bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protection from Rapamycin-Induced Apoptosis by Insulin-Like Growth Factor-I Is Partially Dependent on Protein Kinase C Signaling
Authors: Thimmaiah Kuntebommanahalli N. , Easton John B. , Houghton Peter J. 
Published: February 2010

Abstract
Rapamycin-induced apoptosis in sarcoma cells is inhibited by insulin-like growth factor-I (IGF-I) through a signaling pathway independent of Ras-extracellular signal-regulated kinase 1/2 and Akt. IGF-I induces Bad phosphorylation (Ser112, Ser136, and Ser155) in a pathway involving phosphoinositide 3′ kinase (PI3K) and protein kinase C (PKC; μ, ϵ, or θ) resulting in sequestering Bad from mitochondria and subsequently interacting with 14-3-3γ in the cytosol. Gene knockdown of Bad, Bid, Akt1, Akt2, PKC-μ, PKC-ϵ, or PKC-θ was achieved by transient transfection using small interfering RNAs. Results indicate that IGF-I signaling to Bad requires activation of PI3K and PKC (μ, θ, ϵ) but not mTOR, Ras-extracellular signal-regulated kinase 1/2, protein kinase A, or p90RSK. Wortmannin blocked the phosphorylation of PKC-μ (Ser744/Ser748), suggesting that PI3K is required for the activation of PKCs. PKCs phosphorylate Bad under in vitro conditions, and the association of phosphorylated Bad with PKC-μ or PKC-ϵ, as shown by immunoprecipitation, indicated direct involvement of PKCs in Bad phosphorylation. To confirm these results, cells overexpressing pEGFP-N1, wt-Bad, or Bad with a single site mutated (Ser112Ala; Ser136Ala; Ser155Ala), two sites mutated (Ser112/136Ala; Ser112/155Ala; Ser136/155Ala), or the triple mutant were tested. IGF-I protected completely against rapamycin-induced apoptosis in cells overexpressing wt-Bad and mutants having either one or two sites of phosphorylation mutated. Knockdown of Bid using small interfering RNA showed that Bid is not required for rapamycin-induced cell death. Collectively, these data suggest that IGF-I–induced phosphorylation of Bad at multiple sites via a pathway involving PI3K and PKCs is important for protecting sarcoma cells from rapamycin-induced apoptosis. Cancer Res; 70(5); 2000–9
Maternally Expressed Gene 3, an Imprinted Noncoding RNA Gene, Is Associated with Meningioma Pathogenesis and Progression
Authors: Zhang Xun , Gejman Roger , Mahta Ali , Zhong Ying , Rice Kimberley A. , Zhou Yunli , Cheunsuchon Pornsuk , Louis David N. , Klibanski Anne 
Published: February 2010

Abstract
Meningiomas are common tumors, representing 15% to 25% of all central nervous system tumors. NF2 gene inactivation on chromosome 22 has been shown as an early event in tumorigenesis; however, few factors underlying tumor growth and progression have been identified. The chromosomal abnormalities of 14q32 are often associated with meningioma pathogenesis and progression; therefore, it has been proposed that an as yet unidentified tumor suppressor is present at this locus. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes a noncoding RNA with an antiproliferative function. We found that MEG3 mRNA is highly expressed in normal arachnoidal cells. However, MEG3 is not expressed in the majority of human meningiomas or the human meningioma cell lines IOMM-Lee and CH157-MN. There is a strong association between loss of MEG3 expression and tumor grade. Allelic loss at the MEG3 locus is also observed in meningiomas, with increasing prevalence in higher grade tumors. In addition, there is an increase in CpG methylation within the promoter and the imprinting control region of MEG3 gene in meningiomas. Functionally, MEG3 suppresses DNA synthesis in both IOMM-Lee and CH157-MN cells by ∼60% in bromodeoxyuridine incorporation assays. Colony-forming efficiency assays show that MEG3 inhibits colony formation in CH157-MN cells by ∼80%. Furthermore, MEG3 stimulates p53-mediated transactivation in these cell lines. Therefore, these data are consistent with the hypothesis that MEG3, which encodes a noncoding RNA, may be a tumor suppressor gene at chromosome 14q32 involved in meningioma progression via a novel mechanism. Cancer Res; 70(6); 2350–8
Estrogen Receptor-α Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
Authors: Bostner Josefine , Skoog Lambert , Fornander Tommy , Nordenskjöld Bo , Stål Olle 
Published: February 2010

