bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157
Authors: Hahn Noah M. , Bivalacqua Trinity J. , Ross Ashley E. , Netto George J. , Baras Alex , Park Jong Chul , Chapman Carolyn , Masterson Timothy A. , Koch Michael O. , Bihrle Richard , Foster Richard S. , Gardner Thomas A. , Cheng Liang , Jones David R. , McElyea Kyle , Sandusky George E. , Breen Timothy , Liu Ziyue , Albany Costantine , Moore Marietta L. , Loman Rhoda L. , Reed Angela , Turner Scott A. , De Abreu Francine B. , Gallagher Torrey , Tsongalis Gregory J. , Plimack Elizabeth R. , Greenberg Richard E. , Geynisman Daniel M. 
Published: December 2016

Abstract
Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non–muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.
Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (&gt;2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate.
Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut−, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3–4 event. Six-month CR rate was 8% (0% in IHC+ Mut−; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94–5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment.
Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003–11. ©2016 AACR.
Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses
Authors: Kumai Takumi , Lee Sujin , Cho Hyun-Il , Sultan Hussein , Kobayashi Hiroya , Harabuchi Yasuaki , Celis Esteban 
Published: December 2016

AbstractSubstantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor–associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell–based immunotherapies. Cancer Immunol Res; 5(1); 72–83. ©2016 AACR.
Role of Noncanonical Wnt Signaling Pathway in Human Aortic Valve Calcification
Authors: Albanese Isabella , Yu Bin , Al-Kindi Hamood , Barratt Bianca , Ott Leah , Al-Refai Mohammad , de Varennes Benoit , Shum-Tim Dominique , Cerruti Marta , Gourgas Ophélie , Rhéaume Eric , Tardif Jean-Claude , Schwertani Adel 
Published: December 2016

Objective—
The mechanisms underlying the pathogenesis of aortic valve calcification remain unclear. With accumulating evidence demonstrating that valve calcification recapitulates bone development, the crucial roles of noncanonical Wnt ligands WNT5a, WNT5b, and WNT11 in osteogenesis make them critical targets in the study of aortic valve calcification.

Approach and Results—

Using immunohistochemistry, real-time qPCR, Western blotting, and tissue culture, we examined the tissue distribution of WNT5a, WNT5b, and WNT11 in noncalcified and calcified aortic valves and their effects on human aortic valve interstitial cells (HAVICs). Only focal strong immunostaining for WNT5a was seen in and around areas of calcification. Abundant immunostaining for WNT5b and WNT11 was seen in inflammatory cells, fibrosis, and activated myofibroblasts in areas of calcified foci. There was significant correlation between WNT5b and WNT11 overall staining and presence of calcification, lipid score, fibrosis, and microvessels (
P
<0.05). Real-time qPCR and Western blotting revealed abundant expression of both Wnts in stenotic aortic valves, particularly in bicuspid valves. Incubation of HAVICs from noncalcified valves with the 3 noncanonical Wnts significantly increased cell apoptosis and calcification (
P
<0.05). Treatment of HAVICs with the mitogen-activated protein kinase-38β and GSK3β inhibitors significantly reduced their mineralization (
P
<0.01). Raman spectroscopy identified the inorganic phosphate deposits as hydroxyapatite and showed a significant increase in hydroxyapatite deposition in HAVICs in response to WNT5a and WNT11 (
P
<0.05). Similar crystallinity was seen in the deposits found in HAVICs treated with Wnts and in calcified human aortic valves.

Conclusions—
These findings suggest a potential role for noncanonical Wnt signaling in the pathogenesis of aortic valve calcification.
Extracorporeal Membrane Oxygenation in New York State
Authors: Batra Jaya , Toyoda Nana , Goldstone Andrew B. , Itagaki Shinobu , Egorova Natalia N. , Chikwe Joanna 
Published: December 2016

Background—
Utilization of extracorporeal membrane oxygenation (ECMO) is expanding despite limited outcome data defining appropriate use.

