bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms
Authors: Tukachinsky Hanna , Madison Russell W. , Chung Jon H. , Gjoerup Ole V. , Severson Eric A. , Dennis Lucas , Fendler Bernard J. , Morley Samantha , Zhong Lei , Graf Ryon P. , Ross Jeffrey S. , Alexander Brian M. , Abida Wassim , Chowdhury Simon , Ryan Charles J. , Fizazi Karim , Golsorkhi Tony , Watkins Simon P. , Simmons Andrew , Loehr Andrea , Venstrom Jeffrey M. , Oxnard Geoffrey R. 
Published: February 2021

AbstractPurpose:Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care.Experimental Design:Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP.Results:A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.Conclusions:Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.See related commentary by Hawkey and Armstrong, p. 2961
Electrical Substrate Ablation for Refractory Ventricular Fibrillation
Authors: Krummen David E. , Ho Gordon , Hoffmayer Kurt S. , Schweis Franz N. , Baykaner Tina , Rogers A.J. , Han Frederick T. , Hsu Jonathan C. , Viswanathan Mohan N. , Wang Paul J. , Rappel Wouter-Jan , Narayan Sanjiv M. 
Published: February 2021

Background:
Refractory ventricular fibrillation (VF) is a challenging clinical entity, for which ablation of triggering premature ventricular complexes is described. When premature ventricular complexes are infrequent and multifocal, the optimal treatment strategy is uncertain.

Methods:
We prospectively enrolled consecutive patients presenting with multiple implantable cardioverter-defibrillator shocks for VF refractory to antiarrhythmic drug therapy, exhibiting infrequent (≤3%), multifocal premature ventricular complexes (≥3 morphologies). Procedurally, VF was induced with rapid pacing and mapped, identifying sites of conduction slowing and rotation or rapid focal activation. VF electrical substrate ablation was then performed. Outcomes were compared against reference patients with VF who were unable or unwilling to undergo catheter ablation. The primary outcome was a composite of implantable cardioverter-defibrillator shock, electrical storm, or all-cause mortality.

Results:

VF was induced and mapped in 6 patients (60±10 years; left ventricular ejection fraction, 46±19%) with ischemic (n=3) and nonischemic cardiomyopathy. An average of 3.3±0.5 sites of localized reentry during VF were targeted for radiofrequency ablation (38.3±10.9 minutes) during sinus rhythm, rendering VF noninducible with pacing. Freedom from the primary outcome was 83% in the VF ablation group versus 17% in 6 nonablation reference patients at a median of 1.0 years (interquartile range, 0.5–1.5 years;
P
=0.046) of follow-up.

Conclusions:
VF electrical substrate ablation is associated with a reduction in the combined end point compared with the nonablation reference group. Additional work is required to understand the precise pathophysiologic changes that promote VF to improve preventative and therapeutic strategies.
Anticoagulation Before Hospitalization Is a Potential Protective Factor for COVID‐19: Insight From a French Multicenter Cohort Study
Authors: Chocron Richard , Galand Vincent , Cellier Joffrey , Gendron Nicolas , Pommier Thibaut , Bory Olivier , Khider Lina , Trimaille Antonin , Goudot Guillaume , Weizman Orianne , Alsac Jean Marc , Geneste Laura , Schmeltz Armand , Panagides Vassili , Philippe Aurélien , Marsou Wassima , Ben Abdallah Iannis , Deney Antoine , El Batti Salma , Attou Sabir , Juvin Philippe , Delmotte Thomas , Messas Emmanuel , Pezel Théo , Planquette Benjamin , Duceau Baptiste , Gaussem Pascale , Sutter Willy , Sanchez Olivier , Waldman Victor , Diehl Jean‐Luc , Mirault Tristan , Bonnet Guillaume , Cohen Ariel , Smadja David M. ,   for the Critical COVID‐19 France Investigators
Published: February 2021

Background
Coronavirus disease 2019 (COVID‐19) is a respiratory disease associated with thrombotic outcomes with coagulation and endothelial disorders. Based on that, several anticoagulation guidelines have been proposed. We aimed to determine whether anticoagulation therapy modifies the risk of developing severe COVID‐19.

