tape casting and co‐sintering (1,300 °C/8 h), while the Sm0.5Sr0.5CoO3–δ (SSC) cathodes were prepared by thermal spray deposition. Well adhered planar SOFCs were obtained and the test results indicated that the SOFC with an AFL containing 10 wt.% pore former content showed the best performance: area specific resistance as low as 0.39 Ω cm2 and peak power density as high as 0.863 W cm–2 were obtained at 700 °C. High open circuit voltages ranging from 1.00 to 1.12 V in 700–500 °C also indicated negligible leakage of fuel gas through the electrolyte.
Physiologic and anatomic characterization of the brain surface glia barrier of Drosophila
Authors: Desalvo Michael K. , Mayer Nasima , Mayer Fahima , Bainton Roland J.
Published: February 2011

Central nervous system (CNS) physiology requires special chemical, metabolic, and cellular privileges for normal function, and blood–brain barrier (BBB) structures are the anatomic and physiologic constructs that arbitrate communication between the brain and body. In the vertebrate BBB, two primary cell types create CNS exclusion biology, a polarized vascular endothelium (VE), and a tightly associated single layer of astrocytic glia (AG). Examples of direct action by the BBB in CNS disease are constantly expanding, including key pathophysiologic roles in multiple sclerosis, stroke, and cancer. In addition, its role as a pharmacologic treatment obstacle to the brain is long standing; thus, molecular model systems that can parse BBB functions and understand the complex integration of sophisticated cellular anatomy and highly polarized chemical protection physiology are desperately needed. Compound barrier structures that use two primary cell types (i.e., functional bicellularity) are common to other humoral/CNS barrier structures. For example, invertebrates use two cell layers of glia, perineurial and subperineurial, to control chemical access to the brain, and analogous glial layers, fenestrated and pseudocartridge, to maintain the blood–eye barrier. In this article, we summarize our current understanding of brain‐barrier glial anatomy in Drosophila, demonstrate the power of live imaging as a screening methodology for identifying physiologic characteristics of BBB glia, and compare the physiologies of Drosophila barrier layers to the VE/AG interface of vertebrates. We conclude that many unique BBB physiologies are conserved across phyla and suggest new methods for modeling CNS physiology and disease. © 2011 Wiley‐Liss, Inc.
Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity
Authors: Ni Mingwei , Li Xin , Yin Zhaobao , Sidoryk‐Węgrzynowicz Marta , Jiang Haiyan , Farina Marcelo , Rocha Joao B. T. , Syversen Tore , Aschner Michael
Published: February 2011

As the two major glial cell types in the brain, astrocytes and microglia play pivotal but different roles in maintaining optimal brain function. Although both cell types have been implicated as major targets of methylmercury (MeHg), their sensitivities and adaptive responses to this metal can vary given their distinctive properties and physiological functions. This study was carried out to compare the responses of astrocytes and microglia following MeHg treatment, specifically addressing the effects of MeHg on cell viability, reactive oxygen species (ROS) generation and glutathione (GSH) levels, as well as mercury (Hg) uptake and the expression of NF‐E2‐related factor 2 (Nrf2). Results showed that microglia are more sensitive to MeHg than astrocytes, a finding that is consistent with their higher Hg uptake and lower basal GSH levels. Microglia also demonstrated higher ROS generation compared with astrocytes. Nrf2 and its downstream genes were upregulated in both cell types, but with different kinetics (much faster in microglia). In summary, microglia and astrocytes each exhibit a distinct sensitivity to MeHg, resulting in their differential temporal adaptive responses. These unique sensitivities appear to be dependent on the cellular thiol status of the particular cell type. © 2011 Wiley‐Liss, Inc
Age and anxiety and depressive symptoms: the effect on domains of quality of life
Authors: Brown Patrick J. , Roose Steven P.
Published: February 2011

Objectives

The present study investigated whether anxiety and depressive symptomatology moderates the relationship between age and quality of life.

Methods

The study was a community‐based survey using mailed questionnaires conducted within the Department of Psychology at Washington University in St. Louis. The community‐based sample consisted of 443 adults ages 30–98 years recruited from university maintained volunteer registries. Quality of life was assessed using the World Health Organization Quality of Life‐BREF assessment; depression was assessed using 15‐item Geriatric Depression Scale and anxiety was assessed using the Social Interaction Anxiety Scale, a measure of social anxiety.

