bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the In Vitro and In Vivo Efficacy of the JAK Inhibitor AZD1480 against JAK-Mutated Acute Lymphoblastic Leukemia
Authors: Suryani Santi , Bracken Lauryn S. , Harvey Richard C. , Sia Keith C.S. , Carol Hernan , Chen I-Ming , Evans Kathryn , Dietrich Philipp A. , Roberts Kathryn G. , Kurmasheva Raushan T. , Billups Catherine A. , Mullighan Charles G. , Willman Cheryl L. , Loh Mignon L. , Hunger Stephen P. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: December 2014

Abstract
Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL. Mol Cancer Ther; 14(2); 364–74. ©2014 AACR.
Fibroblast Growth Factor Signaling Pathway in Endothelial Cells Is Activated by BMPER to Promote Angiogenesis
Authors: Esser Jennifer S. , Rahner Susanne , Deckler Meike , Bode Christoph , Patterson Cam , Moser Martin 
Published: December 2014

Objective—
Previously, we have identified bone morphogenetic protein endothelial cell precursor–derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation.

Approach and Results—

To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper
+/−
mice. Aortic ring assays of C57BL/6_Bmper
+/−
mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor.

Conclusions—
Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis.
Inactivation of PI3Kδ Induces Vascular Injury and Promotes Aneurysm Development by Upregulating the AP-1/MMP-12 Pathway in Macrophages
Authors: Zheng Lingyun , Xing Liying , Zeng Cuiling , Wu Teng , Gui Yali , Li Weidong , Lan Tian , Yang Yongxia , Gu Quliang , Qi Cuiling , Zhang Qianqian , Tang Futian , He Xiaodong , Wang Lijing 
Published: December 2014

Objective—
An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases δ is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3-kinases δ and aneurysm development has not yet been elucidated.

Approach and Results—

Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110δ
D910A/D910A
mice (n=25;
P
<0.001 versus wild-type). Besides, p110δ inactivation exacerbated CaCl
2
-induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110δ
D910A/D910A
mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10;
P
<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110δ
D910A/D910A
mice (n=10;
P
<0.01 versus wild-type). In vitro, p110δ inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-α–induced recruitment. A specific phosphatidylinositol 3-kinases δ inhibitor (IC87114) or genetic p110δ inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6;
P
<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6;
P
<0.001 versus control) and enhanced the effect of tumor necrosis factor-α on activator protein-1–binding activity (n=5;
P
<0.01 versus tumor necrosis factor-α treatment groups). Knockdown of c-Jun suppressed the effect of the IC87114 and tumor necrosis factor-α on MMP-12 mRNA expression (n=5 in each group;
P
<0.01 versus scrRNA treatment groups).

Conclusions—
Our findings demonstrate that p110δ inactivation leads to extracellular matrix degradation in vessels and promotes aneurysm development by inducing macrophages migration and upregulating the activator protein-1/MMP-12 pathway in macrophages.
Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice
Authors: Lübkemeier Indra , Bosen Felicitas , Kim Jung-Sun , Sasse Philipp , Malan Daniela , Fleischmann Bernd K. , Willecke Klaus 
Published: December 2014

Background—
Sudden infant death syndrome (SIDS) describes the sudden, unexplained death of a baby during its first year of age and is the third leading cause of infant mortality. It is assumed that ≤20% of all SIDS cases are because of cardiac arrhythmias resulting from mutations in ion channel proteins. Besides ion channels also cardiac gap junction channels are important for proper conduction of cardiac electric activation. In the mammalian heart Connexin43 (Cx43) is the major gap junction protein expressed in ventricular cardiomyocytes. Recently, a novel Connexin43 loss-of-function mutation (Cx43E42K) was identified in a 2-month-old SIDS victim.

Methods and Results—
We have generated Cx43E42K-expressing mice as a model for SIDS. Heterozygous cardiac-restricted Cx43E42K-mutated mice die neonatally without major cardiac morphological defects. Electrocardiographic recordings of embryonic Cx43+/E42K mice reveal severely disturbed ventricular activation, whereas immunohistochemical analyses show normal localization and expression patterns of gap junctional Connexin43 protein in the Cx43E42K-mutated newborn mouse heart.

