bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluorescence studies of a series of monodisperse telechelic α,ω-dipyrenyl poly(N-isopropylacrylamide)s in ethanol and in water
Authors: Yip Jamie , Duhamel Jean , Qiu Xing Ping , Winnik Françoise M. 
Published: February 2011

Steady-state and time-resolved fluorescence measurements were performed on solutions in ethanol and in water (23 °C) of a series of poly(N-isopropylacrylamide)s labeled with a pyrenyl group at each chain end (Py2-PNIPAM) and ranging in molecular weight (Mn) from 5 900 to 44 500 g·mol−1. Water and ethanol are of similar solvent quality towards the PNIPAM chain. The pyrene labels, in contrast, are soluble in ethanol but not in water. The efficiency of excimer formation for Py2-PNIPAM samples in ethanol decreased with increasing chain length, a trend typical of pyrene end-labeled polymers in good solvents. The ratio IE/IM, where IE is the Py excimer emission intensity and IM is the Py monomer emission intensity, scaled as Mn−1.4, where Mn is the number-average molecular weight of the sample. The kinetics of excimer formation were more complex for aqueous Py2-PNIPAM solutions, as a consequence of pyrene–pyrene association prior to excitation. The excimer time-dependent profiles exhibited significantly faster rise times, compared with the situation in ethanol, and they could not be fitted with the traditional Birks scheme. The results are discussed in the context of the solution properties of telechelic amphiphilic PNIPAMs and are compared with data gathered previously in studies of dipyrenyl end-labeled poly(ethylene oxides), the only other polymers soluble in water and organic solvents subjected to similar studies in the past.
Functional EGFR Germline Polymorphisms May Confer Risk for EGFR Somatic Mutations in Non–Small Cell Lung Cancer, with a Predominant Effect on Exon 19 Microdeletions
Authors: Liu Wanqing , He Lijun , Ramírez Jacqueline , Krishnaswamy Soundararajan , Kanteti Rajani , Wang Yi-Ching , Salgia Ravi , Ratain Mark J. 
Published: February 2011

Abstract
Somatic mutations in the EGFR tyrosine kinase domain play a critical role in the development and treatment of non–small cell lung cancer (NSCLC). Strong genetic influence on susceptibility to these mutations has been suggested. To identify the genetic factors conferring risk for the EGFR tyrosine kinase mutations in NSCLC, a case–control study was conducted in 141 Taiwanese NSCLC patients by focusing on three functional polymorphisms in the EGFR gene [−216G/T, intron 1 (CA)n, and R497K]. Allelic imbalance of the EGFR −216G/T polymorphism was also tested in the heterozygous patients and in the NCI-60 cancer cell lines to further verify its function. We found that the frequencies of the alleles −216T and CA-19 are significantly higher in the patients with any mutation (P = 0.032 and 0.01, respectively), in particular in those with exon 19 microdeletions (P = 0.006 and 0.033, respectively), but not in the patients with L858R mutation. The −216T allele is favored to be amplified in both tumor DNA of lung cancer patients and cancer cell lines. We conclude that the local haplotype structures across the EGFR gene may favor the development of cellular malignancies and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19 microdeletions. Cancer Res; 71(7); 2423–7. ©2011 AACR.
CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis
Authors: Stagg John , Divisekera Upulie , Duret Helene , Sparwasser Tim , Teng Michele W.L. , Darcy Phillip K. , Smyth Mark J. 
Published: February 2011

Abstract
CD73 is a cell-surface enzyme that suppresses immune responses by producing extracellular adenosine. In this study, we employed CD73 gene-targeted mice to investigate the role of host-derived CD73 on antitumor immunity and tumor cell metastasis. We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8+ T cells and associated with an increased frequency of antigen-specific CD8+ T cells in peripheral blood and tumors and increased antigen-specific IFN-γ production. Replicate studies in bone marrow chimeras established that both hematopoietic and nonhematopoietic expression of CD73 was important to promote tumor immune escape. Using adoptive reconstitution of T regulatory cell (Treg)–depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73. CD73-deficient mice were also protected against pulmonary metastasis of B16F10 melanoma cells after intravenous injection. Unexpectedly, we found that the prometastatic effect of host-derived CD73 was dependent on CD73 expression on nonhematopoietic cells. CD73 expression on nonhematopoietic cells, most likely endothelial cells, was critical for promoting lung metastasis in a manner independent from immunosuppressive effects. Notably, in vivo blockade of CD73 with a selective inhibitor or anti-CD73 monoclonal antibody significantly reduced tumor growth and metastasis of CD73-negative tumors. Taken together, our findings indicate that CD73 may be targeted at multiple levels to induce anticancer effects including at the level of tumor cells, Tregs, and nonhematopoietic cells. Cancer Res; 71(8); 2892–900. ©2011 AACR.
Bortezomib Enhances the Efficacy of Fulvestrant by Amplifying the Aggregation of the Estrogen Receptor, Which Leads to a Proapoptotic Unfolded Protein Response
Authors: Ishii Yuki , Papa Luena , Bahadur Urvashi , Yue Zhenyu , Aguirre-Ghiso Julio , Shioda Toshi , Waxman Samuel , Germain Doris 
Published: February 2011

