bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of RBC alloimmunization in multiple myeloma patients treated by Daratumumab
Authors: Ye Zhan , Wolf Laurie A. , Mettman Daniel , Plapp Fred V. 
Published: November 2019

BackgroundDaratumumab (DARA) is a human monoclonal antibody for the treatment of multiple myeloma (MM). DARA binds to CD38 on RBCs and interferes with detection of RBC alloantibodies. The objective of this study was to evaluate the risk of RBC alloimmunization in MM patients treated with DARA.Materials and methodsA retrospective study of the complete serological profile and transfusion history of 45 MM patients received transfusion and treated with DARA from July 2015 to December 2018 was undertaken. All cases with positive Ab screens were treated with DTT to identify RBC alloantibodies. RBC transfusion history was monitored between the first DARA dose to the last or extending to the first negative Ab screen after the last DARA dose if the Ab screen was ever positive. Forty‐six MM patients received transfusion but not DARA were studied as control group.ResultsTotally 184 Ab screens were done on 45 patients transfused with ABO‐Rh compatible RBCs, phenotypically matched units or both. None of them showed detectable alloantibodies after DTT treatment. The duration of Ab screening positivity varied markedly, ranging from 25 days to 5 months after the last dose. Two of 46 patients in the control group had preexisting alloantibodies but no new alloantibodies were detected during study period.ConclusionsOur results indicate that the risk of forming new RBC alloantibodies after transfusion in MM patients treated with current regimens is very low and no DARA‐associated difference in the alloimmunization risk. No significant difference in alloimmunization is detected between ABO‐Rh compatible and phenotypically matched transfusion.
Molecular phylogeny places the enigmatic subfamily Masoninae within the Ichneumonidae, not the Braconidae
Authors: Quicke Donald L. J. , Austin Andrew D. , Fagan‐Jeffries Erinn P. , Hebert Paul D. N. , Butcher Buntika A. 
Published: November 2019

AbstractThe Masoninae (type genus Masona van Achterberg) is a widespread but seldom collected group of morphologically aberrant tiny (body length 2 mm or less) wasps that have always been considered as a subfamily of Braconidae, albeit on little supporting evidence. Discovery of a fully winged female of Masona from remote Australia has enabled a reassessment of its relationships. This specimen yielded sequence data for the nuclear 28S and 18S rDNA genes, the barcoding fragment of mitochondrial cytochrome oxidase subunit 1 and the mitochondrial 16S rDNA gene. These were analysed separately and together, along with representatives of Braconidae and Ichneumonidae. Maximum likelihood analyses of all four genes separately and combined concur that Masona is nested within the Ichneumonidae and, therefore, is not a member of Braconidae. This is also supported by the position of the sternaulus low on mesopleuron, absence of fore wing vein (RS + M)a (though the great reduction in wing venation makes further interpretation problematic) and the articulated junction of metasomal tergites 2 and 3. On balance, molecular analyses place Masona basally among the ophioniformes lineage of Ichneumonidae. Formal description of the Australian species as Masona timpaynei Quicke sp. n. and a revised diagnosis of Masoninae are provided in S1 together with illustration of the holotype.
Spatiotemporal Integration of an Agent-Based First Responder Performance Model With a Fire Hazard Propagation Model for Probabilistic Risk Assessment of Nuclear Power Plants
Authors: Bui Ha , Sakurahara Tatsuya , Reihani Seyed , Kee Ernie , Mohaghegh Zahra 
Published: November 2019