Results

Depression and anxiety were negatively associated with quality of life in the Psychological and Social domains (all p's < 0.001), but age was not (Psychological, p = 0.07; Social, p = 0.98). In addition to depression and anxiety, age was also associated with quality of life in the other two domains, negatively for the Physical domain and positively for the Environmental domain. These main effects were qualified by significant three‐way interactions in both domains.

Conclusions

Although both anxiety and depression negatively affect Psychological and Social quality of life, age does not. Environmental quality of life increased with age, while Physical quality of life decreased. The deleterious relationship between anxiety and depressive symptomatology and Physical and Environmental quality of life was moderated by age. Older adults with high levels of anxiety and depressive symptoms reported better Environmental and less severe decrements in Physical quality of life compared with middle‐aged adults with similar symptomatology. Copyright © 2011 John Wiley & Sons, Ltd.
The effectiveness of crisis resolution/home treatment teams for older people with mental health problems: a systematic review and scoping exercise
Authors: Toot Sandeep , Devine Mike , Orrell Martin
Published: February 2011

Objective

To assess the effectiveness of crisis resolution/home treatment services for older people with mental health problems.

Design

A systematic review was conducted to report on the effectiveness of crisis resolution/home treatment teams (CRHTTs) for older people with mental health problems. As part of the review, we also carried out a scoping exercise to assess the typologies of older people's CRHTTs in practice, and to review these in the context of policy and research findings.

Results

The literature contains Grade C evidence, according to the Oxford Centre of Evidence Based Medicine (CEBM) guidelines, that CRHTTs are effective in reducing numbers of admissions to hospitals. Outcomes such as length of hospital stay and maintenance of community residence were reviewed but evidence was inadequate for drawing conclusions. The scoping exercise defined three types of home treatment service model: generic home treatment teams; specialist older adults home treatment teams; and intermediate care services. These home treatment teams seemed to be effectively managing crises and reducing admissions.

Conclusion

This review has shown a lack of evidence for the efficacy of crisis resolution/home treatment teams in supporting older people with mental health problems to remain at home. There is clearly a need for a randomised controlled trial to establish the efficacy of crisis resolution/home treatment services for older people with mental health problems, as well as a more focussed assessment of the different home treatment service models which have developed in the UK. Copyright © 2011 John Wiley & Sons, Ltd.
Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in persistent hepatitis B virus infection
Authors: Schurich Anna , Khanna Pooja , Lopes Ross A. , Han Ki Jun , Peppa Dimitra , Micco Lorenzo , Nebbia Gaia , Kennedy Patrick T.F. , Geretti Anna-Maria , Dusheiko Geoffrey , Maini Mala K.
Published: February 2011

An excess of coinhibitory signals has been proposed to drive the T-cell exhaustion characteristic of persistent viral infections. In this study we examined the contribution of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) to CD8 T cell tolerance in chronic hepatitis B virus (HBV) infection (CHB). CD8 T cells in patients with CHB have an increased propensity to express the coinhibitory receptor CTLA-4 and this correlates with viral load. CTLA-4 is up-regulated on those HBV-specific CD8 T cells with the highest levels of the proapoptotic protein Bim, which we have previously shown mediates their premature attrition; abrogation of CTLA-4-mediated coinhibition can reduce Bim expression. Longitudinal study of CHB patients beginning antiviral therapy reveals that HBV DNA suppression induces transient reconstitution of HBV-specific CD8 T cells but does not reprogram their CTLA-4hiBimhi tolerogenic phenotype. Blocking CTLA-4 is able to increase the expansion of interferon gamma (IFN-γ)-producing HBV-specific CD8 T cells in both the peripheral and intrahepatic compartments. The rescue of anti-HBV responses by either CTLA-4 or PD-L1 blockade is nonredundant.

Conclusion:

CTLA-4 is expressed by HBV-specific CD8 T cells with high levels of Bim and helps to drive this proapoptotic phenotype. CTLA-4 blockade could form one arm of a therapeutic approach to modulate the diverse patterns of coregulation of T-cell exhaustion in this heterogeneous disease. (Hepatology 2011;)
Sorafenib inhibits transforming growth factor β1-Mediated Epithelial-Mesenchymal Transition and apoptosis in mouse hepatocytes
Authors: Chen Yue-Lei , Lv Jing , Ye Xiao-Lei , Sun Ming-Yu , Xu Qin , Liu Cheng-Hai , Min Li-Hua , Li Hui-Ping , Liu Ping , Ding Xiaoyan
Published: February 2011

