bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors
Authors: Geoerger Birgit , Bourdeaut Franck , DuBois Steven G. , Fischer Matthias , Geller James I. , Gottardo Nicholas G. , Marabelle Aurélien , Pearson Andrew D.J. , Modak Shakeel , Cash Thomas , Robinson Giles W. , Motta Marlyane , Matano Alessandro , Bhansali Suraj G. , Dobson Jason R. , Parasuraman Sudha , Chi Susan N. 
Published: April 2017

Abstract
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D–CDK4/6–INK4–retinoblastoma pathway-altered tumors.
Experimental Design: Patients (aged 1–21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.
Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m2. Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m2; n = 1) or grade 4 thrombocytopenia (470 mg/m2; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m2 [equivalent to 600 (RP2D)–900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.
Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m2) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433–41. ©2017 AACR.
Systolic Blood Pressure Trajectory, Frailty, and All-Cause Mortality >80 Years of Age
Authors: Ravindrarajah Rathi , Hazra Nisha C. , Hamada Shota , Charlton Judith , Jackson Stephen H.D. , Dregan Alex , Gulliford Martin C. 
Published: April 2017

Background:
Clinical trials show benefit from lowering systolic blood pressure (SBP) in people ≥80 years of age, but nonrandomized epidemiological studies suggest lower SBP may be associated with higher mortality. This study aimed to evaluate associations of SBP with all-cause mortality by frailty category >80 years of age and to evaluate SBP trajectories before death.

Methods:
A population-based cohort study was conducted using electronic health records of 144 403 participants ≥80 years of age registered with family practices in the United Kingdom from 2001 to 2014. Participants were followed for ≤5 years. Clinical records of SBP were analyzed. Frailty status was classified using the e-Frailty Index into the categories of fit, mild, moderate, and severe. All-cause mortality was evaluated by frailty status and mean SBP in Cox proportional-hazards models. SBP trajectories were evaluated using person months as observations, with mean SBP and antihypertensive treatment status estimated for each person month. Fractional polynomial models were used to estimate SBP trajectories over 5 years before death.

Results:
During follow-up, 51 808 deaths occurred. Mortality rates increased with frailty level and were greatest at SBP <110 mm Hg. In fit women, mortality was 7.7 per 100 person years at SBP 120 to 139 mm Hg, 15.2 at SBP 110 to 119 mm Hg, and 22.7 at SBP <110 mm Hg. For women with severe frailty, rates were 16.8, 25.2, and 39.6, respectively. SBP trajectories showed an accelerated decline in the last 2 years of life. The relative odds of SBP <120 mm Hg were higher in the last 3 months of life than 5 years previously in both treated (odds ratio, 6.06; 95% confidence interval, 5.40–6.81) and untreated (odds ratio, 6.31; 95% confidence interval, 5.30–7.52) patients. There was no evidence of intensification of antihypertensive therapy in the final 2 years of life.

Conclusions:
A terminal decline of SBP in the final 2 years of life suggests that nonrandomized epidemiological associations of low SBP with higher mortality may be accounted for by reverse causation if participants with lower blood pressure values are closer, on average, to the end of life.
Incidence of First Stroke in Pregnant and Nonpregnant Women of Childbearing Age: A Population‐Based Cohort Study From England
Authors: Ban Lu , Sprigg Nikola , Abdul Sultan Alyshah , Nelson‐Piercy Catherine , Bath Philip M. , Ludvigsson Jonas F. , Stephansson Olof , Tata Laila J. 
Published: April 2017

Background
Pregnant women may have an increased risk of stroke compared with nonpregnant women of similar age, but the magnitude and the timing of such risk are unclear. We examined the risk of a first stroke event in women of childbearing age and compared the risk during pregnancy and in the early postpartum period with the background risk outside these periods.

