bluuebunny/crossref_metadata_2025_split huggingface dataset:
MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis
Authors: Floros Konstantinos V. , Cai JinYang , Jacob Sheeba , Kurupi Richard , Fairchild Carter K. , Shende Mayuri , Coon Colin M. , Powell Krista M. , Belvin Benjamin R. , Hu Bin , Puchalapalli Madhavi , Ramamoorthy Sivapriya , Swift Kimberly , Lewis Janina P. , Dozmorov Mikhail G. , Glod John , Koblinski Jennifer E. , Boikos Sosipatros A. , Faber Anthony C. 
Published: January 2021

Abstract

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer–related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway.

Significance:
This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.
Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy
Authors: Zhou Caicun , Wang Yina , Zhao Jun , Chen Gongyan , Liu Zhihua , Gu Kangsheng , Huang Meijuan , He Jianxing , Chen Jianhua , Ma Zhiyong , Feng Jifeng , Shi Jianhua , Yu Xinmin , Cheng Ying , Yao Yu , Chen Yuan , Guo Renhua , Lin Xiaoyan , Wang Zhehai , Gao Guanghui , Wang Quanren , Li Weixia , Yang Xinfeng , Wu Lihong , Zhang Jun , Ren Shengxiang 
Published: January 2021

Abstract

Purpose:
Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8+ T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced non–small cell lung cancer (NSCLC).

Patients and Methods:
The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250–500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks.

Results:
From March 2017 to October 2018, 105 chemotherapy-pretreated patients with nonsquamous NSCLC were enrolled and received apatinib 250 mg (recommended phase II dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population (n = 94), objective response rate (ORR) was 30.9% [95% confidence interval (CI), 21.7–41.2]. The median progression-free survival was 5.7 months (95% CI, 4.5–8.8) and overall survival was 15.5 months (95% CI, 10.9–24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs. 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed.

Conclusions:
Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485).
Microthrombi as a Major Cause of Cardiac Injury in COVID-19
Authors: Pellegrini Dario , Kawakami Rika , Guagliumi Giulio , Sakamoto Atsushi , Kawai Kenji , Gianatti Andrea , Nasr Ahmed , Kutys Robert , Guo Liang , Cornelissen Anne , Faggi Lara , Mori Masayuki , Sato Yu , Pescetelli Irene , Brivio Matteo , Romero Maria , Virmani Renu , Finn Aloke V. 
Published: January 2021

Background:
Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain.

Methods:
We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury.

Results:

Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, >75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm
2
area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (>20 necrotic myocytes with an area of ≥0.05 mm
2
but <1 cm
2
) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19–positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment–elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19–negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19–positive and –negative patients with ST-segment–elevation myocardial infarction.

Conclusions:
The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19–negative subjects and from coronary thrombi retrieved from COVID-19–positive and –negative patients with ST-segment–elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.
Straightening the Uterus with Epicurus
Authors: Nijs Wim 
Published: January 2021

Abstract
Despite Lucretius’ observations about fertility and marriage at the end of book 4, the Epicurean view on procreation is to a great extent still uncharted territory, due to the shortage of textual evidence other than Lucretius. An important, but often neglected source of information can be found in the few remaining columns of the, unfortunately rather badly preserved, Herculaneum papyrus PHerc. 908/1390, conventionally known as the treatise On Procreation. This paper aims to draw attention to the Gynecological treatise of Soranus of Ephesus as a hitherto unnoticed textual parallel for col. 6-7 of our papyrus. Additionally, I will use these columns to shed some light on the background for Lucretius’ observations in DRN 4.1263-1277, where he discusses the importance of adopting the proper coital position during intercourse.
“To the Moles”? A Note on Isaiah 2:20
Authors: Yurovitskaya Maria 
Published: January 2021

Abstract
The corrupt Masoretic reading לַחְפֹּר פֵּרוֹת at Isa 2:20 is usually restored as לַחֲפַרְפָּרוֹת, which is interpreted as “to the moles.” The alternative interpretation of לחפרפרות as “to the bats,” first attested in Ibn Ezra, may in fact be preferable, as it is supported by the (previously ignored) evidence of the Fragmentary Targum, which use חפרפרא to translate Hebrew עֲטַלֵּף (“bat”) at Deut 14:18.
Foreshadowing Spinoza
Authors: Kato Yoshi 
Published: January 2021