Methods and Results
Patients with COVID‐19 initially admitted in medical wards of 24 French hospitals were included prospectively from February 26 to April 20, 2020. We used a Poisson regression model, Cox proportional hazard model, and matched propensity score to assess the effect of anticoagulation on outcomes (intensive care unit admission or in‐hospital mortality). The study enrolled 2878 patients with COVID‐19, among whom 382 (13.2%) were treated with oral anticoagulation therapy before hospitalization. After adjustment, anticoagulation therapy before hospitalization was associated with a better prognosis with an adjusted hazard ratio of 0.70 (95% CI, 0.55–0.88). Analyses performed using propensity score matching confirmed that anticoagulation therapy before hospitalization was associated with a better prognosis, with an adjusted hazard ratio of 0.43 (95% CI, 0.29–0.63) for intensive care unit admission and adjusted hazard ratio of 0.76 (95% CI, 0.61–0.98) for composite criteria intensive care unit admission or death. In contrast, therapeutic or prophylactic low‐ or high‐dose anticoagulation started during hospitalization were not associated with any of the outcomes.

Conclusions
Anticoagulation therapy used before hospitalization in medical wards was associated with a better prognosis in contrast with anticoagulation initiated during hospitalization. Anticoagulation therapy introduced in early disease could better prevent COVID‐19–associated coagulopathy and endotheliopathy, and lead to a better prognosis.
Treating Restless Legs Syndrome Was Associated With Low Risk of Cardiovascular Disease: A Cohort Study With 3.4 Years of Follow‐Up
Authors: Gao Xiang , Ba Djibril M. , Bagai Kanika , Liu Guodong , Ma Chaoran , Walters Arthur S. 
Published: February 2021

Background
Restless legs syndrome (RLS) is associated with higher cardiovascular disease (CVD) risk. However, it remains unknown whether treatment of RLS lowers the cardiovascular risk associated with RLS.

Methods and Results

All data were collected retrospectively, but subjects were prospectively followed forward in time to determine outcomes of interest. We used the Truven Health MarketScan Commercial Claims and Encounters database from January 1, 2006, through December 31, 2014. Participants were 169 393 individuals, which included 24 199 nonpregnant participants with an RLS diagnosis (16 694 receiving treatments for RLS and 7505 without treatment) during 2006 to 2008 and 145 194 age‐ and sex‐matched participants without RLS. All participants were free of CVD before January 1, 2009 (analysis baseline). Incident CVD cases (myocardial infarction, angina, stroke, atrial fibrillation, and heart failure) were identified. We adjusted for potential confounders, such as presence of chronic conditions and medication use. We identified 16 574 incident CVD cases during 2009 to 2014. Relative to the non‐RLS group, the adjusted hazard ratio (HR) for future CVD was 1.26 (95% CI, 1.20–1.32) (
P
<0.001) for the RLS with treatment group, and 1.53 (95% CI, 1.42–1.65) (
P
<0.001) for the RLS without treatment group. Significant lower CVD risk was observed for all different RLS treatments, including dopaminergics, anticonvulsants, benzodiazepines, and opiates (adjusted HRs range, 0.71‐0.84;
P
<0.001 for all), except for ergot‐dopamine use.

Conclusions
RLS was associated with higher future CVD risk. However, RLS was associated with statistically significantly less future cardiovascular risk in RLS patients with treatment than in those without treatment.
Neuraminidases 1 and 3 Trigger Atherosclerosis by Desialylating Low‐Density Lipoproteins and Increasing Their Uptake by Macrophages
Authors: Demina Ekaterina P. , Smutova Victoria , Pan Xuefang , Fougerat Anne , Guo Tianlin , Zou Chunxia , Chakraberty Radhika , Snarr Brendan D. , Shiao Tze C. , Roy Rene , Orekhov Alexander N. , Miyagi Taeko , Laffargue Muriel , Sheppard Donald C. , Cairo Christopher W. , Pshezhetsky Alexey V. 
Published: February 2021

Background
Chronic vascular disease atherosclerosis starts with an uptake of atherogenic modified low‐density lipoproteins (LDLs) by resident macrophages, resulting in formation of arterial fatty streaks and eventually atheromatous plaques. Increased plasma sialic acid levels, increased neuraminidase activity, and reduced sialic acid LDL content have been previously associated with atherosclerosis and coronary artery disease in human patients, but the mechanism underlying this association has not been explored.

Methods and Results

We tested the hypothesis that neuraminidases contribute to development of atherosclerosis by removing sialic acid residues from glycan chains of the LDL glycoprotein and glycolipids. Atherosclerosis progression was investigated in apolipoprotein E and LDL receptor knockout mice with genetic deficiency of neuraminidases 1, 3, and 4 or those treated with specific neuraminidase inhibitors. We show that desialylation of the LDL glycoprotein, apolipoprotein B 100, by human neuraminidases 1 and 3 increases the uptake of human LDL by human cultured macrophages and by macrophages in aortic root lesions in

Apoe
−/−

mice via asialoglycoprotein receptor 1. Genetic inactivation or pharmacological inhibition of neuraminidases 1 and 3 significantly delays formation of fatty streaks in the aortic root without affecting the plasma cholesterol and LDL levels in

Apoe
−/−

and

Ldlr
−/−

mouse models of atherosclerosis.

