bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Telomerase Reverse Transcriptase Activated by E6 Oncoprotein Is Required for Human Papillomavirus-16/18-Infected Lung Tumorigenesis
Authors: Cheng Ya-Wen , Wu Tzu-Chin , Chen Chih-Yi , Chou Ming-Chih , Ko Jiunn-Liang , Lee Huei 
Published: November 2008

Abstract
Purpose: Our recent report indicates that human papillomavirus (HPV)-16/18 E6 oncoprotein is expressed in lung tumors and is related to p53 inactivation. We further explored whether human telomerase reverse transcriptase (hTERT) transcription is up-regulated by E6 and contributes to lung tumor development.
Experimental Design: Immunohistochemistry detected HPV-16 E6 oncoprotein in 135 lung tumors, and hTERT mRNA was evaluated by real-time reverse transcription-PCR and in situ hybridization, respectively. A small RNA interference (RNAi), Western blotting, and chromatin immunoprecipitation analysis were used to clarify whether hTERT transcription was regulated by c-Myc and Sp1. The telomerase activity and oncogenic potential of TL-1 with or without E6- or hTERT-RNAi was determined by real-time quantitative telomeric repeat amplification protocol analysis and soft-agar assay, respectively.
Results: hTERT mRNA levels in E6-positive tumors, which were prevalent in females, nonsmokers, and adenocarcinomas, were significantly higher than in E6-negative tumors. In addition, hTERT mRNA levels in early tumors (stage I) were greater than levels in advanced tumors (stages II and III). Chromatin immunoprecipitation assay showed that Sp1 cooperated with c-Myc to activate hTERT transcription in TL-1 cells, which was similar to the SiHa cells. The telomerase activity of the TL-1 cells decreased concomitantly with the transfection of various doses of E6- or hTERT-RNAi. A soft-agar assay showed that the oncogenic potential of TL-1 cells was significantly reduced after being transfected with E6-RNAi. Moreover, a colony of TL-1 cells could not form after transfection with hTERT-RNAi.
Conclusion: Transcriptional activation of hTERT by E6 oncoprotein is required for HPV-16/18-infected lung tumorigenesis.
Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer
Authors: Soltermann Alex , Tischler Verena , Arbogast Stefanie , Braun Julia , Probst-Hensch Nicole , Weder Walter , Moch Holger , Kristiansen Glen 
Published: November 2008

Abstract
Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC).
Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative sum scoring system was done on three tissue microarrays.
Results: Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin, respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin were inconsistent (all P values &lt;0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate analysis (P = 0.007).
Conclusions: Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins may be integrated in progression models of NSCLC.
Relapse-Free Survival in Breast Cancer Patients Is Associated with a Gene Expression Signature Characteristic for Inflammatory Breast Cancer
Authors: Van Laere Steven , Beissbarth Tim , Van der Auwera Ilse , Van den Eynden Gert , Trinh Xuan Bich , Elst Hilde , Van Hummelen Paul , van Dam Peter , Van Marck Eric , Vermeulen Peter , Dirix Luc 
Published: November 2008