Abstract
Purpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor α (ERα) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pERαser305 on breast cancer prognosis and results of tamoxifen therapy.
Experimental Design: We examined Pak1 and pERαser305 protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment.
Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pERαser305 correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pERαser305 predicted reduced response to tamoxifen in patients with ERα-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P &lt; 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment.
Conclusion: Our results suggest that patients with tumors expressing Pak1 and pERαser305 in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus. Clin Cancer Res; 16(5); 1624–33
The Prolyl Isomerase Pin1 Enhances HER-2 Expression and Cellular Transformation via Its Interaction with Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase 1
Authors: Khanal Prem , Namgoong Gwang Mo , Kang Bong Seok , Woo Eun-Rhan , Choi Hong Seok 
Published: February 2010

Abstract
The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1−/− mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)–induced MEK1/2 phosphorylation compared with Pin1+/+ mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2α and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2α signaling in breast cancer. Mol Cancer Ther; 9(3); 606–16
Identification of Expression Signatures Predictive of Sensitivity to the Bcl-2 Family Member Inhibitor ABT-263 in Small Cell Lung Carcinoma and Leukemia/Lymphoma Cell Lines
Authors: Tahir Stephen K. , Wass John , Joseph Mary K. , Devanarayan Viswanath , Hessler Paul , Zhang Haichao , Elmore Steve W. , Kroeger Paul E. , Tse Christin , Rosenberg Saul H. , Anderson Mark G. 
Published: February 2010

AbstractABT-263 inhibits the antiapoptotic proteins Bcl-2, Bcl-xL, and Bcl-w and has single-agent efficacy in numerous small cell lung carcinoma (SCLC) and leukemia/lymphoma cell lines in vitro and in vivo. It is currently in clinical trials for treating patients with SCLC and various leukemia/lymphomas. Identification of predictive markers for response will benefit the clinical development of ABT-263. We identified the expression of Bcl-2 family genes that correlated best with sensitivity to ABT-263 in a panel of 36 SCLC and 31 leukemia/lymphoma cell lines. In cells sensitive to ABT-263, expression of Bcl-2 and Noxa is elevated, whereas expression of Mcl-1 is higher in resistant cells. We also examined global expression differences to identify gene signature sets that correlated with sensitivity to ABT-263 to generate optimal signature sets predictive of sensitivity to ABT-263. Independent cell lines were used to verify the predictive power of the gene sets and to refine the optimal gene signatures. When comparing normal lung tissue and SCLC primary tumors, the expression pattern of these genes in the tumor tissue is most similar to sensitive SCLC lines, whereas normal tissue is most similar to resistant SCLC lines. Most of the genes identified using global expression patterns are related to the apoptotic pathway; however, all but Bcl-rambo are distinct from the Bcl-2 family. This study leverages global expression data to identify key gene expression patterns for sensitivity to ABT-263 in SCLC and leukemia/lymphoma and may provide guidance in the selection of patients in future clinical trials. Mol Cancer Ther; 9(3); 545–57
The Impact of Fish Oil on the Chemopreventive Efficacy of Tamoxifen against Development ofN-Methyl-N-Nitrosourea–Induced Rat Mammary Carcinogenesis
Authors: Manni Andrea , Xu Haifang , Washington Sharlene , Aliaga Cesar , Cooper Timothy , Richie John P. , Bruggeman Richard , Prokopczyk Bogdan , Calcagnotto Ana , Trushin Neil , Mauger David , Verderame Michael F. , El-Bayoumy Karam 
Published: February 2010

AbstractThe antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-γ (PPARγ), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARγ receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea–induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARγ is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA–rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies. Cancer Prev Res; 3(3); 322–30
Genome-wide linkage scan for factors of metabolic syndrome in a Chinese population
Authors: Tam Claudia HT , Lam Vincent KL , So Wing-Yee , Ma Ronald CW , Chan Juliana CN , Ng Maggie CY 
Published: February 2010