Methods and Results
We conducted an open cohort study of 2 046 048 women aged 15 to 49 years between April 1, 1997, and March 31, 2014, using linked primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care records in England. Risk of first stroke was assessed by calculating the incidence rate of stroke in antepartum, peripartum (2 days before until 1 day after delivery), and early (first 6 weeks) and late (second 6 weeks) postpartum periods compared with nonpregnant time using a Poisson regression model with adjustment for maternal age, socioeconomic group, and calendar time. A total of 2511 women had a first stroke. The incidence rate of stroke was 25.0 per 100 000 person‐years (95% CI 24.0–26.0) in nonpregnant time. The rate was lower antepartum (10.7 per 100 000 person‐years, 95% CI 7.6–15.1) but 9‐fold higher peripartum (161.1 per 100 000 person‐years, 95% CI 80.6–322.1) and 3‐fold higher early postpartum (47.1 per 100 000 person‐years, 95% CI 31.3–70.9). Rates of ischemic and hemorrhagic stroke both increased peripartum and early postpartum.

Conclusions
Although the absolute risk of first stroke is low in women of childbearing age, healthcare professionals should be aware of a considerable increase in relative risk during the peripartum and early postpartum periods.
ARTEMIDA Trial (A Randomized Trial of Efficacy, 12 Months International Double-Blind Actovegin)
Authors: Guekht Alla , Skoog Ingmar , Edmundson Sally , Zakharov Vladimir , Korczyn Amos D. 
Published: April 2017

Background and Purpose—
Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke.

Methods—
This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer’s Disease Assessment Scale, cognitive subscale, extended version at 6 months.

Results—

Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer’s Disease Assessment Scale, cognitive subscale, extended version was −6.8 for Actovegin and −4.6 for placebo; the estimated treatment difference was −2.3 (95% confidence interval, −3.9, −0.7;
P
=0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo.

Conclusions—
Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01582854.
Quantitative Imaging of Cerebral Thromboemboli In Vivo
Authors: Kim Dong-Eog , Kim Jeong-Yeon , Schellingerhout Dawid , Ryu Ju Hee , Lee Su-Kyoung , Jeon Sangmin , Lee Ji Sung , Kim Jiwon , Jang Hee Jeong , Park Jung E. , Kim Eo Jin , Kwon Ick Chan , Ahn Cheol-Hee , Nahrendorf Matthias , Kim Kwangmeyung 
Published: April 2017

Background and Purpose—
Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan–coated gold nanoparticles and microcomputed tomography, with/without tPA therapy.

Methods—
We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan–coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment.

Results—

Thrombus burden at baseline was 784×10
3
±59×10
3
μm
2
for the tPA group (n=42) and 655×10
3
±103×10
3
μm
2
for the saline group (n=8;
P
=0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm
2
/min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm
2
, equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm
2
;
P
<0.01). Infarct size correlated to final thrombus burden (
r
=0.71;
P
<0.01). Time to thrombolysis, completeness of thrombolysis, and tPA therapy were independent predictors of infarct size.

Conclusions—
Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.
Low expression of hexokinase-2 is associated with false-negative FDG–positron emission tomography in multiple myeloma
Authors: Rasche Leo , Angtuaco Edgardo , McDonald James E. , Buros Amy , Stein Caleb , Pawlyn Charlotte , Thanendrarajan Sharmilan , Schinke Carolina , Samant Rohan , Yaccoby Shmuel , Walker Brian A. , Epstein Joshua , Zangari Maurizio , van Rhee Frits , Meissner Tobias , Goldschmidt Hartmut , Hemminki Kari , Houlston Richard , Barlogie Bart , Davies Faith E. , Morgan Gareth J. , Weinhold Niels 
Published: April 2017

Key Points
PET false-negativity was seen in 11% of MM patients. PET false-negativity was associated with low hexokinase-2 expression.
Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production
Authors: Shinde Paurvi , Liu Wenhai , Ménoret Antoine , Luster Andrew D , Vella Anthony T 
Published: April 2017

