bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polycomb Group Protein Enhancer of Zeste 2 Is an Oncogene That Promotes the Neoplastic Transformation of a Benign Prostatic Epithelial Cell Line
Authors: Karanikolas Breanne D.W. , Figueiredo Marxa L. , Wu Lily 
Published: September 2009

Abstract
Polycomb group protein enhancer of zeste 2 (EZH2) is a master regulatory protein that plays a critical role in development as part of the polycomb repressive complex 2. Polycomb repressive complex 2 controls numerous cell cycle and regulatory genes through trimethylation of histone 3, which results in chromatin condensation and transcriptional silencing. EZH2 overexpression has been correlated with high incidence of more aggressive, metastatic prostate cancers. Although this correlation means EZH2 could prove valuable as a biomarker in clinical settings, the question remains whether EZH2 is actually responsible for the initiation of these more aggressive tumor types. In this study, EZH2-mediated neoplastic transformation of the normal prostate epithelial cell line benign prostate hyperplasia 1 (BPH1) was confirmed by in vivo tumor growth and in vitro colony formation. Furthermore, EZH2 transformation resulted in increased invasive behavior of BPH1 cells, indicating that EZH2 may be responsible for aggressive behavior in prostate cancers. BPH1 was also transformed with the classic oncogenes myristoylated Akt and activated Ras(V12) to allow phenotype comparisons with the EZH2-transformed cells. This study marks the first demonstration of neoplastic transformation in prostate cells mediated by EZH2 and establishes that EZH2 possesses stronger transforming activity than Akt but weaker activity than activated Ras. (Mol Cancer Res 2009;7(9):1456–65)
Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-Regulation of Hexokinase 2 and Poor Prognosis
Authors: Palmieri Diane , Fitzgerald Daniel , Shreeve S. Martin , Hua Emily , Bronder Julie L. , Weil Robert J. , Davis Sean , Stark Andreas M. , Merino Maria J. , Kurek Raffael , Mehdorn H. Maximilian , Davis Gary , Steinberg Seth M. , Meltzer Paul S. , Aldape Kenneth , Steeg Patricia S. 
Published: September 2009

Abstract
Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. (Mol Cancer Res 2009;7(9):1438–45)
Chemoprevention of Mouse Intestinal Tumorigenesis by the Cyclin-Dependent Kinase Inhibitor SNS-032
Authors: Boquoi Amelie , Chen Tina , Enders Greg H. 
Published: September 2009

Abstract
Despite advances in screening and treatment, colorectal cancer remains the second leading cause of cancer-related death in the United States. Cyclin-dependent kinases (Cdk) are deregulated in colorectal cancer by silencing of the Cdk inhibitor p16Ink4a and other mechanisms. We tested whether the small molecule Cdk inhibitor SNS-032 (formerly BMS-387032), which targets Cdk2, Cdk7, and Cdk9, can prevent intestinal tumorigenesis in mouse models. We generated mice with high intestinal tumor loads by combining the multiple intestinal neoplasia (Min) mutation with Ink4a/Arf mutations and inducing colitis with dextran sulfate sodium. p16-null Min mice (n = 17) began dextran sulfate sodium treatment at week 5 and i.p. injection of carrier or SNS-032 at week 6. Mice were sacrificed at week 12. SNS-032 was well tolerated and reduced colon tumor burden to 36% of that in carrier-treated mice (P &lt; 0.001). We then extended the study to Ink4/Arf-null Min mice (n = 14) and increased the drug dose frequency. SNS-032 treatment reduced the intestinal tumor number to 25% and intestinal tumor burden to 16% of carrier-treated mice (P &lt; 0.0001). DNA synthesis in non-neoplastic and tumor epithelial cells, detected by bromodeoxyuridine incorporation, was modestly reduced by acute SNS-032 treatment. The mitotic index, detected by histone H3 phosphorylation, was distinctly decreased (P &lt; 0.03), and apoptosis, detected by caspase 3 activation, was increased (P &lt; 0.005). These results show the chemoprevention of intestinal tumorigenesis by SNS-032. Our findings support further study of Cdk inhibitors for chemoprevention and therapy of colon cancer.
The Tropical Response to Extratropical Thermal Forcing in an Idealized GCM: The Importance of Radiative Feedbacks and Convective Parameterization
Authors: Kang Sarah M. , Frierson Dargan M. W. , Held Isaac M. 
Published: September 2009