Abstract
Purpose: Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death.
Experimental Design: The rate of aggregation of the ER was monitored in ER+ breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant.
Results: We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance.
Conclusions: Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER+ but estrogen independent. Clin Cancer Res; 17(8); 2292–300. ©2011 AACR.
Comparison of Genomics and Functional Imaging from Canine Sarcomas Treated with Thermoradiotherapy Predicts Therapeutic Response and Identifies Combination Therapeutics
Authors: Chi Jen-Tsan , Thrall Donald E. , Jiang Chen , Snyder Stacey , Fels Diane , Landon Chelsea , McCall Linda , Lan Lan , Hauck Marlene , MacFall James R. , Viglianti Benjamin L. , Dewhirst Mark W. 
Published: February 2011

Abstract
Purpose: While hyperthermia is an effective adjuvant treatment to radiotherapy, we do not completely understand the nature of the response heterogeneity.
Experimental Design: We performed gene expression analysis of 22 spontaneous canine sarcomas before and after the first hyperthermia treatment administered as an adjuvant to radiotherapy. In parallel, diffusion-weighted MRI (DWI) was done prior to the treatment course and at the end of therapy.
Results: From the integrative analysis of gene expression and DWI, we identified significant correlation between tumor responses with genes involved in VEGF signaling, telomerase, DNA repair, and inflammation. The treatment-induced changes in gene expression identified 2 distinct tumor subtypes with significant differences in their gene expression and treatment response, as defined by changes in DWI. The 2 tumor subtypes could also be readily identified by pretreatment gene expression. The tumor subtypes, with stronger expression response and DWI increase, had higher levels of HSP70, POT1, and centrosomal proteins, and lower levels of CD31, vWF, and transferrin. Such differential gene expression between the 2 subtypes was used to interrogate connectivity map and identify linkages to an HSP90 inhibitor, geldanamycin. We further validated the ability of geldanamycin to enhance cell killing of human tumor cells with hyperthermia and radiotherapy in clonogenic assays.
Conclusions: To our knowledge, this is one of the first successful attempts to link changes in gene expression and functional imaging to understand the response heterogeneity and identify compounds enhancing thermoradiotherapy. This study also demonstrates the value of canine tumors to provide information generalizable to human tumors. Clin Cancer Res; 17(8); 2549–60. ©2011 AACR.
Tissue Factor Pathway Inhibitor
Authors: Regnault Veronique , Perret-Guillaume Christine , Kearney-Schwartz Anna , Max Jean-Pierre , Labat Carlos , Louis Huguette , Wahl Denis , Pannier Bruno , Lecompte Thomas , Weryha Georges , Challande Pascal , Safar Michel E. , Benetos Athanase , Lacolley Patrick 
Published: February 2011

Objective—
To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro.

Methods and Results—
Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect.

Conclusion—
In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.
Tissue Kallikrein Inhibits Retinal Neovascularization via the Cleavage of Vascular Endothelial Growth Factor-165
Authors: Nakamura Shinsuke , Morimoto Nobutaka , Tsuruma Kazuhiro , Izuta Hiroshi , Yasuda Yoshika , Kato Noriaki , Ikeda Tsunehiko , Shimazawa Masamitsu , Hara Hideaki 
Published: February 2011

Objective—
Tissue kallikrein, a widely used vasodilator for the treatment of hypertension and peripheral circulatory disorder, acts by releasing kinin, a potent vasodilator peptide. To identify the role of tissue kallikrein in retinal neovascularization, we investigated the antiangiogenic effect by using an in vitro and in vivo angiogenesis model.

Methods and Results—

Tissue kallikrein in vitreous fluid was markedly elevated in proliferative diabetic retinopathy patients compared with that in control patients with macular hole and epiretinal membrane. Tissue kallikrein inhibited vascular endothelial growth factor-165 (VEGF
165
)–induced tube formation, proliferation, and migration in vitro angiogenesis model via suppression of the VEGF
165
-induced phosphorylation of VEGF receptor-2. Furthermore, tissue kallikrein cleavage of VEGF
165
was on the C-terminal side, which was analyzed by Western blotting and mass spectrometry. When administered subcutaneously, tissue kallikrein reduced the pathological vascular changes in retinal neovascularization induced in neonatal mice by returning the retina to normoxia after exposure to hyperoxia.