Conclusions—
Because we did not find heterogeneous gap junction loss in Cx43E42K mouse hearts, we conclude that the Cx43E42K gap junction channel creates an arrhythmogenic substrate leading to lethal ventricular arrhythmias. The strong cardiac phenotype of Cx43E42K expressing mice supports the association between the human Cx43E42K mutation and SIDS and indicates that Connexin43 mutations should be considered in future studies when SIDS cases are to be molecularly explained.
Honouring Seppo Koponen on the occasion of this 70th Birthday
Authors: MARUSIK YURI , FET VICTOR 
Published: December 2014

Seppo Koponen was born in Turku, Finland, on November 2, 1944. After graduating from high school, Seppo was admitted to the University of Turku in 1963. He specialised in Ecology and Zoosystematics, and studied also Botany, Genetics, and Geography. He did his M.S. work (1969) on peat bog spiders, and his doctorate research (Phil. Lic. Thesis, 1978), on herbivorous insects living on birch trees in Lapland and Greenland. Seppo’s mentor and supervisor in Arachnology was Pekka T. Lehtinen (see Marusik & Koponen 2014). While studying in the University of Turku, in the late 1960s Seppo worked as an assistant in the Department of Zoology. After his military service, Seppo was appointed a Curator in the Zoological Museum of the University of Turku in 1971, and continued to work there for 40 years, until his retirement in 2011.
Blown Away: Interns Experience Science, Research, and Life on Top of Mount Washington
Authors: Kelsey Eric , Briedé Cyrena-Marie , O’Brien Kaitlyn , Padham Thomas , Cann Matthew , Davis Luke , Carne Alexander 
Published: December 2014

Abstract
With extreme winds, rapidly changing weather, and myriad weather conditions during any given month, Mount Washington, New Hampshire (1,917 m MSL), is an ideal location to observe and learn about atmospheric sciences. During the summer of 2013, Mount Washington Observatory (MWO) welcomed a select group of interns to experience life at the “Home of the World’s Worst Weather” and develop scientific and meteorological skills. The goals of the internship program are to learn how to observe and forecast mountain weather; develop data analysis and critical thinking skills through individual research projects; and live, work, and collaborate effectively with others at a remote mountain-top observatory. Interns are typically undergraduate students or recent graduates of atmospheric science programs and are selected from a highly competitive field of applicants.
The summer 2013 interns worked on a variety of research projects, ranging from developing a forecast tool for the gustiness of wind at the summit to understanding the evolution of atmospheric and environmental conditions that lead to avalanches in nearby Tuckerman Ravine. To accomplish their research projects, the interns learned how hourly weather observations are made, used data analysis software, and practiced critical thinking about their methods and results. Weekly meetings with the interns and the MWO director of research allowed for the sharing of research progress, peer feedback, and practice presenting scientific results. The internships ended with presentations of their scientific research to MWO observers, staff, and observatory members. Post-internship survey responses revealed the program was highly effective at meeting its goals and provided constructive suggestions for future internship programs.
Global Precipitation Measurement Cold Season Precipitation Experiment (GCPEX): For Measurement’s Sake, Let It Snow
Authors: Skofronick-Jackson Gail , Hudak David , Petersen Walter , Nesbitt Stephen W. , Chandrasekar V. , Durden Stephen , Gleicher Kirstin J. , Huang Gwo-Jong , Joe Paul , Kollias Pavlos , Reed Kimberly A. , Schwaller Mathew R. , Stewart Ronald , Tanelli Simone , Tokay Ali , Wang James R. , Wolde Mengistu 
Published: December 2014