Abstract
Purpose: We hypothesize that a gene expression profile characteristic for inflammatory breast cancer (IBC), an aggressive form of breast cancer associated with rapid cancer dissemination and poor survival, might be related to tumor aggressiveness in non-IBC (nIBC).
Experimental Design: RNA from 17 IBC samples and 40 nIBC samples was hybridized onto Affymetrix chips. A gene signature predictive of IBC was identified and applied onto 1,157 nIBC samples with survival data of 881 nIBC samples. Samples were classified as IBC-like or nIBC-like. The IBC signature classification was compared with the classifications according to other prognostically relevant gene signatures and clinicopathologic variables. In addition, relapse-free survival (RFS) was compared by the Kaplan-Meyer method.
Results: Classification according to the IBC signature is significantly (P &lt; 0.05) associated with the cell-of-origin subtypes, the wound healing response, the invasive gene signature, the genomic grade index, the fibroblastic neoplasm signature, and the 70-gene prognostic signature. Significant associations (P &lt; 0.01) were found between the IBC signature and tumor grade, estrogen receptor status, ErbB2 status, and patient age at diagnosis. Patients with an IBC-like phenotype show a significantly shorter RFS interval (P &lt; 0.05). Oncomine analysis identified cell motility as an important concept linked with the IBC signature.
Conclusions: We show that nIBC carcinomas having an IBC-like phenotype have a reduced RFS interval. This suggests that IBC and nIBC show comparable phenotypic traits, for example augmented cell motility, with respect to aggressive tumor cell behavior. This observation lends credit to the use of IBC to study aggressive tumor cell behavior.
Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells
Authors: Kim Min-Jung , Choi Soon-Young , Park In-Chul , Hwang Sang-Gu , Kim Changil , Choi Young-Hyun , Kim Haekwon , Lee Kee-Ho , Lee Su-Jae 
Published: November 2008

Abstract
Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death. (Mol Cancer Res 2008;6(11):1718–31)
Mesothelin-Induced Pancreatic Cancer Cell Proliferation Involves Alteration of Cyclin E via Activation of Signal Transducer and Activator of Transcription Protein 3
Authors: Bharadwaj Uddalak , Li Min , Chen Changyi , Yao Qizhi 
Published: November 2008

AbstractMesothelin (MSLN) is a cell surface glycoprotein that is overexpressed in human pancreatic cancer. Although its value as a tumor marker for diagnosis and prognosis and as a preferred target of immunointervention has been evaluated, there is little information on the growth advantage of MSLN on tumor cells. In this study, we examined the effect of MSLN on pancreatic cancer cell proliferation, cell cycle progression, expression of cell cycle regulatory proteins, and signal transduction pathways in two pancreatic cancer cell lines, MIA-MSLN (overexpressing MSLN in MIA PaCa-2 cells) and BxPC-siMSLN (silencing MSLN in BxPC-3 cells). Increased cyclin E and cyclin-dependent kinase 2 expression found in MIA-MSLN cells correlated with significantly increased cell proliferation and faster cell cycle progression compared with control cells. BxPC-siMSLN cells showed slower proliferation and slower entry into the S phase than control cells. Signal transducer and activator of transcription protein 3 (Stat3) was constitutively activated in MIA-MSLN cells, but not in control cells. Inhibition of Stat3 activation in MIA-MSLN cells by the Janus-activated kinase–selective inhibitor tyrphostin AG490 was followed by a marked decrease in proliferation of the cells. Small interfering RNA against Stat3 significantly reduced the MIA-MSLN cell cycle progression with a concomitant decrease in cyclin E expression. Our data indicate that overexpression of MSLN in pancreatic cancer cells leads to constitutive activation of the transcription factor Stat3, which results in enhanced expression of cyclin E and cyclin E/cyclin-dependent kinase 2 complex formation as well as increased G1-S transition. (Mol Cancer Res 2008;6(11):1755–65)
Convectively Coupled Equatorial Waves in High-Resolution Hadley Centre Climate Models
Authors: Yang Gui-Ying , Slingo Julia , Hoskins Brian 
Published: November 2008

