bluuebunny/crossref_metadata_2025 huggingface dataset:
Cementation of sand soil by microbially induced calcite precipitation at various degrees of saturation
Authors: Cheng Liang , Cord-Ruwisch Ralf , Shahin Mohamed A.
Published: January 2013

A newly emerging microbiological soil stabilization method, known as microbially induced calcite precipitation (MICP), has been tested for geotechnical engineering applications. MICP is a promising technique that utilizes the metabolic pathways of bacteria to form calcite precipitation throughout the soil matrix, leading to an increase in soil strength and stiffness. This paper investigates the geotechnical properties of sand bio-cemented under different degrees of saturation. A series of laboratory experiments was conducted, including sieve analysis, permeability, unconfined compressive strength, consolidated undrained triaxial, and durability tests. The results indicate that higher soil strength can be obtained at similar CaCO3 content when the treatment is performed under a low degree of saturation. The experimental results are further explained with a mathematical model, which shows that the crystallization efficiency, i.e., actual volume of crystals forming at the contact point where they contribute the most to strength, can be calculated from the degree of saturation and grain size. Fine sand samples exhibited higher cohesion, but lower friction angle than coarse sand samples with similar CaCO3 content. The results also confirm the potential of MICP as a viable alternative technique for soil improvement in many geotechnical engineering applications, including liquefiable sand deposits, slope stabilization, and subgrade reinforcement. The freeze–thaw and acid rain resistance of MICP-treated sand has also been tested.
MClx (M = Hg, Au, Ru; x = 2, 3) catalyzed hydrochlorination of acetylene — A density functional theory study
Authors: Zhu Mingyuan , Kang Lihua , Su Yan , Zhang Shanzheng , Dai Bin
Published: January 2013

Density functional theory (DFT) calculations were used to study the mechanism for the hydrochlorination of acetylene catalyzed by MClx (M = Hg, Au, Ru; x = 2, 3). For the three catalysts, the reaction occurs via a one-shift chlorine atom transfer, which avoids the formation of highly stable complex species. The adsorbed HCl acts as a chlorine donor, while the C2H2 favors the chlorine abstraction. The calculated real activation barrier decreases in the order: HgCl2 > AuCl3 > RuCl3, which suggests that the RuCl3 would be a good candidate catalyst for the hydrochlorination of acetylene.
NEW PERSPECTIVE ON SPACE AND TIME FROM LORENTZ VIOLATION
Authors: MA BO-QIANG
Published: January 2013

I present a brief review on space and time in different periods of physics, and then talk on the nature of space and time from physical arguments. I discuss the ways to test such a new perspective on space and time through searching for Lorentz violation in some physical processes. I also make an introduce to a newly proposed theory of Lorentz violation from basic considerations.
FOUNDATIONS OF CLASSICAL ELECTRODYNAMICS, EQUIVALENCE PRINCIPLE AND COSMIC INTERACTIONS: A SHORT EXPOSITION AND AN UPDATE
Authors: NI WEI-TOU , MEI HSIEN-HAO , WU SHAN-JYUN
Published: January 2013

We look at the foundations of electromagnetism in this 1st LeCosPA Symposium. For doing this, after some review (constraints on photon mass etc.), we use two approaches. The first one is to formulate a Parametrized Post-Maxwellian (PPM) framework to include QED corrections and a pseudoscalar photon interaction. PPM framework includes lowest corrections to unified electromagnetism-gravity theories based on connection approach. It may also overlap with corrections implemented from generalized uncertainty principle (GUP) when electromagnetism-gravity coupling is considered. We discuss various vacuum birefringence experiments — ongoing and proposed — to measure these parameters. The second approach — the χ-g framework is to look at electromagnetism in gravity and various experiments and observations to determine its empirical foundation. The SME (Standard Model Extension) and SMS (Standard Model Supplement) overlap with the χ-g framework in their photon sector. We found that the foundation is solid with the only exception of a potentially possible pseudoscalar-photon interaction. We discussed its experimental constraints and look forward to more future experiments.
ON-LINE SUPPLY VOLTAGE SCALING BASED ON IN SITU DELAY MONITORING TO ADAPT FOR PVTA VARIATIONS
Authors: WIRNSHOFER MARTIN , ARYAN NASIM POUR , HEISS LEONHARD , SCHMITT-LANDSIEDEL DORIS , GEORGAKOS GEORG
Published: January 2013

