bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABT-869 Inhibits the Proliferation of Ewing Sarcoma Cells and Suppresses Platelet-Derived Growth Factor Receptor β and c-KIT Signaling Pathways
Authors: Ikeda Alan K. , Judelson Dejah R. , Federman Noah , Glaser Keith B. , Landaw Elliot M. , Denny Christopher T. , Sakamoto Kathleen M. 
Published: March 2010

Abstract
The Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of &lt;30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multitargeted small-molecule inhibitor that targets Fms-like tyrosine kinase-3, c-KIT, vascular endothelial growth receptors, and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC50 of 1.25 and 2 μmol/L after 72 h of treatment, respectively. The phosphorylation of PDGFRβ, c-KIT, and extracellular signal-regulated kinases was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRβ and c-KIT pathways. Mol Cancer Ther; 9(3); 653–60
Interactions of the p53 Protein Family in Cellular Stress Response in Gastrointestinal Tumors
Authors: Vilgelm Anna E. , Washington Mary K. , Wei Jinxiong , Chen Heidi , Prassolov Vladimir S. , Zaika Alexander I. 
Published: March 2010

Abstract
p53, p63, and p73 are members of the p53 protein family involved in regulation of cell cycle, apoptosis, differentiation, and other critical cellular processes. Here, we investigated the contribution of the entire p53 family in chemotherapeutic drug response in gastrointestinal tumors. Real-time PCR and immunohistochemistry revealed complexity and variability of expression profiles of the p53 protein family. Using colon and esophageal cancer cells, we found that the integral transcription activity of the entire p53 family, as measured by the reporter analysis, associated with response to drug treatment in studied cells. We also found that p53 and p73, as well as p63 and p73, bind simultaneously to the promoters of p53 target genes. Taken together, our results support the view that the p53 protein family functions as an interacting network of proteins and show that cellular responses to chemotherapeutic drug treatment are determined by the total activity of the entire p53 family rather than p53 alone. Mol Cancer Ther; 9(3); 693–705
Anacardic Acid Inhibits Estrogen Receptor α–DNA Binding and Reduces Target Gene Transcription and Breast Cancer Cell Proliferation
Authors: Schultz David J. , Wickramasinghe Nalinie S. , Ivanova Margarita M. , Isaacs Susan M. , Dougherty Susan M. , Imbert-Fernandez Yoannis , Cunningham Albert R. , Chen Chunyuan , Klinge Carolyn M. 
Published: March 2010

Abstract
Anacardic acid (AnAc; 2-hydroxy-6-alkylbenzoic acid) is a dietary and medicinal phytochemical with established anticancer activity in cell and animal models. The mechanisms by which AnAc inhibits cancer cell proliferation remain undefined. AnAc 24:1ω5 was purified from geranium (Pelargonium × hortorum) and shown to inhibit the proliferation of estrogen receptor α (ERα)–positive MCF-7 and endocrine-resistant LCC9 and LY2 breast cancer cells with greater efficacy than ERα-negative primary human breast epithelial cells, MCF-10A normal breast epithelial cells, and MDA-MB-231 basal-like breast cancer cells. AnAc 24:1ω5 inhibited cell cycle progression and induced apoptosis in a cell-specific manner. AnAc 24:1ω5 inhibited estradiol (E2)–induced estrogen response element (ERE) reporter activity and transcription of the endogenous E2 target genes pS2, cyclin D1, and cathepsin D in MCF-7 cells. AnAc 24:1ω5 did not compete with E2 for ERα or ERβ binding, nor did AnAc 24:1ω5 reduce ERα or ERβ steady-state protein levels in MCF-7 cells; rather, AnAc 24:1ω5 inhibited ER-ERE binding in vitro. Virtual screening with the molecular docking software Surflex evaluated AnAc 24:1ω5 interaction with ERα ligand binding (LBD) and DNA binding (DBD) domains in conjunction with experimental validation. Molecular modeling revealed AnAc 24:1ω5 interaction with the ERα DBD but not the LBD. Chromatin immunoprecipitation experiments revealed that AnAc 24:1ω5 inhibited E2-ERα interaction with the endogenous pS2 gene promoter region containing an ERE. These data indicate that AnAc 24:1ω5 inhibits cell proliferation, cell cycle progression, and apoptosis in an ER-dependent manner by reducing ER-DNA interaction and inhibiting ER-mediated transcriptional responses. Mol Cancer Ther; 9(3); 594–605
Molecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor
Authors: Meuillet Emmanuelle J. , Zuohe Song , Lemos Robert , Ihle Nathan , Kingston John , Watkins Ryan , Moses Sylvestor A. , Zhang Shuxing , Du-Cuny Lei , Herbst Roy , Jacoby Jörg J. , Zhou Li Li , Ahad Ali M. , Mash Eugene A. , Kirkpatrick D. Lynn , Powis Garth 
Published: March 2010