Epithelial-mesenchymal transition (EMT) is a physiological process that has been recognized to occur during the progression of an increasingly large number of human diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. The activation of transforming growth factor β (TGF-β) signaling is considered a critical event during EMT, and efforts have been made to screen small molecules that interfere with the TGF-β signaling pathway during EMT. Here we report the identification of sorafenib, a clinical agent that inhibits TGF-β signaling. When applied to AML12 cells and primary hepatocytes, sorafenib strikingly suppressed TGF-β1-induced EMT and apoptosis. Additionally, sorafenib inhibited TGF-β1-induced signal transducer and activator of transcription 3 phosphorylation. We further present

in vitro

evidence that sorafenib ameliorates the proapoptotic and profibrotic effects of TGF-β1 in mouse primary hepatocytes, suggesting that this drug exerts a protective effect on hepatocytes and has therapeutic potential for the treatment of liver fibrosis. (Hepatology 2011;)
Invasive breast cancer incidence trends by detailed race/ethnicity and age
Authors: Liu Lihua , Zhang Juanjuan , Wu Anna H. , Pike Malcolm C. , Deapen Dennis
Published: February 2011

Racial/ethnic disparities in breast cancer incidence may contain important evidence for understanding and control of the disease. Monitoring the incidence trends of breast cancer by race/ethnicity allows identification of high risk groups and development of targeted prevention programs. Using population‐based cancer registry data from the Los Angeles Cancer Surveillance Program, we examined the invasive female breast cancer incidence trends among the diverse racial/ethnic populations in Los Angeles County, California, from 1972 to 2007. Age‐adjusted incidence rates (AAIRs) and age‐specific incidence rates (ASIRs) were calculated and examined respectively for non‐Hispanic (NH) white, black, Hispanic, Chinese, Filipina, Japanese and Korean women by calendar year and time period. Rising trends of AAIRs were found in all racial/ethnic groups during the 1980s and 1990s. The breast cancer risk increased more substantially in Japanese and Filipinas than in Chinese and Koreans. During 2000–2007, the trends of AAIRs declined significantly among NH white women and slightly in blacks, remained unchanged for Hispanics and continued to rise significantly among all Asian subgroups. The patterns of ASIRs by race/ethnicity changed dramatically over time. By 2000–2007, younger Hispanic women had the lowest breast cancer risk, replacing the Chinese and Koreans who formerly had the lowest risk. Rapidly increasing breast cancer incidence trends among Asian–Americans underline the importance of behavioral and lifestyle changes as a result of acculturation on the development of the disease. The unique trends of breast cancer incidence by race/ethnicity suggest the need for targeted breast cancer control programs for different racial/ethnic populations.
MKK4 suppresses metastatic colonization by multiple highly metastatic prostate cancer cell lines through a transient impairment in cell cycle progression
Authors: Szmulewitz Russell Z. , Clark Robert , Lotan Tamara , Otto Kristen , Taylor Veneris Jennifer , Macleod Kay , Rinker‐Schaeffer Carrie
Published: February 2011

Metastatic dissemination in prostate cancer is often early, but not all cancer cells form clinical metastases. Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model. We hypothesize that MKK4 will specifically inhibit metastatic colonization through impaired proliferation. Three highly metastatic rat prostate cancer cell lines (AT6.1, Mat‐Lu and AT3.1) were employed. Stably over‐expressing HA‐MKK4 or vector control lines were injected into immunocompromised mice. These experiments validated that HA‐MKK4 specifically affects metastatic colonization and increases survival. Median survival (days) with HA‐MKK4 vs. vector was 42 vs. 28 (p < 0.0001) for AT6.1, 25 vs. 19 (p < 0.0001) for Mat‐Lu and 27 vs. 20 (p < 0.0001) for AT3.1. HA‐MKK4 suppresses colonization within 14 days post dissemination, after which exponential proliferation resumes. Although overt metastases retain HA‐MKK4, it is inactive within these lesions. Nonetheless, metastasis‐derived cell lines were shown to retain functional HA‐MKK4 and like their parental HA‐MKK4 line are suppressed for experimental metastasis formation in vivo. Disseminated AT6.1‐HA‐MKK4 cells were analyzed and were found to have an alteration in cell cycle. Specifically, there was an accumulation of cells in G1‐phase (p = 0.024) and decrease in S‐phase (p = 0.037) compared with vector. In multiple prostate cancer lines, HA‐MKK4 suppresses an early step in metastatic colonization. These data support a model in which MKK4 activation at the metastatic site causes a cell‐cycle arrest, which is eventually overcome despite presence of functional HA‐MKK4. Further studies will specifically interrogate the regulation of MKK4 activation within the metastatic microenvironment and the down‐stream molecular events critical for metastasis suppression.
Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas
Authors: Hubackova Miluse , Vaclavikova Radka , Ehrlichova Marie , Mrhalova Marcela , Kodet Roman , Kubackova Katerina , Vrána David , Gut Ivan , Soucek Pavel
Published: February 2011

