bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Inhibition of the Wnt Acyltransferase PORCN Prevents Growth of WNT-Driven Mammary Cancer
Authors: Proffitt Kyle David , Madan Babita , Ke Zhiyuan , Pendharkar Vishal , Ding Lijun , Lee May Ann , Hannoush Rami N. , Virshup David M. 
Published: November 2012

Abstract
Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatment for cancers dependent on excess Wnt activity. In this study, we evaluated the PORCN inhibitor Wnt-C59 (C59), to determine its activity and toxicity in cultured cells and mice. C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity. In mice, C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC50. C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Surprisingly, mice exhibit no apparent toxicity, such that at a therapeutically effective dose there were no pathologic changes in the gut or other tissues. These results offer preclinical proof-of-concept that inhibiting mammalian Wnts can be achieved by targeting PORCN with small-molecule inhibitors such as C59, and that this is a safe and feasible strategy in vivo. Cancer Res; 73(2); 502–7. ©2012 AACR.
CD103 or LFA-1 Engagement at the Immune Synapse between Cytotoxic T Cells and Tumor Cells Promotes Maturation and Regulates T-cell Effector Functions
Authors: Franciszkiewicz Katarzyna , Le Floc'h Audrey , Boutet Marie , Vergnon Isabelle , Schmitt Alain , Mami-Chouaib Fathia 
Published: November 2012

AbstractT-cell adhesion/costimulatory molecules and their cognate receptors on target cells play a major role in T-cell receptor (TCR)–mediated activities. Here, we compared the involvement of CD103 and LFA-1, and their respective ligands, in the maturation of the cytotoxic immune synapse (cIS) and in the activation of CTL effector functions. Our results indicate that cytotoxicity toward cancer cells and, to a lesser extent, cytokine production by specific CTL require, together with TCR engagement, the interaction of either CD103 with E-cadherin or LFA-1 with ICAM-1. Flow-based adhesion assay showed that engagement of CD103 or LFA-1, together with TCR, enhances the strength of the T-cell/target cell interaction. Moreover, electron microscopic analyses showed that integrin-dependent mature cIS (mcIS) displays a cohesive ultrastructure, with tight membrane contacts separated by extensive clefts. In contrast, immature cIS (icIS), which is unable to trigger target cell lysis, is loose, with multiple protrusions in the effector cell membrane. Experiments using confocal microscopy revealed polarized cytokine release and degranulation at the mcIS associated with target cell killing, whereas icIS is characterized by failure of IFN-γ and granzyme B relocalization. Thus, interactive forces between CTL and epithelial tumor cells, mainly regulated by integrin engagement, correlate with maturity and the ultrastructure of the cIS and influence CTL effector functions. These results provide new insights into molecular mechanisms regulating antitumor CTL responses and may lead to the development of more efficient cancer immunotherapy strategies. Cancer Res; 73(2); 617–28. ©2012 AACR.
Molecular Markers in Key Steroidogenic Pathways, Circulating Steroid Levels, and Prostate Cancer Progression
Authors: Lévesque Éric , Huang Shu-Pin , Audet-Walsh Étienne , Lacombe Louis , Bao Bo-Ying , Fradet Yves , Laverdière Isabelle , Rouleau Mélanie , Huang Chao-Yuan , Yu Chia-Cheng , Caron Patrick , Guillemette Chantal 
Published: November 2012

Abstract
Purpose: Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression.
Experimental Design: The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen–deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan–Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry–based methods.
Results: After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29–4.10; P = 0.0014–2 × 10−7) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71–8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05).
Conclusion: This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression. Clin Cancer Res; 19(3); 699–709. ©2012 AACR.
A Glucagon-Like Peptide-1 Analog Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity
Authors: Noyan-Ashraf Mohammad Hossein , Shikatani Eric Akihiko , Schuiki Irmgard , Mukovozov Ilya , Wu Jun , Li Ren-Ke , Volchuk Allen , Robinson Lisa Annette , Billia Filio , Drucker Daniel J. , Husain Mansoor 
Published: November 2012

Background—
Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.

Methods and Results—

C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet–fed mice at 16 and 32 weeks, respectively (both
P
<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase–dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α–activated human endothelial cells in vitro.