Abstract
A methodology for diagnosing convectively coupled equatorial waves is applied to output from two high-resolution versions of atmospheric models, the Hadley Centre Atmospheric Model, version 3 (HadAM3), and the new Hadley Centre Global Atmospheric Model, version 1 (HadGAM1), which have fundamental differences in dynamical formulation. Variability, horizontal and vertical structures, and propagation characteristics of tropical convection and equatorial waves, along with their coupled behavior in the models, are examined and evaluated against a previous comprehensive study of observed convectively coupled equatorial waves using the 15-yr ECMWF Re-Analysis (ERA-15) and satellite observed data. The extent to which the models are able to represent the coupled waves found in real atmospheric observations is investigated. It is shown that, in general, the models perform well for equatorial waves coupled with off-equatorial convection. However, they perform poorly for waves coupled with equatorial convection. Convection in both models contains much-reduced variance in equatorial regions, but reasonable off-equatorial variance.
The models fail to simulate coupling of the waves with equatorial convection and the tendency for equatorial convection to appear in the region of wave-enhanced near-surface westerlies. In addition, the simulated Kelvin wave and its associated convection generally tend to have lower frequency and slower phase speed than that observed. The models are also not able to capture the observed vertical tilt structure and signatures of energy conversion in the Kelvin wave, particularly in HadAM3. On the other hand, models perform better in simulating westward-moving waves coupled with off-equatorial convection, in terms of horizontal and vertical structures, zonal propagation, and energy conversion signals. In most cases both models fail to simulate well a key picture emerging from the observations, that some wave modes in the lower troposphere can act as a forcing agent for equatorial convection, and that the upper-tropospheric waves generally appear to be forced by the convection both on and off the equator.
Stable, Intelligible Ultrasonic Strain Imaging
Authors: Gee Andrew , Lindop Joel , Treece Graham , Prager Richard , Freeman Susan 
Published: November 2008

Background: Freehand quasistatic strain imaging can reveal qualitative information about tissue stiffness with good spatial accuracy. Clinical trials, however, repeatedly cite instability and variable signal-to-noise ratio as significant drawbacks. Methods: This study investigates three post-processing strategies for quasistatic strain imaging. Normalization divides the strain by an estimate of the stress field, the intention being to reduce sensitivity to variable applied stress. Persistence aims to improve the signal-to-noise ratio by time-averaging multiple frames. The persistence scheme presented in this article operates at the pixel level, weighting each frame's contribution by an estimate of the strain precision. Precision-based display presents the clinician with an image in which regions of indeterminate strain are obscured behind a colour wash. This is achieved using estimates of strain precision that are faithfully propagated through the various stages of signal processing. Results and discussion: The post-processing strategy is evaluated qualitatively on scans of a breast biopsy phantom and in vivo head and neck examinations. Strain images processed in this manner are observed to benefit from improved stability and signal-to-noise ratio. There are, however, limitations. In unusual though conceivable circumstances, the normalization procedure might suppress genuine stiffness variations evident in the unprocessed strain images. In different circumstances, the raw strain images might fail to capture significant stiffness variations, a situation that no amount of post-processing can improve. Conclusion: The clinical utility of freehand quasistatic strain imaging can be improved by normalization, precision-weighted pixel-level persistence and precision-based display. The resulting images are stable and generally exhibit a better signal-to-noise ratio than any of the original, unprocessed strain images.
Profile of Women Seeking Fetal Gender at Ultrasound in a Nigerian Obstetric Population
Authors: Ekele Bissallah A. , Maaji Sadisu M. , Bello Shaibu O. , Morhason-Bello Imran O. 
Published: November 2008

Objective: To determine the proportion of women that wanted to know fetal gender at ultrasound, characterize them and document reasons for wanting to know fetal gender. Methodology: A cross-sectional study on consecutive pregnant women at 20 weeks or more gestation that presented for prenatal ultrasound at a private hospital in Nigeria from May to December 2005. Results: Of the 1135 women, 167 (14·7%) sought to know the fetal gender. Significant independent factors included ethnic group, as women from the predominant Hausa–Fulani were less likely when compared to those of other ethnic groups (OR: 0·4, 95% CI: 0·2–0·7). Women with tertiary education were 6·6 times (OR: 6·6, 95% CI: 3·3–13·2) more likely. Women with a previous male baby were 30·6 times more likely (OR: 30·6, 95% CI: 13·6–68·5), while those with previous female baby were 54·3 times more likely (OR: 54·3; 95% CI: 23·4–125·8) to seek fetal gender. Main reasons for seeking fetal gender were preference for a particular fetal gender (57%); what wears to buy for the baby (24%) and curiosity (18%). Conclusion: About 15% of the study group requested to know fetal gender and it was associated with ethnic group, maternal educational level and gender of the previous baby. The most common reason for wanting to know fetal gender was the desire for a particular gender.
CEACAM1 negatively regulates platelet-collagen interactions and thrombus growth in vitro and in vivo
Authors: Wong Cyndi , Liu Yong , Yip Jana , Chand Rochna , Wee Janet L. , Oates Lisa , Nieswandt Bernhard , Reheman Adili , Ni Heyu , Beauchemin Nicole , Jackson Denise E. 
Published: November 2008

AbstractCarcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) is a surface glycoprotein expressed on various blood cells, epithelial cells, and vascular cells. CEACAM1 possesses adhesive and signaling properties mediated by its intrinsic immunoreceptor tyrosine-based inhibitory motifs that recruit SHP-1 protein-tyrosine phosphatase. In this study, we demonstrate that CEACAM1 is expressed on the surface and in intracellular pools of platelets. In addition, CEACAM1 serves to negatively regulate signaling of platelets by collagen through the glycoprotein VI (GPVI)/Fc receptor (FcR)–γ-chain. ceacam1−/− platelets displayed enhanced type I collagen and GPVI-selective ligand, collagen-related peptide (CRP), CRP-mediated platelet aggregation, enhanced platelet adhesion on type I collagen, and elevated CRP-mediated alpha and dense granule secretion. Platelets derived from ceacam1−/− mice form larger thrombi when perfused over a collagen matrix under arterial flow compared with wild-type mice. Furthermore, using intravital microscopy to ferric chloride-injured mesenteric arterioles, we show that thrombi formed in vivo in ceacam1−/− mice were larger and were more stable than those in wild-type mice. GPVI depletion using monoclonal antibody JAQ1 treatment of ceacam1−/− mice showed a reversal in the more stable thrombus growth phenotype. ceacam1−/− mice were more susceptible to type I collagen–induced pulmonary thromboembolism than wild-type mice. Thus, CEACAM1 acts as a negative regulator of platelet-collagen interactions and of thrombus growth involving the collagen GPVI receptor in vitro and in vivo.
Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia
Authors: Vogler Meike , Butterworth Michael , Majid Aneela , Walewska Renata J. , Sun Xiao-Ming , Dyer Martin J. S. , Cohen Gerald M. 
Published: November 2008

Abstract
ABT-737 and its orally active analog, ABT-263, are rationally designed inhibitors of BCL2 and BCL-XL. ABT-263 shows promising activity in early phase 1 clinical trials in B-cell malignancies, particularly chronic lymphocytic leukemia (CLL). In vitro, peripheral blood CLL cells are extremely sensitive to ABT-737 (EC50 ∼7 nM), with rapid induction of apoptosis in all 60 patients tested, independent of parameters associated with disease progression and chemotherapy resistance. In contrast to data from cell lines, ABT-737–induced apoptosis in CLL cells was largely MCL1-independent. Because CLL cells within lymph nodes are more resistant to apoptosis than those in peripheral blood, CLL cells were cultured on CD154-expressing fibroblasts in the presence of interleukin-4 (IL-4) to mimic the lymph node microenvironment. CLL cells thus cultured developed an approximately 1000-fold resistance to ABT-737 within 24 hours. Investigations of the underlying mechanism revealed that this resistance occurred upstream of mitochondrial perturbation and involved de novo synthesis of the antiapoptotic proteins BCL-XL and BCL2A1, which were responsible for resistance to low and high ABT-737 concentrations, respectively. Our data indicate that after therapy with ABT-737–related inhibitors, resistant CLL cells might develop in lymph nodes in vivo and that treatment strategies targeting multiple BCL2 antiapoptotic members simultaneously may have synergistic activity.
Colony-stimulating factor-1 (CSF-1) delivers a proatherogenic signal to human macrophages
Authors: Irvine Katharine M , Andrews Melanie R , Fernandez-Rojo Manuel A , Schroder Kate , Burns Christopher J , Su Stephen , Wilks Andrew F , Parton Robert G , Hume David A , Sweet Matthew J 
Published: November 2008