Abstract
LPS is a powerful adjuvant, and although LPS-mediated TLR4 signaling has been exquisitely delineated, the in vivo mechanism of how TLR4 responses impact T cell priming is far less clear. Besides costimulation, TNF and type 1 IFN are dominant cytokines released after TLR4 activation and can shape T cell responses, but other downstream factors have not been examined extensively. Depending on context, we show that IFNαR1 blockade resulted in minor to major effects on specific CD4 T cell clonal expansion. To help explain these differences, it was hypothesized that IFNαR1 blockade would inhibit specific T cell migration by reducing chemokine receptor signaling, but specific CD4 T cells from IFNαR1-blocked mice were readily able to migrate in response to specific chemokines. Next, we examined downstream factors and found that type 1 IFN signaling was necessary for chemokine production, even when mice were immunized with specific Ag with LPS and CD134 costimulation. IFNαR1 signaling promoted CXCL9 and CXCL10 synthesis, suggesting that these chemokines might be involved in the LPS and CD134 costimulation response. After immunization, we show that CXCL9 blockade inhibited CD4 T cell accumulation in the liver but also in LNs, even in the presence of elevated serum IFN-β levels. Thus, whereas type 1 IFN might have direct effects on primed CD4 T cells, the downstream chemokines that play a role during migration also impact accumulation. In sum, CXCL9 production is a key benchmark for productive CD4 T cell vaccination strategies.
Hydrogen degradation of pre-oxidized zirconium alloys
Authors: Szoka A. , Gajowiec G. , Zieliński A. , Serbiński W. , Olive J.-M. , Ossowska A. 
Published: April 2017

Abstract
The presence of the oxide layers on Zr alloys may retard or enhance the hydrogen entry and material degradation, depending on the layer features. This research has been aimed to determine the effects of pre-oxidation of the Zircaloy-2 alloy at a different temperature on hydrogen degradation. The specimens were oxidised in laboratory air at 350°C, 700°C, and 900°C. After, some samples were tensed at 10-5 strain rate and simultaneously charged with hydrogen under constant direct voltage in 1 N sulfuric acid at room temperature. Other specimens were charged without any tension, then annealed at 400°C for 4 h and finally tensed at above strain rate. The SEM examinations were performed on the cross-sections and fracture faces of specimens. The obtained results demonstrate the effects of the oxide layer on the cathodic current and hydrogen entry, mechanical properties and the appearance of hydrides and fracture behaviour.
Comparison of Estimation Accuracy of EKF, UKF and PF Filters
Authors: Konatowski Stanisław , Kaniewski Piotr , Matuszewski Jan 
Published: April 2017

Abstract Several types of nonlinear filters (EKF – extended Kalman filter, UKF – unscented Kalman filter, PF – particle filter) are widely used for location estimation and their algorithms are described in this paper. In the article filtering accuracy for non-linear form of measurement equation is presented. The results of complex simulations that compare the quality of estimation of analyzed non-linear filters for complex non-linearities of state vector are presented. The moves of maneuvering object are described in two-dimensional Cartesian coordinates and the measurements are described in the polar coordinate system. The object dynamics is characterized by acceleration described by the univariate non-stationary growth model (UNGM) function. The filtering accuracy was evaluated not only by the root-mean-square errors (RMSE) but also by statistical testing of innovations through the expected value test, the whiteness test and the WSSR (weighted sum squared residual) test as well. The comparison of filtering quality was done in the MATLAB environment. The presented results provide a basis for designing more accurate algorithms for object location estimation.
An Analysis of Possibilities How the Collision Between M/V ‘Baltic Ace’ and M/V ‘Corvus J’ Could Have Been Avoided
Authors: Kulbiej Eric , Wołejsza Piotr 
Published: April 2017

Abstract The report presents the simulation results of collision between m/v ‘Baltic Ace’ and m/v ‘Corvus J’. The analysis was performed by means of navigation decision support system (NDSS) in collision situations. This system (NAVDEC) works out anti-collision manoeuvre using AIS (Automatic Identification System) and ARPA (Automatic Radar Plotting Aids) data. Then they are processed by specialized computing algorithms and presented to the operator on a display in the alphanumeric and graphic forms. The data on the specific navigational situation from the report of Bahamas Maritime Authority was used for the generation of signals transmitted to NDSS as a sequence of NMEA strings.
Methods of Improving the Jamming Resistance of GNSS Receiver
Authors: Felski Andrzej 
Published: April 2017

