bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1
Authors: Wang Xing , He Zhiheng , Xia Tian , Li Xiaofan , Liang Deguang , Lin Xianzhi , Wen Hao , Lan Ke 
Published: February 2014

Abstract
Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma–associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and γ-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. Cancer Res; 74(7); 2026–37. ©2014 AACR.
Diagnostic Delay and Sociodemographic Predictors of Stage at Diagnosis and Mortality in Unilateral and Bilateral Retinoblastoma
Authors: Ramírez-Ortiz Marco A. , Ponce-Castañeda M. Veronica , Cabrera-Muñoz M. Lourdes , Medina-Sansón Aurora , Liu Xinhua , Orjuela Manuela A. 
Published: February 2014

AbstractBackground: More invasive retinoblastoma, characterized by increased morbidity and mortality, with lower rates of eye salvage and higher rates of extraocular dissemination, seems more prevalent in resource-poor countries. The relationship of diagnostic delay (lag time) and sociodemographic factors on the extent of disease at diagnosis has not been examined separately for unilateral and bilateral retinoblastoma.Methods: At diagnosis, consenting parents of 179 Mexican children with retinoblastoma were interviewed about initial symptoms and household demographic characteristics. Clinical presentation was classified using St. Jude's, International Staging System (ISS), and International Intraocular Retinoblastoma Classification (IIRC) criteria. Lag time (delay between noting symptoms and diagnosis) and sociodemographic factors were examined as predictors for higher stage at diagnosis and overall survival (OS).Results: In bilateral disease, lag time predicts stage at diagnosis using St. Jude's, and ISS criteria (P &lt; 0.005 in multivariate regression), and OS (P &lt; 0.05, Cox hazards), but not extent of intraocular disease (by IIRC). In unilateral disease, lag time predicts neither extent of disease (using ISS, St Jude's, and IIRC), nor OS. Indicators of prenatal poverty, including lower maternal education and the presence of dirt flooring in the home, predict more advanced disease by IIRC for bilateral retinoblastoma, and for unilateral by ISS, and St Jude's (P &lt; 0.001) as well as OS (P &lt; 0.05).Conclusion: These results suggest unilateral and bilateral retinoblastoma differs in factors governing progression and extraretinal extension, possibly reflecting underlying biologic heterogeneity.Impact: This demonstrates differing effect of social factors on extent of intra- and extraocular disease depending on laterality with implications for screening strategies. Cancer Epidemiol Biomarkers Prev; 23(5); 784–92. ©2014 AACR.
A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors
Authors: Rodon Jordi , Tawbi Hussein A. , Thomas Anne L. , Stoller Ronald G. , Turtschi Christian P. , Baselga Jose , Sarantopoulos John , Mahalingam Devalingam , Shou Yaping , Moles Melissa A. , Yang Lin , Granvil Camille , Hurh Eunju , Rose Kristine L. , Amakye Dereck D. , Dummer Reinhard , Mita Alain C. 
Published: February 2014

Abstract
Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.
Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.
Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.
Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer
Authors: Gross Matt I. , Demo Susan D. , Dennison Jennifer B. , Chen Lijing , Chernov-Rogan Tania , Goyal Bindu , Janes Julie R. , Laidig Guy J. , Lewis Evan R. , Li Jim , MacKinnon Andrew L. , Parlati Francesco , Rodriguez Mirna L.M. , Shwonek Peter J. , Sjogren Eric B. , Stanton Timothy F. , Wang Taotao , Yang Jinfu , Zhao Frances , Bennett Mark K. 
Published: February 2014

AbstractGlutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor–positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2+ cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors. Mol Cancer Ther; 13(4); 890–901. ©2014 AACR.
HIFs Enhance the Transcriptional Activation and Splicing of Adrenomedullin
Authors: Sena Johnny A. , Wang Liyi , Pawlus Matthew R. , Hu Cheng-Jun 
Published: February 2014

