bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity
Authors: Olwill Shane A. , Joffroy Christian , Gille Hendrik , Vigna Elisa , Matschiner Gabriele , Allersdorfer Andrea , Lunde Bradley M. , Jaworski Jakub , Burrows James F. , Chiriaco Cristina , Christian Hans Jürgen , Hülsmeyer Martin , Trentmann Stefan , Jensen Kristian , Hohlbaum Andreas M. , Audoly Laurent 
Published: September 2013

Abstract
Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be “fit for purpose” for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients. Mol Cancer Ther; 12(11); 2459–71. ©2013 AACR.
Cultivated Sea Lettuce is a Multiorgan Protector from Oxidative and Inflammatory Stress by Enhancing the Endogenous Antioxidant Defense System
Authors: Ratnayake Ranjala , Liu Yanxia , Paul Valerie J. , Luesch Hendrik 
Published: September 2013

Abstract
The health-promoting effects of seaweeds have been linked to antioxidant activity that may counteract cancer-causing oxidative stress-induced damage and inflammation. Although antioxidant activity is commonly associated with direct radical scavenging activity, an alternative way to increase the antioxidant status of a cell is to enhance the endogenous (phase II) defense system consisting of cytoprotective antioxidant enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). These enzymes are transcriptionally regulated by the antioxidant response element (ARE) via the transcription factor Nrf2. Extracts derived from cultivated Ulva sp., a green alga regarded as a marine vegetable (sea lettuce), potently activated the Nrf2-ARE pathway in IMR-32 neuroblastoma and LNCaP prostate cancer cells. RNA interference studies showed that Nrf2 and phosphoinositide 3-kinase (PI3K) are essential for the phase II response in IMR-32 cells. Activity-enriched fractions induced Nrf2 nuclear translocation and target gene transcription, and boosted the cellular glutathione level and therefore antioxidant status. A single-dose gavage feeding of Ulva-derived fractions increased Nqo1 transcript levels in various organs. Nqo1 induction spiked in different tissues, depending on the specific chemical composition of each administered fraction. We purified and characterized four ARE inducers in this extract, including loliolide (1), isololiolide (2), a megastigmen (3), and a novel chlorinated unsaturated aldehyde (4). The ARE-active fractions attenuated lipopolysaccharide-induced iNOS and Cox2 gene expression in macrophagic RAW264.7 cells, decreasing nitric oxide (NO) and prostaglandin E2 (PGE2) production, respectively. Nqo1 activity and NO production were abrogated in nrf2−/− mouse embryonic fibroblasts, providing a direct link between the induction of phase II response and anti-inflammatory activity. Cancer Prev Res; 6(9); 989–99. ©2013 AACR.
Cardiac Resynchronization Therapy Device Implantation Using a New Sensor-Based Navigation System
Authors: Richter Sergio , Döring Michael , Gaspar Thomas , John Silke , Rolf Sascha , Sommer Philipp , Hindricks Gerhard , Piorkowski Christopher 
Published: September 2013

Background—
Cardiac resynchronization therapy (CRT) device implantation can be challenging, time consuming, and fluoroscopy intense. To facilitate left ventricular lead placement, a novel sensor-based electromagnetic tracking system (MediGuide Technology [MGT], St. Jude Medical) has been developed. We report the results of the First Human Use study evaluating the feasibility, safety, and performance of a novel CRT implantation approach using electromagnetic trackable operation equipment.

Methods and Results—
Fifteen consecutive patients (66±8 years, 53% male) with an established indication for CRT were implanted using the new tracking technology. Demographics, anatomical information, detailed fluoroscopy need, procedure time, and adverse events were collected. Patients were followed up for 4 weeks after implantation. The CRT system was successfully implanted with a lateral or posterolateral left ventricular lead position in all patients. The total procedure time was 116±43 minutes, the median total fluoroscopy time (skin to skin) was 5.2 (Q1–Q3, 3.0–8.4) minutes, and the median fluoroscopy time for left ventricular lead deployment (coronary sinus [CS] cannulation to withdrawal of CS sheath) measured 2.6 (Q1–Q3, 1.6–5.6) minutes. There were no severe complications that required an acute intervention or reoperation during the perioperative and postoperative periods.