Associations of transcript levels of oxidative stress‐modifying genes SOD2, SOD3, NQO1 and NQO2 and their functional single nucleotide polymorphisms (SNPs) rs4880, rs1799895, rs2536512, rs699473, rs1800566 and rs1143684 with prognosis of breast cancer patients were studied. SNPs were assessed by allelic discrimination in a cohort of 321 breast cancer patients from the Czech Republic. Transcript levels were determined by real‐time polymerase chain reaction (PCR) with absolute quantification in tumor and adjacent non‐neoplastic control tissues. Both genotypes and transcript levels were then compared with available clinical data on patients. Patients carrying low activity allele Leu in NQO2 rs1143684 had a greater incidence of stage 0 or I disease (i.e., better prognosis) than patients with the Phe/Phe genotype. This association was more evident in patients without expression of progesterone receptors (p = 0.031). Patients carrying the Thr allele in SOD3 rs2536512 SNP had a significantly greater incidence of tumors expressing estrogen receptors than patients carrying the Ala/Ala genotype (p = 0.007). SOD3 transcript level was significantly higher in grade 1 or 2 tumors than in grade 3 tumors (p = 0.006). Patients carrying T allele in SOD3 rs699473 SNP had significantly poorer progression‐free survival (PFS) than patients carrying the CC genotype (p = 0.038). The same applied to the subgroup of patients treated by hormonal regimens (p = 0.021). Patients carrying the high activity Ala/Ala genotype in SOD2 (rs4880) had significantly poorer PFS than Val allele carriers in the group treated by cyclophosphamide but not hormonal regimens (p = 0.004). Our results suggest that NQO2, SOD2 and SOD3 may significantly modify prognosis of breast cancer patients and that their significance should be further characterized.
Krebs von den Lungen‐6 (KL‐6) is a prognostic biomarker in patients with surgically resected nonsmall cell lung cancer
Authors: Tanaka Sonosuke , Hattori Noboru , Ishikawa Nobuhisa , Shoda Hiroyasu , Takano Atsushi , Nishino Ryohei , Okada Morihito , Arihiro Koji , Inai Kouki , Hamada Hironobu , Yokoyama Akihito , Kohno Nobuoki
Published: February 2011

By immunizing mice with a lung adenocarcinoma cell line, we previously established a murine IgG1 monoclonal antibody that recognizes a sialylated sugar chain designated Krebs von den Lungen‐6 (KL‐6). KL‐6 is a high–molecular‐weight glycoprotein classified as a human MUC1 mucin. The aim of this study was to determine whether KL‐6 expression in tumors correlates with circulating KL‐6 levels and whether circulating KL‐6 has any prognostic value in patients with surgically resected non‐small cell lung cancer (NSCLC). Immunohistochemical analysis of KL‐6 expression was performed on 103 NSCLC tissues, and its associations with serum KL‐6 levels and survival were examined. We also evaluated whether KL‐6 expression patterns and/or serum KL‐6 levels could predict prognosis in these NSCLC patients. Immunohistochemical analysis of KL‐6 in NSCLC tissues showed that a depolarized KL‐6 expression pattern was associated with a high level of circulating KL‐6 and a poor prognosis in NSCLC patients who underwent curative surgery. Furthermore, a high circulating KL‐6 level was associated with both poorer progression‐free survival (PFS) and overall survival (OS), and multivariate analyses confirmed its independent prognostic value for both PFS and OS (p = 0.041 and 0.023, respectively). Our data suggest that preoperative serum KL‐6 level reflects KL‐6 expression patterns in NSCLC tissue, and can serve as a useful prognostic biomarker in NSCLC patients who undergo curative surgery.
The importance of integrin‐linked kinase in the regulation of bladder cancer invasion
Authors: Matsui Yoshiyuki , Assi Kiran , Ogawa Osamu , Raven Peter A. , Dedhar Shoukat , Gleave Martin E. , Salh Baljinder , So Alan I.
Published: February 2011