Abstract
As a component of Earth’s hydrologic cycle, and especially at higher latitudes, falling snow creates snowpack accumulation that in turn provides a large proportion of the freshwater resources required by many communities throughout the world. To assess the relationships between remotely sensed snow measurements with in situ measurements, a winter field project, termed the Global Precipitation Measurement (GPM) Cold Season Precipitation Experiment (GCPEx), was carried out in the winter of 2011/12 in Ontario, Canada. Its goal was to provide information on the precipitation microphysics and processes associated with cold season precipitation to support GPM snowfall retrieval algorithms that make use of a dual-frequency precipitation radar and a passive microwave imager on board the GPM core satellite and radiometers on constellation member satellites. Multiparameter methods are required to be able to relate changes in the microphysical character of the snow to measureable parameters from which precipitation detection and estimation can be based. The data collection strategy was coordinated, stacked, high-altitude, and in situ cloud aircraft missions with three research aircraft sampling within a broader surface network of five ground sites that in turn were taking in situ and volumetric observations. During the field campaign 25 events were identified and classified according to their varied precipitation type, synoptic context, and precipitation amount. Herein, the GCPEx field campaign is described and three illustrative cases detailed.
The Curious Case of the EL Niño That Never Happened: A Perspective from 40 Years of Progress in Climate Research and Forecasting
Authors: McPhaden Michael J. , Timmermann Axel , Widlansky Matthew J. , Balmaseda Magdalena A. , Stockdale Timothy N. 
Published: December 2014

Abstract
Forty years ago, Klaus Wyrtki of the University of Hawaii launched an “El Niño Watch” expedition to the eastern equatorial Pacific to document oceanographic changes that were expected to develop during the onset of an El Niño event in early 1975. He and his colleagues used a very simple atmospheric pressure index to predict the event and convinced the National Science Foundation and Office of Naval Research to support an expedition to the eastern Pacific on relatively short notice. An anomalous warming was detected during the first half of the expedition, but it quickly dissipated. Given the state of the art in El Niño research at the time, Wyrtki and colleagues could offer no explanation for why the initial warming failed to amplify, nor could they connect what they observed to what was happening in other parts of the basin prior to and during the expedition. With the benefit of hindsight, the authors provide a basin-scale context for what the expedition observed, elucidate the dynamical processes that gave rise to the abbreviated warming that was detected, and present retrospective forecasts of the event using modern coupled ocean–atmosphere dynamical model prediction systems. Reviewing this history highlights how early pioneers in El Niño research, despite the obstacles they faced, were able to make significant progress through bold initiatives that advanced the frontiers of our knowledge. It is also evident that, even though the scientific community today has a much deeper understanding of climate variability, more advanced observational capabilities, and sophisticated seasonal forecasting tools, skillful predictions of El Niño and its cold counterpart La Niña remain a major challenge.
Biomechanical testing of an innovative fixation procedure to stabilize olecranon osteotomy
Authors: Reising Kilian , Konstantinidis Lukas , Helwig Peter , Wagner Ferdinand C , Südkamp Norbert P , Strohm Peter C 
Published: December 2014

For the treatment of distal humerus an approach involving olecranon osteotomy is frequently preferred as it offers a clearer view, especially in cases of complex intraarticular fractures. It is however associated with the high risk of osteotomy-related complications such as nonunion, delayed healing, implant failure and migration of wires. The aim of the present study was to evaluate the stability of different new procedures that stabilize olecranon osteotomy compared with conventional tension band wiring. We hypothesize that the new implants provide equivalent stability as the conventional tension band wiring. To test the hypothesis 27 biomechanically evaluated synthetic ulnae were osteotomized and stabilized with either the application of tension band wiring, the Olecranon Hook LCP (Synthes, Switzerland), or the Olecranon Osteotomy nail (Synthes, Switzerland). Loading was performed providing a tensile load to simulate the tensile force applied by the triceps muscle. Cyclic force-controlled loading was performed at 300 alternating forces between 10N and 500N at a speed of 200N/sec. An ultrasound-based system measured displacement to an accuracy of 0.1 mm. Statistical analysis showed significantly less displacement in the Olecranon Hook LCP and Olecranon Osteotomy nail groups compared with tension banding. Comparison of plate and nail yielded no differences in stability. Biomechanical testing did however show significantly higher stability for newer fixation methods for olecranon osteotomies compared with the frequently applied technique of tension band wiring. Whether the use of these implants will also lower complication rates remains to be evaluated in future clinical studies. Level of evidence: Basic Science Study, Biomechanical Study.
Proteinuria with first-line therapy of metastatic renal cell cancer
Authors: Land Josiah D , Chen Adrienne H , Atkinson Bradley J , Cauley Diana H , Tannir Nizar M 
Published: December 2014