Abstract
This paper examines two interpretations of a passage in Descartes’s text. Johannes Clauberg and Benedict Spinoza comment on the same paragraph in the Principles of Philosophy (1646). Descartes, in the paragraph, argues that the same amount of motion remains in the universe because of God’s immutable essence and operation. On the one hand, Clauberg embraces Descartes’s physics in general but modifies it to suit the theological tradition of the Reformed church, which held the official confession for where his professional career mattered. Spinoza, on the other hand, gets rid of all traces of the biblical religion from Descartes’s physics. While particular theological (or anti-theological) positions of these thinkers dictate their interpretations of Descartes’s text, their solutions are surprisingly similar.
Method vs. Metaphysics
Authors: van Ruler Han 
Published: January 2021

Abstract
This article discusses Descartes’s preferred focus on morally and theologically neutral subjects and points out the impact of this focus on the scientific status of theology. It does so by linking Descartes’s method to his transformation of the notion of substance. Descartes’s Meditations centred around epistemological questions rather than non-human intelligences or the life of the mind beyond this world. Likewise, in his early works, Descartes consistently avoided referring to causal operators. Finally, having first redefined the notion of substance in the Principia, Descartes would completely abandon making use of this notion in his later years. Indeed, in contrast to many authors before and after him, Descartes never showed any interest in the long-established metaphysical interpretation of substances as being causal factors of natural change. With God, nature, and mind commonly serving as instances of substantial causality, Descartes’s philosophy had a huge impact on the place of God in science and discreetly excluded theology as a subject to which his method might be applied.
“Church Sweat”
Authors: Randolph Jacob R. 
Published: January 2021

Abstract
Martin Luther’s ideas about vocational identity were forged in the early years of the Reformation, but were nuanced and reshaped throughout his life as new challenges arose. In this article, I examine the ways in which his conflict with Andreas Karlstadt over the propriety of an academic lifestyle from 1523 to 1525 provided an essential element of Luther’s masculine identity, an element that he continued to draw on throughout his life of lecturing. By 1535, Luther had come to a fully-formed masculine vocational identity, and Karlstadt had become the foil against which Luther measured himself and all other Christian men.
Climate Field Completion via Markov Random Fields: Application to the HadCRUT4.6 Temperature Dataset
Authors: Vaccaro Adam , Emile-Geay Julien , Guillot Dominque , Verna Resherle , Morice Colin , Kennedy John , Rajaratnam Bala 
Published: January 2021

AbstractSurface temperature is a vital metric of Earth’s climate state but is incompletely observed in both space and time: over half of monthly values are missing from the widely used HadCRUT4.6 global surface temperature dataset. Here we apply the graphical expectation–maximization algorithm (GraphEM), a recently developed imputation method, to construct a spatially complete estimate of HadCRUT4.6 temperatures. GraphEM leverages Gaussian Markov random fields (also known as Gaussian graphical models) to better estimate covariance relationships within a climate field, detecting anisotropic features such as land–ocean contrasts, orography, ocean currents, and wave-propagation pathways. This detection leads to improved estimates of missing values compared to methods (such as kriging) that assume isotropic covariance relationships, as we show with real and synthetic data. This interpolated analysis of HadCRUT4.6 data is available as a 100-member ensemble, propagating information about sampling variability available from the original HadCRUT4.6 dataset. A comparison of Niño-3.4 and global mean monthly temperature series with published datasets reveals similarities and differences due in part to the spatial interpolation method. Notably, the GraphEM-completed HadCRUT4.6 global temperature displays a stronger early twenty-first-century warming trend than its uninterpolated counterpart, consistent with recent analyses using other datasets. Known events like the 1877/78 El Niño are recovered with greater fidelity than with kriging, and result in different assessments of changes in ENSO variability through time. Gaussian Markov random fields provide a more geophysically motivated way to impute missing values in climate fields, and the associated graph provides a powerful tool to analyze the structure of teleconnection patterns. We close with a discussion of wider applications of Markov random fields in climate science.
Statistical Postprocessing of Wind Speed Forecasts Using Convolutional Neural Networks
Authors: Veldkamp Simon , Whan Kirien , Dirksen Sjoerd , Schmeits Maurice 
Published: January 2021