Abstract
Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non–small cell lung cancer. When given &gt;5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity. Mol Cancer Ther; 9(3); 706–17
The Tumor Suppressor Maspin Mediates E2F1-Induced Sensitivity of Cancer Cells to Chemotherapy
Authors: Ben Shachar Berta , Feldstein Orit , Hacohen Dalia , Ginsberg Doron 
Published: March 2010

Abstract
The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 can induce cell proliferation and/or apoptosis. In addition, E2F1 overexpression sensitizes cancer cells to chemotherapeutic drugs. In a screen for genes that are regulated synergistically by E2F1 and chemotherapy in cancer cells, we identified the proapoptotic tumor suppressor gene maspin (mammary serine protease inhibitor) as a novel E2F1-regulated gene. In line with being an E2F-regulated gene, maspin expression is inhibited by short hairpin RNA directed against E2F1 and increases upon activation of endogenous E2F. Furthermore, maspin mRNA and protein levels are elevated upon activation of exogenous E2F1. Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization. Mol Cancer Res; 8(3); 363–72
3-Phosphoinositide–Dependent Protein Kinase-1 Regulates Proliferation and Survival of Cancer Cells with an Activated Mitogen-Activated Protein Kinase Pathway
Authors: Lu Zhuomei , Cox-Hipkin Mary Ann , Windsor William T. , Boyapati Anita 
Published: March 2010

Abstract
Engagement of cell surface receptor tyrosine kinases by insulin and growth factors activates phosphatidylinositol 3-kinase (PI3K) and generates the second messenger, phosphatidylinositol 3,4,5-trisphosphate. This second messenger leads to the recruitment of 3-phosphoinositide–dependent protein kinase-1 (PDK1) to the proximal side of the plasma membrane, which results in the activation of AKT kinase. In addition, PDK1 can phosphorylate numerous other kinases, including p90RSK, a kinase downstream of mitogen-activated protein kinase (MAPK) that is important for cell proliferation and survival. Previous studies have shown that the loss of PDK1 sensitizes tumor cells to chemotherapeutic agents and radiation but have not focused on delineating the contribution of PDK1 to pathway-specific mutations associated with various cancers other than the PI3K/AKT pathway. In this study, we show that the reduction of PDK1 by RNAi in melanoma and colon cancer cell lines activated in the MAPK pathway results in significant cell growth inhibition and apoptosis. Furthermore, PDK1 reduction in tumor cells resulted in impaired PAK kinase signaling, altered actin polymerization, and reduced cell migration. These studies show that PDK1 plays a pivotal role in MAPK and PI3K signaling in tumor cells. Mol Cancer Res; 8(3); 421–32
Autotaxin Signaling via Lysophosphatidic Acid Receptors Contributes to Vascular Endothelial Growth Factor–Induced Endothelial Cell Migration
Authors: Ptaszynska Malgorzata M. , Pendrak Michael L. , Stracke Mary L. , Roberts David D. 
Published: March 2010

