bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase
Authors: Cerone Maria Antonietta , Burgess Darren J , Naceur-Lombardelli Cristina , Lord Christopher J. , Ashworth Alan 
Published: April 2011

Abstract
Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere maintenance and cancer cell proliferation are not yet available. Here, we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA). This analysis identified a number of novel telomerase modulators, including ERK8 kinase, whose inhibition reduces TA and elicited characteristics of telomere dysfunction. Given that kinases represent attractive drug targets, we addressed the therapeutic implications of our findings, such as demonstrating how limiting TA via kinase blockade could sensitize cells to inhibition of the telomere-associated protein tankyrase. Taken together, our findings suggest novel combinatorial approaches to targeting telomere maintenance as a strategy for cancer therapy. Cancer Res; 71(9); 3328–40. ©2011 AACR.
Association of Specific Genotypes in Metastatic Suppressor HTPAP with Tumor Metastasis and Clinical Prognosis in Hepatocellular Carcinoma
Authors: Ren Ning , Wu Jin-Cai , Dong Qiong-Zhu , Sun Hai-Jing , Jia Hu-Liang , Li Guo-Cai , Sun Bing-Sheng , Dai Chun , Shi Jiong , Wei Jin-Wang , Sheng Yuan-Yuan , Zhou Hai-Jun , Ye Qing-Hai , Qin Lun-Xiu 
Published: April 2011

Abstract
The phosphatidic acid phosphatase HTPAP has been defined as a metastatic suppressor of hepatocellular carcinoma (HCC), but little is known about its function or potential applications as a prognostic marker. In this study, we analyzed patterns of HTPAP genetic variation and gene expression in 864 patients who underwent HCC resection, assessing these patterns for correlations to tumor metastasis potential. Focusing on two tagSNPs that were selected (+357G/C and +1838A/G), we found that only the +357G/C genotype was significantly associated with HTPAP mRNA and protein expression levels and the probability of metastasis. In an independent cohort of 665 HCC patients, we determined that the +357G/C genotype was associated with shorter time to recurrence and overall survival. Together, these results indicated that the HTPAP tagSNP +357 GG+GC genotypes may influence HCC metastatic potential and clinical prognosis by down-regulating HTPAP expression. Extending these results, a global expression profiling analysis identified 41 genes including the pro-inflammatory genes IL-8 and TLR2 that were significantly overexpressed in the +357 GG+GC group, as possible coregulated markers with HTPAP. Together, our findings identify an HTPAP genotype and associated gene expression pattern that favors metastasis progression and that could be used to predict tumor metastasis and prognosis in HCC patients. Cancer Res; 71(9); 3278–86. ©2011 AACR.
Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling
Authors: Chen Jian , Shen Qiong , Labow Mark , Gaither L. Alex 
Published: April 2011

Abstract
RAS mutations occur in more than 30% of all human cancers but efforts to directly target mutant RAS signaling as a cancer therapy have yet to succeed. As alternative strategies, RAF and MEK inhibitors have been developed to block oncogenic signaling downstream of RAS. As might be expected, studies of these inhibitors have indicated that tumors with RAS or BRAF mutations display resistance RAF or MEK inhibitors. In order to better understand the mechanistic basis for this resistance, we conducted a RNAi-based screen to identify genes that mediated chemoresistance to the RAF kinase inhibitor RAF265 in a BRAF (V600E) mutant melanoma cell line that is resistant to this drug. In this way, we found that knockdown of protein kinase D3 (PRKD3) could enhance cell killing of RAF and MEK inhibitors across multiple melanoma cell lines of various genotypes and sensitivities to RAF265. PRKD3 blockade cooperated with RAF265 to prevent reactivation of the MAPK signaling pathway, interrupt cell cycle progression, trigger apoptosis, and inhibit colony formation growth. Our findings offer initial proof-of-concept that PRKD3 is a valid target to overcome drug resistance being encountered widely in the clinic with RAF or MEK inhibitors. Cancer Res; 71(12); 4280–91. ©2011 AACR.
Sirtuin 1 Is Upregulated in a Subset of Hepatocellular Carcinomas where It Is Essential for Telomere Maintenance and Tumor Cell Growth
Authors: Chen Juan , Zhang Bin , Wong Nathalie , Lo Anthony W.I. , To Ka-Fai , Chan Anthony W.H. , Ng Margaret H.L. , Ho Cecilia Y.S. , Cheng Suk-Hang , Lai Paul B.S. , Yu Jun , Ng Ho-Keung , Ling Ming-Tat , Huang Ai-Long , Cai Xue-Fei , Ko Ben C.B. 
Published: April 2011

Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction–induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelterin complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and PTOP in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy. Cancer Res; 71(12); 4138–49. ©2011 AACR.
Prospective Analysis of Parametric Response Map–Derived MRI Biomarkers: Identification of Early and Distinct Glioma Response Patterns Not Predicted by Standard Radiographic Assessment
Authors: Galbán Craig J. , Chenevert Thomas L. , Meyer Charles R. , Tsien Christina , Lawrence Theodore S. , Hamstra Daniel A. , Junck Larry , Sundgren Pia C. , Johnson Timothy D. , Galbán Stefanie , Sebolt-Leopold Judith S. , Rehemtulla Alnawaz , Ross Brian D. 
Published: April 2011

Abstract
Purpose: Currently, radiologic response of brain tumors is assessed according to the Macdonald criteria 10 weeks from the start of therapy. There exists a critical need to identify nonresponding patients early in the course of their therapy for consideration of alternative treatment strategies. Our study assessed the effectiveness of the parametric response map (PRM) imaging biomarker to provide for an earlier measure of patient survival prediction.
Experimental Design: Forty-five high-grade glioma patients received concurrent chemoradiation. Quantitative MRI including apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired pretreatment and 3 weeks midtreatment on a prospective institutional-approved study. PRM, a voxel-by-voxel image analysis method, was evaluated as an early prognostic biomarker of overall survival. Clinical and conventional MR parameters were also evaluated.
Results: Multivariate analysis showed that PRMADC+ in combination with PRMrCBV− obtained at week 3 had a stronger correlation to 1-year and overall survival rates than any baseline clinical or treatment response imaging metric. The composite biomarker identified three distinct patient groups, nonresponders [median survival (MS) of 5.5 months, 95% CI: 4.4–6.6 months], partial responders (MS of 16 months, 95% CI: 8.6–23.4 months), and responders (MS has not yet been reached).
Conclusions: Inclusion of PRMADC+ and PRMrCBV− into a single imaging biomarker metric provided early identification of patients resistant to standard chemoradiation. In comparison to the current standard of assessment of response at 10 weeks (Macdonald criteria), the composite PRM biomarker potentially provides a useful opportunity for clinicians to identify patients who may benefit from alternative treatment strategies. Clin Cancer Res; 17(14); 4751–60. ©2011 AACR.
Inclusion of Patients with Brain Metastases in Phase I Trials: An Unmet Need
Authors: Gounder Mrinal M. , Spriggs David R. 
Published: April 2011

Abstract
Patients with brain metastases are increasing in number; however, these patients are often excluded in phase I/II trials due to perceived poor prognosis, risk of hemorrhage, inefficient drug delivery, and confounding toxicities. Tsimberidou and colleagues demonstrate that selected patients can be appropriately enrolled in phase I trials and have outcomes representative of the general cancer population. Clin Cancer Res; 17(12); 3855–7. ©2011 AACR.
Amyloid β Enhances Migration of Endothelial Progenitor Cells by Upregulating CX3CR1 in Response to Fractalkine, Which May Be Associated With Development of Choroidal Neovascularization
Authors: Wang Jiying , Ohno-Matsui Kyoko , Nakahama Ken-ichi , Okamoto Aikou , Yoshida Takeshi , Shimada Noriaki , Mochizuki Manabu , Morita Ikuo 
Published: April 2011