Abstract
The response of tropical precipitation to extratropical thermal forcing is reexamined using an idealized moist atmospheric GCM that has no water vapor or cloud feedbacks, simplifying the analysis while retaining the aquaplanet configuration coupled to a slab ocean from the authors’ previous study. As in earlier studies, tropical precipitation in response to high-latitude forcing is skewed toward the warmed hemisphere. Comparisons with a comprehensive GCM in an identical aquaplanet, mixed-layer framework reveal that the tropical responses tend to be much larger in the comprehensive GCM as a result of positive cloud and water vapor feedbacks that amplify the imposed extratropical thermal forcing.
The magnitude of the tropical precipitation response in the idealized model is sensitive to convection scheme parameters. This sensitivity as well as the tropical precipitation response can be understood from a simple theory with two ingredients: the changes in poleward energy fluxes are predicted using a one-dimensional energy balance model and a measure of the “total gross moist stability” [Δm, which is defined as the total (mean plus eddy) atmospheric energy transport per unit mass transport] of the model tropics converts the energy flux change into a mass flux and a moisture flux change. The idealized model produces a low level of compensation of about 25% between the imposed oceanic flux and the resulting response in the atmospheric energy transport in the tropics regardless of the convection scheme parameter. Because Geophysical Fluid Dynamics Laboratory Atmospheric Model 2 (AM2) with prescribed clouds and water vapor exhibits a similarly low level of compensation, it is argued that roughly 25% of the compensation is dynamically controlled through eddy energy fluxes. The sensitivity of the tropical response to the convection scheme in the idealized model results from different values of Δm: smaller Δm leads to larger tropical precipitation changes for the same response in the energy transport.
Financialization and Changes in the Social Relations along Commodity Chains: The Case of Coffee
Authors: Newman Susan A. 
Published: September 2009

This article examines distributional implications of the restructuring of international coffee markets that has occurred since the collapse of the International Coffee Agreement in 1989 and market liberalization in coffee producing countries under structural adjustment programs. It is argued that increased financial investment on international commodity exchanges, together with market liberalization, have given rise to opportunities and challenges for actors in the coffee industry. Given the heterogeneity of market actors, these tend to exacerbate inequalities already present in the structure of production and marketing of coffee. JEL classification: L11, O13, G19
Efficacy and Safety of Ezetimibe Plus Orlistat or Rimonabant in Statin-Intolerant Nondiabetic Overweight/Obese Patients With Dyslipidemia
Authors: Florentin Matilda , Kostapanos Michael S. , Nakou Eleni S. , Elisaf Moses , Liberopoulos Evangelos N. 
Published: September 2009

Aims: To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia. Methods and results: Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/ rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (—8.3%, —8.6%, and —5.2% in the EO group and —7.3%, —7.2%, and —7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (—20.4% vs —14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups. Conclusion: For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides.
MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9
Authors: Gilles Laure , Bluteau Dominique , Boukour Siham , Chang Yunhua , Zhang Yanyan , Robert Thomas , Dessen Philippe , Debili Najet , Bernard Olivier A. , Vainchenker William , Raslova Hana 
Published: September 2009

AbstractMegakaryoblastic leukemia 1 (MAL) is a transcriptional coactivator of serum response factor (SRF). In acute megakaryoblastic leukemia, the MAL gene is translocated and fused with the gene encoding one twenty-two (OTT). Herein, we show that MAL expression increases during the late differentiation steps of neonate and adult human megakaryopoiesis and localized into the nucleus after Rho GTPase activation by adhesion on collagen I or convulxin. MAL knockdown in megakaryocyte progenitors reduced the percentage of cells forming filopodia, lamellipodia, and stress fibers after adhesion on the same substrates, and reduced proplatelet formation. MAL repression led to dysmorphic megakaryocytes with disorganized demarcation membranes and α granules heterogeneously scattered in the cytoplasm. Gene expression profiling revealed a marked decrease in metalloproteinase 9 (MMP-9) and MYL9 expression after MAL inhibition. Luciferase assays in HEK293T cells and chromatin immunoprecipitation in primary megakaryocytes showed that the MAL/SRF complex directly regulates MYL9 and MMP9 in vitro. Megakaryocyte migration in response to stromal cell–derived factor 1, through Matrigel was considerably decreased after MAL knockdown, implicating MMP9 in migration. Finally, the use of a shRNA to decrease MYL9 expression showed that MYL9 was involved in proplatelet formation. MAL/SRF complex is thus involved in platelet formation and megakaryocyte migration by regulating MYL9 and MMP9.
On the adaptation of endosteal stem cell niche function in response to stress
Authors: Jiang Yi , Bonig Halvard , Ulyanova Tatiana , Chang KaiHsin , Papayannopoulou Thalia 
Published: September 2009

