bluuebunny/crossref_metadata_2025_split huggingface dataset:
Practical reliability analysis of slope stability by advanced Monte Carlo simulations in a spreadsheet
Authors: Wang Yu , Cao Zijun , Au Siu-Kui 
Published: December 2010

This paper develops a Monte Carlo simulation (MCS)-based reliability analysis approach for slope stability problems and utilizes an advanced MCS method called “subset simulation” for improving efficiency and resolution of the MCS at relatively small probability levels. Reliability analysis is operationally decoupled from deterministic slope stability analysis and implemented using a commonly available spreadsheet software, Microsoft Excel. The reliability analysis spreadsheet package is validated through comparison with other reliability analysis methods and commercial software. The spreadsheet package is then used to explore the effect of spatial variability of the soil properties and critical slip surface. It is found that, when spatial variability of soil properties is ignored by assuming perfect correlation, the variance of the factor of safety (FS) is overestimated, which may result in either over (conservative) or under (unconservative) estimation of the probability of failure (Pf = P(FS < 1)). When the spatial variability of soil properties is considered, the critical slip surface varies spatially and such spatial variability should be properly accounted for. Otherwise, the probability of failure can be significantly underestimated and unconservative.
Landslide hazard assessment of the 2008 Wenchuan earthquake: a case study in Beichuan area
Authors: Tang Chuan , Zhu Jing , Qi Xin 
Published: December 2010

The Wenchuan earthquake (magnitude Ms = 8.0) of 12 May 2008 triggered widespread and large-scale landslides over an area of about 50 000 km2. A study was undertaken to determine the primary factors associated with seismic landslide occurrence. An index-based approach used to assess earthquake-triggered landslide hazard in the central part of the Wenchuan earthquake area affected is described. Slope gradient, relief amplitude, lithology, bedding–slope relations, fault proximity, stream proximity, and antecedent rainfall are recognized as factors that may have had an important influence on landslide occurrence. The assessment of the influence of each of these factors is presented through use of a series of maps showing areas of low, moderate, high, and very high landslide hazard. Areas identified as having “very high and high landslide hazard” were located along the earthquake-source fault and along both banks of the Jian River. The role of rainfall is very significant for future landslide occurrence in the earthquake area. The results of this study will assist decision makers in the selection of safe sites during the reconstruction process. The maps can also be used for landslide risk management in the study area.
Making the Investigational Oncology Pipeline More Efficient and Effective: Are We Headed in the Right Direction?
Authors: LoRusso Patricia M. , Anderson Aparna B. , Boerner Scott A. , Averbuch Steven D. 
Published: December 2010

Abstract
Advances in our knowledge of the molecular mechanisms involved in cancer biology have contributed to an increase in novel target-specific oncology therapeutics. Unfortunately, clinical development of new drugs is an expensive and slow process, and the patient and financial resources needed to study the vast number of potential therapies are limited, requiring novel approaches to clinical trial design and patient recruitment. In addition, traditional efficacy endpoints may not be adequate to fully determine the therapeutic worth of the new classes of targeted agents. In this new era of drug development, it has become increasingly clear that new clinical trial design paradigms that examine nontraditional endpoints have become necessary to assist in prioritizing the development of the most promising agents. It is also vital that individual patient management be considered, and the subpopulations of patients most likely to derive benefit or experience harm from a new therapy be identified as early as possible. Phase I and II clinical trials allow investigators doing clinical research the opportunity to define these critical endpoints and subpopulations early on, before conducting large-scale randomized phase III clinical trials, which require an abundance of financial and patient resources. Clin Cancer Res; 16(24); 5956–62. ©2010 AACR.
The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance
Authors: Schreck Karisa C. , Taylor Pete , Marchionni Luigi , Gopalakrishnan Vidya , Bar Eli E. , Gaiano Nicholas , Eberhart Charles G. 
Published: December 2010