It is important to understand the molecular mechanisms of bladder cancer progression not only to prevent cancer progression but also to detect new therapeutic targets against advanced bladder cancer. The integrin‐linked kinase (ILK) is a major signaling integrator in mammalian cells and plays an important role in epithelial–mesenchymal transition (EMT) of human cancers, but its mechanisms are not completely understood. In this study, we investigated the importance and mechanisms of ILK in bladder cancer progression. When the expression of ILK in bladder cancer cell lines and N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine (BBN)‐induced murine bladder cancer was evaluated, ILK has a tendency to be overexpressed in invasive cell lines and invasive BBN‐induced murine bladder cancer. Overexpression of ILK in 253J bladder cancer cells suppressed E‐cadherin expression, resulting in the promotion of cell invasion. Conversely, ILK knockdown by siRNA suppresses cell invasion in invasive bladder cancer cells through the regulation of E‐cadherin or matrix metalloprotease 9 (MMP‐9). To regulate E‐cadherin expression, our results showed that the glycogen synthase kinase 3β (GSK3β)‐Zeb1 pathway may play an important role downstream of ILK. Finally, the results of a human bladder tissue microarray (TMA) showed that ILK expression correlates with the invasiveness of human bladder cancer. Our study suggests that ILK is overexpressed in invasive bladder cancer and plays an important role in the EMT of bladder cancer via the control of E‐cadherin and MMP‐9 expression. ILK may be a new molecular target to suppress tumor progression in advanced and high‐risk bladder cancer patients.
Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells
Authors: Liby Tiera A. , Spyropoulos Perry , Buff Lindner Haley , Eldridge Juanita , Beeson Craig , Hsu Tien , Muise‐Helmericks Robin C.
Published: February 2011

The PI3 kinase/Akt pathway is commonly deregulated in human cancers, functioning in such processes as proliferation, glucose metabolism, survival and motility. We have previously described a novel function for one of the Akt isoforms (Akt3) in primary endothelial cells: the control of VEGF‐induced mitochondrial biogenesis. We sought to determine if Akt3 played a similar role in carcinoma cells. Because the PI3 kinase/Akt pathway has been strongly implicated as a key regulator in ovarian carcinoma, we tested the role of Akt3 in this tumor type. Silencing of Akt3 by shRNA did not cause an overt reduction in mitochondrial gene expression in a series of PTEN positive ovarian cancer cells. Rather, we find that blockade of Akt3, results in smaller, less vascularized tumors in a xenograft mouse model that is correlated with a reduction in VEGF expression. We find that blockade of Akt3, but not Akt1, results in a reduction in VEGF secretion and retention of VEGF protein in the endoplasmic reticulum (ER). The reduction in secretion under conditions of Akt3 blockade is, at least in part, due to the down regulation of the resident golgi protein and reported tumor cell marker, RCAS1. Conversely, over‐expression of Akt3 results in an increase in RCAS1 expression and in VEGF secretion. Silencing of RCAS1 using siRNA inhibits VEGF secretion. These findings suggest an important role for Akt3 in the regulation of RCAS1 and VEGF secretion in ovarian cancer cells.
Low‐dose docetaxel enhances the sensitivity of S‐1 in a xenograft model of human castration resistant prostate cancer
Authors: Hasegawa Masanori , Miyajima Akira , Kosaka Takeo , Yasumizu Yota , Tanaka Nobuyuki , Maeda Takahiro , Shirotake Suguru , Ide Hiroki , Kikuchi Eiji , Oya Mototsugu
Published: February 2011

S‐1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5‐Fluorouracil (5‐FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S‐1 or S‐1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4‐2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4‐2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5‐FU, than the ADPC specimens and LNCaP cells. In vitro, C4‐2 cells exhibited higher sensitivity to 5‐FU than LNCaP cells. In C4‐2 xenograft model, S‐1 monotherapy suppressed tumor growth and low‐dose DOC enhanced the anti‐tumor effect of S‐1. In vitro, low‐dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down‐regulation of TS in C4‐2 cells, and down‐regulation of TS is considered to be responsible for the synergistic effect of S‐1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5‐FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options.
Potentiation of tumor radiotherapy by a radiation‐inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts
Authors: Wang Haibo , Song Xin , Zhang He , Zhang Jianjun , Shen Xiaodi , Zhou Yixiong , Fan Xianqun , Dai Liyan , Qian Guanxiang , Hoffman Andrew R. , Hu Ji‐Fan , Ge Shengfang
Published: February 2011