Abstract
Although the influence of microenvironmental “niche” on the function of a variety of stem cells is undisputed, the details of hematopoietic stem cell/niche interactions at the cellular and molecular level have sparked a continuous debate. We studied the microanatomic partitioning of transplanted normal and α4 integrin-deficient Lin−kit+ cells in trabecular and compact bone before and after irradiation and present robust quantitative data on both. We found that (1) the microanatomic distribution of normal highly enriched progenitor cells is random in nonirradiated recipients based on area distribution analyses, (2) in contrast, in irradiated hosts normal cells distribute preferentially near the endosteum, (3) the overall cell seeding efficiency was higher in trabecular versus compact bone both before and after irradiation, and (4) α4 integrin-deficient cells not only lodge with reduced overall efficiency confirming previous data, but fail to preferentially partition themselves into endosteal regions in irradiated hosts, as normal cells do. A similar phenotype was observed with cells rendered Gi-protein signaling incompetent by pertussis toxin treatment, supporting an active stromal-derived factor 1 (SDF-1) gradient near endosteum after irradiation.
Deferasirox pharmacokinetics in patients with adequate versus inadequate response
Authors: Chirnomas Deborah , Smith Amber Lynn , Braunstein Jennifer , Finkelstein Yaron , Pereira Luis , Bergmann Anke K. , Grant Frederick D. , Paley Carole , Shannon Michael , Neufeld Ellis J. 
Published: September 2009

AbstractTens of thousands of transfusion-dependent (eg, thalassemia) patients worldwide suffer from chronic iron overload and its potentially fatal complications. The oral iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral deferoxamine has been a major advance for patients with transfusional hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative iron balance. We performed a prospective study of oral deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate deferasirox response (rising ferritin trend or rising liver iron on deferasirox doses > 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments: deferoxamine infusion and urinary iron measurement to assess readily chelatable iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour deferasirox PK study following a single 35-mg/kg dose of oral deferasirox; and pharmacogenomic analysis. Patients with inadequate response to deferasirox had significantly lower systemic drug exposure compared with control patients (P < .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t1/2) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.
Pancreatic iron loading predicts cardiac iron loading in thalassemia major
Authors: Noetzli Leila J. , Papudesi Jhansi , Coates Thomas D. , Wood John C. 
Published: September 2009

Abstract
Diabetes mellitus and cardiomyopathy are common in chronically transfused thalassemia major patients, occurring in the second and third decades of life. We postulated that pancreatic iron deposition would precede cardiac iron loading, representing an environment favorable for extrahepatic iron deposition. To test this hypothesis, we examined pancreatic and cardiac iron in 131 thalassemia major patients over a 4-year period. Cardiac iron (R2* > 50 Hz) was detected in 37.7% of patients and pancreatic iron (R2* > 28 Hz) in 80.4% of patients. Pancreatic and cardiac R2* were correlated (r2 = 0.52), with significant pancreatic iron occurring nearly a decade earlier than cardiac iron. A pancreatic R2* less than 100 Hz was a powerful negative predictor of cardiac iron, and pancreatic R2* more than 100 Hz had a positive predictive value of more than 60%. In serial analysis, changes in cardiac iron were correlated with changes in pancreatic iron (r2 = 0.33, P < .001), but not liver iron (r2 = 0.025, P = .25). As a result, pancreatic R2* measurements offer important early recognition of physiologic conditions suitable for future cardiac iron deposition and complementary information to liver and cardiac iron during chelation therapy. Staging abdominal and cardiac magnetic resonance imaging examinations could significantly reduce costs, magnet time, and need for sedation in young patients.
The small heat shock protein (sHSP) genes in the silkworm, Bombyx mori, and comparative analysis with other insect sHSP genes
Authors: Li Zi-Wen , Li Xue , Yu Quan-You , Xiang Zhong-Huai , Kishino Hirohisa , Zhang Ze 
Published: September 2009

Abstract

Background
Small heat shock proteins (sHSPs) are products of heat shock response and of other stress responses, and ubiquitous in all three domains of life, archaea, bacteria, and eukarya. They mainly function as molecular chaperones to protect proteins from being denatured in extreme conditions. Study on insect sHSPs could provide some insights into evolution of insects that have adapted to diverse niches in the world.

