bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Antibiofilm Chemotherapy Targets Exopolysaccharide Synthesis and Stress Tolerance in Streptococcus mutans To Modulate Virulence Expression
In Vivo
Authors: Falsetta Megan L. , Klein Marlise I. , Lemos José A. , Silva Bruno B. , Agidi Senyo , Scott-Anne Kathy K. , Koo Hyun 
Published: September 2012

ABSTRACT

Fluoride is the mainstay of dental caries prevention, and yet current applications offer incomplete protection and may not effectively address the infectious character of the disease. Therefore, we evaluated the effectiveness of a novel combination therapy (CT; 2 mM myricetin, 4 mM
tt
-farnesol, 250 ppm of fluoride) that supplements fluoride with naturally occurring, food-derived, antibiofilm compounds. Treatment regimens simulating those experienced clinically (twice daily for ≤60 s) were used both
in vitro
over a saliva-coated hydroxyapatite biofilm model and
in vivo
with a rodent model of dental caries. The effectiveness of CT was evaluated based on the incidence and severity of carious lesions (compared to fluoride or vehicle control). We found that CT was superior to fluoride (positive control,
P
< 0.05); topical applications dramatically reduced caries development in Sprague-Dawley rats, all without altering the
Streptococcus mutans
or total populations within the plaque. We subsequently identified the underlying mechanisms through which applications of CT modulate biofilm virulence. CT targets expression of key
Streptococcus mutans
genes during biofilm formation
in vitro
and
in vivo
. These are associated with exopolysaccharide matrix synthesis (
gtfB
) and the ability to tolerate exogenous stress (e.g.,
sloA
), which are essential for cariogenic biofilm assembly. We also identified a unique gene (
SMU.940
) that was severely repressed and may represent a potentially novel target; its inactivation disrupted exopolysaccharide accumulation and matrix development. Altogether, CT may be clinically more effective than current anticaries modalities, targeting expression of bacterial virulence associated with pathogenesis of the disease. These observations may have relevance for development of enhanced therapies against other biofilm-dependent infections.
Evaluation of Single and Combination Therapies with Tenofovir Disoproxil Fumarate and Emtricitabine
In Vitro
and in a Robust Mouse Model Supporting High Levels of Hepatitis B Virus Replication
Authors: Schinazi Raymond F. , Bassit Leda , Clayton Marcia M. , Sun Bill , Kohler James J. , Obikhod Aleksandr , Arzumanyan Alla , Feitelson Mark A. 
Published: September 2012

ABSTRACT

Next-generation therapies for chronic hepatitis B virus (HBV) infection will involve combinations of established and/or experimental drugs. The current study investigated the
in vitro
and
in vivo
efficacy of tenofovir disoproxil fumarate (TDF) and/or emtricitabine [(−)-FTC] alone and in combination therapy for HBV infection utilizing the HepAD38 system (human hepatoblastoma cells transfected with HBV). Cellular pharmacology studies demonstrated increased levels of (−)-FTC triphosphate with coincubation of increasing concentrations of TDF, while (−)-FTC had no effect on intracellular tenofovir (TFV) diphosphate levels. Quantification of extracellular HBV by real-time PCR from hepatocytes demonstrated the anti-HBV activity with TDF, (−)-FTC, and their combination. Combination of (−)-FTC with TDF or TFV (ratio, 1:1) had a weighted average combination index of 0.7 for both combination sets, indicating synergistic antiviral effects. No cytotoxic effects were observed with any regimens. Using an
in vivo
murine model which develops robust HBV viremia in nude mice subcutaneously injected with HepAD38 cells, TDF (33 to 300 mg/kg of body weight/day) suppressed virus replication for up to 10 days posttreatment. At 300 mg/kg/day, (−)-FTC strongly suppressed virus titers to up to 14 days posttreatment. Combination therapy (33 mg/kg/day each drug) sustained suppression of virus titer/ml serum (<1 log
10
unit from pretreatment levels) at 14 days posttreatment, while single-drug treatments yielded virus titers 1.5 to 2 log units above the initial virus titers. There was no difference in mean alanine aminotransferase values or mean wet tumor weights for any of the groups, suggesting a lack of drug toxicity. TDF–(−)-FTC combination therapy provides more effective HBV suppression than therapy with each drug alone.
CD22 Antigen Is Broadly Expressed on Lung Cancer Cells and Is a Target for Antibody-Based Therapy
Authors: Tuscano Joseph M. , Kato Jason , Pearson David , Xiong Chengyi , Newell Laura , Ma Yunpeng , Gandara David R. , O'Donnell Robert T. 
Published: September 2012

