bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of a Canine Anti-EGFR (ErbB-1) Antibody for Passive Immunotherapy in Dog Cancer Patients
Authors: Singer Josef , Fazekas Judit , Wang Wei , Weichselbaumer Marlene , Matz Miroslawa , Mader Alexander , Steinfellner Willibald , Meitz Sarah , Mechtcheriakova Diana , Sobanov Yuri , Willmann Michael , Stockner Thomas , Spillner Edzard , Kunert Renate , Jensen-Jarolim Erika 
Published: April 2014

Abstract
Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuximab in human clinical oncology, we present here a “caninized” version of this antibody, can225IgG, for comparative oncology studies. Variable region genes of 225, the murine precursor of cetuximab, were fused with canine constant heavy gamma and kappa chain genes, respectively, and transfected into Chinese hamster ovary (CHO) DUKX-B11 cells. Of note, 480 clones were screened and the best clones were selected according to productivity and highest specificity in EGFR-coated ELISA. Upon purification with Protein G, the recombinant cetuximab-like canine IgG was tested for integrity, correct assembly, and functionality. Specific binding to the surface of EGFR-overexpressing cells was assessed by flow cytometry and immunofluorescence; moreover, binding to canine mammary tissue was demonstrated by immunohistochemistry. In cell viability and proliferation assays, incubation with can225IgG led to significant tumor cell growth inhibition. Moreover, this antibody mediated significant tumor cell killing via phagocytosis in vitro. We thus present here, for the first time, the generation of a canine IgG antibody and its hypothetical structure. On the basis of its cetuximab-like binding site, on the one hand, and the expression of a 91% homologous EGFR molecule in canine cancer, on the other hand, this antibody may be a promising research compound to establish passive immunotherapy in dog patients with cancer. Mol Cancer Ther; 13(7); 1777–90. ©2014 AACR.
Metronomic Docetaxel in PRINT Nanoparticles and EZH2 Silencing Have Synergistic Antitumor Effect in Ovarian Cancer
Authors: Gharpure Kshipra M. , Chu Kevin S. , Bowerman Charles J. , Miyake Takahito , Pradeep Sunila , Mangala Selanere L. , Han Hee-Dong , Rupaimoole Rajesha , Armaiz-Pena Guillermo N. , Rahhal Tojan B. , Wu Sherry Y. , Luft J. Christopher , Napier Mary E. , Lopez-Berestein Gabriel , DeSimone Joseph M. , Sood Anil K. 
Published: April 2014

Abstract
The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (P &lt; 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer. Mol Cancer Ther; 13(7); 1750–7. ©2014 AACR.
Short- and Long-term Lung Cancer Risk Associated with Noncalcified Nodules Observed on Low-Dose CT
Authors: Pinsky Paul F. , Nath P. Hrudaya , Gierada David S. , Sonavane Sushil , Szabo Eva 
Published: April 2014

Abstract
Chemoprevention is an important potential tool in reducing lung cancer incidence. Noncalcified nodules (NCN) observed on low-dose computed tomography (LDCT) have been proposed as intermediate endpoints in chemoprevention trials, but whether NCNs represent cancer precursors is unclear. We analyzed data from subjects in the LDCT arm of the National Lung Screening Trial (NLST) to examine short- and long-term lung cancer risks associated with NCNs and to elucidate whether some NCNs may be cancer precursors. NLST subjects received a baseline and two additional LDCT screens and were followed for a median of 6.5 years. We examined lung cancer incidence over three distinct periods from baseline—0–23 months (short-term), 24–59 months (medium-term), and 60–84 months (long-term)—in relation to baseline NCN characteristics. Spatially, lung cancer incidence was analyzed at the person, lung, and lobe levels relative to NCN location. A total of 26,272 subjects received the baseline LDCT screen, with 468, 413, and 190 lung cancers observed in the three periods. The presence of an NCN gave significantly elevated long-term lung cancer risk ratios (RR) of 1.8, 2.4, and 3.5 at the person, lung, and lobe levels; corresponding short-term RRs were 10.3, 16.8, and 38.0. Ground-glass attenuation was positively associated with long-term lung cancer risk but inversely associated with short-term risk; NCN size was positively associated with short-term risk but not significantly associated with long-term risk. That NCNs convey significantly elevated excess long-term of lung cancer lends evidence to the hypothesis that some NCNs may be cancer precursors. Cancer Prev Res; 7(12); 1179–85. ©2014 AACR.
Validity of Deterministic Record Linkage Using Multiple Indirect Personal Identifiers
Authors: Setoguchi Soko , Zhu Ying , Jalbert Jessica J. , Williams Lauren A. , Chen Chih-Ying 
Published: April 2014