Abstract
Important roles for vascular endothelial growth factor (VEGF) and autotaxin (ATX) have been established for embryonic vasculogenesis and cancer progression. We examined whether these two angiogenic factors cooperate in regulation of endothelial cell migratory responses. VEGF stimulated expression of ATX and LPA1, a receptor for the ATX enzymatic product lysophosphatidic acid (LPA), in human umbilical vein endothelial cells. Knockdown of ATX expression significantly decreased mRNA levels for the receptors LPA1, LPA2, S1P1, S1P2, S1P3, and VEGFR2 and abolished cell migration to lysophosphatidylcholine, LPA, recombinant ATX, and VEGF. Migration to sphingosylphosphorylcholine and sphinogosine-1-phosphate was also reduced in ATX knockdown cells, whereas migration to serum remained unchanged. Furthermore, ATX knockdown decreased Akt2 mRNA levels, whereas LPA treatment strongly stimulated Akt2 expression. We propose that VEGF stimulates LPA production by inducing ATX expression. VEGF also increases LPA1 signaling, which in turn increases Akt2 expression. Akt2 is strongly associated with cancer progression, cellular migration, and promotion of epithelial-mesenchymal transition. These data show a role for ATX in maintaining expression of receptors required for VEGF and lysophospholipids to accelerate angiogenesis. Because VEGF and ATX are upregulated in many cancers, the regulatory mechanism proposed in these studies could apply to cancer-related angiogenesis and cancer progression. These data further suggest that ATX could be a prognostic factor or a target for therapeutic intervention in several cancers. Mol Cancer Res; 8(3); 309–21
Doppler Echocardiography in Advanced Systolic Heart Failure
Authors: Temporelli Pier Luigi , Scapellato Francesco , Eleuteri Ermanno , Imparato Alessandro , Giannuzzi Pantaleo 
Published: March 2010

Background—
Although several studies have demonstrated a good correlation between Doppler echocardiographic and invasive measurements of single hemodynamic variables, the accuracy of echocardiography in providing a comprehensive assessment in individual patients has not been validated. The aim of this study was to assess the accuracy and clinical applicability of Doppler echocardiography in determining the entire hemodynamic profile in stable patients with advanced systolic heart failure.

Methods and Results—

Doppler echocardiography and Swan-Ganz catheterization were simultaneously performed in 43 consecutive patients with advanced heart failure. Echocardiographic data required for estimation of right atrial, pulmonary artery systolic, and pulmonary capillary wedge pressures; cardiac output; and pulmonary vascular resistance were obtained and compared with hemodynamic data. For all variables, invasive and noninvasive hemodynamic values were highly correlated (
P
<0.0001), with very low bias and narrow 95%confidence limits. In 16 patients with elevated pulmonary vascular resistance (>3 Wood U) and pulmonary capillary wedge pressures (>20 mm Hg) at baseline, hemodynamic and Doppler measurements were simultaneously repeated after unloading manipulations. Absolute values and changes of pulmonary vascular resistance and pulmonary capillary wedge pressures after unloading were still accurately predicted (
r
=0.96 and
r
=0.92, respectively).

Conclusions—
Doppler echocardiography may offer a valid alternative to invasive cardiac catheterization for the comprehensive hemodynamic assessment of patients with advanced heart failure, and it may assist in monitoring and optimization of therapy in potential heart transplant recipients.
Intraseasonal Variability of Satellite-Derived Rainfall and Vegetation over Southern Africa
Authors: Chikoore Hector , Jury Mark R. 
Published: March 2010