AbstractPurpose: Multiple developmental pathways including Notch, Hedgehog, and Wnt are active in malignant brain tumors such as medulloblastoma and glioblastoma (GBM). This raises the possibility that tumors might compensate for therapy directed against one pathway by upregulating a different one. We investigated whether brain tumors show resistance to therapies against Notch, and whether targeting multiple pathways simultaneously would kill brain tumor cells more effectively than monotherapy.Experimental Design: We used GBM neurosphere lines to investigate the effects of a gamma-secretase inhibitor (MRK-003) on tumor growth, and chromatin immunoprecipitation to study the regulation of other genes by Notch targets. We also evaluated the effect of combined therapy with a Hedgehog inhibitor (cyclopamine) in GBM and medulloblastoma lines, and in primary human GBM cultures.Results: GBM cells are at least partially resistant to long-term MRK-003 treatment, despite ongoing Notch pathway suppression, and show concomitant upregulation of Wnt and Hedgehog activity. The Notch target Hes1, a repressive transcription factor, bound the Gli1 first intron, and may inhibit its expression. Similar results were observed in a melanoma-derived cell line. Targeting Notch and Hedgehog simultaneously induced apoptosis, decreased cell growth, and inhibited colony-forming ability more dramatically than monotherapy. Low-passage neurospheres isolated from freshly resected human GBMs were also highly susceptible to coinhibition of the two pathways, indicating that targeting multiple developmental pathways can be more effective than monotherapy at eliminating GBM-derived cells.Conclusions: Notch may directly suppress Hedgehog via Hes1 mediated inhibition of Gli1 transcription, and targeting both pathways simultaneously may be more effective at eliminating GBMs cells. Clin Cancer Res; 16(24); 6060–70. ©2010 AACR.
Value and Cancer Care: Toward an Equitable Future
Authors: Schnipper Lowell E. , Meropol Neal J. , Brock Dan W. 
Published: December 2010

Abstract
Health care expenses in the United States are increasing inexorably. At the current rate of growth, it is anticipated that 20% of the gross national product will consist of health-related expenditures within the next decade. Cancer is the second leading cause of death in the United States, and it is increasing in prevalence because of the aging of the population and the limited number of successful prevention strategies. As the biological characteristics of cancer come into sharper focus, targeted therapies are being developed that offer the promise of increased clinical benefit with fewer toxicities than are associated with conventional treatment. Although spectacular successes are infrequent with this approach, to date, the majority of targeted therapies are modestly effective at best, and extremely costly. This observation suggests that a broadly acceptable definition of value in a cancer therapeutic agent is not at hand, but is sorely needed from the vantage points of the patient and society. A corollary issue of enormous import is how to equitably distribute the health care dollar in the service of achieving the greatest good for the greatest number. Although cancer is responsible for only 5% of the health care budget, its cost is increasing and it can be viewed as paradigmatic when contemplating the problem of equity in health care. Here, a number of concepts are discussed that focus on this goal and its implications for the cancer patient and society at large. Clin Cancer Res; 16(24); 6004–8. ©2010 AACR.
The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations
Authors: Comin-Anduix Begoña , Chodon Thinle , Sazegar Hooman , Matsunaga Douglas , Mock Stephen , Jalil Jason , Escuin-Ordinas Helena , Chmielowski Bartosz , Koya Richard C , Ribas Antoni 
Published: December 2010

Abstract
Purpose: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAFV600E mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma.
Experimental Design: Peripheral blood mononuclear cells (PBMC) and BRAFV600E mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigen-specific T-cell function were analyzed by specific cytokine release and cytotoxicity activity.
Results: The 50% inhibition concentration (IC50) of PLX4032 for resting human PBMC was between 50 and 150 μmol/L compared with an IC50 below 1 μmol/L for sensitive BRAFV600E mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 μmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-μmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 μmol/L.
Conclusions: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAFV600E mutant melanoma. Clin Cancer Res; 16(24); 6040–8. ©2010 AACR.
Drug Transporters and Imatinib Treatment: Implications for Clinical Practice
Authors: Eechoute Karel , Sparreboom Alex , Burger Herman , Franke Ryan M. , Schiavon Gaia , Verweij Jaap , Loos Walter J. , Wiemer Erik A.C. , Mathijssen Ron H.J. 
Published: December 2010

Abstract
Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as “acquired pharmacokinetic drug resistance.” This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations. Clin Cancer Res; 17(3); 406–15. ©2010 AACR.
Toward a Better Understanding of Race and Cancer
Authors: Brawley Otis W. 
Published: December 2010

Abstract
A better understanding of breast cancer subtypes is allowing their use as prognostic markers. For some time, it has been documented that black women with breast cancer have a poorer prognosis than white women of the same stage. Advances in immunohistochemistry and the appreciation of breast cancer subtypes are enabling investigators to study the distribution of these subtypes among populations. Clin Cancer Res; 16(24); 5920–2. ©2010 AACR.
Cost Utility of Prostate Cancer Chemoprevention with Dutasteride in Men with an Elevated Prostate Specific Antigen
Authors: Svatek Robert S. , Lotan Yair 
Published: December 2010