Conclusion—

These findings indicate that tissue kallikrein is partly involved in pathogenesis of proliferative diabetic retinopathy and may be a promising therapeutic agent that could cleave VEGF
165
itself when administered by a peripheral route.
The Effect of Survival Bias on Case-Control Genetic Association Studies of Highly Lethal Diseases
Authors: Anderson Christopher D. , Nalls Michael A. , Biffi Alessandro , Rost Natalia S. , Greenberg Steven M. , Singleton Andrew B. , Meschia James F. , Rosand Jonathan 
Published: February 2011

Background—
Survival bias is the phenomenon by which individuals are excluded from analysis of a trait because of mortality related to the expression of that trait. In genetic association studies, variants increasing risk for disease onset as well as risk of disease-related mortality (lethality) could be difficult to detect in genetic association case-control designs, possibly leading to underestimation of a variant's effect on disease risk.

Methods and Results—
We modeled cohorts for 3 diseases of high lethality (intracerebral hemorrhage, ischemic stroke, and myocardial infarction) using existing longitudinal data. Based on these models, we simulated case-control genetic association studies for genetic risk factors of varying effect sizes, lethality, and minor allele frequencies. For each disease, erosion of detected effect size was larger for case-control studies of individuals of advanced age (age >75 years) and/or variants with very high event-associated lethality (genotype relative risk for event-related death >2.0). We found that survival bias results in no more than 20% effect size erosion for cohorts with mean age <75 years, even for variants that double lethality risk. Furthermore, we found that increasing effect size erosion was accompanied by depletion of minor allele frequencies in the case population, yielding a “signature” of the presence of survival bias.

Conclusions—
Our simulation provides formulas to allow estimation of effect size erosion given a variant's odds ratio of disease, odds ratio of lethality, and minor allele frequencies. These formulas will add precision to power calculation and replication efforts for case-control genetic studies. Our approach requires validation using prospective data.
The Hidden Mismatch
Authors: Ma Henry K. , Zavala Jorge A. , Churilov Leonid , Ly John , Wright Perter M. , Phan Thanh G. , Arakawa Shuji , Davis Stephen M. , Donnan Geoffrey A. 
Published: February 2011

Background and Purpose—
In ischemic stroke, MR perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) mismatch represents tissue at risk for infarction. Infarct growth should only take place in the presence of mismatch, although there have been reports of this occurring. We hypothesized that this observation may be attributable to the presence of undetected “hidden mismatch,” which may become obvious when coregistration techniques are used.

Methods—
MR PWI/DWI was performed within 48 hours of stroke onset and a final T2-weighted image at ≈3 months. Volumetric-subtraction mismatch volume was defined as PWI minus DWI volume and infarct growth was defined as T2 minus DWI volume. Coregistration mismatch volume was PWI not overlapped by DWI. Mismatch salvage was the proportion of coregistered mismatch tissue that had not progressed to infarction.

Results—
Thirty-four patients were studied with MR at a median of 4.9 hours (interquartile range, 2.9–21.1 hours). With the volumetric-subtraction technique, 5 patients (14.7%; 95% CI, 0.05%–0.31%) had infarct growth exceeding mismatch volume, 11 patients (32.0%) had no mismatch and, among these, 3 (27.3%) had infarct growth (median volume, 2.2 mL; interquartile range, 1.0–6.5 mL). All patients had mismatch volume identified by coregistration method that was greater than infarct growth volume. The proportion of this volume salvaged was 77.7% (interquartile range, 63.0%–98.9%).

Conclusions—
The illogical finding of infarct growth volume being greater than the presence of mismatch volume can be explained by the presence of “hidden mismatch,” which may be detected by coregistration methods.
Intracortical Infarcts in Small Vessel Disease
Authors: Jouvent Eric , Poupon Cyril , Gray Françoise , Paquet Claire , Mangin Jean-François , Le Bihan Denis , Chabriat Hugues 
Published: February 2011

Background and Purpose—
The purpose of this study was to report the detection of infarcts of the cerebral cortex in a patient with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using high-resolution postmortem 7-T MRI in association with pathological examination.

Methods—
Whole brain high-resolution MRI data were obtained postmortem at 7 T in a 53-year-old patient with CADASIL. These MRI data were used to guide the neuropathological examination of the cortex.

Results—
Combined with neuropathology, MRI allowed the delineation of intracortical infarcts confirmed by histological examination in this case. These lesions were not visible on the last in vivo MRI obtained at 1.5 T and were difficult to detect on neuropathological examination only.