Methods and Results—

To quantify determinants of early and 1-year survival after ECMO in adult patients, we conducted a retrospective cohort analysis of 1286 patients aged ≥18 years who underwent ECMO in New York State from 2003 to 2014. Median follow-up time was 4.9 months (range, 0–12 months). ECMO utilization increased from 13 patients in 8 hospitals in 2003 to 330 patients in 30 hospitals in 2014. Compared with patients undergoing ECMO before 2009, later patients were older (54.4 versus 52.3 years;
P
=0.013) and more likely to have major comorbidity including chronic kidney disease (25.2% versus 13.2%;
P
=0.02) and liver disease (20.0% versus 10.7%;
P
=0.001). In the overall cohort, 30-day mortality was 52.2% (95% confidence interval, 49.5–54.9). Mortality at 30 days was 65.2% for patients aged ≥75 years (n=73/112) and 74.6% in patients who required cardiopulmonary resuscitation (n=91/122). Survival at 1 year was 38.4% (95% confidence interval, 35.7–41.0). The 30-day mortality and 1-year survival improved across the study period. In multivariable analysis, earlier year of ECMO, lower hospital volume, indication for ECMO after a cardiac procedure, cardiopulmonary resuscitation before ECMO placement, and age >65 years were independent predictors of worse survival.

Conclusions—
Outcomes of ECMO have improved despite increasing comorbidity. Extreme mortality after ECMO in elderly patients and patients requiring cardiopulmonary resuscitation indicates that less invasive therapeutic or palliative modalities may be more appropriate in this end-of-life setting.
Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism
Authors: Watts Gerald F. , Chan Dick C. , Dent Ricardo , Somaratne Ransi , Wasserman Scott M. , Scott Rob , Burrows Sally , R. Barrett P. Hugh 
Published: December 2016

Background:
Monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9), such as evolocumab, lower plasma low-density lipoprotein (LDL)-cholesterol concentrations. Evolocumab is under investigation for its effects on cardiovascular outcomes in statin-treated, high-risk patients. The mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism remains to be fully evaluated. Stable isotope tracer kinetics can effectively elucidate the mode of action of new lipid-regulating pharmacotherapies.

Methods:
We conducted a 2-by-2 factorial trial of the effects of atorvastatin (80 mg daily) and subcutaneous evolocumab (420 mg every 2 weeks) for 8 weeks on the plasma kinetics of very-low-density lipoprotein (VLDL)–apolipoprotein B-100 (apoB), intermediate-density lipoprotein–apoB, and LDL-apoB in 81 healthy, normolipidemic, nonobese men. The kinetics of apoB in these lipoproteins was studied using a stable isotope infusion of D3-leucine, gas chromatography/mass spectrometry, and multicompartmental modeling.

Results:

Atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL-apoB (
P
<0.001 and
P
.032, respectively), intermediate-density lipoprotein–apoB (
P
=0.021 and
P
=.002, respectively), and LDL-apoB (
P
<0.001, both interventions). Evolocumab but not atorvastatin decreased the production rate of intermediate-density lipoprotein–apoB (
P
=0.043) and LDL-apoB (
P
<0.001), which contributed to the reduction in the plasma pool sizes of these lipoprotein particles. The reduction in LDL-apoB and LDL-cholesterol concentrations was significantly greater with combination versus either monotherapy (
P
<0.001). Whereas evolocumab but not atorvastatin lowered the concentration of free PCSK9, atorvastatin lowered the lathosterol/campesterol ratio (a measure of cholesterol synthesis/absorption) and apoC-III concentration. Both interventions decreased plasma apoE, but neither significantly altered lipoprotein lipase and cholesteryl ester protein mass or measures of insulin resistance.

