bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attitudes and Practices of Resident Physicians Regarding Hypertension in the Inpatient Setting
Authors: Neal Axon Robert , Garrell Robin , Pfahl Kyle , Fisher Julie E. , Zhao Yumin , Egan Brent , Weder Alan 
Published: May 2010

J Clin Hypertens (Greenwich). 2010;12:698–705. ©2010 Wiley Periodicals, Inc.Hypertension is prevalent in the population at large and among hospitalized patients. Little has been reported regarding the attitudes and patterns of care of physicians managing nonemergent elevated blood pressure (BP) among inpatients. Resident physicians in internal medicine (IM), family medicine (FM), and surgery were surveyed regarding inpatient BP management. One hundred eighty‐one questionnaires were completed across 3 sites. Respondents generally considered inpatient BP control a high priority. A majority of IM and FM residents indicated following the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) consensus guidelines for inpatients compared to 20% of surgery residents (P<.001). While trainees did not appear to strictly follow JNC 7 guidelines for goal BP of 140/90 mm Hg, they did report making frequent BP medication changes (∼51% reported changing regimens for >50% of hypertensive patients). Overall ∼90% indicated that discharging a hypertensive patient on a drug regimen established during hospitalization is preferable to reverting to the regimen in place at the time of admission. Resident physicians regard elevated BP inpatient management as important, but attitudes and practice vary between specialties. JNC 7 guidelines may not be appropriate for inpatient use. Future research should focus on developing functional diagnostic criteria for hypertension in the inpatient setting and determining best practices inpatient BP management.
Public Dying: Death in the Media and Jade Goody
Authors: Woodthorpe Kate 
Published: May 2010

AbstractAbundant in books, on television, in film, on the internet, and in newspapers and magazines, in the twenty‐first century death is hugely accessible. Within recent years, sociologists have responded to this visibility by examining death in the media, including its role and status in popular culture and ‘public mourning’, seen for example following the death of Diana, Princess of Wales in 1997. This article considers a third strand of death in the media that requires sociological attention: public dying. Drawing on the extensive media coverage of reality TV personality Jade Goody’s dying and subsequent death in early 2009, the article examines the way in which Goody’s dying illustrated how it can be commodified.
Coupled Fixed Point Theorems for Nonlinear Contractions Satisfied Mizoguchi-Takahashi's Condition in Quasiordered Metric Spaces
Authors: Du Wei-Shih 
Published: May 2010

AbstractThe main aim of this paper is to study and establish some new coupled fixed point theorems for nonlinear contractive maps that satisfied Mizoguchi-Takahashi's condition in the setting of quasiordered metric spaces or usual metric spaces.
In vitro Progression of Human Papillomavirus 16 Episome-Associated Cervical Neoplasia Displays Fundamental Similarities to Integrant-Associated Carcinogenesis
Authors: Gray Elizabeth , Pett Mark R. , Ward Dawn , Winder David M. , Stanley Margaret A. , Roberts Ian , Scarpini Cinzia G. , Coleman Nicholas 
Published: May 2010

Abstract
An important event in the development of cervical squamous cell carcinoma (SCC) is deregulated expression of high-risk human papillomavirus (HR-HPV) oncogenes, most commonly related to viral integration into host DNA. Mechanisms of development of the ∼15% of SCCs that contain extrachromosomal (episomal) HR-HPV are poorly understood due to limited longitudinal data. We therefore used the W12 model to study mechanisms of cervical carcinogenesis associated with episomal HPV16. In vitro progression of W12 normally occurs through selection of cells containing integrated HPV16. However, in one long-term culture, keratinocytes developed a selective growth advantage and invasive phenotype while retaining HPV16 episomes at increased copy number in the absence of transcriptionally active integrants. Longitudinal investigations revealed similarities between the episome- and integrant-associated routes of neoplastic progression. Most notable were dynamic changes in viral early gene expression in episome-retaining cells, consistent with continually changing selective pressures. An early increase in viral transcription preceded elevated episome copy number and was followed by a reduction to near baseline after the development of invasiveness. Episomal transcriptional deregulation did not require selection of a specific sequence variant of the HPV16 upstream regulatory region, although increased levels of acetylated histone H4 around the late promoter implicated a role for altered chromatin structure. Interestingly, invasive episome-retaining cells showed high levels of HPV16 E2/E6 proteins (despite decreased transcript levels) and reduced expression of IFN-stimulated genes, adaptations that support viral persistence and cell survival. Our findings suggest a unified working model for events important in cervical neoplastic progression regardless of HR-HPV physical state. Cancer Res; 70(10); 4081–91. ©2010 AACR.
Phospholipase D1 Drives a Positive Feedback Loop to Reinforce the Wnt/β-Catenin/TCF Signaling Axis
Authors: Kang Dong Woo , Lee Soung-Hoon , Yoon Jeong Whan , Park Won-Sang , Choi Kang-Yell , Min Do Sik 
Published: May 2010