Abstract
Satellite-derived rainfall and vegetation [normalized difference vegetation index (NDVI)] data for the period 1981–2000 are used to reveal spatial and temporal interrelationships via principal component analysis. The unimodal seasonal cycle peaks in austral summer over the Zambezi Valley and interior plateau. Spectral analysis indicates major cycles of intraseasonal rainfall events at ∼20 and 40 days in response to atmospheric wave forcing that is partially phase locked to the annual cycle. The spatial loadings exhibit a “center of action” along the eastern edge of the Kalahari (±23°E), extending from the western Zambezi toward central South Africa, spanning 20° of latitude. The loading pattern is consistent with tropical–temperate troughs and associated northwest (NW) cloud bands. Twenty-day rainfall oscillations occur over the Agulhas Current and Angola, hence NW cloud bands are a slower terrestrial harmonic of the faster modes at either end. NDVI also exhibits intraseasonal cycles operating near 40 days with spatial loadings collocated with the slow rainfall mode at a 10–20-day lag. It is postulated that an earlier rainfall event and subsequent “greening” results in a moisture flux that promotes the next rainfall event. This is reflected in a composite analysis of low-level velocity potential. The vegetation draws airflow toward itself in a self-sustaining way.
Cellular Statistical Models of Broken Cloud Fields. Part I: Theory
Authors: Alexandrov Mikhail D. , Marshak Alexander , Ackerman Andrew S. 
Published: March 2010

Abstract
A new analytical statistical model describing the structure of broken cloud fields is presented. It depends on two parameters (cell size and occupancy probability) and provides chord distributions of clouds and gaps between them by length, as well as the cloud fraction distribution. This approach is based on the assumption that the structure of a cloud field is determined by a semiregular grid of cells (an abstraction of the atmospheric convective cells), which are filled with cloud with some probability. First, a simple discrete model is introduced, where clouds and gaps can occupy an integer number of cells, and then a continuous analog is developed, allowing for arbitrary cloud and gap sizes. The influence of a finite sample size on the retrieved statistics is also described.
Numerical Simulations of Low-CAPE Flows over a Mountain Ridge
Authors: Miglietta Mario Marcello , Rotunno Richard 
Published: March 2010

Abstract
In a recent study, the authors performed numerical simulations of conditionally unstable flows past a mesoscale mountain ridge in order to investigate the statistically stationary features of the solution precipitation characteristics for intermediate-to-high values of convective available potential energy (CAPE). That study proposed a functional dependence of the rain rate on three parameters, related respectively to the triggering and the orographic forcing of convection and to the ratio of the advective to convective time scales. The present study extends that analysis to cover larger regions of the parameter space, including experiments corresponding to a wider range of CAPE. It is found here that the low-CAPE, moderate-wind experiments do not fit the functional dependence for rain rate amount and location proposed in the authors’ previous study. The analysis of the present solutions suggests that two additional nondimensional parameters should be taken into account.
Performance of the New NCAR CAM3.5 in East Asian Summer Monsoon Simulations: Sensitivity to Modifications of the Convection Scheme
Authors: Chen Haoming , Zhou Tianjun , Neale Richard B. , Wu Xiaoqing , Zhang Guang Jun 
Published: March 2010