The presented Pre-Error Adaptive Voltage Scaling (AVS) approach tunes the supply voltage of digital circuits dependent on the present Process, Voltage and Temperature variations as well as Aging (PVTA). By exploiting unused timing margin, produced by state-of-the-art worst-case designs, power consumption is minimized. Timing information of the circuit is obtained by in situ delay monitors (Pre-Error flip-flops), detecting late-arriving signals (pre-errors) in critical paths. Based on the occurrence of pre-errors, the voltage is adjusted by a low-overhead control unit connected to the on-chip voltage regulator. As the voltage is adapted during normal circuit operation (on-line), the randomness of the applied input pattern has to be considered. We developed a Markov chain model, based on transistor level simulations, to describe the resulting statistics of the closed-loop voltage control. With this model, the risk of overcritical voltage reductions and the effect of global and local variations on the closed-loop control can be analyzed. For an arithmetic circuit, synthesized in an industrial 65nm design-flow, an average power saving of 23% (including all overheads) is achieved for very low error rates below 1E-11.
GENETIC ALGORITHM BASED FEATURE SELECTION FOR PARAPHRASE RECOGNITION
Authors: CHITRA A. , RAJKUMAR ANUPRIYA
Published: January 2013

Paraphrase Recognition systems most often use various lexical, syntactic and semantic features to recognize paraphrases. This paper presents the work done in designing a Support Vector Machine (SVM) based Paraphrase Recognizer and then improving its performance using feature selection strategy. Wrapper method of feature selection has been adopted by combining Genetic Algorithms with Support Vector Machine Classifiers. Experimental results show that applying Feature selection improves the accuracy besides reducing the number of features. The developed paraphrase recognizer has been applied for the Student Answer Evaluation task. The results obtained show that the performance of Answer Evaluation systems which use only half the number of features is comparable to systems using the original feature set.
SYNTHETIC OVERSAMPLING OF INSTANCES USING CLUSTERING
Authors: SÁNCHEZ ATLÁNTIDA I. , MORALES EDUARDO F. , GONZALEZ JESUS A.
Published: January 2013

Imbalanced data sets in the class distribution is common to many real world applications. As many classifiers tend to degrade their performance over the minority class, several approaches have been proposed to deal with this problem. In this paper, we propose two new cluster-based oversampling methods, SOI-C and SOI-CJ. The proposed methods create clusters from the minority class instances and generate synthetic instances inside those clusters. In contrast with other oversampling methods, the proposed approaches avoid creating new instances in majority class regions. They are more robust to noisy examples (the number of new instances generated per cluster is proportional to the cluster's size). The clusters are automatically generated. Our new methods do not need tuning parameters, and they can deal both with numerical and nominal attributes. The two methods were tested with twenty artificial datasets and twenty three datasets from the UCI Machine Learning repository. For our experiments, we used six classifiers and results were evaluated with recall, precision, F-measure, and AUC measures, which are more suitable for class imbalanced datasets. We performed ANOVA and paired t-tests to show that the proposed methods are competitive and in many cases significantly better than the rest of the oversampling methods used during the comparison.
MULTISYMPLECTIC GEOMETRY AND k-COSYMPLECTIC STRUCTURE FOR THE FIELD THEORIES AND THE RELATIVISTIC MECHANICS
Authors: LOUMI-FERGANE H. , BELAIDI A.
Published: January 2013

The aim of this work is twofold: First, we extend the multisymplectic geometry already done for field theories to the relativistic mechanics by introducing an appropriate configuration bundle. In particular, we developed the model to obtain the Hamilton–De Donder–Weyl equations to the movement of a relativistic charged particle immerged in an electromagnetic field. Second, we have found a direct relationship between the multisymplectic geometry and the k-cosymplectic structure of a physical system.
Second order nonlinear optical properties of corroles: experimental and theoretical investigations
Authors: Ying Xiao , Long Xiao-Yan , Mahmood Mian HR , Hu Quan-Yuan , Liu Hai-Yang , Chang Chi-K.
Published: January 2013

The first hyperpolarizabilities, βHRS, of corrole derivatives have been measured by using Hyper–Rayleigh Scattering technique. The results showed that βHRS of corroles could be greatly enhanced by modifying its periphery with donor–acceptor groups. Maximum value reaches 354 × 10-30 esu at an incident wavelength of 1500 nm. βHRS of investigated corroles were also calculated with the Zerner's intermediate neglect of differential overlap/configuration interaction/sum-over-states method. The calculated and experimental results are in good agreement and conclude that βHRS arises mainly from the charge transfer along molecule's non-symmetrical axis and strong coupling between two different excited states of the Soret band.
Multiply biphenyl substituted zinc(II) porphyrin and phthalocyanine as components for molecular materials
Authors: Penon Oriol , Marsico Filippo , Santucci Davide , Rodríguez Laura , Amabilino David B. , Pérez-García Lluïsa
Published: January 2013