The p53 tumor suppressor pathway is impaired in more than 90% of cervical cancers and cancer‐derived cell lines as a result of infection by human papillomavirus (HPV). The HPV E6 oncoprotein forms complexes with p53 and promotes its degradation via ubiquitin‐dependent mechanism. In our study, we attempted to improve the clinical outcomes of this combined therapy by modifying the p53‐targeted adenovirus to become radiation‐responsive. The antitumor adenovirus was constructed by inserting a radiation‐responsive expression cassette composed of the promoter of early growth response‐1 (Egr‐1) and the proapoptotic protein TRAIL. We showed that the addition of adenovirus containing Egr‐1/TRAIL significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, intratumoral administration of the Egr‐1/TRAIL adenovirus followed by radiation significantly reduced tumor growth and enhanced tumor survival. Our Egr‐1/TRAIL adenoviral gene product may offer a novel “one‐two punch” tumor therapy for cervical cancers not only by potentiating radiation treatment but also by preserving p53 defect‐specific tumor killing of the oncolytic adenovirus.
Effect of hypoxia on the expression of iron regulatory proteins 1 and the mechanisms involved
Authors: Luo Qian‐Qian , Wang Dan , Yu Min‐Yan , Zhu Li
Published: February 2011

Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Iron regulatory proteins (IRPs, IRP1 and IRP2) are master regulators of cellular iron metabolism. Hypoxia triggers a broad range of gene responses that are primarily mediated by hypoxia‐inducible factor‐1 (HIF‐1). In this study, we have shown that hypoxia could not only upregulate the expression of hypoxia inducible factor‐1 but also downregulate the expression of IRP1. However, the molecular mechanisms that govern the IRP1 response to hypoxia are not known. Herein we suggested that HIF/HRE system was an essential link between IRP1 and hypoxia. The HRE of IRP1 5′‐regulation regions could combine with HIF‐1 in vitro. Dual‐luciferase reporter assay showed that IRP1 was directly downregulated by HIF/HRE system. © 2011 IUBMB IUBMB Life, 63(2): 120–128, 2011
Heparin plays a key regulatory role via a p53/FAK‐dependent signaling in melanoma cell adhesion and migration
Authors: Chalkiadaki Georgia , Nikitovic Dragana , Berdiaki Aikaterini , Katonis Pavlos , Karamanos Nikos K. , Tzanakakis George N.
Published: February 2011

Heparin and its various derivatives affect cancer progression in humans. In this study, we show that heparin uptaken intracellularly by melanoma cells activated a signaling cascade, which in turn inhibited melanoma cell adhesion and migration. The reduced ability of M5 cells to adhere onto the fibronectin (FN) substrate was directly correlated to a decrease in the expression of focal adhesion kinase (FAK), which is a key regulator of melanoma motility. Cell treatment with heparin caused a marked downregulation in FAK expression (P ≤ 0.01). This is followed by an analogous inhibition of both constitutive and FN‐induced FAK Y397‐phosphorylation (P ≤ 0.01). Moreover, heparin stimulated the p53 expression (P ≤ 0.001) of M5 cells and its increased accumulation in the nucleus. This favors a decrease in FAK promoter activation and explains the reduced FAK transcript and protein levels. In conclusion, the results of this study clearly demonstrate that the action of heparin in the regulation of melanoma cell adhesion and migration involves a p53/FAK/signaling pathway, which may be of importance in molecular targeted therapy of the disease. © 2011 IUBMB IUBMB Life, 63(2): 109–119, 2011
The mammalian zinc finger transcription factor Krüppel‐like factor 3 (KLF3/BKLF)
Authors: Pearson Richard C.M. , Funnell Alister P.W. , Crossley Merlin
Published: February 2011

KLF3 is a member of the Krüppel‐like factor (KLF) family of transcription factors. These proteins are classified by the presence of three C‐terminal C2H2 zinc fingers that allow sequence‐specific binding to CACCC boxes and GC‐rich motifs found in the promoters, enhancers, and other control regions of target genes. KLFs have diverse biological roles, regulating proliferation, differentiation, and apoptosis in many tissues throughout development. KLF3 is a transcriptional repressor that binds the cofactor C‐terminal binding protein, which in turn recruits a large repressor complex to mediate transcriptional silencing. In addition to an understanding of the molecular mechanisms that allow KLF3 to regulate the expression of its target genes, the biological roles of this transcription factor are now being defined. In agreement with the widespread expression pattern of this transcription factor, it is becoming clear that KLF3 is an important regulator of several biological processes, including adipogenesis, erythropoiesis, and B cell development. © 2011 IUBMB IUBMB Life, 63(2): 86–93, 2011
A novel single‐chain variable fragment antibody against FGF‐1 inhibits the growth of breast carcinoma cells by blocking the intracrine pathway of FGF‐1
Authors: Shi Heng‐Liang , Yang Tao , Deffar Khalissa , Dong Chun‐Guang , Liu Jing‐Ying , Fu Chun‐Ling , Zheng Da‐Xue , Qin Bo , Wang Jun‐Jie , Wang Xing‐Zhi , Zhu Xiao‐Juan
Published: February 2011

