bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing Macrophage Diversity in Metastasis-Bearing Lungs Reveals a Lipid-Associated Macrophage Subset
Authors: Huggins Danielle N. , LaRue Rebecca S. , Wang Ying , Knutson Todd P. , Xu Yingzheng , Williams Jesse W. , Schwertfeger Kathryn L. 
Published: August 2021

Abstract

While macrophages are among the most abundant immune cell type found within primary and metastatic mammary tumors, how their complexity and heterogeneity change with metastatic progression remains unknown. Here, macrophages were isolated from the lungs of mice bearing orthotopic mammary tumors for single-cell RNA sequencing (scRNA-seq). Seven distinct macrophage clusters were identified, including populations exhibiting enhanced differential expression of genes related to antigen presentation (H2-Aa, Cd74), cell cycle (Stmn1, Cdk1), and interferon signaling (Isg15, Ifitm3). Interestingly, one cluster demonstrated a profile concordant with lipid-associated macrophages (Lgals3, Trem2). Compared with nontumor-bearing controls, the number of these cells per gram of tissue was significantly increased in lungs from tumor-bearing mice, with the vast majority costaining positively with the alveolar macrophage marker Siglec-F. Enrichment of genes implicated in pathways related to lipid metabolism as well extracellular matrix remodeling and immunosuppression was observed. In addition, these cells displayed reduced capacity for phagocytosis. Collectively, these findings highlight the diversity of macrophages present within metastatic lesions and characterize a lipid-associated macrophage subset previously unidentified in lung metastases.

Significance:
scRNA-seq of macrophages isolated from lung metastases reveals extensive macrophage heterogeneity and identifies a novel subpopulation enriched for genes involved in lipid metabolism, extracellular matrix remodeling, and immunosuppression.
Going with the Flow: The Promise of Plasma-Only Circulating Tumor DNA Assays
Authors: Bent Alisha , Kopetz Scott 
Published: August 2021

Abstract
Circulating tumor DNA (ctDNA) has emerged as a noninvasive diagnostic and prognostic tool for colorectal cancer. Here, we discuss studies that evaluate the ability of plasma-only ctDNA assays to detect minimal residual disease and the potential benefit of integration of methylation into ctDNA assays.
See related articles by Parikh et al., p. 5586 and Taieb et al., p. 5638
Interpreting the Complex Landscape of Immune–Tumor Interface
Authors: Symmans W. Fraser 
Published: August 2021

Abstract
Predictive biomarkers for immune therapy must address a complex interface between the immune system and triple-negative breast cancer and still be technically reliable for diagnostic use. Two recent articles describe the assessment of spatial heterogeneity using digital methods that promise to improve the quantification of immune infiltrate or molecular targets.
See related articles by Bai et al., p. 5557 and Carter et al., p. 5628
Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer
Authors: Crawford Nyree , Stott Katie J. , Sessler Tamas , McCann Christopher , McDaid William , Lees Andrea , Latimer Cheryl , Fox Jennifer P. , Munck Joanne M. , Smyth Tomoko , Shah Alpesh , Martins Vanessa , Lawler Mark , Dunne Philip D. , Kerr Emma M. , McDade Simon S. , Coyle Vicky M. , Longley Daniel B. 
Published: August 2021

Abstract
Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)–based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8–dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8–proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.
Transcriptome-wideIn VitroEffects of Aspirin on Patient-derived Normal Colon Organoids
Authors: Devall Matthew A.M. , Drew David A. , Dampier Christopher H. , Plummer Sarah J. , Eaton Stephen , Bryant Jennifer , Díez-Obrero Virginia , Mo Jiancheng , Kedrin Dmitriy , Zerjav Dylan C. , Takacsi-Nagy Oliver , Jennelle Lucas T. , Ali Mourad W. , Yilmaz Ömer H. , Moreno Victor , Powell Steven M. , Chan Andrew T. , Peters Ulrike , Casey Graham 
Published: August 2021