AbstractMost patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasis and extended overall survival. The finding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets. Cancer Res; 72(21); 5556–65. ©2012 AACR.
OTX2 Represses Myogenic and Neuronal Differentiation in Medulloblastoma Cells
Authors: Bai Ren-Yuan , Staedtke Verena , Lidov Hart G. , Eberhart Charles G. , Riggins Gregory J. 
Published: September 2012

Abstract
The brain development transcription factor OTX2 is overexpressed and/or genomically amplified in most medulloblastomas, but the mechanistic basis for its contributions in this setting are not understood. In this study, we identified OTX2 as a transcriptional repressor and a gatekeeper of myogenic and neuronal differentiation in medulloblastoma cells. OTX2 binds to the MyoD1 core enhancer through its homeobox domain, and the remarkable repressor activity exhibited by the homeobox domain renders OTX2 transcriptionally repressive. RNA interference–mediated attenuation of OTX2 expression triggered myogenic and neuronal differentiation in vitro and prolonged the survival in an orthotopic medulloblastoma mouse model. Conversely, inducing myogenic conversion of medulloblastoma cells led to the loss of OTX2 expression. In medullomyoblastoma, a medulloblastoma subtype containing muscle elements, myogenic cells share cytogenetic signatures with the primitive tumor cells and OTX2 expression was lost in the differentiated myogenic cells. Thus, OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. Together, our findings illustrate the origin of muscle cells in medullomyoblastomas and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential. Cancer Res; 72(22); 5988–6001. ©2012 AACR.
SIRT1 Pathway Dysregulation in the Smoke-Exposed Airway Epithelium and Lung Tumor Tissue
Authors: Beane Jennifer , Cheng Luis , Soldi Raffaella , Zhang Xiaohui , Liu Gang , Anderlind Christina , Lenburg Marc E. , Spira Avrum , Bild Andrea H. 
Published: September 2012

Abstract
Cigarette smoke produces a molecular field of injury in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly upregulated in cytologically normal bronchial airway epithelial cells from active smokers compared with nonsmokers. In contrast, this activity is strikingly downregulated in non–small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and downregulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Furthermore, our findings suggest that the airway gene expression signatures derived in this study can provide novel insights into signaling pathways altered in the “field of injury” induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer. Cancer Res; 72(22); 5702–11. ©2012 AACR.
O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme
Authors: Chahal Manik , Abdulkarim Bassam , Xu Yaoxian , Guiot Marie-Christine , Easaw Jacob C. , Stifani Nicolas , Sabri Siham 
Published: September 2012

AbstractThe dismal prognosis of glioblastoma multiforme (GBM) is mostly due to the high propensity of GBM tumor cells to invade. We reported an inverse relationship between GBM angiogenicity and expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), which has been extensively characterized for its role in resistance to alkylating agents used in GBM treatment. In the present study, given the major role of angiogenesis and invasion in GBM aggressiveness, we aimed to investigate the relationship between MGMT expression and GBM invasion. Stable overexpression of MGMT in the U87MG cell line significantly decreased invasion, altered expression of invasion-related genes, decreased expression of α5β1 integrin and focal adhesion kinase, and reduced their spindle-shaped morphology and migration compared with the empty vector control. Conversely, short hairpin RNA-mediated stable knockdown of MGMT or its pharmacologic depletion in the MGMT-positive T98G cell line were required for increased invasion. The inverse relationship between MGMT and invasion was further validated in primary GBM patient-derived cell lines. Using paraffin-embedded tumors from patients with newly diagnosed GBM (n = 59), tumor MGMT promoter hypermethylation (MGMT gene silencing) was significantly associated with increased immunohistochemical expression of the proinvasive matricellular protein secreted protein acidic and rich in cysteine (SPARC; P = 0.039, χ2 test). Taken together, our findings highlight for the first time the role of MGMT as a negative effector of GBM invasion. Future studies are warranted to elucidate the role of SPARC in the molecular mechanisms underlying the inverse relationship between MGMT and GBM invasion and the potential use of MGMT and SPARC as biomarkers of GBM invasion. Mol Cancer Ther; 11(11); 2440–50. ©2012 AACR.
Effects of Extreme Temperatures on Years of Life Lost for Cardiovascular Deaths: A Time Series Study in Brisbane, Australia
Authors: Huang Cunrui , Barnett Adrian G. , Wang Xiaoming , Tong Shilu 
Published: September 2012