The preparation and physico-chemical characteristics of zinc(II) porphyrin and phthalocyanine derivatives with biphenyl units are reported. These compounds have been prepared as components for molecular electronics systems and rotor-based molecular machines, where the biphenyl units can act as paddles because they are oriented quasi-perpendicularly to the plane of the aromatic macrocycles which would be coordianted through the transition metal ion by an axial ligand. The minimalist design along with the absence of solubilizing groups leads to a low solubility of the compounds in organic solvents; the phthalocyanines is only sparingly soluble while the porphyrin is more easily manipulated, but in any case the concentration of both compounds is sufficient for surface deposition. The luminescence of the compounds is characteristic of the central unit, although it is clear in the absorption spectra that the phthalocyanine derivative has a particularly strong tendency to aggregate non-specifically. The porphyrin forms microcrystals while the phthalocyanines which bears eight biphenyl units forms amorphous aggregates from 1,2-dichlorobenzene reminiscent of glasses of other biphenyl derivatives, which is interesting for the preparation of amorphous materials for optics applications.
Application of Metabolomics to Diagnosis of Insulin Resistance
Authors: Milburn Michael V. , Lawton Kay A.
Published: January 2013

Metabolomics, the global interrogation of the biochemical components in a biological sample, has become an important complement to genomics and proteomics to aid in the understanding of pathophysiology. Major advantages of metabolomics are the size of the metabolome relative to the genome or proteome and the fact that it provides a view of the existing biochemical phenotype. As such, metabolomics is fast becoming an important discovery tool for new diagnostic and prognostic biomarkers. Although many methods exist for performing metabolomics, relatively few have led to successful development of new diagnostic tests. This review will aid the reader in understanding various metabolomic methods and their applications, as well as some of their inherent advantages and disadvantages. In addition, we present one example of the application of metabolomics to the identification of new fasting blood biomarkers for the diagnosis and monitoring of insulin resistance.
Cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways mediates macrophage foam cell formation
Authors: Li Lung-Chih , Varghese Zac , Moorhead John F. , Lee Chien-Te , Chen Jin-Bor , Ruan Xiong Z.
Published: January 2013

Myeloid differentiation factor 88 (MyD88) and NF-κB play central roles in mediating signal transduction of the Toll-like receptor (TLR) superfamily in human macrophages. The feedback regulation of LDL receptor (LDLR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) are mediated by the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP)-SREBP2 pathway and are key regulatory elements for cholesterol homeostasis in human cells. This study was designed to investigate cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways in macrophage foam cell formation. phorbol 12-myristate 13-acetate-activated THP-1 macrophages were transfected with negative control or MyD88 small interfering (si)RNA. Transfected cells were incubated with LPS in the absence or presence of LDL or IκB kinase (IKK) inhibitor (BMS-345541). Intracellular cholesterol content was assessed. mRNA and protein expression of LDLR, HMG-CoAR, SCAP, and SREBP2 were examined by real-time RT-PCR and Western blot analysis. Intracellular translocation of SCAP in the organelles was detected by immunofluorecence and confocal microscopy. We demonstrated that LPS-induced cholesterol accumulation was attenuated by applying siRNA against MyD88 in the absence or presence of LDL. LPS increased both gene and protein expression of LDLR and HMG-CoAR by increasing expression and abnormal translocation of SCAP from the endoplasmic reticulum to the Golgi. These effects were blocked by knockdown of MyD88 or blockade of IKK or by knockdown of SCAP, suggesting that the cross-talk between NF-κB and SCAP plays an important role in macrophage foam cell formation and that interfering with the cross-talk might be a potential approach in preventing LPS-induced macrophage foam cell formation.
Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity
Authors: Jayaram Bhavaani , Pan Weihong , Wang Yuping , Hsuchou Hung , Mace Aurelien , Cornelissen-Guillaume Germaine G. , Mishra Pramod K. , Koza Robert A. , Kastin Abba J.
Published: January 2013