Results
Taking advantage of the newly assembled genome sequence, we performed a genome-wide analysis of the candidate sHSP genes in the silkworm, Bombyx mori. Based on known silkworm sHSP sequences, we identified 16 silkworm sHSP genes. Most of them are distributed on two silkworm chromosomes 5 and 27, respectively. 15 of 16 silkworm sHSPs have expression evidence. The comparative analysis of insect sHSPs from B. mori, Drosophila melanogaster, Apis mellifera, Tribolium castaneum, and Anopheles gambiae revealed that there is only one orthologous cluster whereas remaining clusters are species-specific on the phylogenetic tree. This suggested that most of sHSPs might have diverged in function across insects investigated. In addition, the data presented in this study also revealed that sHSPs in the insect orthologous cluster are highly conserved in both sequence and expression pattern. In sum, insect sHSPs show a completely different evolutionary pattern from that found in vertebrate sHSPs.

Conclusion

B. mori has the largest number of insect sHSP genes characterized to date, including 16 genes. The inference that most species-specific sHSPs might have diverged in function across insects investigated will help us understand the adaptability of these insects to diverse environments.
Procalcitonin as a biomarker for severe Plasmodium falciparum disease: a critical appraisal of a semi-quantitative point-of-care test in a cohort of travellers with imported malaria
Authors: Hesselink Dennis A , Burgerhart Jan-Steven , Bosmans-Timmerarends Hanna , Petit Pieter , van Genderen Perry JJ 
Published: September 2009

Abstract

Background
Imported malaria occurs as a relatively rare event in developed countries. As a consequence, most clinicians have little experience in making clinical assessments of disease severity and decisions regarding the need for parenteral therapy or high-level monitoring. In this study, the diagnostic accuracy of procalcitonin (PCT) for severe Plasmodium falciparum disease was assessed in a cohort of 100 consecutive travellers with various species of imported malaria.

Methods and results
In all patients, PCT was measured on admission with a semi-quantitative 'point-of-care' test. Patients with severe P. falciparum malaria had significantly higher median PCT levels on admission as compared with patients with uncomplicated P. falciparum disease. In addition, PCT levels in patients with non-falciparum malaria were also higher compared with patients with non-severe falciparum malaria but lower compared with severe P. falciparum malaria. At a cut-off point of 10 ng/mL, PCT had a sensitivity of 0,67 and a specificity of 0,94 for severe falciparum disease. However, at lower cut-off points the specificity and positive predictive value were rather poor although the sensitivity and negative predictive value remained high.

Discussion
Potential drawbacks in the interpretation of elevated PCT levels on admission may be caused by infections with non-falciparum species and by concomitant bacterial infections.

Conclusion
Semi-quantitative determination of PCT on admission is of limited use in the initial clinical assessment of disease severity in travellers with imported malaria, especially in settings with limited experience with the treatment of malaria.
The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria
Authors: Ambler Michael T , Dubowitz Lilly M , Arunjerdja Ratree , Hla Eh Paw , Thwai Kyaw Lay , Viladpainguen Jacher , Singhasivanon Pratap , Luxemburger Christine , Nosten François , McGready Rose 
Published: September 2009

AbstractBackgroundMefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children.MethodsChildren, aged between three months and five years, with acute uncomplicatedPlasmodium falciparummalaria were randomized to either 7 days of artesunate monotherapy or the same schedule of artesunate plus mefloquine on day 7 and 8. Neurological testing targeting coordination and behaviour was carried out at day 0, 7, 9, 10, 14 and 28. Non-febrile healthy control children from the same population were tested on days 0, 7, 14 and 28.ResultsFrom December 1994 to July 1997, 91 children with uncomplicatedP. falciparum, 45 treated with artesunate monotherapy, 46 treated with mefloquine and artesunate combination therapy and 36 non-febrile controls, underwent neurological testing. Malaria and fever had a significant negative impact on testing performance. By contrast, the anti-malarial treatments were not associated with worsening performances in the various components of the test. Artesunate and mefloquine do not appear to have a significant influence on coordination and behaviour. Children treated with mefloquine were significantly less likely to suffer recurrent malaria infection during follow-up compared to those treated with artesunate alone (P = 0.033).ConclusionIn keeping with the results of randomized controlled trials in adults, mefloquine was not associated with a decrease in specific items of neurological performance. Likewise, children treated with artesunate did not perform significantly differently to control children. This study does not exclude subtle or rare treatment CNS effects of artesunate or mefloquine. Treatment of acute uncomplicated malaria results in a significant improvement on items of neurological performance.