Conclusions—
Use of the MGT tracking technology allows for safe and successful CRT implantation with the potential for reduced fluoroscopy time. Future randomized studies are needed to validate these data.

Clinical Trial Registration—

URL
http://www.clinicaltrials.gov
. Unique identifier: NCT01519739.
Prediction of Poststroke Hemorrhagic Transformation Using Computed Tomography Perfusion
Authors: Yassi Nawaf , Parsons Mark W. , Christensen Søren , Sharma Gagan , Bivard Andrew , Donnan Geoffrey A. , Levi Christopher R. , Desmond Patricia M. , Davis Stephen M. , Campbell Bruce C.V. 
Published: September 2013

Background and Purpose—
Intracerebral hemorrhage is a serious potential complication of stroke thrombolysis. We investigated the optimal computed tomography perfusion (CTP) parameter to predict cerebral parenchymal hematoma (PH) in acute ischemic stroke.

Methods—

Patients with hyperacute ischemic stroke had whole-brain CTP and follow-up computed tomography/MRI to identify hemorrhagic transformation. The association of the 3 parameters relative cerebral blood flow, relative cerebral blood volume, and time to maximum (
T
max
) with PH was examined using receiver operating characteristic analysis and multivariate logistic regression.

Results—

Of 132 patients, 70 were treated with thrombolysis, and 14 (10.6%) developed PH on follow-up imaging. Baseline National Institutes of Health Stroke Scale score (
P
=0.033) and thrombolysis (
P
=0.003) were both predictive of PH. Receiver operating characteristic analysis revealed that
T
max
>14 s (area under the curve=0.748;
P
=0.002) and relative cerebral blood flow <30% of contralateral mean (area under the curve=0.689,
P
=0.021) were the optimal thresholds, and the Bayesian information criterion (+2.6) indicated that
T
max
was more strongly associated with PH than relative cerebral blood flow.
T
max
>14 s volumes of >5 mL allowed prediction of PH with sensitivity of 79%, specificity of 68%, and negative likelihood ratio of 3.16.
T
max
>14 s volume and thrombolysis were both independently predictive of PH in a multivariate logistic regression model (
P
<0.05).

Conclusions—

T
max
>14 s was the CTP parameter most strongly associated with PH. This outperformed relative cerebral blood flow <30%, which closely equates to CTP estimates of ischemic core volume. Although ischemic core volume on CTP is useful in the pretreatment prediction of PH, severe hypoperfusion on
T
max
is more strongly associated and may allow better prediction of the likely anatomic location of hemorrhage.
Impact of Both Ends of the Hemoglobin Range on Clinical Outcomes in Acute Ischemic Stroke
Authors: Park Young Ho , Kim Beom Joon , Kim Jun-Soon , Yang Mi Hwa , Jang Myung Suk , Kim Nayoung , Han Moon-Ku , Lee Ji Sung , Lee Juneyoung , Kim SangYun , Bae Hee-Joon 
Published: September 2013

Background and Purpose—
Although both ends of the hemoglobin range may negatively influence clinical outcomes in acute ischemic stroke, most studies have examined the linear relationship or focused on the lower end of the range. Furthermore, it is unclear whether hemoglobin concentrations at different time points during hospitalization correlate with clinical outcomes in the same manner.

Methods—
We identified 2681 consecutive patients with acute ischemic stroke from a prospective stroke registry database and grouped them into hemoglobin concentration quintiles using the following 5 indices: initial, nadir, time-averaged, discharge hemoglobin, and hemoglobin drop. To examine the effect of both ends of hemoglobin range, the third quintile was selected as a reference category except for hemoglobin drop, for which the first quintile was used. As outcome variables, 3-month modified Rankin Scale as an ordinal scale and 3-month mortality were used.