To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling.
Transcription Factor YY1 Contributes to Tumor Growth by Stabilizing Hypoxia Factor HIF-1α in a p53-Independent Manner
Authors: Wu Shourong , Kasim Vivi , Kano Mitsunobu R. , Tanaka Sayaka , Ohba Shinsuke , Miura Yutaka , Miyata Kanjiro , Liu Xueying , Matsuhashi Ako , Chung Ung-il , Yang Li , Kataoka Kazunori , Nishiyama Nobuhiro , Miyagishi Makoto
Published: January 2013

In response to hypoxic stress, hypoxia-inducible factor (HIF)-1α is a critical transcription factor regulating fundamental cellular processes, and its elevated expression level and activity are associated with poor outcomes in most malignancies. The transcription factor Yin Yang 1 (YY1) is an important negative regulator of the tumor suppressor factor p53. However, the role of YY1 under tumor hypoxic condition is poorly understood. Herein, we show that inhibition of YY1 reduced the accumulation of HIF-1α and its activity under hypoxic condition, and consequently downregulated the expression of HIF-1α target genes. Interestingly, our results revealed that the downregulation of HIF-1α by inhibiting YY1 is p53-independent. Functionally, the in vivo experiments revealed that inhibition of YY1 significantly suppressed growth of metastatic cancer cells and lung colonization and also attenuated angiogenesis in a p53-null tumor. Collectively, our findings unraveled a novel mechanism by which YY1 inhibition disrupts hypoxia-stimulated HIF-1α stabilization in a p53-independent manner. Therefore, YY1 inhibition could be considered as a potential tumor therapeutic strategy to give consistent clinical outcomes independent of p53 status. Cancer Res; 73(6); 1787–99. ©2012 AACR.
Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model
Authors: Bachawal Sunitha V. , Jensen Kristin C. , Lutz Amelie M. , Gambhir Sanjiv S. , Tranquart Francois , Tian Lu , Willmann Jürgen K.
Published: January 2013

While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MBVEGFR2) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MBVEGFR2 than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R2 = 0.84; 95% confidence interval (CI), 0.72–0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78–88) and specificity of 89% (95% CI, 81–94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97–99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women. Cancer Res; 73(6); 1689–98. ©2012 AACR.
HLA-Restricted CTL That Are Specific for the Immune Checkpoint Ligand PD-L1 Occur with High Frequency in Cancer Patients
Authors: Munir Shamaila , Andersen Gitte Holmen , Met Özcan , Donia Marco , Frøsig Thomas Mørch , Larsen Stine Kiaer , Klausen Tobias Wirenfeldt , Svane Inge Marie , Andersen Mads Hald
Published: January 2013

PD-L1 (CD274) contributes to functional exhaustion of T cells and limits immune responses in patients with cancer. In this study, we report the identification of an human leukocyte antigen (HLA)-A2–restricted epitope from PD-L1, and we describe natural, cytolytic T-cell reactivity against PD-L1 in the peripheral blood of patients with cancer and healthy individuals. Notably, PD-L1–specific T cells were able not only to recognize and kill tumor cells but also PD-L1–expressing dendritic cells in a PD-L1–dependent manner, insofar as PD-L1 ablation rescued dendritic cells from killing. Furthermore, by incubating nonprofessional antigen-presenting cells with long peptides from PD-L1, we found that PD-L1 was rapidly internalized, processed, and cross-presented by HLA-A2 on the cell surface. Apparently, this cross-presentation was TAP-independent, as it was conducted not only by B cells but in addition by TAP-deficient T2-cells. This is intriguing, as soluble PD-L1 has been detected in the sera from patients with cancer. PD-L1–specific CTL may boost immunity by the killing of immunosuppressive tumor cells as well as regulatory cells. However, PD-L1–specific CTLs may as well suppress immunity by the elimination of normal immune cells especially PD-L1 expressing mature dendritic cells. Cancer Res; 73(6); 1764–76. ©2012 AACR.
Phenotypic Profiling of DPYD Variations Relevant to 5-Fluorouracil Sensitivity Using Real-time Cellular Analysis and In Vitro Measurement of Enzyme Activity
Authors: Offer Steven M. , Wegner Natalie J. , Fossum Croix , Wang Kangsheng , Diasio Robert B.
Published: January 2013