Background—
Linking patient registries with administrative databases can enhance the utility of the databases for epidemiological and comparative effectiveness research. However, registries often lack direct personal identifiers, and the validity of record linkage using multiple indirect personal identifiers is not well understood.

Methods and Results—
Using a large contemporary national cardiovascular device registry and 100% Medicare inpatient data, we linked hospitalization-level records. The main outcomes were the validity measures of several deterministic linkage rules using multiple indirect personal identifiers compared with rules using both direct and indirect personal identifiers. Linkage rules using 2 or 3 indirect, patient-level identifiers (ie, date of birth, sex, admission date) and hospital ID produced linkages with sensitivity of 95% and specificity of 98% compared with a gold standard linkage rule using a combination of both direct and indirect identifiers.

Conclusions—
Ours is the first large-scale study to validate the performance of deterministic linkage rules without direct personal identifiers. When linking hospitalization-level records in the absence of direct personal identifiers, provider information is necessary for successful linkage.
The Learning Curve for Transradial Percutaneous Coronary Intervention Among Operators in the United States
Authors: Hess Connie N. , Peterson Eric D. , Neely Megan L. , Dai David , Hillegass William B. , Krucoff Mitchell W. , Kutcher Michael A. , Messenger John C. , Pancholy Samir , Piana Robert N. , Rao Sunil V. 
Published: April 2014

Background—
Adoption of transradial percutaneous coronary intervention (TRI) in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator TRI volume and procedural metrics and outcomes.

Methods and Results—
We used CathPCI Registry data from July 2009 to December 2012 to identify new radial operators, defined by an exclusively femoral percutaneous coronary intervention approach for 6 months after their first percutaneous coronary intervention in the database and ≥15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed by using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54 561 TRI procedures performed at 704 sites, 942 operators performed 1 to 10 procedures, 942 operators performed 11 to 50 procedures, 375 operators performed 51 to 100 procedures, and 148 operators performed 101 to 200 procedures. As radial caseload increased, more TRIs were performed in women, in patients presenting with ST-segment elevation myocardial infarction, and for emergency indications. Decreased fluoroscopy time and contrast use were nonlinearly associated with greater operator TRI experience, with faster reductions observed for newer (<30–50 cases) compared with more experienced (>30–50 cases) operators. Procedure success was high, whereas mortality, bleeding, and vascular complications remained low across TRI volumes.

Conclusions—
As operator TRI volume increases, higher-risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30 to 50 cases.
CD3 Antibody and IL‐2 Complex Combination Therapy Inhibits Atherosclerosis by Augmenting a Regulatory Immune Response
Authors: Kasahara Kazuyuki , Sasaki Naoto , Yamashita Tomoya , Kita Tomoyuki , Yodoi Keiko , Sasaki Yoshihiro , Takeda Masafumi , Hirata Ken‐ichi 
Published: April 2014

Background

Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti‐
CD
3 antibody (
CD
3‐Ab) and
IL
‐2/anti‐
IL
‐2 monoclonal antibody complex (
IL
‐2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice.