Abstract
To advance emergency response (ER) modeling in probabilistic risk assessment (PRA), this research offers a new methodology that explicitly incorporates the spatiotemporal evolution of underlying physical and social phenomena and their bidirectional interactions. While this methodology is applicable for various ER scenarios on different spatial and temporal scales, this paper focuses on advancing ER modeling for a nuclear power plant (NPP) internal fire. This paper provides a thorough review and categorization of existing studies on internal fire ER modeling for NPPs and highlights the contributions of this research. This paper then develops a new methodology for fire ER modeling by integrating an agent-based model of first responder performance (FRP) with a fire hazard propagation (FHP) model through a shared geographical information system (GIS)-based spatial simulation environment. This research is the first to explicitly incorporate space (in addition to time) into the FRP modeling within ER modeling of NPP fire probabilistic risk assessment (fire PRA). In addition, this research develops a GIS-based interface between FRP and FHP that has the capability of transferring both spatial and temporal information in a bidirectional way. Although this paper is focused on a fire ER scenario, the new methodology developed in this paper can contribute to modeling external control room (ExCR) human performance in other contexts, such as diverse and flexible coping strategy (FLEX), maintenance, and offsite first responders in level 3 PRA.
Biomass Chitosan-Induced Fe3O4 Functionalized Halloysite Nanotube Composites: Preparation, Characterization and Flame-Retardant Performance
Authors: Zhang Mengmeng , Cheng Yamin , Li Zhiwei , Li Xiaohong , Yu Laigui , Zhang Zhijun 
Published: November 2019

An inorganic–organic nanohybrid flame retardant, HNT@CS@Fe3O4, is prepared by Halloysite nanotubes (HNT) as nanotemplate, chitosan (CS) as char-forming agent and ferroferric oxide (Fe3O[Formula: see text] playing in a catalytic role, aiming to endow enhanced flame-retardant performance of its nanohybrid. Results show that HNT@CS@Fe3O4 nanohybrids have a corn-like structure and can significantly improve the flame retardancy and thermal stability of epoxy resin (EP). Especially, the initial thermal degradation temperature of EP/HNT@CS@Fe3O4 is significantly improved by [Formula: see text]C relative to pure EP, and the residual carbon yield under air atmosphere is 8.8[Formula: see text]wt.%, which is significantly higher than other EP composites, indicating a higher thermal stability is offered by the as-prepared nanohybrid. The limiting oxygen index of EP/10HNT@CS@Fe3O4 is 31.3%, which is 10.2% higher than that of pure EP. Meanwhile, the HNT@CS@Fe3O4 nanofiller reduces the peak heat release rate, CO production and peak smoke production release of EP nanocomposite by 32.0%, 44.0% and 33.0% in a cone calorimeter test, respectively. This is because the HNT-based composite can form a three-dimensional network structure into the EP matrix to inhibit heat release and diffusion of flammable moieties upon burning of EP. In the meantime, the incorporated Fe3O4 nanoparticle can in situ catalyze the charring of CS and EP matrix on the surface of HNT during the combustion process, which also contributes to the significantly increased fire safety of EP.
ALEXIA
Authors: Krishnakumar Gnanambikai , REDDY Kommuru Alekhya , Rebeiro Chester 
Published: November 2019

Illegal use of memory pointers is a serious security vulnerability. A large number of malwares exploit the spatial and temporal nature of these vulnerabilities to subvert execution or glean sensitive data from an application. Recent countermeasures attach metadata to memory pointers, which define the pointer’s capabilities. The metadata is used by the hardware to validate pointer-based memory accesses. However, recent works have considerable overheads. Further, the pointer validation is decoupled from the actual memory access. We show that this could open up vulnerabilities in multithreaded applications and introduce new vulnerabilities due to speculation in out-of-order processors.
In this article, we demonstrate that the overheads can be reduced considerably by efficient metadata management. We show that the hardware can be designed in a manner that would remain safe in multithreaded applications and immune to speculative vulnerabilities. We achieve these by ensuring that the pointer validations and the corresponding memory access is always done atomically and in order. To evaluate our scheme, which we call ALEXIA, we enhance an OpenRISC processor to perform the memory validation at runtime and also add compiler support. ALEXIA is the first hardware countermeasure scheme for memory protection that provides such an end-to-end solution. We evaluate the processor on an Altera FPGA and show that the runtime overhead, on average, is 14%, with negligible impact on the processor’s size and clock frequency. There is also a negligible impact on the program’s code and data sizes.
The glucagon-like peptide 1 receptor agonist liraglutide attenuates placental ischemia-induced hypertension
Authors: Younes Subhi Talal , Maeda Kenji J. , Sasser Jennifer , Ryan Michael J. 
Published: November 2019