Background—
Extreme temperatures are associated with cardiovascular disease (CVD) deaths. Previous studies have investigated the relative CVD mortality risk of temperature, but this risk is heavily influenced by deaths in frail elderly people. To better estimate the burden of extreme temperatures, we estimated their effects on years of life lost due to CVD.

Methods and Results—
The data were daily observations on weather and CVD mortality for Brisbane, Australia, between 1996 and 2004. We estimated the association between daily mean temperature and years of life lost due to CVD, after adjusting for trend, season, day of the week, and humidity. To examine the nonlinear and delayed effects of temperature, a distributed lag nonlinear model was used. The model’s residuals were examined to investigate whether there were any added effects due to cold spells and heat waves. The exposure–response curve between temperature and years of life lost was U-shaped, with the lowest years of life lost at 24°C. The curve had a sharper rise at extremes of heat than of cold. The effect of cold peaked 2 days after exposure, whereas the greatest effect of heat occurred on the day of exposure. There were significantly added effects of heat waves on years of life lost.

Conclusions—
Increased years of life lost due to CVD are associated with both cold and hot temperatures. Research on specific interventions is needed to reduce temperature-related years of life lost from CVD deaths.
ANDRO: An Argo-Based Deep Displacement Dataset
Authors: Ollitrault Michel , Rannou Jean-Philippe 
Published: September 2012

Abstract
During the first decade of the twenty-first century, more than 6000 Argo floats have been launched over the World Ocean, gathering temperature and salinity data from the upper 2000 m, at a 10-day or so sampling period. Meanwhile their deep displacements can be used to map the ocean circulation at their drifting depth (mostly around 1000 m). A comprehensive processing of the whole Argo dataset collected prior to 1 January 2010 has been performed to produce a world-wide dataset of deep displacements. This numerical atlas, named ANDRO, after a traditional dance of Brittany meaning a swirl, comprises some 600 000 deep displacements. These displacements, based on Argo or GPS surface locations only, have been fully checked and corrected for possible errors found in the public Argo data files (due to incorrect decoding or instrumental failure). Park pressures measured by the floats while drifting at depth are preserved in ANDRO (less than 2% of the park pressures are unknown): 63% of the float displacements are in the layer (900, 1100) dbar with a good (more or less uniform) degree of coverage of all the oceans, except around Antarctica (south of 60°S). Two deeper layers—(1400, 1600) and (1900, 2100) dbar—are also sampled (11% and 8% of the float displacements, respectively) but with poorer geographical coverage. Grounded cycles (i.e., if the float hits the sea bottom) are excluded. ANDRO is available online as an ASCII file.
What Percentage of Western North Pacific Tropical Cyclones Form within the Monsoon Trough?
Authors: Molinari John , Vollaro David 
Published: September 2012

Abstract
It is frequently stated that 70%–80% of western North Pacific tropical cyclones form “within the monsoon trough,” but without an objective definition of the term. Several definitions are tested here. When the monsoon trough (MT) is defined as the contiguous region where long-term (1988–2010) mean July–November 850-hPa relative vorticity is positive, 73% of all July–November tropical cyclones form within the MT. This percentage varies interannually, however, from as low as 50% to nearly 100%. The percentage correlates with the Niño-3.4 index, with more storms forming within the MT during warm periods. When the MT is defined instead using long-term monthly mean ζ850, more than 80% of tropical cyclones form within the MT in all months except July and August, when more than 30% of storms form poleward of the MT. It is hypothesized that the known peak in the frequency of upper-tropospheric midlatitude wave breaking in July and August is responsible. It is argued that any long-term mean provides a suitable definition of the MT. Defining it on less than seasonal time scales, however, creates a lack of conceptual separation between the MT and other tropical disturbances such as the MJO, equatorial waves, and easterly waves. The term monsoon trough should represent a climatological feature that provides an asymmetric background state within which other disturbances evolve.
Control Task Substitution in Semiautomated Driving
Authors: Carsten Oliver , Lai Frank C. H. , Barnard Yvonne , Jamson A. Hamish , Merat Natasha 
Published: September 2012