Abstract
Activation of the Wnt signaling pathway occurs frequently in human cancers, but an understanding of the targets and regulation of this important pathway remains incomplete. In this study, we report that phospholipase D (PLD), a cell survival mediator that is upregulated in cancer, is an important target of the Wnt signaling pathway that functions in a positive feedback loop to reinforce pathway output. PLD1 expression and activity was enhanced by treatment with Wnt3a and glycogen synthase kinase-3 inhibitors, and the Wnt pathway–regulated transcription factors β-catenin and TCF-4 were required for this effect. Three functional TCF-4–binding sites were identified within the PLD1 promoter. Interestingly, suppressing PLD1 blocked the ability of β-catenin to transcriptionally activate PLD1 and other Wnt target genes by preventing β-catenin/TCF-4 complex formation. Conversely, tactics to elevate intracellular levels of phosphatidic acid, the product of PLD1 enzyme activity, enhanced β-catenin/TCF-4 complex formation as well as β-catenin–dependent TCF transcriptional activity. In cell-based assays, PLD1 was necessary for the anchorage-independent growth driven by Wnt/β-catenin signaling, whereas β-catenin/TCF-4 was necessary for the anchorage-independent growth driven by PLD1 activation. Taken together, our findings define a function for PLD1 in a positive feedback loop of Wnt/β-catenin/TCF-4 signaling that provides new mechanistic insights into cancer, with implications of novel strategies to disrupt Wnt signaling in cancer. Cancer Res; 70(10); 4233–42. ©2010 AACR.
In vivo Dynamics and Distinct Functions of Hypoxia in Primary Tumor Growth and Organotropic Metastasis of Breast Cancer
Authors: Lu Xin , Yan Carol H. , Yuan Min , Wei Yong , Hu Guohong , Kang Yibin 
Published: May 2010

Abstract
Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis, invasion, and metastasis. However, a comparative analysis of the potentially distinct functions of hypoxia in primary tumor growth and organ-specific metastasis has not been reported. Here, we show distinct hypoxia kinetics in tumors generated by the MDA-MB-231 breast cancer sublines with characteristically different primary tumor growth rates and organotropic metastasis potentials. Hypoxia-induced angiogenesis promotes both primary tumor growth and lung metastasis but is nonessential for bone metastasis. Microarray profiling revealed that hypoxia enhances the expression of a significant number of genes in the lung metastasis signature, but only activates a few bone metastasis genes, among which DUSP1 was functionally validated in this study. Despite the different mechanisms by which hypoxia promotes organ-specific metastasis, inhibition of HIF-1α with a dominant-negative form of HIF-1α or 2-methoxyestradiol reduced metastasis to both lung and bone. Consistent with the extensive functional overlap of hypoxia in promoting primary tumor growth and lung metastasis, a 45-gene hypoxia response signature efficiently stratifies breast cancer patients with low or high risks of lung metastasis, but not for bone metastasis. Our study shows distinct functions of hypoxia in regulating angiogenesis and metastasis in different organ microenvironments and establishes HIF-1α as a promising target for controlling organotropic metastasis of breast cancer. Cancer Res; 70(10); 3905–14. ©2010 AACR.
ΔNp63α Repression of the Notch1 Gene Supports the Proliferative Capacity of Normal Human Keratinocytes and Cervical Cancer Cells
Authors: Yugawa Takashi , Narisawa-Saito Mako , Yoshimatsu Yuki , Haga Kei , Ohno Shin-ichi , Egawa Nagayasu , Fujita Masatoshi , Kiyono Tohru 
Published: May 2010