AbstractBackground: In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, dutasteride reduced the relative risk of prostate cancer (CaP) diagnosis over a 4-year period by 22.8%, but questions remain regarding the cost–effectiveness of widespread utilization. We evaluated the cost utility of chemoprevention using dutasteride in men at elevated risk for CaP.Methods: A Markov decision analysis model with probabilistic sensitivity analysis was designed to determine the lifetime prostate-health-related costs, beginning at age 50, for men treated with dutasteride compared with placebo who are at elevated risk for CaP. Model assumptions were based on data in REDUCE; surveillance, epidemiology, and end-results program; literature review of costs, utilities, and transition rates among various prostate cancer health states; and local institutional cost data.Results: Under the assumptions of the base case analysis, dutasteride chemoprevention is associated with a gain of 108 quality-adjusted life-years (QALYs) per 1,000 men and the quality-adjusted cost–effectiveness ratio for dutasteride compared with men not receiving chemoprevention was $140,240 per QALYs. At a cost of $626 per year, down from the current cost of $1,400, the model predicts a cost benefit from dutasteride with a willingness-to-pay threshold lower than $50 K. Assuming a 15% period prevalence renders, an incremental cost–effectiveness ratio of $576,630 per QALYs and a 30% period prevalence would yield a $98,059 per QALYs.Conclusions: Dutasteride is unlikely to be cost effective when considering the impact on survival differences among treated versus untreated groups. However, chemoprevention may be cost effective in high-risk populations when taking into consideration adjustments for the impact on quality of life. Cancer Prev Res; 4(2); 277–83. ©2010 AACR.
Inhibition of EGFR-STAT3 Signaling with Erlotinib Prevents Carcinogenesis in a Chemically-Induced Mouse Model of Oral Squamous Cell Carcinoma
Authors: Leeman-Neill Rebecca J. , Seethala Raja R. , Singh Shivendra V. , Freilino Maria L. , Bednash Joseph S. , Thomas Sufi M. , Panahandeh Mary C. , Gooding William E. , Joyce Sonali C. , Lingen Mark W. , Neill Daniel B. , Grandis Jennifer R. 
Published: December 2010

Abstract
Chemoprevention of head and neck squamous cell carcinoma (HNSCC), a disease associated with high mortality rates and frequent occurrence of second primary tumor (SPT), is an important clinical goal. The epidermal growth factor receptor (EGFR)-signal transducer and activator of transcription (STAT)-3 signaling pathway is known to play a key role in HNSCC growth, survival, and prognosis, thereby serving as a potential therapeutic target in the treatment of HNSCC. In the current study, the 4-nitroquinoline-1-oxide (4-NQO)–induced murine model of oral carcinogenesis was utilized to investigate the chemopreventive activities of compounds that target the EGFR-STAT3 signaling pathway. This model mimics the process of oral carcinogenesis in humans. The drugs under investigation included erlotinib, a small molecule inhibitor of the EGFR, and guggulipid, the extract of an Ayurvedic medicinal plant, which contains guggulsterone, a compound known to inhibit STAT3. Dietary administration of guggulipid failed to confer protection against oral carcinogenesis. On the other hand, the mice placed on erlotinib-supplemented diet exhibited a 69% decrease (P &lt; 0.001) in incidence of preneoplastic and neoplastic lesions compared with mice on the control diet. Immunostaining of dysplastic lesions demonstrated modest decreases in STAT3 levels, with both drug treatments, that were not statistically significant. The results of the present study provide the basis for exploring the efficacy of erlotinib for prevention of HNSCC in a clinical setting. Cancer Prev Res; 4(2); 230–7. ©2010 AACR.
Genetic Influences on Peripheral Arterial Disease in a Twin Population
Authors: Wahlgren Carl Magnus , Magnusson Patrik K.E. 
Published: December 2010

Objective—
To analyze the contribution of genetic and environmental factors to the development of peripheral arterial disease (PAD) in a large population-based sample of twins.