Results—
With respect to higher modified Rankin Scale scores, the adjusted odds ratios and 95% confidence intervals of the first quintiles of initial, nadir, time-averaged, and discharge hemoglobin were 1.74 (1.31−2.31), 2.64 (2.09−3.33), 1.81 (1.42−2.30), and 1.65 (1.29−2.13), respectively. The opposite ends of these hemoglobin indices were not significantly associated. The adjusted odds ratio of the fifth quintile of hemoglobin drop (greatest hemoglobin drop) was 2.09 (1.51−2.89). The mortality analysis showed similar results except for initial hemoglobin.

Conclusions—
In acute ischemic stroke, poor outcome was related to the lower but not the higher end of the hemoglobin range, regardless of when and how hemoglobin concentrations were measured.
Severe Renal Impairment Is Associated With Symptomatic Intracerebral Hemorrhage After Thrombolysis for Ischemic Stroke
Authors: Tütüncü Serdar , Ziegler Annerose M. , Scheitz Jan F. , Slowinski Torsten , Rocco Andrea , Endres Matthias , Nolte Christian H. 
Published: September 2013

Background and Purpose—
Patients with renal impairment (RI) have an increased risk of both thrombotic and hemorrhagic events. We aimed to clarify whether RI increases the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis with recombinant tissue plasminogen activator.

Methods—

Patients who received intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset were retrospectively analyzed. Creatinine levels on admission served to calculate glomerular filtration rate (GFR) to estimate RI according to
International Classification of Diseases
criteria. Effect of RI on symptomatic ICH (sICH) was assessed using dichotomized (GFR <90 and <30 mL/min) and continuous GFR (centered data to test for linear and centered and squared data to test for curvilinear association).

Results—

Of the 740 patients included, 83% had any RI (GFR <90 mL/min) and 5% had severe RI (GFR <30 mL/mL); 4.6% experienced sICH. Univariate comparisons revealed higher prevalence of sICH in patients with severe RI (
P
<0.01) but not with any RI. GFR as a continuous variable (centered and squared) was also associated with sICH (
P
=0.02), but GFR on its own was not. Severe RI and GFR (centered and squared) remained independently associated with sICH in multiple regression analyses.

Conclusions—
Severe RI (GFR <30 mL/min) is associated with sICH after intravenous thrombolysis with recombinant tissue plasminogen activator. The association is curvilinear. Severe RI must be taken into account when balancing the risk–benefit ratio of intravenous thrombolysis with recombinant tissue plasminogen activator.
Influence of Soil Moisture on Urban Microclimate and Surface-Layer Meteorology in Oklahoma City
Authors: Husain Syed Zahid , Bélair Stéphane , Leroyer Sylvie 
Published: September 2013

AbstractThe influence of soil moisture on the surface-layer atmosphere is examined in this paper by analyzing the outputs of model simulations for different initial soil moisture configurations, with particular emphasis on urban microclimate. In addition to a control case, four different soil moisture distributions within the urban and surrounding rural areas are considered in this study. Outputs from the Global Environmental Multiscale atmospheric model simulations are compared with observations from the Joint Urban 2003 experiment held in Oklahoma City, Oklahoma, and the relevant conclusions drawn in this paper are therefore valid for similar medium-size cities. In general, high soil moisture is found to be associated with colder near-surface temperature and lower near-surface wind speed, whereas drier soil resulted in warmer temperatures and enhanced low-level wind. Relative to urban soil moisture content, rural soil conditions are predicted to have larger impacts on both rural and urban surface-layer meteorological conditions. Dry rural and wet urban soil configurations are shown to have a strong influence on the urban–rural temperature contrast and resulted in city-induced secondary circulations that considerably affect the near-surface wind speed. Dry rural soil in particular is found to intensify the nocturnal low-level jet and significantly affect the thermal stability of nocturnal near-neutral urban surface layer by altering both thermal and mechanical generation of turbulence.
North Atlantic SSTs as a Link between the Wintertime NAO and the Following Spring Climate
Authors: Herceg-Bulić Ivana , Kucharski Fred 
Published: September 2013