The fibroblast growth factors (FGFs) are important for embryo development, wound healing, hematopoiesis, and angiogenesis. FGF‐1, a member of FGF family, is involved in both receptor‐dependent pathways and an intracrine pathway. Studies have recently shown that FGF‐1 is overexpressed in the early stages of several kinds of cancer. Thus, FGF‐1 is a candidate for cancer immunotargeting. To study the potential use of therapeutic antibodies against FGF‐1, a monoclonal hybridoma 1C9 secreting monoclonal antibody specific for FGF‐1 was developed. Then, a single‐chain variable fragment (scFv) antibody was genetically engineered from hybridama 1C9. The binding of the scFv1C9 to the antigen FGF‐1 was demonstrated by ELISA and immunoprecipitation assays. Functional analysis showed that the overexpressed scFv1C9 in MCF‐7 cells targeted endogenous FGF‐1 and prevented the translocation of FGF‐1 into the nucleus, resulting in the blockade of the intracrine pathway of FGF‐1, which caused the G1 arrest by p21 up‐regulation. These results suggest that the generated scFv1C9 is an effective inhibitor of the intracrine pathway of FGF‐1 and has a potential application as anti‐tumoral agent in breast cancer. © 2011 IUBMB IUBMB Life, 63(2): 129–137, 2011
Physiological role and potential clinical interest of mycobacterial pigments
Authors: Robledo Jaime A. , Murillo Ana M. , Rouzaud Francois
Published: February 2011

The production of pigments by bacterial colonies has sparked interest among bacteriologists since the 19th century, whether for taxonomy or, in the case of carotenoids for their association with antibiotics resistance. Mycobacteria have gained a very special place in the bacterial world due to their clinical importance. Alone, Mycobacterium tuberculosis is responsible for about two million deaths annually worldwide making tuberculosis one of the most influential diseases in the history of mankind. Almost half of the Nontuberculous Mycobacteria species identified are associated with opportunistic infections in animals and humans. Mycobacterial pigmentary characteristics started to be documented about 80 years ago; but to date, their main use has been only for limited taxonomic and identification purposes. While mycobacterial pigments, especially carotenoids have been clearly associated with cellular photoprotection and survival, the regulation of their production and their physiological role have been largely unstudied. Recent advances in deciphering mycobacterial genomes and characterization of carotenoid synthesis genes, combined with an urgent need for innovative approaches to understand Mycobacterium tuberculosis pathogenic properties open new avenues for exciting research opportunities that might lead to new therapeutic strategies against a devastating secular disease. © 2011 IUBMB IUBMB Life, 63(2): 71–78, 2011
miR‐210: More than a silent player in hypoxia
Authors: Devlin Cecilia , Greco Simona , Martelli Fabio , Ivan Mircea
Published: February 2011

Multiple studies have consistently established that miR (microRNA)‐210 induction is a feature of the hypoxic response in both normal and transformed cells. Here, we discuss the emerging biochemical functions of this miRNA and anticipate potential clinical applications. miR‐210 is a robust target of hypoxia‐inducible factor, and its overexpression has been detected in a variety of cardiovascular diseases and solid tumors. High levels of miR‐210 have been linked to an in vivo hypoxic signature and associated with adverse prognosis in cancer patients. A wide spectrum of miR‐210 targets have been identified, with roles in mitochondrial metabolism, angiogenesis, DNA repair, and cell survival. Such targets may broadly affect the evolution of tumors and other pathological settings, such as ischemic disorders. Harnessing the knowledge of miR‐210's actions may lead to novel diagnostic and therapeutic approaches. © 2011 IUBMB IUBMB Life, 63(2): 94–100, 2011
Signaling to the ribosome in cancer—It is more than just mTORC1
Authors: Hannan Katherine M. , Sanij Elaine , Hein Nadine , Hannan Ross D. , Pearson Richard B.
Published: February 2011

Signaling network controlling ribosome synthesis and function by Katherine M. Hannan et al., pp 79–85.
Cytocompatibility study of a natural biomaterial crosslinker—Genipin with therapeutic model cells
Authors: Wang Chunming , Lau Ting Ting , Loh Wei Li , Su Kai , Wang Dong‐An
Published: February 2011