Abstract
The p53 family member p63 is a master regulator of epithelial development. One of its isoforms, ΔNp63α, is predominantly expressed in the basal cells of stratified epithelia and plays a fundamental role in control of regenerative potential and epithelial integrity. In contrast to p53, p63 is rarely mutated in human cancers, but it is frequently overexpressed in squamous cell carcinomas (SCC). However, its functional relevance to tumorigenesis remains largely unclear. We previously identified the Notch1 gene as a novel transcriptional target of p53. Here, we show that ΔNp63α functions as a transcriptional repressor of the Notch1 gene through the p53-responsive element. Knockdown of p63 caused upregulation of Notch1 expression and marked reduction in proliferation and clonogenicity of both normal human keratinocytes and cervical cancer cell lines overexpressing ΔNp63α. Concomitant silencing of Notch1 significantly rescued this phenotype, indicating the growth defect induced by p63 deficiency to be, at least in part, attributable to Notch1 function. Conversely, overexpression of ΔNp63α decreased basal levels of Notch1, increased proliferative potential of normal human keratinocytes, and inhibited both p53-dependent and p53-independent induction of Notch1 and differentiation markers upon genotoxic stress and serum exposure, respectively. These results suggest that ΔNp63α maintains the self-renewing capacity of normal human keratinocytes and cervical cancer cells partly through transcriptional repression of the Notch1 gene and imply a novel pathogenetical significance of frequently observed overexpression of ΔNp63α together with p53 inactivation in SCCs. Cancer Res; 70(10); 4034–44. ©2010 AACR.
Hypoxia Modulates EWS-FLI1 Transcriptional Signature and Enhances the Malignant Properties of Ewing's Sarcoma Cells In vitro
Authors: Aryee Dave N.T. , Niedan Stephan , Kauer Maximilian , Schwentner Raphaela , Bennani-Baiti Idriss M. , Ban Jozef , Muehlbacher Karin , Kreppel Michael , Walker Robert L. , Meltzer Paul , Poremba Christopher , Kofler Reinhard , Kovar Heinrich 
Published: May 2010

Abstract
Hypoxia is an important condition in the tumor cell microenvironment and approximately 1% to 1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. Because, by immunohistochemistry, HIF-1α expression was readily detectable in 18 of 28 primary Ewing's sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, we studied the effect of hypoxia on ESFT cell lines in vitro. Intriguingly, we found that EWS-FLI1 protein expression, which characterizes ESFT, is upregulated by hypoxia in a HIF-1α–dependent manner. Hypoxia modulated the EWS-FLI1 transcriptional signature relative to normoxic conditions. Both synergistic as well as antagonistic transcriptional effects of EWS-FLI1 and of hypoxia were observed. Consistent with alterations in the expression of metastasis-related genes, hypoxia stimulated the invasiveness and soft agar colony formation of ESFT cells in vitro. Our data represent the first transcriptome analysis of hypoxic ESFT cells and identify hypoxia as an important microenvironmental factor modulating EWS-FLI1 expression and target gene activity with far-reaching consequences for the malignant properties of ESFT. Cancer Res; 70(10); 4015–23. ©2010 AACR.
Involvement of the Tubulin Tyrosine Ligase-Like Family Member 4 Polyglutamylase in PELP1 Polyglutamylation and Chromatin Remodeling in Pancreatic Cancer Cells
Authors: Kashiwaya Kotoe , Nakagawa Hidewaki , Hosokawa Masayo , Mochizuki Yasuo , Ueda Koji , Piao Lianhua , Chung Suyoun , Hamamoto Ryuji , Eguchi Hidetoshi , Ohigashi Hiroaki , Ishikawa Osamu , Janke Carsten , Shinomura Yasuhisa , Nakamura Yusuke 
Published: May 2010