In the 45 years since its development, the pyrimidine analog 5-fluorouracil (5-FU) has become an integral component of many cancer treatments, most notably for the management of colorectal cancer. An appreciable fraction of patients who receive 5-FU suffer severe adverse toxicities, which in extreme cases may result in death. Dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) rapidly degrades 85% of administered 5-FU, and as such, limits the amount of drug available for conversion into active metabolites. Clinical studies have suggested that genetic variations in DPYD increase the risk for 5-FU toxicity, however, there is not a clear consensus about which variations are relevant predictors. In the present study, DPYD variants were expressed in mammalian cells, and the enzymatic activity of expressed protein was determined relative to wild-type (WT). Relative sensitivity to 5-FU for cells expressing DPYD variations was also measured. The DPYD*2A variant (exon 14 deletion caused by IVS14+1G>A) was confirmed to be catalytically inactive. Compared with WT, two variants, S534N and C29R, showed significantly higher enzymatic activity. Cells expressing S534N were more resistant to 5-FU–mediated toxicity compared with cells expressing WT DPYD. These findings support the hypothesis that selected DPYD alleles are protective against severe 5-FU toxicity, and, as a consequence, may decrease the effectiveness of 5-FU an antitumor drug in carriers. In addition, this study shows a method that may be useful for phenotyping other genetic variations in pharmacologically relevant pathways. Cancer Res; 73(6); 1958–68. ©2013 AACR.
Biomonitoring the Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine in Hair: Impact of Exposure, Hair Pigmentation, and Cytochrome P450 1A2 Phenotype
Authors: Turesky Robert J. , Liu Lin , Gu Dan , Yonemori Kim M. , White Kami K. , Wilkens Lynne R. , Le Marchand Loïc
Published: January 2013

Background: Hair is a promising tissue to assess exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogen formed in cooked meats. However, an understanding of how dietary exposure to PhIP, cytochrome P450 1A2 activity—a key enzyme involved in PhIP metabolism, and hair pigmentation affect the level of PhIP accrued in hair is required to determine the reliability of the PhIP hair level as a biomarker of exposure to this carcinogen.

Methods: We examined the impact of PhIP exposure, cytochrome P450 1A2 activity, and hair pigmentation on the levels of PhIP accumulated in the hair of volunteers on a 4-week semicontrolled diet of cooked meat containing known quantities of PhIP.

Results: The amount of PhIP in hair increased, on average, 15-fold in light- and dark-haired individuals during consumption of cooked meat. PhIP levels in hair were correlated to PhIP intake (ρ = 0.53; P < 0.001), and the relationship was strengthened when PhIP levels were normalized for the melanin content of hair (ρ = 0.71; P < 0.001). However, PhIP accrual in hair was not correlated to cytochrome P450 1A2 activity, as assessed by the caffeine test, or to the levels of unmetabolized PhIP in urine or to the metabolic ratio of the major urinary metabolite N2-(β-1-glucosiduronyl-2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine to unmetabolized PhIP.

Conclusions: The use of the PhIP hair biomarker should take hair pigmentation into account for accurate exposure assessment of PhIP.

Impact: PhIP hair levels can serve as a biomarker in epidemiologic studies investigating the association of heterocyclic aromatic amine (HAA), cooked meat, and cancer risk. Cancer Epidemiol Biomarkers Prev; 22(3); 356–64. ©2013 AACR.
Genetic Profiling Identifies Two Classes of Soft-Tissue Leiomyosarcomas with Distinct Clinical Characteristics
Authors: Italiano Antoine , Lagarde Pauline , Brulard Céline , Terrier Philippe , Laë Marick , Marques Bernard , Ranchere-Vince Dominique , Michels Jean-Jacques , Trassard Martine , Cioffi Angela , Piperno-Neumann Sophie , Chevreau Christine , Blay Jean-Yves , Delcambre Corinne , Isambert Nicolas , Penel Nicolas , Bay Jacques-Olivier , Bonvalot Sylvie , Le Cesne Axel , Coindre Jean-Michel , Chibon Frédéric
Published: January 2013

Purpose: Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited.

Experimental Design: From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases.

Results: Median age was 59 years (range, 21–98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59–67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome.

Conclusion: Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients. Clin Cancer Res; 19(5); 1190–6. ©2013 AACR.
Modeling Boundary Conditions for Balanced Proliferation in Metastatic Latency
Authors: Taylor Donald P. , Wells Jakob Z. , Savol Andrej , Chennubhotla Chakra , Wells Alan
Published: January 2013

Purpose: Nearly half of cancer metastases become clinically evident five or more years after primary tumor treatment; thus, metastatic cells survived without emerging for extended periods. This dormancy has been explained by at least two countervailing scenarios: cellular quiescence and balanced proliferation; these entail dichotomous mechanistic etiologies. To examine the boundary parameters for balanced proliferation, we conducted in silico modeling.