Conclusions—
Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.
Three-dimensional Shape Coding in Grasping Circuits: A Comparison between the Anterior Intraparietal Area and Ventral Premotor Area F5a
Authors: Theys Tom , Pani Pierpaolo , van Loon Johannes , Goffin Jan , Janssen Peter 
Published: November 2012

Abstract
Depth information is necessary for adjusting the hand to the three-dimensional (3-D) shape of an object to grasp it. The transformation of visual information into appropriate distal motor commands is critically dependent on the anterior intraparietal area (AIP) and the ventral premotor cortex (area F5), particularly the F5p sector. Recent studies have demonstrated that both AIP and the F5a sector of the ventral premotor cortex contain neurons that respond selectively to disparity-defined 3-D shape. To investigate the neural coding of 3-D shape and the behavioral role of 3-D shape-selective neurons in these two areas, we recorded single-cell activity in AIP and F5a during passive fixation of curved surfaces and during grasping of real-world objects. Similar to those in AIP, F5a neurons were either first- or second-order disparity selective, frequently showed selectivity for discrete approximations of smoothly curved surfaces that contained disparity discontinuities, and exhibited mostly monotonic tuning for the degree of disparity variation. Furthermore, in both areas, 3-D shape-selective neurons were colocalized with neurons that were active during grasping of real-world objects. Thus, area AIP and F5a contain highly similar representations of 3-D shape, which is consistent with the proposed transfer of object information from AIP to the motor system through the ventral premotor cortex.
Retrieval Search and Strength Evoke Dissociable Brain Activity during Episodic Memory Recall
Authors: Reas Emilie T. , Brewer James B. 
Published: November 2012

Abstract
Neuroimaging studies of episodic memory retrieval have revealed activations in the human frontal, parietal, and medial-temporal lobes that are associated with memory strength. However, it remains unclear whether these brain responses are veritable signals of memory strength or are instead regulated by concomitant subcomponents of retrieval such as retrieval effort or mental search. This study used event-related fMRI during cued recall of previously memorized word-pair associates to dissociate brain responses modulated by memory search from those modulated by the strength of a recalled memory. Search-related deactivations, dissociated from activity due to memory strength, were observed in regions of the default network, whereas distinctly strength-dependent activations were present in superior and inferior parietal and dorsolateral PFC. Both search and strength regulated activity in dorsal anterior cingulate and anterior insula. These findings suggest that, although highly correlated and partially subserved by overlapping cognitive control mechanisms, search and memory strength engage dissociable regions of frontoparietal attention and default networks.
A New Statistical–Dynamical Downscaling Procedure Based on EOF Analysis for Regional Time Series Generation
Authors: Martinez Yosvany , Yu Wei , Lin Hai 
Published: November 2012

AbstractA new statistical–dynamical downscaling procedure is developed and then applied to high-resolution (regional) time series generation and wind resource assessment. The statistical module of the new procedure uses empirical orthogonal function (EOF) analysis for the generation of large-scale atmospheric component patterns. The dominant atmospheric patterns (associated with the EOF modes explaining most of the statistical variance) are then dynamically downscaled or adjusted to high-resolution terrain and surface roughness by using the Global Environmental Multiscale–Limited Area Model (GEM-LAM). Regional time series are constructed using the model outputs. The new method is applied to the Gaspé region of Québec in Canada. The dataset used is the NCEP–NCAR reanalysis of wind, temperature, humidity, and geopotential height during the period 1958–2004. Regional time series of wind speed and temperature are constructed, and a numerical wind atlas of the Gaspé region is generated. The generated time series and the numerical wind atlas are compared with observations at different masts located in the Gaspé Peninsula and are also compared with a numerical wind atlas for the same region generated in Yu et al. The results suggest that the newly developed procedure can be useful to generate regional time series and reasonably accurate numerical wind atlases using large-scale data with much less computational effort than previous techniques.
Modulation of Western North Pacific Tropical Cyclone Activity by the ISO. Part II: Tracks and Landfalls
Authors: Li Richard C. Y. , Zhou Wen 
Published: November 2012