Background Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. Objective Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. Methods We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011–April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. Results In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% ( n = 35) for pazopanib, 64% ( n = 25) for bevacizumab, and 96% ( n = 44) for everolimus. At peak proteinuria, 80% ( n = 28), 64% ( n = 16), and 80% ( n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% ( n = 6) and found in the bevacizumab group. Conclusion A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria.
Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses
Authors: Kim Yong Chan , Zhang Ai-Hong , Su Yan , Rieder Sadiye Amcaoglu , Rossi Robert J. , Ettinger Ruth A. , Pratt Kathleen P. , Shevach Ethan M. , Scott David W. 
Published: December 2014

Key Points
Generation and function of specific human Tregs. Specific regulation of FVIII responses by engineered human Tregs.
The second transferrin receptor regulates red blood cell production in mice
Authors: Nai Antonella , Lidonnici Maria Rosa , Rausa Marco , Mandelli Giacomo , Pagani Alessia , Silvestri Laura , Ferrari Giuliana , Camaschella Clara 
Published: December 2014

Key Points
TFR2, a gene mutated in hemochromatosis and a partner of the EPO receptor, limits erythropoiesis expansion in mice. Iron deficiency mimics TFR2 deletion in the erythroid compartment.
Multi-step extragradient method with regularization for triple hierarchical variational inequalities with variational inclusion and split feasibility constraints
Authors: Ceng Lu-Chuan , Pang Chin-Tzong , Wen Ching-Feng 
Published: December 2014

AbstractBy combining Korpelevich’s extragradient method, the viscosity approximation method, the hybrid steepest-descent method, Mann’s iteration method, and the gradient-projection method with regularization, a hybrid multi-step extragradient algorithm with regularization for finding a solution of triple hierarchical variational inequality problem is introduced and analyzed. It is proven that under appropriate assumptions, the proposed algorithm converges strongly to a unique solution of a triple hierarchical variational inequality problem which is defined over the set of solutions of a hierarchical variational inequality problem defined over the set of common solutions of finitely many generalized mixed equilibrium problems (GMEP), finitely many variational inclusions, fixed point problems, and the split feasibility problem (SFP). We also prove the strong convergence of the proposed algorithm to a common solution of the SFP, finitely many GMEPs, finitely many variational inclusions, and the fixed point problem of a strict pseudocontraction. The results presented in this paper improve and extend the corresponding results announced by several others.MSC:49J30, 47H09, 47J20, 49M05.
Association between Pseudomonas aeruginosa type III secretion, antibiotic resistance, and clinical outcome: a review
Authors: Sawa Teiji , Shimizu Masaru , Moriyama Kiyoshi , Wiener-Kronish Jeanine P 
Published: December 2014

AbstractPseudomonas aeruginosa uses a complex type III secretion system to inject the toxins ExoS, ExoT, ExoU, and ExoY into the cytosol of target eukaryotic cells. This system is regulated by the exoenzyme S regulon and includes the transcriptional activator ExsA. Of the four toxins, ExoU is characterized as the major virulence factor responsible for alveolar epithelial injury in patients with P. aeruginosa pneumonia. Virulent strains of P. aeruginosa possess the exoU gene, whereas non-virulent strains lack this particular gene. The mechanism of virulence for the exoU
+
genotype relies on the presence of a pathogenic gene cluster (PAPI-2) encoding exoU and its chaperone, spcU. The ExoU toxin has a patatin-like phospholipase domain in its N-terminal, exhibits phospholipase A2 activity, and requires a eukaryotic cell factor for activation. The C-terminal of ExoU has a ubiquitinylation mechanism of activation. This probably induces a structural change in enzymatic active sites required for phospholipase A2 activity. In P. aeruginosa clinical isolates, the exoU
+
genotype correlates with a fluoroquinolone resistance phenotype. Additionally, poor clinical outcomes have been observed in patients with pneumonia caused by exoU
+
-fluoroquinolone-resistant isolates. Therefore, the potential exists to improve clinical outcomes in patients with P. aeruginosa pneumonia by identifying virulent and antimicrobial drug-resistant strains through exoU genotyping or ExoU protein phenotyping or both.