Abstract
Polyglutamylation is a new class of posttranslational modification in which glutamate side chains are formed in proteins, although its biological significance is not well known. Through our genome-wide gene expression profile analyses of pancreatic ductal adenocarcinoma (PDAC) cells, we identified the overexpression of tubulin tyrosine ligase-like family member 4 (TTLL4) in PDAC cells. Subsequent reverse transcription-PCR and Northern blot analyses confirmed its upregulation in several PDACs. TTLL4 belongs to the TTLL family which was reported to have polyglutamylase activity. Knockdown of TTLL4 by short hairpin RNA in PDAC cells attenuated the growth of PDAC cells and exogenous introduction of TTLL4 enhanced cell growth. We also found that TTLL4 expression was correlated with polyglutamylation levels of a glutamate stretch region of the proline, glutamate, and leucine–rich protein 1 (PELP1) that was shown to interact with various proteins such as histone H3, and was involved in several signaling pathways through its function as a scaffold protein. PELP1 polyglutamylation could influence its interaction with histone H3 and affect histone H3 acetylation. We also identified the interaction of PELP1 with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involving chromatin remodeling. Our findings imply that TTLL4 could play important roles in pancreatic carcinogenesis through its polyglutamylase activity and subsequent coordination of chromatin remodeling, and might be a good molecular candidate for the development of new therapeutic strategies for pancreatic cancer. Cancer Res; 70(10); 4024–33. ©2010 AACR.
The α-Receptor for Platelet-Derived Growth Factor Confers Bone-Metastatic Potential to Prostate Cancer Cells by Ligand- and Dimerization-Independent Mechanisms
Authors: Russell Mike R. , Liu Qingxin , Lei Hetian , Kazlauskas Andrius , Fatatis Alessandro 
Published: May 2010

Abstract
Prostate adenocarcinoma is the second leading cause of cancer death among men, due primarily to the fact that the majority of prostate cancers will eventually spread to the skeleton. Metastatic dissemination requires a complex series of coordinated events that result in cells that escape from the primary tumor into the circulation and eventually colonize a distant organ. The ability of these cells to evolve into macroscopic metastases depends strongly on their compatibility with, and ability to utilize, this new microenvironment. We previously showed that bone-metastatic prostate cancer cells exposed to human bone marrow respond by activation of cell survival pathways, such as phosphoinositide 3-kinase/Akt, and that these events are mediated by the α-receptor for platelet-derived growth factor (PDGFRα). Our studies and others have shown that PDGFRα may be activated by mechanisms independent of PDGF ligand binding. Here, we provide conclusive evidence that soluble components of human bone marrow can activate PDGFRα through a mechanism that does not require the canonical binding of PDGF ligand(s) to the receptor. In particular, we found that dimerization of PDGFRα monomers is not induced by human bone marrow, but this does not prevent receptor phosphorylation and downstream signaling from occurring. To establish the relevance of this phenomenon in vivo, we used a PDGFRα mutant lacking the extracellular ligand-binding domain. Our studies show that this truncated PDGFRα is able to restore bone-metastatic potential of prostate cancer cells as effectively as the full-length form of the receptor. Cancer Res; 70(10); 4195–203. ©2010 AACR.
Association of SPINK1 Expression and TMPRSS2:ERG Fusion with Prognosis in Endocrine-Treated Prostate Cancer
Authors: Leinonen Katri A. , Tolonen Teemu T. , Bracken Hazel , Stenman Ulf-Håkan , Tammela Teuvo L.J. , Saramäki Outi R. , Visakorpi Tapio 
Published: May 2010

Abstract
Purpose: The aim of the study was to examine whether TMPRSS2:ERG fusion or SPINK1 protein expression is associated with hormone responsiveness of prostate cancer and can thus be used as a biomarker.
Experimental Design: Diagnostic needle biopsies from prostate cancer patients primarily treated by endocrine therapy were evaluated for TMPRSS2:ERG fusion with fluorescence in situ hybridization and SPINK1 protein expression with immunohistochemistry.
Results: The frequency of TMPRSS2:ERG fusion in 178 biopsies of hormonally treated patients was 34%. Of the fusion-positive cases, 71% showed deletion between the two genes, and 23% showed gain of the fusion. The fusion was associated with high Ki-67 staining (P = 0.001), age at diagnosis (P = 0.024), and tumor area (P = 0.006), but not with Gleason score, T stage, M stage, prostate-specific antigen (PSA), or progression-free survival. Strong positive SPINK1 expression was found in 11% (21 of 186) of the biopsies. SPINK1-positive cases had significantly shorter progression-free survival compared with SPINK1-negative cases (P = 0.001). The expression was not associated with any other clinicopathologic variables studied. In a multivariate analysis, SPINK1 expression showed independent prognostic value, with a relative risk of 2.3 (95% confidence interval, 1.1-4.6). SPINK1 expression and the fusion were not associated with each other.
Conclusions: There was no association between TMPRSS2:ERG fusion and prognosis, suggesting that TMPRSS2:ERG rearrangement does not implicate hormone dependence of the cancer. SPINK1 expression, found in ∼10% of prostate cancers, was associated with aggressive form of the disease and could serve as a biomarker in endocrine-treated prostate cancer. Clin Cancer Res; 16(10); 2845–51. ©2010 AACR.
Inhibition of Histone Deacetylase Attenuates Hypoxia-Induced Migration and Invasion of Cancer Cells via the Restoration of RECK Expression
Authors: Jeon Hye Won , Lee You Mie 
Published: May 2010