AbstractCurrent statistical postprocessing methods for probabilistic weather forecasting are not capable of using full spatial patterns from the numerical weather prediction (NWP) model. In this paper, we incorporate spatial wind speed information by using convolutional neural networks (CNNs) and obtain probabilistic wind speed forecasts in the Netherlands for 48 h ahead, based on KNMI’s deterministic HARMONIE-AROME NWP model. The probabilistic forecasts from the CNNs are shown to have higher Brier skill scores for medium to higher wind speeds, as well as a better continuous ranked probability score (CRPS) and logarithmic score, than the forecasts from fully connected neural networks and quantile regression forests. As a secondary result, we have compared the CNNs using three different density estimation methods [quantized softmax (QS), kernel mixture networks, and fitting a truncated normal distribution], and found the probabilistic forecasts based on the QS method to be best.
Pneumatic tube validation: Reducing the need for donor samples by integrating a vial-embedded data logger
Authors: Stangerup Ida , Broell Franziska , Hoop Julie van der , Sennels Henriette P 
Published: January 2021

Background The most common way to validate a pneumatic tube system is to compare pneumatic tube system-transported blood samples to blood samples carried by hand. The importance of measuring the forces inside the pneumatic tube system has also been emphasized. The aim of this study was to define a validation protocol using a mini data logger (VitalVial, Motryx Inc., Canada) to reduce the need for donor samples in pneumatic tube system validation. Methods As an indicator of the total vibration, the blood samples are exposed to under pneumatic tube system transportation; the area under the curve was determined by a VitalVial for all hospital Tempus600 lines using a five-day validation protocol. Only the three lines with the highest area under the curves were clinically validated by analysing potassium, lactate dehydrogenase and aspartate aminotransferase. A month after pneumatic tube system commissioning, a follow-up on laboratory data was performed. Results Mean area under the curve of the six lines ranged between 347 and 581. The variability of the area under the curve was between 1.51 and 11.55%. In the laboratory data follow-up, an increase in lactate dehydrogenase haemolysis was seen from the three lines with the highest area under the curve and the emergency department, which was not detected in the clinical validation. When the Tempus600 system was in commission, a higher mean area under the curve was measured. Conclusion A three-day validation protocol using VitalVials is enough to determine the stability of a Tempus600 system and can greatly reduce the need for donor samples. When in commission, the stability of the pneumatic tube system should be verified and lactate dehydrogenase haemolysis should be routinely checked.
Technology Uncertainty and Incompleteness in Trade Agreements: Reflections from the Design of India’s Bilateral Agreements Covering Services
Authors: Goyal Tanu M. 
Published: January 2021

International trade agreements are incomplete contracts. The international environment is non-stationary, and technological progress affects both the nature of services and modes of service delivery. This creates uncertainty about future developments in technology-based services. In the presence of transactions costs and due to limited foresight, it is difficult to specify all contingencies within trade agreements ex ante, resulting in contractual incompleteness. This article investigates the design of India’s services agreements to assess the approach followed while listing the ex ante commitment and its implication on technology-based services. It also discusses the ex post mechanism under these agreements to address the gaps in the commitments with respect to new services, and the enforcement mechanism to facilitate the inclusion of these services. It is found that India’s bilateral agreements leave the inclusion of services that may not be technically feasible, ex ante, at the discretion of the trading partners, ex post. Some of India’s agreements also institute a governance mechanism for facilitating this inclusion. The article argues that there is a need for addressing the issue of technology uncertainty both at an international-trade-policy level and under bilateral agreements. Internationally, efforts are underway for a technology-neutral classification of services. Bilateral agreements must include a robust mechanism within the scope of the Agreement for filling gaps that may arise with technological advancements. For furthering the objective of trade agreements, these mechanisms must be backed by sound governance structure. JEL Codes: L80, L84, L86, F13, K33, F53, F55
India’s Response to COVID-19 Crisis
Authors: Jha Abhay Kumar , Jha Raghbendra 
Published: January 2021