Methods and Results

We treated apolipoprotein E‐deficient mice fed a high‐cholesterol diet with vehicle,
CD
3‐Ab,
IL
‐2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with
CD
3‐Ab or
IL
‐2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C
high
inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions.

Conclusions
Our results indicate that in addition to suppressing Teff responses, enhancing Treg‐mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.
Delayed Hyperbaric Oxygen Therapy Promotes Neurogenesis Through Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/β-Catenin Pathway in Middle Cerebral Artery Occlusion Rats
Authors: Hu Qin , Liang Xiping , Chen Di , Chen Yujie , Doycheva Desislava , Tang Junjia , Tang Jiping , Zhang John H. 
Published: April 2014

Background and Purpose—
Hyperbaric oxygen (HBO) has been reported to be neuroprotective and to improve neurofunctional outcomes in acute stroke. However, it is not clear whether delayed HBO enhances endogenous neurogenesis and promotes neurofunctional recovery. The aim of this study is to evaluate the effects of delayed HBO therapy on neurogenesis and its potential mechanisms.

Methods—
One hundred eleven male Sprague–Dawley rats that survived for 7 days from 2 hours of middle cerebral artery occlusion and reperfusion were used. Delayed and multiple HBO were administrated beginning at 7 days after middle cerebral artery occlusion and lasting for 42 days with 3 HBO-free intervals (5 days each). Motor sensory deficits were measured by foot-fault test, and learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double immunostaining of bromodeoxyuridine and doublecortin, bromodeoxyuridine and neuronal nuclei at day 42. For mechanism studies, inhibitors for reactive oxygen species (ROS), hypoxia-inducible factor (HIF)-1α, and β-catenin were administrated, and the levels of ROS, HIF-1α, β-catenin, lymphoid enhancer–binding factor-1, T-cell factor-1, neurogenin-1, doublecortin, and synapsin-1 were assessed by ELISA or Western blot at day 14.

Results—
Delayed HBO treatment promoted neurogenesis and improved neurofunctional recovery at day 42, and the improvements were reversed by inhibition of ROS and HIF-1α. Delayed HBO significantly increased ROS and HIF-1α, and upregulated the expression of neurogenin-1, doublecortin, and synapsin-1. Inhibition of ROS and HIF-1α removed the effects of delayed HBO.

Conclusions—
Delayed HBO enhanced endogenous neurogenesis and improved neurofunctional recovery in the late-chronic phase of stroke possibly mediated by ROS/HIF-1α/β-catenin pathway. Delayed HBO may serve as an alternative treatment to improve long-term recovery of stroke survivors.
Numerical Simulations of Spatial Distributions and Diurnal Variations of Low-Level Jets in China during Early Summer
Authors: Du Yu , Zhang Qinghong , Chen Yi-leng , Zhao Yangyang , Wang Xu 
Published: April 2014

Abstract
The detailed spatial distributions and diurnal variations of low-level jets (LLJs) during early summer (May–July) in China are documented using 2006–11 hourly model data from the Weather Research and Forecasting (WRF) Model with a 9-km horizontal resolution. It was found that LLJs frequently occur in the following regions of China: the Tarim basin, northeastern China, the Tibetan Plateau (TP), and southern China. The LLJs over China are classified into two types: boundary layer jets (BLJs, below 1 km) and synoptic-system-related LLJs (SLLJs, within 1–4 km). The LLJs in the Tarim basin and the TP are mainly BLJs. The SLLJs over southern China and northeastern China are associated with the mei-yu front and northeast cold vortex (NECV), respectively.
The BLJs in all regions show pronounced diurnal variations with maximum occurrences at nighttime or in the early morning, whereas diurnal variations of SLLJs vary, depending on the location. From the analysis of model data, the diurnal variation of BLJs is mainly caused by inertial oscillation at nighttime and vertical mixing in the boundary layer during daytime. Over northeastern China, SLLJ occurrences show little diurnal variation. Over southern China, two diurnal modes of SLLJs, propagation and stationary, exist and have seasonal variations, which is generally consistent with diurnal variations of precipitation.
Interdecadal Change in South China Sea Tropical Cyclone Frequency in Association with Zonal Sea Surface Temperature Gradient
Authors: Li Richard C. Y. , Zhou Wen 
Published: April 2014