Conclusions
Together, our results suggest that neuraminidases 1 and 3 trigger the initial phase of atherosclerosis and formation of aortic fatty streaks by desialylating LDL and increasing their uptake by resident macrophages.
Like Nobody's Business
Authors: Comrie Andrew C. 
Published: February 2021

How do university finances really work?
From flagship public research universities to small, private liberal arts colleges, there are few aspects of these institutions associated with more confusion, myths or lack of understanding than how they fund themselves and function in the business of higher education. Using simple, approachable explanations supported by clear illustrations, this book takes the reader on an engaging and enlightening tour of how the money flows. How does the university really pay for itself? Why do tuition and fees rise so fast? Why do universities lose money on research? Do most donations go to athletics?
Grounded in hard data, original analyses, and the practical experience of a seasoned administrator, this book provides refreshingly clear answers and comprehensive insights for anyone on or off campus who is interested in the business of the university: how it earns its money, how it spends it, and how it all works.
Combined Effects of the British–Baikal Corridor Pattern and the Silk Road Pattern on Eurasian Surface Air Temperatures in Summer
Authors: Li Xinyu , Lu Riyu , Ahn Joong-Bae 
Published: February 2021

AbstractThe summer British–Baikal Corridor pattern (BBC) and the Silk Road pattern (SRP) manifest as zonally oriented teleconnections in the high and middle latitudes, respectively, of the Eurasian continent. In this study, we investigate the combined effects of the BBC and SRP on surface air temperatures over the Eurasian continent. It is found that the combination of the BBC and SRP results in two kinds of well-organized, large-scale circulation anomalies: the zonal tripole pattern and the Ω-like pattern in the 200-hPa geopotential height anomalies. The zonal tripole pattern is characterized by opposite variations between western Siberia/western Asia and Europe/central Asia/central Siberia, and the Ω-like pattern manifests as consistent variations over midlatitude Europe, western Siberia, and central Asia. Correspondingly, the resultant large-scale surface air temperature anomalies feature the same zonal tripole pattern and Ω-like pattern, respectively. Further results indicate that these two patterns resemble the two leading modes of surface air temperature anomalies over the middle to high latitudes of Eurasia. This study indicates that the temperature variations in the middle and high latitudes of Eurasia can be coordinated and evidently explained by the combination of the BBC and SRP, and it contributes to a more comprehensive understanding of the large-scale Eurasian climate variability.
Radiative and Dynamic Controls on Atmospheric Heat Transport over Different Planetary Rotation Rates
Authors: Cox Tyler , Armour Kyle C. , Roe Gerard H. , Donohoe Aaron , Frierson Dargan M. W. 
Published: February 2021

AbstractAtmospheric heat transport is an important piece of our climate system, yet we lack a complete theory for its magnitude or changes. Atmospheric dynamics and radiation play different roles in controlling the total atmospheric heat transport (AHT) and its partitioning into components associated with eddies and mean meridional circulations. This work focuses on two specific controls: a radiative one, namely atmospheric radiative temperature tendencies, and a dynamic one, the planetary rotation rate. We use an idealized gray radiation model to employ a novel framework to lock the radiative temperature tendency and total AHT to climatological values, even while the rotation rate is varied. This setup allows for a systematic study of the effects of radiative tendency and rotation rate on AHT. We find that rotation rate controls the latitudinal extent of the Hadley cell and the heat transport efficiency of eddies. Both the rotation rate and radiative tendency influence the strength of the Hadley cell and the strength of equator–pole energy differences that are important for AHT by eddies. These two controls do not always operate independently and can reinforce or dampen each other. In addition, we examine how individual AHT components, which vary with latitude, sum to a total AHT that varies smoothly with latitude. At slow rotation rates the mean meridional circulation is most important in ensuring total AHT varies smoothly with latitude, while eddies are most important at rotation rates similar to, and faster than, those of Earth.
Applying a Physically Based Blowing Snow Diagnostic Parameterization to Improve Wintertime Visibility Forecasts in the WRF Model
Authors: Letcher Theodore W. , LeGrand Sandra L. , Polashenski Christopher 
Published: February 2021