Methods and Results—
The understanding of genetics in PAD is still limited. From the Swedish Twin Registry and the national patient discharge registry, 1464 twins with PAD were identified, including 33 monozygotic (MZ) and 42 dizygotic (DZ) concordant pairs and 298 MZ and 1008 DZ discordant pairs. Traditional cardiovascular risk factors were significantly more prevalent in twins with PAD than in those without PAD. Concordances and correlations were higher in MZ compared with DZ twins, indicating genetic influences in PAD. The risk of PAD for persons whose twin had PAD compared with persons whose twin did not have PAD, estimated as an odds ratio, was 17.7 (95% CI, 11.7 to 26.6) for MZ twins and 5.7 (95% CI, 4.1 to 7.9) for DZ twins. In the structural equation models, Mx analyses, genetic effects accounted for 58% (95% CI, 50% to 64%) and nonshared environmental effects for 42% (95% CI, 36% to 50%) of the phenotypic variance among twins.

Conclusion—
Heritability is an important component, along with unique environmental factors, for the development of PAD. The proportion of the overall PAD heritability attributed to the heritability of cardiovascular risk factors needs to be resolved. Traditional risk factors could explain a major proportion of PAD heritability. A better understanding of the genetics in PAD could identify individuals at increased risk who may benefit from targeted therapies.
Mitral Valve Endothelial Cells With Osteogenic Differentiation Potential
Authors: Wylie-Sears Jill , Aikawa Elena , Levine Robert A. , Yang Jeong-Hee , Bischoff Joyce 
Published: December 2010

Objective—
Cardiac valvular endothelium is unique in its ability to undergo endothelial-to-mesenchymal transformation, a differentiation process that is essential for valve development and has been proposed as mechanism for replenishing the interstitial cells of mature valves. We hypothesized that the valvular endothelium contains endothelial cells that are direct precursors to osteoblastic valvular interstitial cells (VICs).

Methods and Results—
Clonal cell populations from ovine mitral valve leaflets were isolated by single cell plating. Mitral valvular endothelial and mesenchymal clones were tested for osteogenic, adipogenic, and chondrogenic differentiation, determined by the expression of lineage-specific markers. Mitral valvular endothelial clones showed a propensity for osteogenic, as well as chondrogenic differentiation that was comparable to a mitral valvular VIC clone and to bone marrow–derived mesenchymal stem cells. Osteogenic differentiation was not detected in nonvalvular endothelial cells. Regions of osteocalcin expression, a marker of osteoblastic differentiation, were detected along the endothelium of mitral valves that had been subjected in vivo to mechanical stretch.

Conclusion—
Mitral valve leaflets contain endothelial cells with multilineage mesenchymal differentiation potential, including osteogenic differentiation. This unique feature suggests that postnatal mitral valvular endothelium harbors a reserve of progenitor cells that can contribute to osteogenic and chondrogenic VICs.
Enhanced Dispersion of Repolarization Explains Increased Arrhythmogenesis in Severe Versus Therapeutic Hypothermia
Authors: Piktel Joseph S. , Jeyaraj Darwin , Said Tamer H. , Rosenbaum David S. , Wilson Lance D. 
Published: December 2010

Background—
Hypothermia is proarrhythmic, and, as the use of therapeutic hypothermia (TH) increases, it is critically important to understand the electrophysiological effects of hypothermia on cardiac myocytes and arrhythmia substrates. We tested the hypothesis that hypothermia-enhanced transmural dispersion of repolarization (DOR) is a mechanism of arrhythmogenesis in hypothermia. In addition, we investigated whether the degree of hypothermia, the rate of temperature change, and cooling versus rewarming would alter hypothermia-induced arrhythmia substrates.

Methods and Results—

Optical action potentials were recorded from cells spanning the transmural wall of canine left ventricular wedge preparations at baseline (36°C), during cooling and during rewarming. Electrophysiological parameters were examined while varying the depth of hypothermia. On cooling to 26°C, DOR increased from 26±4 ms to 93±18 ms (
P
=0.021); conduction velocity decreased from 35±5 cm/s to 22±5 cm/s (
P
=0.010). On rewarming to 36°C, DOR remained prolonged, whereas conduction velocity returned to baseline. Conduction block and reentry was observed in all severe hypothermia preparations. Ventricular fibrillation/ventricular tachycardia was seen more during rewarming (4/5) versus cooling (2/6). In TH (n=7), cooling to 32°C mildly increased DOR (31±6 to 50±9,
P
=0.012), with return to baseline on rewarming and was associated with decreased arrhythmia susceptibility. Increased rate of cooling did not further enhance DOR or arrhythmogenesis.

Conclusions—
Hypothermia amplifies DOR and is a mechanism for arrhythmogenesis. DOR is directly dependent on the depth of cooling and rewarming. This provides insight into the clinical observation of a low incidence of arrhythmias in TH and has implications for protocols for the clinical application of TH.