Objective—
Deposits that accumulate beneath retinal pigment epithelium, called drusen, are early signs of age-related macular degeneration (AMD). We have shown that amyloid β (Aβ) is present in drusen, and Aβ may be involved in AMD development. We have also shown that endothelial progenitor cells (EPCs) may contribute to the development of choroidal neovascularization (CNV). Thus, the purpose of this study was to investigate the role played by CX3CR1, a chemokine receptor, in EPC migration and CNV formation.

Methods and Results—

EPCs collected from human umbilical cords were found to express higher levels of CX3CR1 than human umbilical vein endothelial cells, and exposure of EPCs to Aβ caused further upregulation of CX3CR1. This upregulation was decreased by blocking fractalkine, a ligand of CX3CR1. Exposure of EPCs to fractalkine increased their migration, but pretreatment with Aβ enhanced the migration. The fractalkine-induced EPC migration was more inhibited by EPCs derived from CX3CR1
−/−
mice than wild-type mice. The area of laser-induced CNV was significantly smaller in wild-type mice that received bone marrow transplantation from CX3CR1
−/−
mice than in those that received transplantation from wild-type mice.

Conclusion—
These data suggest that Aβ enhances EPC migration through the upregulation of CX3CR1. This upregulation might play a role in development of CNV.
Hemodynamic Activation of β-Catenin and T-Cell-Specific Transcription Factor Signaling in Vascular Endothelium Regulates Fibronectin Expression
Authors: Gelfand Bradley D. , Meller Julia , Pryor Andrew W. , Kahn Michael , Bortz Pamela D. Schoppee , Wamhoff Brian R. , Blackman Brett R. 
Published: April 2011

Objective—
The goal of this study was to assess the activity of β-catenin/T-cell-specific transcription factor (TCF) signaling in atherosclerosis development and its regulation of fibronectin in vascular endothelium.

Methods and Results—
Histological staining identified preferential nuclear localization of β-catenin in the endothelium of atheroprone aorta before and during lesion development. Transgenic reporter studies revealed that increased levels of TCF transcriptional activity in endothelium correlated anatomically with β-catenin nuclear localization and fibronectin deposition. Exposure of endothelial cells to human-derived atheroprone shear stress induced nuclear localization of β-catenin, transcriptional activation of TCF, and expression of fibronectin. Activation of fibronectin expression required β-catenin, TCF, and the transcriptional coactivator CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive β-catenin and glycogen synthase kinase-3β activities.

Conclusion—
These data reveal novel constitutive activation of the endothelial β-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.
Heart Rate Contributes to the Vascular Effects of Chronic Mental Stress
Authors: Custodis Florian , Gertz Karen , Balkaya Mustafa , Prinz Vincent , Mathar Ilka , Stamm Christoph , Kronenberg Golo , Kazakov Andrey , Freichel Marc , Böhm Michael , Endres Matthias , Laufs Ulrich 
Published: April 2011

Background and Purpose—
Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia.

Methods—

129S6/SvEv mice were randomized to the I(
f
)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days.

Results—

Stress increased HR from 514±10 bpm to 570±14 bpm, this was prevented by ivabradine (485±7 bpm). Endothelium-dependent relaxation of aortic rings was impaired in mice exposed to stress. HR reduction restored endothelial function to the level of naive controls. Vascular lipid hydroperoxides were increased to 333%±24% and vascular NADPH oxidase activity was upregulated to 223±38% in stressed mice, which was prevented by ivabradine. Stress reduced aortic endothelial nitric oxide synthase mRNA expression to 84%±3% and increased AT1 receptor mRNA to 168%±18%. Both effects were attenuated by HR reduction. In brain tissue, stress resulted in an upregulation of lipid hydroperoxides to 140%±11%, which was attenuated by HR reduction. Ivabradine increased brain capillary density in naive and in stressed mice. Mice exposed to chronic stress before induction of ischemic stroke by transient middle cerebral artery occlusion exhibited increased lesion size (33.7±2.3 mm
3
versus 23.9±2.4 mm
3
). HR reduction led to a marked reduction of the infarct volume to 12.9±3.3 mm
3
.