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic perturbations of nitric oxide function, reflective of generalized endothelial dysfunction. Therapies that target the nitric oxide pathway have shown promise in both clinical and preclinical studies of preeclampsia. The glucagon-like peptide 1 agonists have been shown to increase nitric oxide and lower blood pressure in patients with diabetes, in part, through activation of nitric oxide synthase (NOS). Therefore, we hypothesized that a direct acting glucagon-like peptide 1 receptor agonist would improve stigmata of the preeclampsia syndrome. Using the reduced uterine perfusion pressure rat model, we found that treatment with liraglutide significantly lowered blood pressure, improved renal function, and upregulated NOS3 protein expression in the mesenteric arterial bed. However, there were adverse effects on pup growth that were likely related to diminished food intake in the dams. Collectively, these data support the premise that the use of drugs that improve NOS abundance, including the glucagon-like peptide 1 agonists, is a rational therapeutic approach to the treatment of preeclampsia, but suggest cautious and careful study of their safety before potential clinical use in humans. NEW & NOTEWORTHY Drugs that target the glucagon-like peptide-1 pathway such as liraglutide are already used clinically, and it has been shown to promote endothelial nitric oxide synthase (NOS3) expression. We demonstrate that liraglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, lowers blood pressure, improves renal function, and upregulates NOS3 in a rat model of placental ischemia. These data suggest that drugs that target the nitric oxide system, including GLP-1R agonists, are a potential therapeutic option for preeclampsia.
MEK Inhibitors in Lung Cancer—You Can Teach an Old Drug New Tricks
Authors: Havel Jonathan J. 
Published: November 2019

Abstract
In this issue of Cancer Research, Xie and colleagues reveal an unexpected synergy between MEK inhibitors and immune checkpoint blockade in non–small cell lung cancer (NSCLC). Small-molecule inhibition of MEK led to increased cell surface expression of TNF receptor-1 (TNFR1) and sensitized NSCLC cells to cytokine-induced apoptosis. This study provides preclinical rationale for exploring the combination of MAPK pathway inhibitors with immunotherapy in NSCLC, independent of KRAS mutation status.
See related article by Xie et al., p. 5812
A Th1/IFNγ Gene Signature Is Prognostic in the Adjuvant Setting of Resectable High-Risk Melanoma but Not in Non–Small Cell Lung Cancer
Authors: Dizier Benjamin , Callegaro Andrea , Debois Muriel , Dreno Brigitte , Hersey Peter , Gogas Helen J. , Kirkwood John M. , Vansteenkiste Johan F. , Sequist Lecia V. , Atanackovic Djordje , Goeman Jelle , van Houwelingen Hans , Salceda Susana , Wang Fawn , Therasse Patrick , Debruyne Channa , Spiessens Bart , Brichard Vincent G. , Louahed Jamila , Ulloa-Montoya Fernando 
Published: November 2019

Abstract

Purpose:
Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non–small cell lung cancer (NSCLC) tumor samples from two phase III studies.

Experimental Design:
The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were used as “training set”; the remaining two thirds, constituting the “test set,” were used for the prospective validation of the GS.

Results:
In the melanoma training set, the expression level of eight Th1/IFNγ-related genes in tumor-positive lymph node tissue predicted the duration of disease-free survival (DFS) and overall survival (OS) in the placebo arm. This GS was prospectively and independently validated as prognostic in the test set. Building a multivariate Cox model in the test set placebo patients from clinical covariates and the GS score, an increased number of melanoma-involved lymph nodes and the GS were associated with DFS and OS. This GS was not associated with DFS in NSCLC, although expression of the Th1/IFNγ-related genes was associated with the presence of lymphocytes in tumor samples in both indications.