Abstract
This study investigates how tropical cyclone (TC) tracks and landfalls are modulated by the two major components of the intraseasonal oscillation (ISO), the 30–60-day Madden–Julian oscillation (MJO) and the 10–20-day quasi-biweekly oscillation (QBWO). In the convective phases of the MJO (phases 7 + 8 and 1 + 2), the western North Pacific Ocean (WNP) is mainly clustered with westward- and northwestward-moving TCs. The strong easterlies (southeasterlies) in the southern flank of the subtropical high lead to an increase in TC activity and landfalls in the Philippines and Vietnam (China and Japan) in phase 7 + 8 (phase 1 + 2). In the nonconvective phases (phases 3 + 4 and 5 + 6), TCs change from the original straight-moving type to the recurving type, such that the tendency for landfalls is significantly reduced. The QBWO, on the other hand, has a significant influence on TC landfalls in the Philippines and Japan. The strengthening of the subtropical high in phase 1 + 2 favors the development of westward-moving TCs and results in an increase in landfalls in the Philippines, while in phase 3 + 4 (phase 5 + 6), there is an increase (decrease) in TC activity and landfalls in Japan because of changes in genesis locations and large-scale circulations. The results herein suggest that both the MJO and QBWO exert distinctive impacts on TCs in the WNP.
Seasonal-to-Interannual Prediction of the Asian Summer Monsoon in the NCEP Climate Forecast System Version 2
Authors: Jiang Xingwen , Yang Song , Li Yueqing , Kumar Arun , Liu Xiangwen , Zuo Zhiyan , Jha Bhaskar 
Published: November 2012

Abstract
The NCEP Climate Forecast System (CFS) is an important source of information for seasonal climate prediction in many Asian countries affected by monsoon climate. The authors provide a comprehensive analysis of the prediction of the Asian summer monsoon (ASM) by the new CFS version 2 (CFSv2) using the hindcast for 1983–2010, focusing on seasonal-to-interannual time scales. Many ASM features are well predicted by the CFSv2, including heavy monsoon rainfall centers, large-scale monsoon circulation patterns, and monsoon onset and retreat features. Several commonly used dynamical monsoon indices and their associated precipitation and circulation patterns can be predicted several months in advance. The CFSv2 has better skill in predicting the Southeast Asian monsoon than predicting the South Asian monsoon. Compared to CFS version 1 (CFSv1), the CFSv2 has increased skill in predicting large-scale monsoon circulation and precipitation features but decreased skill for the South Asian monsoon, although some biases in the CFSv1 still exist in the CFSv2, especially the weaker-than-observed western Pacific subtropical high and the exaggerated strong link of the ASM to ENSO.
Comparison of CFSv2 hindcast with output from Atmospheric Model Intercomparison Project (AMIP) and Coupled Model Intercomparison Project (CMIP) simulations indicates that exclusion of ocean–atmosphere coupling leads to a weaker ASM. Compared to AMIP, both hindcast and CMIP show a more realistic annual cycle of precipitation, and the interannual variability of the ASM is better in hindcast. However, CMIP does not show any advantage in depicting the processes associated with the interannual variability of major dynamical monsoon indices compared to AMIP.
The Effect of Topographic Variability on Initial Condition Sensitivity of Low-Level Wind Forecasts. Part II: Experiments Using Real Terrain and Observations
Authors: Bieringer Paul E. , Ray Peter S. , Annunzio Andrew J. 
Published: November 2012

Abstract
A study by Bieringer et al., which is Part I of this two-part study, demonstrated analytically using the shallow-water equations and numerically in controlled experiments that the presence of terrain can result in an enhancement of sensitivities to initial condition adjustments. The increased impact of adjustments to initial conditions corresponds with gradients in the flow field induced by the presence of the terrain obstacle. In cross-barrier flow situations the impact of the initial condition adjustments on the final forecast increases linearly as the height of the terrain obstacle increases. While this property associated with initial condition perturbations may be present in an analytic and controlled numerical environment, it is often difficult to realize these benefits in a more operationally realistic setting. This study extends the prior work to a situation with actual terrain, Doppler radar wind observations over the terrain, and observations from a surface mesonet for model verification. The results indicate that the downstream surface wind forecast was improved more when the initial conditions adjusted through the assimilation of Doppler radar data originated from areas with terrain gradients than from regions where the terrain was relatively flat. This result is consistent with the findings presented in Part I and suggests that when varying terrain elevation is present upstream of a target forecast area, a greater benefit (in terms of forecast accuracy) can be made by targeting additional observations in the regions containing variable terrain than regions where the terrain is relatively flat.
DNA damage in human lymphocytes exposed to four food additives in vitro
Authors: Yilmaz Serkan , Ünal Fatma , Yüzbaşıoğlu Deniz , Çelik Mustafa 
Published: November 2012