Conclusions:
In healthy, normolipidemic subjects, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin. These kinetic findings provide a metabolic basis for understanding the potential benefits of PCSK9 monoclonal antibodies incremental to statins in on-going clinical end point trials.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02189837.
Simulations of MJO Propagation across the Maritime Continent: Impacts of SST Feedback
Authors: Zhu Jieshun , Wang Wanqiu , Kumar Arun 
Published: December 2016

Abstract
The observed Madden–Julian oscillation (MJO) tends to propagate eastward across the Maritime Continent from the eastern equatorial Indian Ocean to the western Pacific. However, numerical simulations present different levels of fidelity in representing the propagation, especially for the tropical convection associated with the MJO. This study conducts a series of coupled simulations using the NCEP CFSv2 to explore the impacts of SST feedback and convection parameterization on the propagation simulations. First, two simulations differing in the model horizontal resolutions are conducted. The MJO propagation in these two simulations is found generally insensitive to the resolution change. Further, based on the CFSv2 with a lower resolution, two additional experiments are performed with model SSTs nudged to climatologies with different time scales representing different air–sea coupling strength. It is demonstrated that weakening the air–sea coupling strength significantly degrades the MJO propagation simulation, suggesting the critical role of SST feedback in maintaining MJO propagation. Last, the sensitivity to convection parameterization is explored by comparing two simulations with different convection parameterization schemes. Analyses of these simulations indicate that including air–sea coupling alone in a dynamical model does not result in realistic maintenance of the MJO eastward propagation without the development of favorable SST conditions in the western Pacific. In both observations and one simulation with realistic MJO propagations, the preconditioning of SSTs is strongly affected by surface latent heat fluxes that are modulated by surface wind anomalies in both zonal and meridional directions. The diagnostics highlight the critical contribution from meridional winds in wind speed variations, which has been neglected in most MJO studies.
Estimating Infrared Radiometric Satellite Sea Surface Temperature Retrieval Cold Biases in the Tropics due to Unscreened Optically Thin Cirrus Clouds
Authors: Marquis Jared W. , Bogdanoff Alec S. , Campbell James R. , Cummings James A. , Westphal Douglas L. , Smith Nathaniel J. , Zhang Jianglong 
Published: December 2016

AbstractPassive longwave infrared radiometric satellite–based retrievals of sea surface temperature (SST) at instrument nadir are investigated for cold bias caused by unscreened optically thin cirrus (OTC) clouds [cloud optical depth (COD) ≤ 0.3]. Level 2 nonlinear SST (NLSST) retrievals over tropical oceans (30°S–30°N) from Moderate Resolution Imaging Spectroradiometer (MODIS) radiances collected aboard the NASA Aqua satellite (Aqua-MODIS) are collocated with cloud profiles from the Cloud–Aerosol Lidar with Orthogonal Polarization (CALIOP) instrument. OTC clouds are present in approximately 25% of tropical quality-assured (QA) Aqua-MODIS Level 2 data, representing over 99% of all contaminating cirrus found. Cold-biased NLSST (MODIS, AVHRR, and VIIRS) and triple-window (AVHRR and VIIRS only) SST retrievals are modeled based on operational algorithms using radiative transfer model simulations conducted with a hypothetical 1.5-km-thick OTC cloud placed incrementally from 10.0 to 18.0 km above mean sea level for cloud optical depths between 0.0 and 0.3. Corresponding cold bias estimates for each sensor are estimated using relative Aqua-MODIS cloud contamination frequencies as a function of cloud-top height and COD (assuming they are consistent across each platform) integrated within each corresponding modeled cold bias matrix. NLSST relative OTC cold biases, for any single observation, range from 0.33° to 0.55°C for the three sensors, with an absolute (bulk mean) bias between 0.09° and 0.14°C. Triple-window retrievals are more resilient, ranging from 0.08° to 0.14°C relative and from 0.02° to 0.04°C absolute. Cold biases are constant across the Pacific and Indian Oceans. Absolute bias is lower over the Atlantic but relative bias is higher, indicating that this issue persists globally.
Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms
Authors: Akamine Yumiko , Sugawara-Kikuchi Yuka , Uno Tsukasa , Shimizu Tetsuo , Miura Masatomo 
Published: December 2016

BackgroundThis study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia.MethodsForty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction.ResultsThe within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C0/dose (C0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C0/D ratios of clozapine ( R2 = 0.139, P = 0.016).ConclusionsAmong the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient’s ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure.
Sequential Revision of Belief, Trust Type, and the Order Effect
Authors: Entin Elliot E. , Serfaty Daniel 
Published: December 2016