Conclusions:
These findings provide evidence that expression of Th1/IFNγ genes in the TME, as measured by this GS, is associated with clinical outcome in melanoma. This suggests that, using this GS, patients with stage IIIB/C melanoma can be classified into different risk groups.
Imaging Phenotypes of Breast Cancer Heterogeneity in Preoperative Breast Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) Scans Predict 10-Year Recurrence
Authors: Chitalia Rhea D. , Rowland Jennifer , McDonald Elizabeth S. , Pantalone Lauren , Cohen Eric A. , Gastounioti Aimilia , Feldman Michael , Schnall Mitchell , Conant Emily , Kontos Despina 
Published: November 2019

Abstract

Purpose:
Identifying imaging phenotypes and understanding their relationship with prognostic markers and patient outcomes can allow for a noninvasive assessment of cancer. The purpose of this study was to identify and validate intrinsic imaging phenotypes of breast cancer heterogeneity in preoperative breast dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) scans and evaluate their prognostic performance in predicting 10 years recurrence.

Experimental Design:
Pretreatment DCE-MRI scans of 95 women with primary invasive breast cancer with at least 10 years of follow-up from a clinical trial at our institution (2002–2006) were retrospectively analyzed. For each woman, a signal enhancement ratio (SER) map was generated for the entire segmented primary lesion volume from which 60 radiomic features of texture and morphology were extracted. Intrinsic phenotypes of tumor heterogeneity were identified via unsupervised hierarchical clustering of the extracted features. An independent sample of 163 women diagnosed with primary invasive breast cancer (2002–2006), publicly available via The Cancer Imaging Archive, was used to validate phenotype reproducibility.

Results:
Three significant phenotypes of low, medium, and high heterogeneity were identified in the discovery cohort and reproduced in the validation cohort (P &lt; 0.01). Kaplan–Meier curves showed statistically significant differences (P &lt; 0.05) in recurrence-free survival (RFS) across phenotypes. Radiomic phenotypes demonstrated added prognostic value (c = 0.73) predicting RFS.

Conclusions:
Intrinsic imaging phenotypes of breast cancer tumor heterogeneity at primary diagnosis can predict 10-year recurrence. The independent and additional prognostic value of imaging heterogeneity phenotypes suggests that radiomic phenotypes can provide a noninvasive characterization of tumor heterogeneity to augment personalized prognosis and treatment.
Extended 5-Year Follow-up Results of a Phase Ib Study (BRIM7) of Vemurafenib and Cobimetinib in BRAF-Mutant Melanoma
Authors: Ribas Antoni , Daud Adil , Pavlick Anna C. , Gonzalez Rene , Lewis Karl D. , Hamid Omid , Gajewski Thomas F. , Puzanov Igor , Wongchenko Matthew , Rooney Isabelle , Hsu Jessie J. , Yan Yibing , Park Erica , McArthur Grant A. 
Published: November 2019

Abstract

Purpose:
To report the 5-year overall survival (OS) landmark and the long-term safety profile of vemurafenib plus cobimetinib (BRAF plus MEK inhibition, respectively) in the BRIM7 study.

Patients and Methods:
This phase Ib, dose-finding, and expansion study evaluated combination treatment with vemurafenib and cobimetinib in two cohorts of patients with advanced BRAFV600-mutated melanoma: patients who were BRAF inhibitor (BRAFi)-naïve (n = 63) or patients who had progressed on prior treatment with BRAFi monotherapy [vemurafenib monotherapy–progressive disease (PD); n = 66]. Patients in the dose-escalation phase received vemurafenib at 720 or 960 mg twice daily in combination with cobimetinib at 60, 80, or 100 mg/d for 14 days on/14 days off, 21 days on/7 days off, or continuously. Two regimens were selected for expansion: vemurafenib (720 and 960 mg twice daily) and cobimetinib (60 mg/d 21/7).

Results:
Median OS was 31.8 months [95% confidence interval (CI), 24.5–not estimable] in the BRAFi-naïve cohort. The landmark OS rate plateaued at 39.2% at years 4 and 5 of follow-up. In the vemurafenib monotherapy–PD cohort, the median OS was 8.5 months (95% CI, 6.7–11.1), and the landmark OS rate plateaued at 14.0% from 3 years of follow-up. No increase was observed in the frequency and severity of adverse events with long-term follow-up. No new toxicities were detected, and there was no increase in the frequency of symptomatic MEK inhibitor class-effect adverse events.