Abstract Jamming of GNSS signals can be both a consequence of accidental activities and an intentional act. This issue is lately discussed as an essential threat for the use of satellite navigation systems. This is especially dangerous in the face of common usage of GPS - like systems in everyday life and the great belief of everyday users in the truth of devices indications. In spite of the legal prohibition of using them, jammers are commonly accessible, especially in the Internet. Until recently even specialists have shared the conviction that the broadband GPS signal is not a subject of disturbances in contrast to older wireless communication techniques because its power level is below natural level of noises and in addition it is randomly coded. But nowadays jammers are very often successfully applied, which is confirmed in many reports. The average user has not the suitable knowledge about the specificity of the jamming and has no technical possibilities of the detection of jammer signals. Receivers, which can indicate the presence of perturbative signals, became accessible a few months ago only. Presently accessible jamming monitors can also determine the direction of interferer signal transmission. There are also specially designed receivers with anti-jamming mechanism, which are, however, not commonly accessible. The possible way of countermeasure the jamming in the GNSS receiver are discussed in this paper.
Implementation of the Contingency Plan On Offshore Units Including Mobile Offshore Drilling Units
Authors: Mrozowska Alicja 
Published: April 2017

Abstract The article discusses practical application of the contingency plan (called also the emergency response plan) to the risks that may occur on an offshore unit. The author, based on her own professional experience, discusses the plan and illustrates its use in practice based on selected elements of the plan for mobile offshore drilling units engaged in the exploration of resources beneath the seabed. The paper discusses the requirements of Directive 2013/30/EU, which is includes obligation to implement the contingency plan relating to offshore units, in order to prevent accidents resulting from offshore oil and gas operations.
Weaker hypotheses for the general projection algorithm with corrections
Authors: Bobe Alexandru , Nicola Aurelian , Popa Constantin 
Published: April 2017

Abstract
In an earlier paper [J. of Appl. Math. and Informatics, 29(3-4)(2011), 697-712] we proposed a general projection-type algorithm with corrections and proved its convergence under a set of special assumptions. In this paper we prove convergence of this algorithm under a much weaker set of assumptions. This new framework gives us the possibility to obtain as a particular case of our method the two-step algorithm analysed in [B I T, 38(2)(1998), 275-282].
Brinkman – Forchheimer – Darcy Flow Past an Impermeable Sphere Embedded in a Porous Medium
Authors: Juncu Gheorghe 
Published: April 2017

Abstract
The flow past an impermeable sphere embedded in a fluid saturated porous medium was studied numerically considering valid the Brinkman-Forchheimer-Darcy (or Brinkman-Hazen-Dupuit-Darcy) model. The flow is viscous, laminar, axisymmetric, steady and incompressible. The porous medium is isotropic, rigid and homogeneous. The stream function - vorticity equations were solved numerically in spherical coordinates system by a multigrid method. The influence of the Darcy number and Forchheimer term on the velocities field was investigated for two boundary conditions on the surface of the sphere: slip and no - slip.
On a conjecture related to the ruin probability for nonhomogeneous insurance claims
Authors: Vernic Raluca 
Published: April 2017

Abstract
Recently, nonhomogeneous claim sizes have been considered in the actuarial literature starting from the fact that the claims are seasonally influenced by the economic environment. In this context, Raducan et al. [8] obtained recursive formulas for the ruin probability at or before claim instants, and stated a conjecture that relates the order of the claims arrival to the magnitude of the corresponding ruin probability, conjecture supported by numerical examples. In this paper, we prove this conjecture in a particular case.
Detection of EGFR mutations in patients with non-small cell lung cancer by high resolution melting. Comparison with other methods
Authors: Martínez-Carretero Carlos , Pascual Fernando Iguaz , Rus Antonio , Bernardo Ivan 
Published: April 2017

AbstractBackground:The discovery of mutations in the epidermal growth factor receptor gene (Methods:We developed a screening method by high resolution melting (HRM) to detectResults:Eight samples showed discordant results between both methods. Three samples with negative results by allele specific PCR and positive by HRM were confirmed by Sanger sequencing (p.S768I+p.V769L, T751_I759del and p.E709K+p.G719A; patients 1, 3 and 4, respectively). One sample with a negative result by HRM, and positive by allele specific PCR (p.T790M; patient 2), was confirmed by Sanger sequencing. Additionally, two positive samples for a deletion in exon 19 by allele-specific PCR, were negative by Sanger sequencing and HRM (patients 2 and 5) and finally, two samples were negative by allele-specific PCR and positive by HRM and Sanger sequencing due to synonymous variants in exon 21.Conclusions:HRM is a good method for mutational screening in