Abstract
In this paper a potential seasonally lagged impact of the wintertime North Atlantic Oscillation (NAO) on the subsequent spring climate over the European region is explored. Supported by the observational indication of the wintertime NAO–spring climate connection, a modeling approach is used that employs the International Centre for Theoretical Physics (ICTP) atmospheric general circulation model (AGCM) as a stand-alone model and that is also coupled with a mixed layer ocean in the North Atlantic. Both observational and modeled data indicate a pattern of sea surface temperatures (SSTs) in North Atlantic as a possible link between wintertime NAO and climate anomalies in the following spring. The SST pattern is associated with wintertime NAO and persists through the following spring. It is argued that these SST anomalies can affect the springtime atmospheric circulation and surface conditions over Europe. The atmospheric response is recognized in observed as well as in modeled data (mean sea level pressure, temperature, and precipitation). Additionally, an impact on springtime storm activity is found as well.
It is demonstrated that the SST anomalies associated with wintertime NAO persist into the subsequent spring. These SST anomalies enable atmosphere–ocean interaction over the North Atlantic and consequently affect the climate variability over Europe. Although it has a relatively weak impact, the described mechanism provides a temporal teleconnection between the wintertime NAO and subsequent spring climate anomalies.
Impact of Agulhas Leakage on the Atlantic Overturning Circulation in the CCSM4
Authors: Weijer Wilbert , van Sebille Erik 
Published: September 2013

Abstract
The impact of Agulhas leakage variability on the strength of the Atlantic meridional overturning circulation (AMOC) in the Community Climate System Model, version 4 (CCSM4) is investigated. In this model an advective connection exists that transports salinity anomalies from the Agulhas region into the North Atlantic on decadal (30–40 yr) time scales. However, there is no identifiable impact of Agulhas leakage on the strength of the AMOC, suggesting that the salinity variations are too weak to significantly modify the stratification in the North Atlantic. It is argued that this study is inconclusive with respect to an impact of Agulhas leakage on the AMOC. Salinity biases leave the South Atlantic and Indian Oceans too homogeneous, in particular erasing the observed salinity front in the Agulhas retroflection region. Consequently, salinity variability in the southeastern South Atlantic is found to be much weaker than observed.
Lethal pulmonary thromboembolism: An autopsy-based study on a rare but legally relevant event
Authors: Mobilia Francesca , Casali Michelangelo B , Gallieni Maurizio , Genovese Umberto R 
Published: September 2013

Context: Pulmonary thromboembolism (PTE) is the severe end stage of many different diseases producing prolonged patient immobilization or a hypercoagulative state. Lethal PTE is also one of the most frequent topics for suspected medical malpractice, especially when dealing with patients originally affected by non-critical illnesses and suddenly killed by a non-prevented embolic event. The crucial forensic question about a lethal PTE is the following one: was this lethal PTE an unpreventable complication or was it a consequence of real medical malpractice? Materials and methods: The authors analyzed the 1999–2009 autopsy archive of the Institute of Forensic Medicine of Milan University and selected all the cases where PTE was the cause of death. For every selected case, the authors also collected all the available demographic and clinical data. Statistical analysis was performed using SPSS V.16.00. Results: In the period 1999–2009, 129 (1.25%) cases out of a total of 10,288 autopsies were diagnosed as having suffered lethal PTE. The male to female ratio was 1:2 (34.1% versus 65.9%). The mean age at death was 67 ± 18 years. In 41% of cases the death occurred outside of the hospital and in the absence of any medical support; in 36.5% of cases it occurred during the territorial paramedical support or during the very first evaluation in the emergency; and in the remaining 22.5% of cases it occurred during a period of hospitalization. In 33.4% of the selected cases, a typical preliminary event was positively identified: a pure major trauma (18.6%); a trauma followed by a major surgery (7%); a major non post-traumatic surgery (7%); and a non-surgical delivery. Symptoms suggesting PTE were detected in 46 cases (35.7%). Nine cases underwent a judicial autopsy in the same original hypothesis of a medical malpractice for incorrect prophylaxis in acutely bed-restricted patients. Conclusions: Post-surgical PTE cannot be automatically labeled a consequence of medical malpractice. The combination of correct prophylaxis, careful diagnostic monitoring of the high-risk patient and the correct therapy surely reduces the occurrence of lethal PTE, but it does not completely erase such an insidious pathology. In the hypothesis of a causative medical malpractice, only careful analysis by an experienced forensic pathologist can make a reliable distinction between an unpreventable complication and real medical malpractice.
Micro Small-sized Enterprises and Bank Credit
Authors: Boateng Agyenim , Abdulrahman Muhammad D. 
Published: September 2013