Objective To investigate how people’s sequential adjustments to their position are impacted by the source of the information. Background There is an extensive body of research on how the order in which new information is received affects people’s final views and decisions as well as research on how they adjust their views in light of new information. Method Seventy college-aged students, 60% of whom were women, completed one of eight different randomly distributed booklets prepared to create the eight different between-subjects treatment conditions created by crossing the two levels of information source with the four level of order conditions. Based on the information provided, participants estimated the probability of an attack, the dependent measure. Results Confirming information from an expert intelligence officer significantly increased the attack probability from the initial position more than confirming information from a longtime friend. Conversely, disconfirming information from a longtime friend decreased the attack probability significantly more than the same information from an intelligence officer. Conclusion It was confirmed that confirming and disconfirming evidence were differentially affected depending on information source, either an expert or a close friend. The difference appears to be due to the existence of two kinds of trust: cognitive-based imbued to an expert and affective-based imbued to a close friend. Application Purveyors of information need to understand that it is not only the content of a message that counts but that other forces are at work such as the order in which information is received and characteristics of the information source.
Do Street Robbery Location Choices Vary Over Time of Day or Day of Week? A Test in Chicago
Authors: Bernasco Wim , Ruiter Stijn , Block Richard 
Published: December 2016

Objectives: This article examines the hypothesis that in street robbery location choices, the importance of location attributes is conditional on the time of day and on the day of the week. Method: The hypothesis is assessed by estimating and comparing separate discrete location choice models for each two-hour time block of the day and for each day of the week. The spatial units of analysis are census blocks. Their relevant attributes include presence of various legal and illegal cash economies, presence of high schools, measures of accessibility, and distance from the offender’s home. Results: The hypothesis is strongly rejected because for almost all census block attributes, their importance hardly depends on time of day or day of week. Only the effect of high schools in census blocks follows expectations, as its effect is only demonstrated at the times and on the days that schools are open. Conclusions: The results suggest that street robbers’ location choices are not as strongly driven by spatial variations in immediate opportunities as has been suggested in previous studies. Rather, street robbers seem to perpetrate in the environs of cash economies and transit hubs most of the time irrespective of how many potential victims are around.
The Uses of Informality: Urban Development and Social Distinction in Mexico City
Authors: Müller Frank , Segura Ramiro 
Published: December 2016

“Urban informality” is a signifier that is disputed by real estate developers, politicians, and residents in undertaking strategies of social distinction and gaining particular political and economic benefits. Research in the western periphery of Mexico City distinguishes three cases of such use of informality. First, real estate developers employ informality as a threat to valorize and justify an enclosed “First World” lifestyle in gated communities. Second, informality motivates homeowners’ associations to take on a neighborhood-defending and state-monitoring role. Third, besides its function in reconstituting class frontiers, it serves as a referent for broader social mobilization against the perceived informality of the local elite. By facilitating social distinction, informality continues to marginalize communities as it influences planning decisions and access to land in urban Latin America. La “informalidad urbana” es un significante que es cuestionado por las empresas de bienes raíces, los políticos y los residentes cuando se involucran en estrategias de distinción social para obtener determinados beneficios políticos y económicos. Nuestra investigación en la periferia occidental de la Ciudad de México establece tres casos de ese uso de la informalidad. Primero, las empresas inmobiliarias emplean la informalidad como una amenaza para valorizar y justificar un estilo de vida del mundo desarrollado en comunidades con acceso controlado. Segundo, la informalidad mueve a las asociaciones de dueños de casa a asumir el papel de defensores del vecindario y la función de vigilancia del estado. Tercero, además de reconstituir las fronteras de clase, también sirve como un referente para una movilidad social más amplia en contra de la presunta informalidad de la élite local. Al facilitar la distinción social, la informalidad continúa marginalizando comunidades ya que sigue influyendo en las decisiones sobre la planificación y el acceso a la tierra en el espacio urbano de América Latina.