AbstractBackgroundShared genetic factors may contribute to the phenotypic clustering of different components of the metabolic syndrome (MES). This study aims to identify genetic loci that contribute to individual or multiple factors related to MES.ResultsWe studied 478 normoglycemic subjects ascertained through 163 families participating in the Hong Kong Family Diabetes Study. Factor analysis on 15 MES-related traits yielded 6 factors including adiposity factor (body mass index, waist and hip circumferences), insulin factor (fasting insulin and insulin AUC during OGTT), glucose factor (fasting glucose and glucose AUC during OGTT), TC-LDLC factor (total cholesterol and LDL-cholesterol), blood pressure factor (systolic and diastolic blood pressure) and TG-HDLC factor (triglycerides and HDL-cholesterol). Genome-wide linkage analyses were performed on these factors using variance component approach. Suggestive evidence for linkage (LOD = 1.24 - 2.46) were observed for adiposity factor (chromosome 1 at 187 cM, chromosome 9 at 34 cM and chromosome 17 at 10 cM), insulin factor (chromosome 2 at 128 cM, chromosome 5 at 21 cM and chromosome 12 at 7 cM), glucose factor (chromosome 7 at 155 cM), TC-LDLC factor (chromosome 7 at 151 cM and chromosome 13 at 15 cM) and TG-HDLC factor (chromosome 7 at 155 cM).ConclusionsIn summary, our findings suggest the presence of susceptibility loci that influence either single (chromosomes 1, 2, 5, 9, 12, 13 and 17) or multiple factors (chromosome 7) for MES in Hong Kong Chinese without diabetes.
Comparative analysis of fungal protein kinases and associated domains
Authors: Kosti Idit , Mandel-Gutfreund Yael , Glaser Fabian , Horwitz Benjamin A 
Published: February 2010

Abstract

Background
Protein phosphorylation is responsible for a large portion of the regulatory functions of eukaryotic cells. Although the list of sequenced genomes of filamentous fungi has grown rapidly, the kinomes of recently sequenced species have not yet been studied in detail. The objective of this study is to apply a comparative analysis of the kinase distribution in different fungal phyla, and to explore its relevance to understanding the evolution of fungi and their taxonomic classification. We have analyzed in detail 12 subgroups of kinases and their distribution over 30 species, as well as their potential use as a classifier for members of the fungal kingdom.

Results
Our findings show that despite the similarity of the kinase distribution in all fungi, their domain distributions and kinome density can potentially be used to classify them and give insight into their evolutionary origin. In general, we found that the overall representation of kinase groups is similar across fungal genomes, the only exception being a large number of tyrosine kinase-like (TKL) kinases predicted in Laccaria bicolor. This unexpected finding underscores the need to continue to sequence fungal genomes, since many species or lineage-specific properties may remain to be discovered. Furthermore, we found that the domain organization significantly varies between the fungal species. Our results suggest that protein kinases and their functional domains strongly reflect fungal taxonomy.

Conclusions
Comparison of the predicted kinomes of sequenced fungi suggests essential signaling functions common to all species, but also specific adaptations of the signal transduction networks to particular species.
Columnar cell lesions of the canine mammary gland: pathological features and immunophenotypic analysis
Authors: Ferreira Enio , Gobbi Helenice , Saraiva Bruna S , Cassali Geovanni D 
Published: February 2010

AbstractBackgroundIt has been suggested that columnar cell lesions indicate an alteration of the human mammary gland involved in the development of breast cancer. They have not previously been described in canine mammary gland. The aim of this paper is describe the morphologic spectrum of columnar cell lesions in canine mammary gland specimens and their association with other breast lesions.MethodsA total of 126 lesions were subjected to a comprehensive morphological review based upon the human breast classification system for columnar cell lesions. The presence of preinvasive (epithelial hyperplasia and in situ carcinoma) and invasive lesions was determined and immunophenotypic analysis (estrogen receptor (ER), progesterone receptor (PgR), high molecular weight cytokeratin (34βE-12), E-cadherin, Ki-67, HER-2 and P53) was perfomed.ResultsColumnar cell lesions were identified in 67 (53.1%) of the 126 canine mammary glands with intraepithelial alterations. They were observed in the terminal duct lobular units and characterized at dilated acini may be lined by several layers of columnar epithelial cells with elongated nuclei. Of the columnar cell lesions identified, 41 (61.2%) were without and 26 (38.8%) with atypia. Association with ductal hyperplasia was observed in 45/67 (67.1%). Sixty (89.5%) of the columnar cell lesions coexisted with neoplastic lesions (20 in situ carcinomas, 19 invasive carcinomas and 21 benign tumors). The columnar cells were ER, PgR and E-cadherin positive but negative for cytokeratin 34βE-12, HER-2 and P53. The proliferation rate as measured by Ki-67 appeared higher in the lesions analyzed than in normal TDLUs.ConclusionsColumnar cell lesions in canine mammary gland are pathologically and immunophenotypically similar to those in human breast. This may suggest that dogs are a suitable model for the comparative study of noninvasive breast lesions.
RNA quantification using gold nanoprobes - application to cancer diagnostics
Authors: Conde João , de la Fuente Jesús M , Baptista Pedro V 
Published: February 2010