Abstract
Adrenomedullin (ADM) is important for tumor angiogenesis, tumor cell growth, and survival. Under normoxic conditions, the ADM gene was found to produce two alternative transcripts, a fully spliced transcript that produces AM and PAMP peptides and intron-3–retaining transcript that produces a less functionally significant PAMP peptide only. ADM is a well-established hypoxia inducible gene; however, it is not clear which ADM isoform is induced by hypoxia. In this study, it was determined that various cancer and normal cells express two predominant types of ADM transcripts, a AM/PAMP peptide producing full-length transcript in which all introns are removed, and a nonprotein producing I1-3 transcript in which all introns are retained. Interestingly, hypoxia preferentially induced the full-length isoform. Moreover, hypoxia-inducible factors (HIF), but not hypoxia per se, are necessary and sufficient to increase splicing of ADM pre-mRNA. ADM splicing reporters confirmed that transcriptional activation by HIF or other transcription factors is sufficient to enhance splicing. However, HIFs are more potent in enhancing ADM pre-mRNA splicing than other transcriptional activators. Thus, ADM intron retention is not a consequence of abnormal splicing, but is an important mechanism to regulate ADM expression. These results demonstrate a novel function of HIFs in regulating ADM expression by enhancing its pre-mRNA splicing. Importantly, using endogenous and cloned ADM gene, further evidence is provided for the coupling of transcription and RNA splicing.
Implications: Here, a novel function of HIFs in regulating ADM gene expression is identified by enhancing ADM pre-mRNA splicing. Mol Cancer Res; 12(5); 728–41. ©2014 AACR.
Extracellular Superoxide Dismutase Ameliorates Skeletal Muscle Abnormalities, Cachexia, and Exercise Intolerance in Mice with Congestive Heart Failure
Authors: Okutsu Mitsuharu , Call Jarrod A. , Lira Vitor A. , Zhang Mei , Donet Jean A. , French Brent A. , Martin Kyle S. , Peirce-Cottler Shayn M. , Rembold Christopher M. , Annex Brian H. , Yan Zhen 
Published: February 2014

Background—
Congestive heart failure (CHF) is a leading cause of morbidity and mortality, and oxidative stress has been implicated in the pathogenesis of cachexia (muscle wasting) and the hallmark symptom, exercise intolerance. We have previously shown that a nitric oxide–dependent antioxidant defense renders oxidative skeletal muscle resistant to catabolic wasting. Here, we aimed to identify and determine the functional role of nitric oxide–inducible antioxidant enzyme(s) in protection against cardiac cachexia and exercise intolerance in CHF.

Methods and Results—

We demonstrated that systemic administration of endogenous nitric oxide donor
S
-nitrosoglutathione in mice blocked the reduction of extracellular superoxide dismutase (EcSOD) protein expression, as well as the induction of
MAFbx/Atrogin-1
mRNA expression and muscle atrophy induced by glucocorticoid. We further showed that endogenous EcSOD, expressed primarily by type IId/x and IIa myofibers and enriched at endothelial cells, is induced by exercise training. Muscle-specific overexpression of EcSOD by somatic gene transfer or transgenesis (muscle creatine kinase [MCK]-EcSOD) in mice significantly attenuated muscle atrophy. Importantly, when crossbred into a mouse genetic model of CHF (α-myosin heavy chain–calsequestrin),
MCK-EcSOD
transgenic mice had significant attenuation of cachexia with preserved whole body muscle strength and endurance capacity in the absence of reduced HF. Enhanced EcSOD expression significantly ameliorated CHF-induced oxidative stress,
MAFbx/Atrogin-1
mRNA expression, loss of mitochondria, and vascular rarefaction in skeletal muscle.

Conclusions—
EcSOD plays an important antioxidant defense function in skeletal muscle against cardiac cachexia and exercise intolerance in CHF.
Predicting Future Brain Tissue Loss From White Matter Connectivity Disruption in Ischemic Stroke
Authors: Kuceyeski Amy , Kamel Hooman , Navi Babak B. , Raj Ashish , Iadecola Costantino 
Published: February 2014

Background and Purpose—
The Network Modification (NeMo) Tool uses a library of brain connectivity maps from normal subjects to quantify the amount of structural connectivity loss caused by focal brain lesions. We hypothesized that the Network Modification Tool could predict remote brain tissue loss caused by poststroke loss of connectivity.