Abstract
This study investigates the interdecadal changes in summertime tropical cyclone (TC) frequency over the South China Sea (SCS) during 1979–2010. Based on changepoint detection algorithms and spectral analysis, two inactive TC periods (period 1: 1979–93 and period 3: 2003–10) and one active TC period (period 2: 1994–2002) have been identified, with a dominant spectral peak of approximately 9–10 yr. Correlation analysis further reveals a significant negative relationship between TC frequency and the zonal sea surface temperature gradient (ZSG) between the northern Indian Ocean (NIO) and the western North Pacific (WNP) at both interannual and interdecadal time scales. That is, a positive ZSG between the NIO and the WNP tends to suppress cyclogenesis over the SCS, whereas a negative ZSG is generally favorable for SCS TC formation.
The negative connection between cyclogenesis and ZSG may be explained by the influences of the ZSG on atmospheric circulations as well as Madden–Julian oscillation (MJO) activity over the SCS, which reveal prominent contrasts during the study periods. A positive ZSG between the tropical Pacific and the Indian Ocean induces an anomalous Walker-like circulation, which results in an anomalous subsidence and boundary layer divergence over the northern SCS. This also suppresses the moisture as well as MJO activity over the SCS, leading to a significant reduction in TC frequency during inactive periods 1 and 3. In contrast, a negative ZSG induces surface westerlies and favorable environmental conditions for TCs, thereby greatly enhancing SCS cyclogenesis during period 2.
Sources of Uncertainty in Precipitation-Type Forecasting
Authors: Reeves Heather Dawn , Elmore Kimberly L. , Ryzhkov Alexander , Schuur Terry , Krause John 
Published: April 2014

Abstract
Five implicit precipitation-type algorithms are assessed using observed and model-forecast sounding data in order to measure their accuracy and to gauge the effects of model uncertainty on algorithm performance. When applied to observed soundings, all algorithms provide very reliable guidance on snow and rain (SN and RA). However, their skills for ice pellets and freezing rain (IP and FZRA) are comparatively low. Most misclassifications of IP are for FZRA and vice versa. Deeper investigation reveals that no method used in any of the algorithms to differentiate between IP and FZRA allows for clear discrimination between the two forms. The effects of model uncertainty are also considered. For SN and RA, these effects are minimal and each algorithm performs reliably. Conversely, IP and FZRA are strongly impacted. When the range of uncertainty is fully accounted for, their resulting wet-bulb temperature profiles are nearly indistinguishable, leading to very poor skill for all algorithms. Although currently available data do not allow for a thorough investigation, comparison of the statistics from only those soundings that are associated with long-duration, horizontally uniform regions of FZRA shows there are significant differences between these profiles and those that are from more transient, highly variable environments. Hence, a five-category (SN, RA, IP, FZRA, and IP–FZRA mix) approach is advocated to differentiate between sustained regions of horizontally uniform FZRA (or IP) from more mixed environments.
Calculation of limits for significant unidirectional changes in two or more serial results of a biomarker based on a computer simulation model
Authors: Lund Flemming , Petersen Per Hyltoft , Fraser Callum G , Sölétormos György 
Published: April 2014