Experimental Design: To illuminate the balanced proliferation hypothesis, we explored the specific boundary probabilities under which proliferating micrometastases would remain dormant. A two-state Markov chain Monte Carlo model simulated micrometastatic proliferation and death according to stochastic survival probabilities. We varied these probabilities across 100 simulated patients each with 1,000 metastatic deposits and documented whether the micrometastases exceeded one million cells, died out, or remained dormant (survived 1,218 generations).

Results: The simulations revealed a narrow survival probability window (49.7–50.8%) that allowed for dormancy across a range of starting cell numbers, and even then for only a small fraction of micrometastases. The majority of micrometastases died out quickly even at survival probabilities that led to rapid emergence of a subset of micrometastases. Within dormant metastases, cell populations depended sensitively on small survival probability increments.

Conclusions: Metastatic dormancy as explained solely by balanced proliferation is bounded by very tight survival probabilities. Considering the far larger survival variability thought to attend fluxing microenvironments, it is more probable that these micrometastatic nodules undergo at least periods of quiescence rather than exclusively being controlled by balanced proliferation. Clin Cancer Res; 19(5); 1063–70. ©2013 AACR.
Bioactive Grape Proanthocyanidins Enhance Immune Reactivity in UV-Irradiated Skin through Functional Activation of Dendritic Cells in Mice
Authors: Vaid Mudit , Singh Tripti , Prasad Ram , Elmets Craig A. , Xu Hui , Katiyar Santosh K.
Published: January 2013

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell–mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4+ T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair–dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242–52. ©2013 AACR.
Three-Dimensional Angioultrasonography for the Prediction of Malignancy in Ovarian Masses
Authors: Perez-Medina Tirso , Orensanz Inmaculada , Pereira Augusto , Valero de Bernabé Javier , Engels Virginia , Troyano Juan , SanFrutos Luis , Iglesias Enrique
Published: January 2013

Objective: To determine the efficacy of the angiographic indexes of 3D power Doppler angiography (3D-PDA) for the diagnosis of malignancy in complex ovarian masses. Methods: A prospective, observational study of 72 patients with complex adnexal mass. Results: In the morphological study, 3D ultrasound showed sensitivity, specificity, PPV, NPV, PLHR and NLHR of 84.6%, 81.9%, 85.1%, 81.8%, 4.65 and 0.19. No differences in vascular indexes (VI, FI, VFI) between malignant and benign masses were found: VI 5.38 (CI 95% 3.06-7.7) vs. 6.29 (CI 95% 4.41-8.17) (p = 0.53); FI 29.6 (CI 95% 25.17-34.08) vs. 33.8 (CI 95% 30.03-37.3) (p = 0.15); VFI 1.68 (CI 95% 0.94-2.42) vs. 2.37 (CI 95% 1.49-3.25) (p = 0.24). When analysed according to different stages, VI was higher in patients with more advanced stages of disease; 4.34 (95% CI 2.21-6.47) vs. 7.38 (95% CI 4.7-10.06) (p = 0.11). FI was significantly lower in patients with early stages of disease; FI 29.07 (95% CI 21.49-36.68) vs. 36.46 (95% CI 32.31-40.62) (p = 0.04). For VFI, differences were not significant, although there was a strong trend; VFI 1.47 (95% CI 0.67-2.28) vs. 2.86 (95% CI 1.57-4.16) (p = 0.11). 3D-PDA indexes were significantly higher in patients with positive adenopathies. Conclusion: 3D-PDA values increase progressively, but not significantly, with the stage of the disease.
MicroRNA Expression and JAK2 Allele Burden in Bone Marrow Trephine Biopsies of Polycythemia Vera, Essential Thrombocythemia and Early Primary Myelofibrosis
Authors: Gebauer Niklas , Bernard Veronica , Gebauer Wolfgang , Feller Alfred C. , Merz Hartmut
Published: January 2013