Objective: The study was designed to show how driver attention to the road scene and engagement of a choice of secondary tasks are affected by the level of automation provided to assist or take over the basic task of vehicle control. It was also designed to investigate the difference between support in longitudinal control and support in lateral control. Background: There is comparatively little literature on the implications of automation for drivers’ engagement in the driving task and for their willingness to engage in non-driving-related activities. Method: A study was carried out on a high-level driving simulator in which drivers experienced three levels of automation: manual driving, semiautomated driving with either longitudinal or lateral control provided, and highly automated driving with both longitudinal and lateral control provided. Drivers were free to pay attention to the roadway and traffic or to engage in a range of entertainment and grooming tasks. Results: Engagement in the nondriving tasks increased from manual to semiautomated driving and increased further with highly automated driving. There were substantial differences in attention to the road and traffic between the two types of semiautomated driving. Conclusion: The literature on automation and the various task analyses of driving do not currently help to explain the effects that were found. Lateral support and longitudinal support may be the same in terms of levels of automation but appear to be regarded rather differently by drivers.
Validation of the Polish version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care in patients with advanced cancer
Authors: Leppert Wojciech , Majkowicz Mikolaj 
Published: September 2012

Background: Limited data exist on the validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care in advanced cancer patients. Aim: To adapt the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care to the Polish clinical setting and to evaluate its psychometric properties in advanced cancer patients. Design: Two quality-of-life measurements were performed at baseline and after 7 days. The concurrent validity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care was established by the Pearson correlation coefficients with the modified Edmonton Symptom Assessment System, the Karnofsky Performance Status and the Brief Pain Inventory – Short Form. Reliability was assessed using Cronbach’s alpha coefficients and the Spearman correlation coefficients of the baseline and of the second measurement of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care items. Setting/participants: A total of 160 consecutive patients in one academic palliative medicine centre were included. Results: A total of 129 patients completed the study. The concurrent validity revealed significant correlations of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care pain scale with the Brief Pain Inventory – Short Form, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care symptom items with the modified Edmonton Symptom Assessment System and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care functional scales with the Karnofsky Performance Status scores. High Cronbach’s alpha and standardised Cronbach’s alpha values were found in the case of both functional (range: 0.830–0.925; 0.830–0.932) and symptom scales (range: 0.784–0.940; 0.794–0.941) of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care, respectively. The Spearman correlation coefficients between the first and the second measurements were significant ( p < 0.0001) for all European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care items. Conclusions: Polish version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 15 – Palliative Care is a valid and reliable tool recommended for quality-of-life assessment and monitoring in advanced cancer patients.
Risk Management in Trading and Investment Portfolios
Authors: Al Janabi Mazin A.M. 
Published: September 2012

The aim of this article is to bridge the gap in equity trading risk management literatures and particularly from the perspective of emerging and illiquid markets, such as in the context of the Gulf Cooperation Council (GCC) financial markets. In this article, we demonstrate a practical approach for the measurement and control of market risk exposure for financial trading portfolios that contain several illiquid equity securities during the unwinding (close-out) period. This approach is based on the renowned concept of Value-at-Risk (VaR) along with the development of an optimisation risk algorithm utilising matrix-algebra technique. Our thorough asset market risk modelling-algorithm can simultaneously handle VaR analysis under normal and severe market conditions, besides it takes into account the effects of illiquidity and short-sales of traded equity securities. In order to illustrate the proper use of VaR and stress-testing methods, real-world structured modelling techniques of trading risk management are presented for the GCC financial markets. To this end, comprehensive simulation case studies are accomplished with the objective of constructing a realistic framework for trading risk measurement and control in addition to the instigation of a risk optimisation algorithm-process for the computation of maximum authorised VaR risk-budgeting limits. JEL Classification: C10, C13, G20, G28