Abstract
Molecular nanodiagnostics applied to cancer may provide rapid and sensitive detection of cancer related molecular alterations, which would enable early detection even when those alterations occur only in a small percentage of cells. The use of gold nanoparticles derivatized with thiol modified oligonucleotides (Au-nanoprobes) for the detection of specific nucleic acid targets has been gaining momentum as an alternative to more traditional methodologies. Here, we present an Au-nanoparticles based approach for the molecular recognition and quantification of the BCR-ABL fusion transcript (mRNA), which is responsible for chronic myeloid leukemia (CML), and to the best of our knowledge it is the first time quantification of a specific mRNA directly in cancer cells is reported. This inexpensive and very easy to perform Au-nanoprobe based method allows quantification of unamplified total human RNA and specific detection of the oncogene transcript. The sensitivity settled by the Au-nanoprobes allows differential gene expression from 10 ng/μl of total RNA and takes less than 30 min to complete after total RNA extraction, minimizing RNA degradation. Also, at later stages, accumulation of malignant mutations may lead to resistance to chemotherapy and consequently poor outcome. Such a method, allowing for fast and direct detection and quantification of the chimeric BCR-ABL mRNA, could speed up diagnostics and, if appropriate, revision of therapy. This assay may constitute a promising tool in early diagnosis of CML and could easily be extended to further target genes with proven involvement in cancer development.
Intra-operative intravenous fluid restriction reduces perioperative red blood cell transfusion in elective cardiac surgery, especially in transfusion-prone patients: a prospective, randomized controlled trial
Authors: Vretzakis George , Kleitsaki Athina , Stamoulis Konstantinos , Bareka Metaxia , Georgopoulou Stavroula , Karanikolas Menelaos , Giannoukas Athanasios 
Published: February 2010

Abstract

Background
Cardiac surgery is a major consumer of blood products, and hemodilution increases transfusion requirements during cardiac surgery under CPB. As intraoperative parenteral fluids contribute to hemodilution, we evaluated the hypothesis that intraoperative fluid restriction reduces packed red-cell (PRC) use, especially in transfusion-prone adults undergoing elective cardiac surgery.

Methods
192 patients were randomly assigned to restrictive (group A, 100 pts), or liberal (group B, 92 pts) intraoperative intravenous fluid administration. All operations were conducted by the same team (same surgeon and perfusionist). After anesthesia induction, intravenous fluids were turned off in Group A (fluid restriction) patients, who only received fluids if directed by protocol. In contrast, intravenous fluid administration was unrestricted in group B. Transfusion decisions were made by the attending anesthesiologist, based on identical transfusion guidelines for both groups.

Results
137 of 192 patients received 289 PRC units in total. Age, sex, weight, height, BMI, BSA, LVEF, CPB duration and surgery duration did not differ between groups. Fluid balance was less positive in Group A. Fewer group A patients (62/100) required transfusion compared to group B (75/92, p < 0.04). Group A patients received fewer PRC units (113) compared to group B (176; p < 0.0001). Intraoperatively, the number of transfused units and transfused patients was lower in group A (31 u in 19 pts vs. 111 u in 62 pts; p < 0.001). Transfusions in ICU did not differ significantly between groups. Transfused patients had higher age, lower weight, height, BSA and preoperative hematocrit, but no difference in BMI or discharge hematocrit. Group B (p < 0.005) and female gender (p < 0.001) were associated with higher transfusion probability. Logistic regression identified group and preoperative hematocrit as significant predictors of transfusion.

Conclusions
Our data suggest that fluid restriction reduces intraoperative PRC transfusions without significantly increasing postoperative transfusions in cardiac surgery; this effect is more pronounced in transfusion-prone patients.

Trial registration
NCT00600704, at the United States National Institutes of Health.
Liver and brain abscess caused by Aggregatibacter paraphrophilus in association with a large patent foramen ovale: a case report
Authors: Ariyaratnam Shaumya , Gajendragadkar Parag R , Dickinson Richard J , Roberts Phil , Harris Kathryn , Carmichael Andrew , Karas Johannis A 
Published: February 2010

Abstract

Introduction

Aggregatibacter paraphrophilus (former name Haemophilus paraphrophilus) is a normal commensal of the oral flora. It is a rare cause of hepatobiliary or intracerebral abscesses.

Case presentation
We report a case of a 53-year-old Caucasian man with a liver abscess and subsequent brain abscesses caused by Aggregatibacter paraphrophilus. The probable source of the infection was the oral flora of our patient following ingestion of a dental filling. The presence of a large patent foramen ovale was a predisposing factor for multifocal abscesses.

Conclusion
In this case report, we describe an unusual case of a patient with both liver and brain abscesses caused by an oral commensal Aggregatibacter paraphrophilus that can occasionally show significant pathogenic potential.