Background/Aims: MicroRNAs (miRNAs) play an important role in cellular differentiation and cancer pathogenesis. However, their role in promoting the malignant phenotype of myeloproliferative diseases and their importance for differential diagnosis of early-stage chronic myeloproliferative diseases (CMPDs) remains widely obscure. Methods: In this study, we systematically evaluated the differential expression of miRNAs previously described to be associated with myelopoiesis and myeloproliferative pathogenesis by quantitative RT-PCR in polycythemia vera, essential thrombocythemia, early primary myelofibrosis (PMF) and normal hematopoiesis. Our goal was to establish certain miRNAs as potential markers for CMPDs to facilitate the differentiation between these diseases and to further investigate molecular differences between the subtypes of myeloproliferative neoplasia. Results: An aberrant expression of miRNAs 10a and 150 could be demonstrated for essential thrombocythemia and PMF as well as for polycythemia vera and PMF, respectively. The expression of miR-150 could further be shown to correlate with both JAK2 allele burden and peripheral blood counts. Conclusion: Thus, the miRNAs investigated in this study seem to be potential marker oncomiRs in the differential diagnosis of CMPDs and possibly hold potential for the elucidation of a JAK2-independent mechanism of pathogenesis.
Large Pancreatic Mucinous Cystic Neoplasm during Pregnancy: What Should Be Done?
Authors: Tica Andrei Adrian , Tica Oana Sorina , Saftoiu Adrian , Camen Dragos , Tica Vlad Iustin
Published: January 2013

Pancreatic mucinous cystic neoplasms are uncommon and their occurrence in pregnancy is extremely rare. The authors report the unique case of a newborn weighing 3,620 g, delivered vaginally with no complications by a patient with a large ‘silent' pancreatic mucinous cystic neoplasms, and analyze the very few other reports. With no available protocol, this case highlights an interesting dilemma on the management of pregnancy and delivery as well on the timing of pancreatic surgery. Despite its limitations, MRI remains the most accurate investigation either for differentiating the mucinous from nonmucinous cysts or for evaluating the malignancy, but echography is also very useful. Without symptoms, all low-grade malignant potential tumors, independent of the moment of their diagnosis during pregnancy, should be resected 2-3 months after delivery and we believe that the best option is a term vaginal birth, even in the presence of a large cyst and large fetus. On the contrary, all high-grade malignant potential tumors, discovered in the first two trimesters of pregnancy should be resected during the second trimester, and followed by a vaginal delivery at term. If high-grade malignant potential tumor is diagnosed in the third trimester, an early vaginal delivery followed by surgery is recommended. Finally, the patient's preference is crucial.
The VEGF/VEGF-R Axis in Sporadic Vestibular Schwannomas Correlates with Irradiation and Disease Recurrence
Authors: Koutsimpelas D. , Bjelopavlovic M. , Yetis R. , Frauenknecht K. , Adryan B. , Schmidtmann I. , Gouveris H. , Fruth K. , Heinrich U.R. , Stauber R.H. , Mann W.J. , Brieger J.
Published: January 2013

Background/Aims: The molecular mechanisms downstream of mutated neurofibromatosis type 2 (NF2) gene resulting in the growth and development of vestibular schwannoma (VS) are controversial. Several lines of evidence suggest the involvement of the vascular endothelial growth factor (VEGF) pathway in VS development. Given that recent studies of VEGF blockade in patients with NF2-associated VS showed positive effects on VS growth control, we initiated this comprehensive study of the VEGF pathway in sporadic VS. Methods: A tissue microarray analysis of 182 sporadic VS was conducted. The expression of VEGF and its receptors as well as the proliferative activity of the tumors were quantified. The expression data were correlated to tumor volumes and diameters as well as to tumor recurrence and previous irradiation. Results: All studied tumors expressed VEGF and its receptors. Proliferative activity was related to the growth characteristics of the tumors. Moreover, we found significantly higher VEGF levels in recurrent tumors (p = 0.0387) and in preoperatively irradiated tumors (p = 0.0213). Conclusion: Our data suggest a relevant role of the VEGF pathway in VS growth and therapy outcome. Therefore, targeting this pathway using antiangiogenic compounds might be beneficial for patients with sporadic VS, especially those with recurrent or irradiated tumors.
Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in Multiple Sclerosis
Authors: D'hooghe M.B. , D'Hooghe T. , De Keyser J.
Published: January 2013

Multiple sclerosis (MS), a chronic inflammatory demyelina-ting and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS.
Effects of argatroban, danaparoid, and fondaparinux on trombin generation in heparin-induced thrombocytopenia
Authors: Combe Marion , Piot Michèle , Chapelle Céline , Akrour Majid , Tardy Bernard , Tardy-Poncet Brigitte
Published: January 2013

There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL-1, argatroban at 600 ng.mL-1, argatroban at 400 ng.mL-1, danaparoid at 0.65 IU.mL-1 and fondaparinux at 1 [uni03BC]g.mL-1. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL-1 was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p = 0.031) but not compared with argatroban at 400 ng.mL-1 and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL-1 was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p = 0.031) and fondaparinux (mean: 71.2 vs. 30; p = 0.031) but not with argatroban at 400 ng.mL-1. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.
Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells
Authors: Prinz Nadine , Clemens Natascha , Canisius Antje , Lackner Karl
Published: January 2013