Methods—
Baseline and follow-up MRIs (10.7±7.5 months apart) from 26 patients with acute ischemic stroke (age, 74.6±14.1 years, initial National Institutes of Health Stroke Scale, 3.1±3.1) were collected. Lesion masks derived from diffusion-weighted images were superimposed on the Network Modification Tool’s connectivity maps, and regional structural connectivity losses were estimated via the Change in Connectivity (ChaCo) score (ie, the percentage of tracks connecting to a given region that pass through the lesion mask). ChaCo scores were correlated with subsequent atrophy.

Results—

Stroke lesions’ size and location varied, but they were more frequent in the left hemisphere. ChaCo scores, generally higher in regions near stroke lesions, reflected this lateralization and heterogeneity. ChaCo scores were highest in the postcentral and precentral gyri, insula, middle cingulate, thalami, putamen, caudate nuclei, and pallidum. Moderate, significant partial correlations were found between baseline ChaCo scores and measures of subsequent tissue loss (
r
=0.43,
P
=4.6×10
–9
;
r
=0.61,
P
=1.4×10
–18
), correcting for the time between scans.

Conclusions—
ChaCo scores varied, but the most affected regions included those with sensorimotor, perception, learning, and memory functions. Correlations between baseline ChaCo and subsequent tissue loss suggest that the Network Modification Tool could be used to identify regions most susceptible to remote degeneration from acute infarcts.
A Total Flow Perspective of Atmospheric Mass and Angular Momentum Circulations: Boreal Winter Mean State
Authors: Cai Ming , Shin Chul-Su 
Published: February 2014

Abstract
This paper reports a comprehensive diagnostic analysis of mass and angular momentum (AM) circulations and their budgets in boreal winter using the 32-yr daily NCEP–Department of Energy (DOE) reanalysis (1979–2010). The diagnosis is performed using instantaneous total flows before taking time and zonal average without decomposition of time mean and transient flows and separation of zonal mean and wavy flows. The analysis reveals that embedded in a broad hemispheric thermally direct meridional mass circulation in each hemisphere are three distinct but interconnected thermally direct meridional cells. They are the tropical Hadley cell, the stratospheric cell, and the extratropical zonally asymmetric Hadley cell. The tropical Hadley cell corresponds to the Hadley cell of the classic three-cell model whereas the extratropical Hadley cell and the stratospheric cell correspond to the eddy-driven extratropical residual circulation.
The joint consideration of meridional mass and AM circulations helps to substantiate Hadley’s original view that the hemispheric-wide thermally direct meridional circulation can have broad surface easterly in the tropics and westerly in the extratropics. Because the mass circulation cannot have a net divergence anywhere in long time mean and the earth’s AM decreases toward the poles, the companion AM transport in the equatorward cold air branch inevitably has to be divergent. The downward transfer of westerly AM to the cold air branch by the pressure torque associated with westward tilted baroclinic waves dominates such divergence in the extratropics, explaining the prevailing surface westerly there. In the tropics and polar region where the meridional circulation is nearly zonally symmetric, the dominance of this divergence results in a surface easterly there.
Performance of a New Convective Parameterization Scheme on Model Convergence in Simulations of a Tropical Cyclone at Grey-Zone Resolutions
Authors: Sun Yuan , Yi Lan , Zhong Zhong , Ha Yao 
Published: February 2014