The onset of the COVID-19 pandemic has presented India with complex economic and public health challenges. Furthermore, these two crises interact with each other in unpredictable ways whence there is considerable uncertainty in designing a policy response. This article purports to place India’s experience with the corona virus with a cutoff date of 30 June 2020 in perspective and to examine the public health and economic challenges as well as the economy’s prospects in a post-COVID world. The article lists key dates in the development of this pandemic in India and globally. We then outline the economic and health strategies followed in India to combat the crisis. We further discuss some consequences of the pandemic and elements of India’s recovery strategy. We also assess elements of India’s recovery. Finally, this article discusses prospects for the Indian economy in the short run. JEL Codes: I15, I18, O11, O40
Prevalence and Risk Factors for Food Insecurity Among Low-Income US Military Veterans
Authors: Pooler Jennifer A. , Srinivasan Mithuna , Miller Zachary , Mian Paula 
Published: January 2021

Objective Ensuring access to sufficient foods at all times is critical to veterans’ health and well-being. Food insecurity has not been well explored in the veteran population. We examined the prevalence and predictors of food insecurity among low-income veterans, because the highest rates of food insecurity are among low-income households. We also examined rates of Supplemental Nutrition Assistance Program (SNAP) participation among subgroups at the highest risk of food insecurity. Methods We used univariate analyses and 2011-2017 National Health Interview Survey (NHIS) data on veterans aged ≥21 with family incomes <200% of the federal poverty level to estimate the prevalence of food insecurity. We used bivariate analyses to identify correlates of food insecurity and estimate SNAP participation rates among subgroups of low-income veterans. Percentages were weighted using NHIS survey weights. Results Of 5146 low-income veterans, 22.5% reported being food insecure in the previous month. Food insecurity was significantly associated with being aged <65 (33.0% aged 45-64 and 29.7% aged 21-44) compared with 15.0% and 6.4% among veterans aged 65-74 and ≥75, respectively ( P < .001); unemployed compared with employed or not in the labor force (39.4%, 22.7%, and 20.2%, respectively; P < .001); in fair or poor health compared with good, very good, or excellent heath (31.8% vs 18.2%; P < .001); and having experienced serious psychological distress in the past month (56.3%) compared with not having experienced such distress (19.7%; P < .001). Although overall SNAP participation among low-income veterans was estimated to be 27.0%, participation rates were highest among veterans who had experienced serious psychological distress (44.1%), were unemployed (39.2%), and were renting their home (39.0%). Conclusions Some low-income veterans are at greater risk of food insecurity than other veterans. Postseparation programs, civilian support services, and veterans’ health providers should be aware of the characteristics that place veterans at highest risk of food insecurity.
Left or bilateral internal mammary artery employment in coronary artery bypass grafting: midterm results
Authors: Fomenko Mikhail Sergeevich , Schneider Yuri Alexandrovich , Tsoi Victor Gennadievich , Pavlov Alexander Anatolyevich , Shilenko Pavel Alexandrovich 
Published: January 2021

Background The gold standard for coronary artery bypass grafting to the left anterior descending artery is use of the left internal mammary artery. Better long-term survival has been reported using bilateral internal mammary arteries compared to left internal mammary artery only, but many surgeons are reluctant to employ bilateral internal mammary arteries in coronary artery bypass grafting. This study aimed to evaluate the effectiveness and safety of bilateral internal mammary artery use. Methods From 2014 to 2017, 1703 patients underwent coronary artery bypass grafting in our institute. Of these, 772 met the inclusion criteria and were randomly assigned to receive bilateral ( n = 387) or left ( n = 385) internal mammary artery grafts. The mean age was 67.1 ± 6.0 years (range 48–85 years) and 474 (61.4%) were male. The mean number of diseased vessels was 3.1 ± 0.9, and mean EuroSCORE II was 3.4% ± 1.1%. Results Hospital mortality was 1.2% in the left internal mammary artery group vs. 1.8% in the bilateral internal mammary artery group ( p = 0.55). There was no difference in procedure-related complications between groups. Mean follow-up was 65.9 months. Survival in the bilateral internal mammary artery group at 1, 3, and 5 years was 98.7%, 98.7%, and 94.8% vs. 98.1%, 98.1%, and 90.9%, respectively, in the left internal mammary artery group ( p = 0.63). Conclusion Application of bilateral internal mammary arteries in coronary artery bypass grafting is safe and effective, with comparable midterm results to those with the left internal mammary artery only.