AbstractM-CSF/CSF-1 supports the proliferation and differentiation of monocytes and macrophages. In mice, CSF-1 also promotes proinflammatory responses in vivo by regulating mature macrophage functions, but little is known about the acute effects of this growth factor on mature human macrophages. Here, we show that in contrast to its effects on mouse bone marrow-derived macrophages, CSF-1 did not induce expression of urokinase plasminogen activator mRNA, repress expression of apolipoprotein E mRNA, or prime LPS-induced TNF and IL-6 secretion in human monocyte-derived macrophages (HMDM) from several independent donors. Instead, we show by expression profiling that CSF-1 modulates the HMDM transcriptome to favor a proatherogenic environment. CSF-1 induced expression of the proatherogenic chemokines CXCL10/IFN-inducible protein 10, CCL2, and CCL7 but repressed expression of the antiatherogenic chemokine receptor CXCR4. CSF-1 also up-regulated genes encoding enzymes of the cholesterol biosynthetic pathway (HMGCR, MVD, IDI1, FDPS, SQLE, CYP51A1, EBP, NSDHL, DHCR7, and DHCR24), and expression of ABCG1, encoding a cholesterol efflux transporter, was repressed. Consistent with these effects, CSF-1 increased levels of free cholesterol in HMDM, and the selective CSF-1R kinase inhibitor GW2580 ablated this response. These data demonstrate that CSF-1 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which CSF-1, which is known to be present in atherosclerotic lesions, may contribute to plaque progression.
Impact of Small-Molecule Glucokinase Activator on Glucose Metabolism and β-Cell Mass
Authors: Nakamura Akinobu , Terauchi Yasuo , Ohyama Sumika , Kubota Junko , Shimazaki Hiroko , Nambu Tadahiro , Takamoto Iseki , Kubota Naoto , Eiki Junichi , Yoshioka Narihito , Kadowaki Takashi , Koike Takao 
Published: November 2008

We investigated the effect of glucokinase activator (GKA) on glucose metabolism and β-cell mass. We analyzed four mouse groups: wild-type mice and β-cell-specific haploinsufficiency of glucokinase gene (Gck+/−) mice on a high-fat (HF) diet. Each genotype was also treated with GKA mixed in the HF diet. Rodent insulinoma cells and isolated islets were used to evaluate β-cell proliferation by GKA. After 20 wk on the above diets, there were no differences in body weight, lipid profiles, and liver triglyceride content among the four groups. Glucose tolerance was improved shortly after the GKA treatment in both genotypes of mice. β-Cell mass increased in wild-type mice compared with Gck+/− mice, but a further increase was not observed after the administration of GKA in both genotypes. Interestingly, GKA was able to up-regulate insulin receptor substrate-2 (Irs-2) expression in insulinoma cells and isolated islets. The administration of GKA increased 5-bromo-2-deoxyuridine (BrdU) incorporation in insulinoma cells, and 3 d administration of GKA markedly increased BrdU incorporation in mice treated with GKA in both genotypes, compared with those without GKA. In conclusion, GKA was able to chronically improve glucose metabolism for mice on the HF diet. Although chronic GKA administration failed to cause a further increase in β-cell mass in vivo, GKA was able to increase beta cell proliferation in vitro and with a 3-d administration in vivo. This apparent discrepancy can be explained by a chronic reduction in ambient blood glucose levels by GKA treatment.
Glucokinase activator is able to improve glucose metabolism and has an effect on β cell proliferation.