Conclusions—
Chronic stress impairs endothelial function and aggravates ischemic brain injury. HR reduction protects from cerebral ischemia via improvement of endothelial function and reduction of oxidative stress. These results identify heart rate as a mediator of vascular effects induced by chronic stress.
Does Impaired Cerebrovascular Reactivity Predict Stroke Risk in Asymptomatic Carotid Stenosis?
Authors: King Alice , Serena Joaquin , Bornstein Natan M. , Markus Hugh S. 
Published: April 2011

Background and Purpose—
Improved methods are required to identify the subgroup of patients with asymptomatic carotid stenosis who will have stroke develop. It has been suggested that impaired cerebral reactivity (CVR) may predict high risk, but no multicenter studies have examined this.

Methods—
In a preplanned substudy of Asymptomatic Carotid Emboli Study, 106 patients were recruited with ≥70% asymptomatic carotid stenosis. Transcranial Doppler was used to measure CVR with a vasodilatory response of carbon dioxide or acetazolamide. A meta-analysis of the data with previously published studies was performed.

Results—

Thirty-two of 106 (30.2%) had severely impaired CVR ipsilateral to the study artery. Mean follow-up was 680 days. There were no ipsilateral strokes. There was a nonsignificant trend to more secondary end points of any stroke/TIA in patients with severely impaired CVR. Three of 32 (9.4%) had impaired CVR compared with 2 of 74 (2.7%) without (hazard ratio, 2.54; 95% CI, 0.61–21.74;
P
=0.158). On meta-analysis of the Asymptomatic Carotid Emboli Study data with previous studies, impaired CVR was associated with increased risk of ipsilateral stroke alone (OR, 6.14; 95% CI, 1.27–29.5;
P
=0.02), ipsilateral stroke or TIA (OR, 4.76; 95% CI, 1.86–12.16;
P
=0.001), and any stroke (OR, 4.66; 95% CI, 1.69–12.85;
P
=0.003).

Conclusions—
In this international multicenter study, we found no association between impaired CVR and recurrent events, but the study was underpowered because of the low event rate. Meta-analysis of available data suggested an association between impaired CVR and future risk. However, currently there are insufficient data to justify the routine clinical use of CVR to stratify risk in patients with asymptomatic carotid stenosis for selection for carotid endarterectomy.
A Daring Hospitality:Towards a Poetics of Time
Authors: Amato Andy 
Published: April 2011

AbstractThe aim of this paper is to approach an understanding of time through the concept of “poetic time,” and to do so by exploring the connections between theorizing, creativity, and ethics. Poetic time, in this sense, is a subjective phenomenon that we experience in our moment-to-moment acceptance of our ethical relationship to others. This acceptance is enacted by the decision to share our own allotment of time—our finite amount of time—with others, and others with us. This sharing of time finds and simultaneously creates spaces of mutuality and moments of poetry; it reveals and constructs worlds of mutuality.
Trends in Precipitable Water and Relative Humidity in China: 1979–2005
Authors: Xie Baoguo , Zhang Qinghong , Ying Yue 
Published: April 2011