AbstractBlowing snow presents substantial risk to human activities by causing severe visibility degradation and snow drifting. Furthermore, blowing snow presents a weather forecast challenge since it is not generally simulated in operational weather forecast models. In this study, we apply a physically based blowing snow model as a diagnostic overlay to output from a reforecast WRF simulation of a significant blowing snow event that occurred over the northern Great Plains of the United States during the winter of 2019. The blowing snow model is coupled to an optics parameterization that estimates the visibility reduction by blowing snow. This overlay is qualitatively evaluated against false color satellite imagery from the GOES-16 operational weather satellite and available surface visibility observations. The WRF-simulated visibility is substantially improved when incorporating blowing snow hydrometeors. Furthermore, the model-simulated plume of blowing snow roughly corresponds to the blowing snow plumes visible in the satellite imagery. Overall, this study illustrates how a blowing snow diagnostic model can aid weather forecasters in making blowing snow visibility forecasts, and demonstrates how the model can be evaluated against satellite imagery.
Coexistence of disseminated Kaposi sarcoma and multicentric Castleman disease in an HIV-infected patient under viral suppression
Authors: Lin I-Fan , Lin Jiun-Nong , Tsai Tsung-Heng , Hsu Chao-Tien , Wu Yu-Ying , Lai Chung-Hsu 
Published: February 2021

Coexistence of multicentric Castleman disease and Kaposi sarcoma is rare and might be missed without an experienced pathologists’ interpretation. A 46-year-old man had been diagnosed with HIV infection and treated with combination antiretroviral therapy of dolutegravir/abacavir/lamivudine (Triumeq) for one year. The latest viral load was 49 copies/mL and CD4 T-cell count was 192 cells/uL. He was admitted due to fever off and on, splenomegaly, general lymphadenopathy, and severe thrombocytopenia for two months. Biopsy of a purplish skin lesion and gastric tissue showed Kaposi sarcoma. The pathology of inguinal lymph nodes revealed coexistence of Kaposi sarcoma and multicentric Castleman disease. The plasma Kaposi sarcoma herpesvirus viral load was 365,000 copies/mL. During hospitalization, progressive pancytopenia and spiking fever persisted, and he died of multi-organ failure before completion of chemotherapeutic treatments with rituximab plus liposomal doxorubicin.
RAR Gamma Activation Sensitizes Human Myeloma Cells to Carfilzomib Treatment through OAS-RNase L Innate Immune Pathway
Authors: Wang Qiang , Lin Zhijuan , Yi Qing 
Published: February 2021

Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) kill MM cells by disrupting the degradation of misfolded proteins, presumably derived from high-level immunoglobulin production, which provides an appealing explanation for why MM cells are so uniquely sensitive to PIs. However, relapses are frequent and acquired resistance to PI treatment emerges in most patients. Therefore, identifying novel and safe drugs overcoming PI resistance in MM will aid in chemo-(re)sensitization, reducing PI-induced side effects, and maximizing the outcomes of PI therapy.
Here we performed a high-throughput screen of 1855 FDA-approved drugs (Figure 1) and identified all-trans retinoic acid (ATRA), a classic pan-retinoic acid receptor (RAR) agonist used successfully to treat acute promyelocytic leukemia (APL), as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and re-sensitized Cfz-resistant MM cells to Cfz in vitro. To determine which RARs are important for ATRA enhancement of Cfz-induced apoptosis in MM, esiRNAs of RARs for knocking down RARs and selective agonists of RARs were used in Cfz-treated MM cells. We identified that RARγ activation is important for ATRA sensitizing MM cells to Cfz treatment.
To determine which signaling pathways are involved in ATRA-treated MM cells, gene-profiling data analysis of Cfz- versus ATRA+Cfz-treated MM cells was performed and real-time PCR was used to validate the microarray results. We found that ATRA treatment activated IFN-β response pathway (Figure 2), leading to upregulated expression of IRF1 and OAS1-3. Interestingly, similar to ATRA, IFN-β, which alone did not induce MM apoptosis, enhanced Cfz-induced MM cell apoptosis. Furthermore, using RNA integrity assay and dsRNA detection assay, we identified that ATRA treatment elevated the expression of OASs, which synthesized 2-5A upon binding to dsRNA induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death (Figure 3). By knocking down each gene of OAS1-3, we demonstrated that OAS1 is essential for ATRA to sensitize MM cells to Cfz-induced apoptosis.
Furthermore, we determined the impact and significance of RARγ and OAS1 in human MM pathogenesis and drug response by analyzing the gene-profiling data of 264 MM patients from Mulligan et al. datasets and 1,143 MM patients from MMRF coMMpass study IA13. In support of these findings, analyses of the large patient's gene-profiling datasets showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment (Figure 4).
Finally, BMS961, a selective RARγ agonist, similar to ATRA, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo (Figure 5). Thus, this study highlights the potential for RARγ agonists to sensitize MM and overcome MM resistance to Cfz treatment in patients.

Disclosures
No relevant conflicts of interest to declare.