Abstract
Hypoxia is a strong signal for cell migration and invasion in cancer. The reversion-inducing cysteine-rich protein with Kazal motif (RECK), a tumor suppressor, inhibits cancer cell migration and invasion and is frequently silenced in aggressive tumor cells by histone deacetylases (HDAC). However, the effect of RECK silencing in several cancer cells in a hypoxic microenvironment has not been fully delineated. In this report, we investigated whether hypoxia suppressed RECK expression and used HDAC inhibitor (HDACI) inhibition to restore RECK expression to inhibit cancer cell migration and invasion. HDACIs, including trichostatin A (TSA), completely rescued RECK expression, which was suppressed by hypoxia, in the H-Ras–transformed human breast MCF10A and the HT1080 cell lines (human fibrosarcoma). TSA suppressed the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, induced by hypoxia, and significantly inhibited hypoxia-stimulated migration and invasion of both cancer cells. RECK overexpression significantly inhibited the migration and invasion of cancer cells induced by hypoxia. The hypoxic effect on the migration and invasion of cells was equivalent to the effect seen using the small interfering RNA (siRNA) of RECK under normoxia, suggesting an inhibitory role for RECK in hypoxic conditions. We also showed that siRNA silencing of HDAC1 suppressed hypoxia-induced RECK downregulation and inhibited the migration and invasion of cancer cells. In conclusion, the inhibition of HDAC successfully restored the expression of RECK under hypoxic conditions. This resulted in the inhibition of cancer cell migration and invasion through the repression of MMP-2 and MMP-9 activity. Mol Cancer Ther; 9(5); 1361–70. ©2010 AACR.
Expression of Oncogenic Kinase Bcr-Abl Impairs Mitotic Checkpoint and Promotes Aberrant Divisions and Resistance to Microtubule-Targeting Agents
Authors: Wolanin Kamila , Magalska Adriana , Kusio-Kobialka Monika , Podszywalow-Bartnicka Paulina , Vejda Susanne , McKenna Sharon L. , Mosieniak Grazyna , Sikora Ewa , Piwocka Katarzyna 
Published: May 2010

Abstract
Recent findings showed that BRCA1, in addition to its role in DNA damage response, acts as an upstream regulator of genes involved in the mitotic checkpoint regulation, thus protecting against promotion of aberrant divisions and aneuploidy. Moreover, there is also an indication that the BRCA1 protein is downregulated in chronic myeloid leukemia (CML) patients. We have investigated a possible functional relationship between BRCA1 and mitotic checkpoint competence in cells with the same genetic background expressing different levels of Bcr-Abl, an oncogene responsible for CML. Herein, we show that Bcr-Abl strongly downregulates the BRCA1 protein level, which is partially reversed on treatment with imatinib, an inhibitor of Bcr-Abl tyrosine kinase. Bcr-Abl leads to decreased expression of genes involved in the mitotic checkpoint activation—Mad2, Bub1, Bub3, and BubR1, resulting in mitosis perturbances, weakened mitotic checkpoint function, and mitotic slippage after nocodazole treatment. Furthermore, high Bcr-Abl–expressing cells showed also postmitotic checkpoint dysfunctions and inability to effectively arrest in the 4NG1 phase of the cell cycle, which was associated with limited p21 induction. These observations had significant biological consequences, as we found a high level of improper divisions, chromosomal missegregation, and generation of polyploid cells on mitotic checkpoint prolonged activation. Additionally, Bcr-Abl–expressing cells showed resistance to death activated by spindle defects, reversed by imatinib. Our study presents new facts and supports the hypothesis concerning the mutator nature of Bcr-Abl itself. The functional interaction between Bcr-Abl and mitosis dysfunctions, due to compromised mitotic checkpoints, may have important implications for the generation of aneuploidy and CML progression. Mol Cancer Ther; 9(5); 1328–38. ©2010 AACR.