AbstractAnnual and seasonal trends of precipitable water (PW) and relative humidity (RH) at 850, 700, and 500 hPa are studied using the data from 106 radiosonde stations over China during the period 1979–2005. Analysis shows evidence of an increase in PW associated with the slight warming observed in the lower to midtroposphere over China. The northern part of China shows a significant upward trend of PW in summer, and drying of the atmosphere in winter is found in most regions over China. Annual and seasonal trends in RH at the 850-, 700-, and 500-hPa levels show no significant trends in most regions in China except for Xinjiang, which shows an upward trend, and central China, where there was a downward trend in RH at 500 hPa. It is found that changes in PW are coincident with the warming of the surface and the lower to midtroposphere. The RH in the lower to midtroposphere in most regions over China has remained steady during the most recent 30 years, as might be expected given the increasing of PW and the warming above the surface. The long-term trend of precipitation over China may be linked to the trends of PW and RH at the lower level and midlevel.
Physics of U.S. Surface Temperature Response to ENSO
Authors: Zhang Tao , Hoerling Martin P. , Perlwitz Judith , Sun De-Zheng , Murray Donald 
Published: April 2011

Abstract
To elucidate physical processes responsible for the response of U.S. surface temperatures to El Niño–Southern Oscillation (ENSO), the surface energy balance is diagnosed from observations, with emphasis on the role of clouds, water vapor, and land surface properties associated with snow cover and soil moisture. Results for the winter season (December–February) indicate that U.S. surface temperature conditions associated with ENSO are determined principally by anomalies in the surface radiative heating—the sum of absorbed solar radiation and downward longwave radiation. Each component of the surface radiative heating is linked with specific characteristics of the atmospheric hydrologic response to ENSO and also to feedbacks by the land surface response. During El Niño, surface warming over the northern United States is physically consistent with three primary processes: 1) increased downward solar radiation due to reduced cloud optical thickness, 2) reduced reflected solar radiation due to an albedo decline resulting from snow cover loss, and 3) increased downward longwave radiation linked to an increase in precipitable water. In contrast, surface cooling over the southern United States during El Niño is mainly the result of a reduction in incoming solar radiation resulting from increased cloud optical thickness. During La Niña, surface warming over the central United States results mainly from snow cover losses, whereas warming over the southern United States results mainly from a reduction in cloud optical thickness that yields increased incoming solar radiation and also from an increase in precipitable water that enhances the downward longwave radiation. For both phases of ENSO the surface radiation budget is closely linked to large-scale horizontal and vertical motions in the free atmosphere through two main processes: 1) the convergence of the atmospheric water vapor transport that largely determines cloud optical thickness and thereby affects incoming shortwave radiation and 2) the changes in tropospheric column temperature resulting from the characteristic atmospheric teleconnections that largely determine column precipitable water and thereby affect downward longwave radiation.
Higher Hydroclimatic Intensity with Global Warming
Authors: Giorgi F. , Im E.-S. , Coppola E. , Diffenbaugh N. S. , Gao X. J. , Mariotti L. , Shi Y. 
Published: April 2011

Abstract
Because of their dependence on water, natural and human systems are highly sensitive to changes in the hydrologic cycle. The authors introduce a new measure of hydroclimatic intensity (HY-INT), which integrates metrics of precipitation intensity and dry spell length, viewing the response of these two metrics to global warming as deeply interconnected. Using a suite of global and regional climate model experiments, it is found that increasing HY-INT is a consistent and ubiquitous signature of twenty-first-century, greenhouse gas–induced global warming. Depending on the region, the increase in HY-INT is due to an increase in precipitation intensity, dry spell length, or both. Late twentieth-century observations also exhibit dominant positive HY-INT trends, providing a hydroclimatic signature of late twentieth-century warming. The authors find that increasing HY-INT is physically consistent with the response of both precipitation intensity and dry spell length to global warming. Precipitation intensity increases because of increased atmospheric water holding capacity. However, increases in mean precipitation are tied to increases in surface evaporation rates, which are lower than for atmospheric moisture. This leads to a reduction in the number of wet days and an increase in dry spell length. This analysis identifies increasing hydroclimatic intensity as a robust integrated response to global warming, implying increasing risks for systems that are sensitive to wet and dry extremes and providing a potential target for detection and attribution of hydroclimatic changes.