In vitro genotoxic effects of antioxidant additives, such as citric acid (CA) and phosphoric acid (PA) and their combination, as well as antimicrobial additives, such as benzoic acid (BA) and calcium propionate (CP), on human lymphocytes were determined using alkaline single-cell gel electrophoresis. There was a significant increase in the DNA damage in human lymphocytes after 1 h of in vitro exposure to CA, PA, BA and CP (200, 25–200, 50–500, 50–1000 μg/mL, respectively). The combination of CA and PA significantly increased the mean tail intensity at all the concentrations used (25–200 μg/mL) and significantly increased the mean tail length mainly after higher concentrations (100 and 200 μg/mL). Data in this study showed that the concentrations of food additives used induce DNA damage and PA was the most genotoxic and CA was less genotoxic additives among them.
Thyroid function in newly diagnosed HIV-infected patients
Authors: Noureldeen Amani FH , Qusti Safaa Y , Khoja Gelan MS 
Published: November 2012

Background: A variety of HIV-related endocrine dysfunctions including adrenal, gonadal and thyroid disorders have been reported. We aimed to compare between the markers of thyroid function in newly diagnosed HIV-infected patients and healthy volunteers as a control group. The prevalence of the thyroid abnormalities in HIV-infected patients was assessed and the levels of thyroid autoantibodies were also determined. Methods: A total of 100 newly diagnosed HIV-infected patients having a CD4 cell count of 180–350 cells/mm3 were enrolled in the study. Same number of healthy volunteers were also included for comparison. Measurements of thyroid function tests including thyroid-stimulating hormone (TSH), free thyroxin and free triiodothyronine levels beside thyroid autoantibodies, including antithyroglobulin (ATBG) and antithyroid peroxidase (ATPO), were carried out for all patients and volunteers. Results: In total, 70% of HIV-infected patients had normal thyroid function tests when compared with control individuals, while 30% of HIV-infected patients had abnormal thyroid function. Of the 30 cases, 11 cases had abnormal TSH values, with increased TSH predominant (7% of HIV cases) than decreased TSH (4% of patients) values. Incidence of thyroid abnormalities ranging from hypothyroidism (subclinical and overt: 6% and 1%, respectively) to hyperthyroidism (2%) and nonthyroidal illness (9%) were estimated in HIV-infected patients. The values of thyroid autoantibodies were almost normal in HIV-infected patients, except the three cases presented with elevated ATBG, indicating that thyroid abnormalities were not due to elevated ATBG and ATPO. Conclusions: Thyroid hormones are of great importance and due to high prevalence of thyroid function abnormality, it is recommended that thyroid function tests should be monitored in all HIV-infected patients before starting the treatment.
Structure elucidation, protein profile and the antitumor effect of the biological active substance extracted from sea cucumber Holothuria polii
Authors: Omran Nahla EE , Khedr Abdalla M 
Published: November 2012

Holothuria polii (Delle Chiaje, 1823) (Holothuriidae) is a sea cucumber inhabiting Mediterranean Sea coast of Egypt. The bioactive compound of its tegument has antifungal, antibacterial and antiparasitic effects. The present study aims to elucidate the structure of the bioactive material of H. polii for pharmacological and chemotaxonomic purposes. Furthermore, the study demonstrates its efficacy as a cytotoxic agents against two tumor cell lines HCT116 (colon adenocarcinoma cell line) and MCF7 (breast adenocarcinoma cell line). The biological active compound of the ethanol extract has been characterized by means of infrared (IR), proton-nuclear magnetic resonance (1H NMR), ultraviolet–visible (UV–Vis) and mass spectra. Protein profile was carried out using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Cytotoxic activity was carried out according to sulforhodamine-B assay. IR, 1H NMR, UV–Vis and mass spectra showed that the extracted bioactive material is a nonsulfated hexaosides called bivittoside. This glycoside is composed of aglycone and a glycosidic chain (carbohydrate chain) enclosed with six sugar units, including xylose, glucose, 3- O-methylglucose and quinovose. There were no traces of dissolved proteins. The preliminary cytotoxic assay of bivittoside exhibited significant cytotoxic activity against two types of cultured tumor cell lines of HCT116 and MCF7. The half-maximal inhibitory concentration was 17.4 µg/ml and 18 µg/ml for MCF7 and HCT116, respectively. Although H. polii belongs to the genus Holothuria, the lacking of sulfate group and the fact that it contains up to six monosaccharides make it different from this genus. The present study suggests separation of H. polii from its genus to a new one. On the other hand, results support the hypothesis that H. polii bioactive compound has an antitumor effect.