Background Reference change values (RCVs) were introduced more than 30 years ago and provide objective tools for assessment of the significance of differences in two consecutive results from an individual. However, in practice, more results are usually available for monitoring, and using the RCV concept on more than two results will increase the number of false-positive results. Therefore, a simple method is needed to interpret the significance of a difference when all available serial biomarker results are considered. Methods A computer simulation model using Excel was developed. Based on 10,000 simulated data from healthy individuals, a series of up to 20 results from an individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial measurement result. These successive serial relative differences were computed to give limits for significant unidirectional differences with a constant cumulated maximum probability of both 95% ( P < 0.05) and 99% ( P < 0.01). Results Factors used to multiply the first result from an individual were calculated to create the limits for constant cumulated significant differences. The factors were shown to become a simple function of the number of results and the total coefficient of variation. Conclusions To interpret unidirectional differences in two or more serial results of a biomarker, the limits for significances are easily calculated using the presented factors. The first result is multiplied by the appropriate factor for increase or decrease, which gives the limits for a significant difference.
The Effect of Key Size of Touch Screen Virtual Keyboards on Productivity, Usability, and Typing Biomechanics
Authors: Kim Jeong Ho , Aulck Lovenoor , Thamsuwan Ornwipa , Bartha Michael C. , Johnson Peter W. 
Published: April 2014

Objective: We investigated whether different virtual keyboard key sizes affected typing force exposures, muscle activity, wrist posture, comfort, and typing productivity. Background: Virtual keyboard use is increasing and the physical exposures associated with virtual keyboard key sizes are not well documented. Method: Typing forces, forearm/shoulder muscle activity, wrist posture, subjective comfort, and typing productivity were measured from 21 subjects while they were typing on four different virtual keyboards with square key sizes, which were 13, 16, 19, and 22 mm on each side with 2-mm between-key spacing. Results: The results showed that virtual keyboard key size had little effect on typing force, forearm muscle activity, and ulnar/radial deviation. However, the virtual keyboard with the 13-mm keys had a 15% slower typing speed ( p < .0001), slightly higher static (10th percentile) shoulder muscle activity (2% maximum voluntary contractions, p = .01), slightly greater wrist extension in both hands (2° to 3°, p < .01), and the lowest subjective comfort and preference ratings ( p < .1). Conclusions: The study findings indicate that virtual keyboards with a key size less than 16 mm may be too small for touch typing given the slower typing speed, higher static shoulder muscle activity, greater wrist extension, and lowest subjective preferences. Applications: We evaluated the effects of virtual keyboard key sizes on typing force exposures, muscle activity, comfort, and typing productivity.
Age of Bioterrorism: Are You Prepared? Review of Bioweapons and Their Clinical Presentation for Otolaryngologists
Authors: Zapanta Philip E. , Ghorab Saba 
Published: April 2014

ObjectivesThis review on Category A bioweapons is intended to help otolaryngologists (1) understand the concepts of bioterrorism, (2) identify a bioterrorism attack, and (3) recognize specific otolaryngologic symptoms and signs of Category A bioweapons.Data SourcesPubMed and Medline databases.Review MethodsReview of current literature regarding Category A agents of biological warfare and their relationships to otolaryngology was performed using PubMed, Medline, and articles written by experts in the field of bioterrorism. Each Category A agent was paired with the term otolaryngology and then paired with epistaxis, sinusitis, airway obstruction, pharyngitis, tonsillitis, hearing loss, otitis media, and lymphadenopathy individually. For the latest accepted treatment and diagnostic strategies, bioterrorism was searched with filters for human studies, English language, and the past 5 years. Titles, abstracts, and papers were read for relevancy.ConclusionWhile the use of bioweapons initially leads to nonspecific symptoms, a high index of suspicion and clustering of abnormal pathology will often lead the astute physician to the correct diagnosis of bioweapons. Some disease presentations of Category A agents (anthrax, smallpox, tularemia, botulism, plague, hemorrhagic fever) will involve the realm of otolaryngology.Implications for PracticeThe head and neck manifestations of a Category A bioweapon attack will require knowledgeable otolaryngologists for prompt diagnosis, treatment, and notification of public authorities. This will help decrease the morbidity and mortality of any potential bioterrorism attack.