Conclusions—
Postmortem high-resolution MRI may help to detect intracortical infarcts in CADASIL and possibly in other small vessel diseases of the brain.
NCX1 Is a Novel Target Gene for Hypoxia-Inducible Factor-1 in Ischemic Brain Preconditioning
Authors: Valsecchi Valeria , Pignataro Giuseppe , Del Prete Annalisa , Sirabella Rossana , Matrone Carmela , Boscia Francesca , Scorziello Antonella , Sisalli Maria Josè , Esposito Elga , Zambrano Nicola , Di Renzo Gianfranco , Annunziato Lucio 
Published: February 2011

Background and Purpose—

The sodium–calcium exchanger-1 (NCX1) represents a key mediator for maintaining [Na
+
]
i
and [Ca
2+
]
i
homeostasis. Although changes in NCX1 protein and transcript expression have been detected during stroke, its transcriptional regulation is still unknown. Thus far, however, there is evidence that hypoxia-inducible factor-1 (HIF-1) is a nuclear factor required for transcriptional activation of several genes implicated in stroke. The main objective of this study was to investigate whether NCX1 gene might be a novel target of HIF-1 in the brain.

Methods and Results—
Here we report that: (1) in neuronal cells, NCX1 increased expression after oxygen and glucose deprivation or cobalt-induced HIF-1 activation was prevented by silencing HIF-1; (2) the brain NCX1 promoter cloned upstream of the firefly-luciferase gene contained 2 regions of HIF-1 target genes called hypoxia-responsive elements that are sensitive to oxygen and glucose deprivation or cobalt chloride; (3) HIF-1 specifically bound hypoxia-responsive elements on brain NCX1, as demonstrated by band-shift and chromatin immunoprecipitation assays; (4) HIF-1α silencing prevented NCX1 upregulation and neuroprotection induced by ischemic preconditioning; and (5) NCX1 silencing partially reverted the preconditioning-induced neuroprotection in rats.

Conclusions—
NCX1 gene is a novel HIF-1 target, and HIF-1 exerts its prosurvival role through NCX1 upregulation during brain preconditioning.
A Mixed Exponential Distribution Model for Retrieving Ground Flash Fraction from Satellite Lightning Imager Data
Authors: Koshak W. J. 
Published: February 2011

Abstract
A Bayesian inversion method is introduced for retrieving the fraction of ground flashes in a set of flashes observed from a (low earth orbiting or geostationary) satellite lightning imager. The method employs a constrained mixed exponential distribution model to describe the lightning optical measurements. Because the method also retrieves certain population statistics of ground and cloud flash optical properties, the method can be applied to an arbitrary geographical region, including those regions where the lightning optical statistics either are not known or are difficult to obtain. The approach is tested by performing simulated retrievals, and retrieval error statistics are provided. A first-attempt retrieval of the global geographical distribution of ground flash fraction is obtained using the 5-yr Optical Transient Detector (OTD) dataset; the spatially averaged ground flash fraction over the global-scale domain studied was 0.151 with a standard deviation of 0.081. The ability to retrieve ground flash fraction has important benefits to the atmospheric chemistry community. For example, using the method to partition the existing OTD/Lightning Imaging Sensor (LIS) satellite global lightning climatology into separate ground and cloud flash climatologies would improve estimates of regional and global lightning nitrogen oxides (NOx) production; this, in turn, would improve both regional air quality and global chemistry/climate model predictions.
The Influence of the Quasi-Biennial Oscillation on the Troposphere in Winter in a Hierarchy of Models. Part I: Simplified Dry GCMs
Authors: Garfinkel Chaim I. , Hartmann Dennis L. 
Published: February 2011

Abstract
A dry primitive equation model is used to explain how the quasi-biennial oscillation (QBO) of the tropical stratosphere can influence the troposphere, even in the absence of tropical convection anomalies and a variable stratospheric polar vortex. QBO momentum anomalies induce a meridional circulation to maintain thermal wind balance. This circulation includes zonal wind anomalies that extend from the equatorial stratosphere into the subtropical troposphere. In the presence of extratropical eddies, the zonal wind anomalies are intensified and extend downward to the surface. The tropospheric response differs qualitatively between integrations in which the subtropical jet is strong and integrations in which the subtropical jet is weak. While fluctuation–dissipation theory provides a guide to predicting the response in some cases, significant nonlinearity in others, particularly those designed to model the midwinter subtropical jet of the North Pacific, prevents its universal application. When the extratropical circulation is made zonally asymmetric, the response to the QBO is greatest in the exit region of the subtropical jet. The dry model is able to simulate much of the Northern Hemisphere wintertime tropospheric response to the QBO observed in reanalysis datasets and in long time integrations of the Whole Atmosphere Community Climate Model (WACCM).