Micro small-sized enterprises play a vital role in poverty reduction and development of many developing countries. Yet the issue of credit availability to small firms continues to be a major problem which impedes the growth of micro-small enterprises. This article examines the factors influencing the extension of bank credit to micro small-sized enterprises based on a sample of 572 in Ghana and Nigeria. The results indicate that size of the firm, age of the firm, ownership type and relationship banking have a positive bearing on a decision to extend credit to small firms in West Africa. JEL Classification: G21, N27
Microbes, metagenomes and marine mammals: enabling the next generation of scientist to enter the genomic era
Authors: Edwards Robert Alan , Haggerty John Matthew , Cassman Noriko , Busch Julia Christine , Aguinaldo Kristen , Chinta Sowmya , Vaughn Meredith Houle , Morey Robert , Harkins Timothy T , Teiling Clotilde , Fredrikson Karin , Dinsdale Elizabeth Ann 
Published: September 2013

Abstract

Background
The revolution in DNA sequencing technology continues unabated, and is affecting all aspects of the biological and medical sciences. The training and recruitment of the next generation of researchers who are able to use and exploit the new technology is severely lacking and potentially negatively influencing research and development efforts to advance genome biology. Here we present a cross-disciplinary course that provides undergraduate students with practical experience in running a next generation sequencing instrument through to the analysis and annotation of the generated DNA sequences.

Results
Many labs across world are installing next generation sequencing technology and we show that the undergraduate students produce quality sequence data and were excited to participate in cutting edge research. The students conducted the work flow from DNA extraction, library preparation, running the sequencing instrument, to the extraction and analysis of the data. They sequenced microbes, metagenomes, and a marine mammal, the Californian sea lion, Zalophus californianus. The students met sequencing quality controls, had no detectable contamination in the targeted DNA sequences, provided publication quality data, and became part of an international collaboration to investigate carcinomas in carnivores.

Conclusions
Students learned important skills for their future education and career opportunities, and a perceived increase in students’ ability to conduct independent scientific research was measured. DNA sequencing is rapidly expanding in the life sciences. Teaching undergraduates to use the latest technology to sequence genomic DNA ensures they are ready to meet the challenges of the genomic era and allows them to participate in annotating the tree of life.
Identification of conserved motifs in the Westnile virus envelope essential for particle secretion
Authors: Garg Himanshu , Lee Raphael TC , Tek Ng Oon , Maurer-Stroh Sebastian , Joshi Anjali 
Published: September 2013

Abstract

Background
Enveloped viruses utilize cellular membranes to bud from infected cells. The process of virion assembly and budding is often facilitated by the presence of certain conserved motifs within viral proteins in conjunction with cellular factors. We hence examined the West Nile Virus (WNV) Envelope protein for the presence of any such motifs and their functional characterization.

Results
We identified conserved 461PXAP464 and 349YCYL352 motifs in the WNV envelope glycoprotein bearing resemblance to retroviral late domains. Disruptive mutations of PXAP to LAAL and of the highly conserved Cys350 in the YCYL motif, led to a severe reduction in WNV particle production. Similar motifs in case of retroviruses are known to interact with components of host sorting machinery like PXAP with Tsg101 and YXXL with Alix. However, in the case of WNV, siRNA mediated depletion of Alix or Tsg101 did not have an effect on WNV release. Molecular modeling suggested that while the 461PXAP464 motif is surface accessible and could potentially interact with cellular proteins required for WNV assembly, the 349YCYL352 motif was found to be internal with Cys350 important for protein folding via disulphide bonding.

Conclusions
The conserved 461PXAP464 and 349YCYL352 motifs in the WNV envelope are indispensable for WNV particle production. Although these motifs bear sequence similarity to retroviral late domains and are essential for WNV assembly, they are functionally distinct suggesting that they are not the typical late domain like motifs of retroviruses and may play a role other than Alix/Tsg101 utilization/dependence.