Abstract
The latest version of the Weather Research and Forecasting model (WRFV3.5) is used to evaluate the performance of the Grell and Freitas (GF13) cumulus parameterization scheme on the model convergence in simulations of a tropical cyclone (TC) at gray-zone resolutions. The simulated TC intensity converges to a finite limit as the grid spacing varies from 7.5 to 1 km. The reasons for the model convergence are investigated from perspectives of subgrid-scale processes and thermodynamic and dynamic structures. It is found that the impacts of above factors are notably different with varying model resolutions. The convective heating and drying increase as the grid spacing decreases, which inhibits the explicit microphysical parameterization preventing the simulated TC from overly intensifying. As the grid spacing decreases from 7.5 to 5 km, the TC intensity increases because of a stronger secondary circulation, a larger magnitude and proportion of strong eyewall updraft, and a greater amount of latent heating in the eyewall. As the grid spacing decreases from 5 to 3 km, the radius of maximum wind (RMW) decreases and the radial pressure gradient increases leading to an increase in TC intensity. The simulated TC intensity changes slightly as the grid spacing decreases from 3 to 1 km since the RMW and the storm structure both change little. The slight changes in the simulated TC intensity at such high resolutions indicate a great model convergence. Therefore, the GF13 presents an appropriate option that increases the model convergence in the TC intensity simulation at gray-zone resolution.
A Comparison of Two Heavy Rainfall Events during the Terrain-Influenced Monsoon Rainfall Experiment (TiMREX) 2008
Authors: Tu Chuan-Chi , Chen Yi-Leng , Chen Ching-Sen , Lin Pay-Liam , Lin Po-Hsiung 
Published: February 2014

Abstract
Two contrasting localized heavy rainfall events during Taiwan’s early summer rainy season with the daily rainfall maximum along the windward mountain range and coast were studied and compared using a combination of observations and numerical simulations. Both events occurred under favorable large-scale settings including the existence of a moisture tongue from the tropics. For the 31 May case, heavy rainfall occurred in the afternoon hours over the southwestern windward slopes after a shallow surface front passed central Taiwan. The orographic lifting of the prevailing warm, moist, west-southwesterly flow aloft, combined with a sea breeze–upslope flow at the surface provided the localized lifting needed for the development of heavy precipitation. On 16 June before sunrise, pronounced orographic blocking of the warm, moist, south-southwesterly flow occurred because of the presence of relatively cold air at low levels as a result of nocturnal and rain evaporative cooling. As a result, convective systems intensified as they moved toward the southwestern coast. During the daytime, the cold pool remained over southwestern Taiwan without the development of onshore/upslope flow. Furthermore, with a south-southwesterly flow aloft parallel to terrain contours, orographic lifting aloft was absent and preexisting rain cells offshore diminished after they moved inland. Over northern Taiwan on the lee side, a sea breeze/onshore flow developed in the afternoon hours, resulting in heavy thundershowers. These results demonstrate the importance of diurnal and local effects on determining the location and timing of the occurrences of localized heavy precipitation during the early summer rainy season over Taiwan.
Ischemic preconditioning reduces apoptosis in open heart surgery
Authors: Rachmat Jusuf , Sastroasmoro Sudigdo , Suyatna Fransiscus D , Soejono Gunanti 
Published: February 2014

Background This study was performed to assess the role of ischemic preconditioning on cardiomyocyte apoptosis after open heart surgery, based on morphology by transmission electron microscopy, caspase-3 activity, biochemical markers, and cardiac performance. Methods 12 piglets were divided into 2 equal groups: an ischemic preconditioning group and a control group. Ventricular muscles were collected to examine apoptotic ultrastructure morphology and caspase-3 activity. Blood samples from the coronary sinus were obtained for measurement of tumor necrosis factor-α, malondialdehyde, and cardiac troponin I. Aortic blood samples were taken for lactate measurements before and after cardiopulmonary bypass. Cardiac performance was measured by echocardiography before and after surgery. Results Cardiomyocyte apoptosis occurred postoperatively, as shown by ultrastructure observation. Caspase-3 activity was less in the ischemic preconditioning group than the control group ( p < 0.05). Measurements of specific markers of cardiomyocyte injury also showed lower increases in the ischemic preconditioning group, although not significantly different. Clinical outcomes showed that ischemic preconditioning was able to preserve cardiac performance in terms of ejection fraction, cardiac index, and stroke volume index; these were statistically significant, except for lactate concentration. Conclusions Cardiomyocyte apoptosis occurs after open heart surgery. Ischemic preconditioning can reduce cardiomyocyte apoptosis and improve cardiac performance. Laboratory findings showed that ischemic preconditioning prevents injury of cardiomyocytes and reduces lactate concentration, although not statistically significant.