Abstract
The performance of an interim version of the NCAR Community Atmospheric Model (CAM3.5) in simulating the East Asian summer monsoon (EASM) is assessed by comparing model results against observations and reanalyses. Both the climate mean states and seasonal cycle of major EASM components are evaluated. Special attention is paid to the sensitivity of model performance to changes in the convection scheme. This is done by analyzing four CAM3.5 runs with identical dynamical core and physical packages but different modifications to their convection scheme, that is, the original Zhang–McFarlane (ZM) scheme, Neale et al.’s modification (NZM), Wu et al.’s modification (WZM), and Zhang’s modification (ZZM). The results show that CAM3.5 can capture the major climate mean states and seasonal features of the EASM circulation system, including reasonable simulations of the Tibetan high in the upper troposphere and the western Pacific subtropical high (WPSH) in the middle and lower troposphere. The main deficiencies are found in monsoon rainfall and the meridional monsoon cell. The weak meridional land–sea thermal contrasts in the model contribute to the weaker monsoon circulation and to insufficient rainfall in both tropical and subtropical regions of EASM. The seasonal migration of rainfall, as well as the northward jump of the WPSH from late spring to summer, is reasonably simulated, except that the northward jump of the monsoon rain belt still needs improvement. Three runs using modified schemes generally improve the model performance in EASM simulation compared to the control run. The monsoon rainfall distribution and its seasonal variation are sensitive to modifications of the ZM convection scheme, which is most likely due to differences in closure assumptions. NZM, which uses a convective available potential energy (CAPE)-based closure assumption, performs better in tropical regions where the rainfall is closely related to CAPE. However, WZM and ZZM, which use quasi-equilibrium (QE) closure, have more realistic subtropical rainfall in the mei-yu/baiu/changma front region, mainly because the rainfall in the subtropics is more sensitive to the rate of destabilization by the large-scale flow.
A Comparison of Levels of Burden in Indian and White Parents With a Son or Daughter With Schizophrenia
Authors: Lloyd Helen , Singh Pratima , Merritt Rowena , Shetty Adarsh , Yiend Jenny , Singh Swaran , Burns Tom 
Published: March 2010

Background: Caregiver burden in mental illness is believed to differ between ethnic groups, but few studies have examined this in schizophrenia in the UK. Aim: To measure burden in British North Indian Sikh and white British parents with a son or daughter with established schizophrenia managed in outpatient care. Method: A cross-cultural cohort study measuring family factors, patient psychopathology and levels of burden and distress. Results: Overall levels of burden were low with no significant differences between the groups. Burden subscale scores showed Indian parents were more affected by psychotic behaviours than white parents. The groups also differed on several sociodemographic variables. Conclusion: In stabilized community patients, the overall extent of burden experienced by both Indian and white parents is low and comparable. However, Indian parents were more burdened by psychotic behaviours. This may be a result of co-residence as Indian patients are more likely to live with their families. Social and economic factors in the country of residence and levels of acculturation may also influence levels of burden and the illness behaviours found most bothersome by parents.
How Black African and White British Women Perceive Depression and Help-Seeking: a Pilot Vignette Study
Authors: Brown June S.L. , Casey Sarah J. , Bishop Amanda J. , Prytys Marta , Whittinger Naureen , Weinman John 
Published: March 2010

Background: The detection of psychological problems of black African people has been found to be substantially lower, compared with white British and black Caribbean people. This may be due to differences in patients’ perceptions of illness. Little research has been carried out on factors that may influence the help-seeking behaviour of black Africans. Aims: To assess differences in the perceptions of depression of black African and white British women that may influence lower detection and to investigate whether there are ethnic group differences in reasons for not seeking formal help. Methods: A short quantitative illness perception measure, the Brief Illness Perception Questionnaire (BIPQ), was used in a community survey, using a standard text vignette methodology to control for variations in previous experiences of depression. Responses from women who indicated that they would not seek formal help for depressive symptoms were qualitatively analyzed. Results: Differences in perceptions of depression were found between black African ( n = 73) and white British groups ( n = 72) on five of the nine BIPQ dimensions. Black women were more likely to perceive depression to have less serious consequences; to be associated with fewer symptoms; to be less chronic; to be less amenable to treatment; and more frequently attributed depression to social factors. Over half the participants ( n = 74) said they would not seek formal help for depressive symptoms. Six qualitative response categories emerged to explain non-consultation. The most common factor for both groups related to GP consultation difficulties. Significantly more white women cited preferring alternative help sources as a reason for non-consultation. The greater number of black women citing anti-medication beliefs was marginally significant. There were no differences between the ethnic groups in their use of the remaining three categories: illness characteristics; service constraints; and stigma/shame. Conclusion: Differing perceptions of depression among black and white women could help explain GPs’ lower detection rates of depressive problems of black women. Differences in views about the formal help available may explain ethnic differences in help-seeking.