Antiphospholipid antibodies (aPL) have been shown to induce tissue factor (TF) expression in monocytes and endothelial cells. However, the underlying signal transduction has been more or less elusive in the past. We have recently shown that aPL enter the lysosomal route in monocytes and dendritic cells, and subsequently activate endosomal NADPH-oxidase (NOX). The generation of superoxide which is dismutated to hydrogen peroxide upregulates the intracellular toll like receptors (TLR) 7 and 8, and leads to robust production of inflammatory cytokines. Here we show that induction of TF by aPL follows the same signaling pathway. Inhibition of endosomal NOX by the anion channel blocker niflumic acid or capture of superoxide by the radical scavenger N-acetylcysteine blocks TF induction by aPL. Furthermore, monocytes from mice deficient in NOX2 do not increase TF surface expression in response to aPL, while cells from mice deficient in glutathione peroxidase- 1 (GPx-1) show an increased response. Unexpectedly, also induction of TF by tumour necrosis factor (TNF)⍺ and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNF⍺ apparently depends almost fully on endosomal NOX, signalling of LPS is only partially dependent on this pathway. These data provide further insight into the well-known role of reactive oxygen species in the induction of TF expression and suggest that endosomal signalling may represent a central coordinating point in this process.
RAD001-mediated STAT3 upregulation and megakaryocytic differentiation
Authors: Su Yu-Chieh , Li Szu-Chin , Peng Hsuan-Yu , Ho Yang-Hui , Chen Li-Jung , Liao Hui-Fen
Published: January 2013

RAD001 is currently used as an immunosuppressant and anticancer drug. Megakaryocyte (MK) differentiation includes development from pluripotent stem cells to proliferation and differentiation toward MK formation and platelet maturation. Our preliminary assay showed that RAD001 might stimulate MK differentiation; however, the exact regulatory mechanisms needed to be elucidated. By the ex vivo assay, RAD001 induced MK differentiation in human haematopoietic stem cells, with both the stimulation of CFU-GM colony formation and CD61 surface marker expression. Then, BALB/c mice were orally administrated with or without agrylin and/or RAD001 for 15 days. The platelet count and bone marrow CFU-MK colony formation were eliminated by agrylin, but unchanged in RAD001 and RAD001 plus agrylin mice. An ex vivo assay of bone marrow-derived stem cells demonstrated that RAD001 increased the number of CFU-MK colonies. The MK count in bone section indicated the decreased effect by agrylin and then recovered by RAD001. The level of plasma thrombopoietin was also enhanced in RAD001-treated mice. The effect of RAD001 on human leukaemic K562 and HEL cells showed the growth inhibition and MK differentiation activities; including morphological observation, CD41 and CD61 expression, and platelet factor 4 secretion. In RAD001-treated HEL cells, p-STAT3 expression, STAT3 translocation, and STAT3-DNA binding activity were up-regulated. Furthermore, STAT3 siRNA decreased the p-STAT3 and CD61 expression, as well as the CD61 fluorescence intensity, indicating that STAT3 may be critical in RAD001-mediated MK differentiation. Conclusion, the present study demonstrated that RAD001 might have the capacity to induce MK differentiation through the up-regulation of STAT3 signalling.
MicroRNAs in Metabolic Disease
Authors: Fernández-Hernando Carlos , Ramírez Cristina M. , Goedeke Leigh , Suárez Yajaira
Published: January 2013

Alterations in the metabolic control of lipid and glucose homeostasis predispose an individual to develop cardiometabolic diseases, such as type 2-diabetes mellitus and atherosclerosis. Work over the last years has suggested that microRNAs (miRNAs) play an important role in regulating these physiological processes. The contribution of miRNAs in regulating metabolism is exemplified by miR-33, an intronic miRNA encoded in the
Srebp
genes. miR-33 controls cellular cholesterol export and fatty acid degradation, whereas its host genes stimulate cholesterol and fatty acid synthesis. Other miRNAs, such as miR-122, also play a critical role in regulating lipid homeostasis by controlling cholesterol synthesis and lipoprotein secretion in the liver. This review article summarizes the recent findings in the field, highlighting the contribution of miRNAs in regulating lipid and glucose metabolism. We will also discuss how the modulation of specific miRNAs may be a promising strategy to treat metabolic diseases.