Conclusions:
A subset of patients with advanced BRAFV600-mutated melanoma treated with a combination regimen of vemurafenib and cobimetinib achieve favorable long-term outcomes.
Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans
Authors: Cacheux Marine , Strauss Benjamin , Raad Nour , Ilkan Zeki , Hu Jun , Benard Ludovic , Feske Stefan , Hulot Jean-Sebastien , Akar Fadi G. 
Published: November 2019

Background:

STIM1 (stromal interaction molecule 1) is a calcium (Ca
2+
) sensor that regulates cardiac hypertrophy by triggering store-operated Ca
2+
entry. Because STIM1 binding to phospholamban increases sarcoplasmic reticulum Ca
2+
load independent of store-operated Ca
2+
entry, we hypothesized that it controls electrophysiological function and arrhythmias in the adult heart.

Methods:

Inducible myocyte-restricted STIM1-KD (STIM1 knockdown) was achieved in adult mice using an αMHC (α-myosin heavy chain)-MerCreMer system. Mechanical and electrophysiological properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen-induced STIM1
flox/flox
-Cre
tg
/−
(STIM1-KD) and littermate controls for STIM1
flox/flox
(referred to as STIM1-Ctl) and for Cre
tg/−
without STIM deletion (referred to as Cre-Ctl).

Results:

STIM1-KD mice (N=23) exhibited poor survival compared with STIM1-Ctl (N=22) and Cre-Ctl (N=11) with >50% mortality after only 8-days of cardiomyocyte-restricted STIM1-KD. STIM1-KD but not STIM1-Ctl or Cre-Ctl hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing-induced ventricular tachycardia/ventricular fibrillation (VT/VF). Examination of the electrophysiological substrate revealed decreased conduction velocity and increased AP duration (APD) heterogeneity in STIM1-KD. These features, however, were comparable in VT/VF(+) and VT/VF(−) hearts. We also uncovered a marked increase in the magnitude of APD alternans during rapid pacing, and the emergence of a spatially discordant alternans profile in STIM1-KD hearts. Unlike conduction velocity slowing and APD heterogeneity, the magnitude of APD alternans was greater (by 80%,
P
<0.05) in VT/VF(+) versus VT/VF(−) STIM1-KD hearts. Detailed phase mapping during the initial beats of VT/VF identified one or more rotors that were localized along the nodal line separating out-of-phase alternans regions.

Conclusions:
In an adult murine model with inducible and myocyte-specific STIM1 depletion, we demonstrate for the first time the regulation of spatially discordant alternans by STIM1. Early mortality in STIM1-KD mice is likely related to enhanced susceptibility to VT/VF secondary to discordant APD alternans.
The Emperor’s New Bookcloths: Friedrich Gottlieb Klopstock’s Presentation Copies for the Imperial Court
Authors: Spoerhase Carlos 
Published: November 2019

Abstract
This paper explores Klopstock’s presentation copies of his drama Hermanns Schlacht in the context of his efforts to gain favor with the imperial court in Vienna. It focuses in particular on Klopstock’s attention to the materiality of the presentation copies and his strategies to adjust to court protocol. In this vein, the essay highlights his dissatisfaction with the quality of German books in general, which he felt undermined his efforts to establish himself with his patrons. At the same time, Klopstock seized on the book’s materiality as an opening to reframe the relationship of author to patron. He envisioned a new kind of relationship, which would be more reciprocal. By trying to redefine the author’s position at court, Klopstock aimed to elevate the authorial role more generally. Klopstock’s leveraging of the material book to elevate the author was part of a wider eighteenth-century debate concerning the status of authors in their relation to patrons. Klopstock aimed not only to redefine this relationship as one of equals but also to commit the emperor to provide recognition and financial support for German writers, thus securing the stature of German letters. In this context, Klopstock’s binding choices are shown to be bold moves through which he tried to break the cultural conventions attached to the medium of the presentation copy. Klopstock’s own designs of his presentation copies to the imperial court have to be seen as—ultimately failed—attempts to recalibrate cultural power structures.