Genipin has been widely used as a natural crosslinker to substitute chemical crosslinkers such as glutaraldehyde to crosslink various biomaterials like gelatin, collagen, and chitosan. However, there are contradicting views on the cytotoxicity and safety of genipin in tissue engineering. Therefore in this study, we aimed to evaluate the toxicity of genipin on skeletal tissues cells—osteoblasts and chondrocytes as they are also representatives of typical anchorage‐dependent cells (ADCs) and nontypical ADCs. Results suggest that genipin toxicity is dose dependent and acute but not time dependent on both osteoblasts and chondrocytes. In particular, chondrocytes exhibit substantial alterations in the gene expression when exposed to Maximum nontoxic concentration (MaxNC) of genipin but there were no significant changes in the genes tested in osteoblasts. Since osteoblasts are typical ADCs, cellular focal adhesion assessment was carried out with F‐actin being more contracted and unorganized when exposed to minimum toxic concentration (MinTC) of genipin. The mechanisms involved in cell deaths in both cell types are believed to be similar and hence using osteoblast as the model, cells were stained positive for Annexin‐V and Reactive oxygen species (ROS) level were elevated at MinTC of genipin. Collectively, genipin induced cell apoptosis via ROS production, and apparently, gene expressions could also be altered at MaxNC. For this reason, we recommend the dose of genipin to be controlled within 0.5 mM. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater , 2011.
The elimination of free radicals in irradiated UHMWPEs with and without vitamin E stabilization by annealing under pressure
Authors: Oral Ebru , Ghali Bassem W. , Muratoglu Orhun K.
Published: February 2011

Radiation crosslinking of ultrahigh molecular weight polyethylene (UHMWPE) has been used to decrease the wear of joint implant bearing surfaces. While radiation crosslinking has been successful in decreasing femoral head penetration into UHMWPE acetabular liners in vivo, postirradiation thermal treatment of the polymer is required to ensure the oxidative stability of joint implants in the long term. Two types of thermal treatment have been used: (i) annealing below the melting point preserves the mechanical properties but the residual free radicals trapped in the crystalline regions are not completely eliminated, leading to oxidation in the long‐term and (ii) annealing above the melting point (melting) eliminates the free radicals but leads to a decrease in mechanical properties through loss of crystallinity during the melting process. In this study, we hypothesized that free radicals could be reduced by annealing below the melting point under pressure effectively without melting due to the elevation of the melting point. By avoiding the complete melting of UHMWPE, mechanical properties would be preserved. Our hypothesis tested positive in that we found the radiation‐induced free radicals to be markedly reduced (below the detection limit of state‐of‐the‐art electron spin resonance) by thermal annealing under pressure in radiation crosslinked virgin UHMWPE and UHMWPE/vitamin‐E blends without loss of mechanical properties. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
An evaluation of electrical stimulation for improving periprosthetic attachment
Authors: Isaacson Brad M. , Brunker Lucille B. , Brown Amalia A. , Beck James P. , Burns Gregory L. , Bloebaum Roy D.
Published: February 2011

Transcutaneous osseointegrated implants (TOI) have been shown to improve functionality for patients with limb loss by allowing direct skeletal attachment between an exoprosthesis and host bone. However, a lengthy rehabilitation period has limited the expansion of TOI and may be accelerated with electrical stimulation. The purpose of this study was to determine the ability of direct current (DC) cathode stimulation to enhance osseointegration of intramedullary implants in skeletally matured rabbits. Bilateral implants were inserted in the hind limbs of 25 adult female rabbits. The left hind limb of each animal was continually stimulated with a potential difference of 0.55 volts based on finite element analysis predictions. After sacrifice, the limbs were divided into two groups: Group I for histology and Group II for biomechanical testing. The bone‐implant construct was evaluated in the Group I animals using appositional bone index (ABI), mineral apposition rates (MAR), histological staining, and scanning electron microscopy (SEM). Group II implants were sectioned and subjected to mechanical push‐out tests. Data indicated no statistical differences for ABI, MAR, and porosity between the electrically stimulated implants (ESI) and the unstimulated control implants (UCI) at three weeks and six weeks. Higher mechanical push‐out forces were observed in the UCI group at six weeks (p = 0.034). Data indicated that DC cathode stimulation may improve suboptimal implant “fit and fill” as an increase in trabecular bone was noted around the cathode in the ESI group. However, longer time duration animal studies and variations in electrical modalities may be required before electrically induced osseointegration becomes clinically feasible. © 2011 Wiley Periodicals, Inc.* J Biomed Mater Res Part B: Appl Biomater, 2011.