AbstractMechanisms underlying aspirin chemoprevention of colorectal cancer remain unclear. Prior studies have been limited because of the inability of preclinical models to recapitulate human normal colon epithelium or cellular heterogeneity present in mucosal biopsies. To overcome some of these obstacles, we performed in vitro aspirin treatment of colon organoids derived from normal mucosal biopsies to reveal transcriptional networks relevant to aspirin chemoprevention. Colon organoids derived from 38 healthy individuals undergoing endoscopy were treated with 50 μmol/L aspirin or vehicle control for 72 hours and subjected to bulk RNA sequencing. Paired regression analysis using DESeq2 identified differentially expressed genes (DEG) associated with aspirin treatment. Cellular composition was determined using CIBERSORTx. Aspirin treatment was associated with 1,154 significant (q &lt; 0.10) DEGs prior to deconvolution. We provide replication of these findings in an independent population-based RNA-sequencing dataset of mucosal biopsies (BarcUVa-Seq), where a significant enrichment for overlap of DEGs was observed (P &lt; 2.2E−16). Single-cell deconvolution revealed changes in cell composition, including a decrease in transit-amplifying cells following aspirin treatment (P = 0.01). Following deconvolution, DEGs included novel putative targets for aspirin such as TRABD2A (q = 0.055), a negative regulator of Wnt signaling. Weighted gene co-expression network analysis identified 12 significant modules, including two that contained hubs for EGFR and PTGES2, the latter being previously implicated in aspirin chemoprevention. In summary, aspirin treatment of patient-derived colon organoids using physiologically relevant doses resulted in transcriptome-wide changes that reveal altered cell composition and improved understanding of transcriptional pathways, providing novel insight into its chemopreventive properties.Prevention Relevance:Numerous studies have highlighted a role for aspirin in colorectal cancer chemoprevention, though the mechanisms driving this association remain unclear. We addressed this by showing that aspirin treatment of normal colon organoids diminished the transit-amplifying cell population, inhibited prostaglandin synthesis, and dysregulated expression of novel genes implicated in colon tumorigenesis.
Preconditioning by Preceding Ischemic Cerebrovascular Events
Authors: Correia Pamela N. , Meyer Ivo A. , Eskandari Ashraf , Amiguet Michael , Hirt Lorenz , Michel Patrik 
Published: August 2021

Background
Emerging yet contrasting evidence from animal and human studies associates ischemic preconditioning with improvement of subsequent stroke severity, although long‐term outcome remains unclear. The purpose of this study was to analyze how preceding cerebral ischemic events influence subsequent stroke severity and outcome.

Methods and Results
Data for this retrospective cohort study were extracted from ASTRAL (Acute Stroke Registry and Analysis of Lausanne). This registry includes a sample of all consecutive patients with acute ischemic strokes admitted to the stroke unit and/or intensive care unit of the Lausanne University Hospital, Switzerland. We investigated associations between preceding ischemic events (transient ischemic attacks or ischemic strokes) and the impact on subsequent stroke severity and clinical improvement within 24 hours, measured through National Institute of Health Stroke Scale, as well as 3‐month outcome, determined through a shift in the modified Rankin Scale. Of 3530 consecutive patients with ischemic stroke (43% women, median age 73 years), 1001 (28%) had ≥1 preceding cerebral ischemic events (45% transient ischemic attack, 55% ischemic stroke; 31% multiple events). After adjusting for multiple prehospital, clinical, and laboratory confounders, admission stroke severity was significantly lower in patients preconditioned through a preceding ischemic event, but 24‐hour improvement was not significant and 3‐month outcome was unfavorable.

Conclusions
Preceding ischemic events were independently associated with a significant reduction in subsequent stroke severity but worsened long‐term clinical outcome. These results, if confirmed by future randomized studies, may help design neuroprotective strategies. The unfavorable effect on stroke outcome is probably a consequence of the cumulative disability burden after multiple ischemic events.
Cerebral Edema in Patients With Large Hemispheric Infarct Undergoing Reperfusion Treatment: A HERMES Meta-Analysis
Authors: Ng Felix C. , Yassi Nawaf , Sharma Gagan , Brown Scott B. , Goyal Mayank , Majoie Charles B.L.M. , Jovin Tudor G. , Hill Michael D. , Muir Keith W. , Saver Jeffrey L. , Guillemin Francis , Demchuk Andrew M. , Menon Bijoy K. , San Roman Luis , Liebeskind David S. , White Philip , Dippel Diederik W.J. , Davalos Antoni , Bracard Serge , Mitchell Peter J. , Wald Michael J. , Davis Stephen M. , Sheth Kevin N. , Kimberly W. Taylor , Campbell Bruce C.V. ,   for the HERMES Collaborators
Published: August 2021

Background and Purpose:
Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline.

Methods:
In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool.

Results:
Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98]; reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08]).

Conclusions:
In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.
Edges in brain networks: Contributions to models of structure and function
Authors: Faskowitz Joshua , Betzel Richard F. , Sporns Olaf 
Published: August 2021

Abstract
Network models describe the brain as sets of nodes and edges that represent its distributed organization. So far, most discoveries in network neuroscience have prioritized insights that highlight distinct groupings and specialized functional contributions of network nodes. Importantly, these functional contributions are determined and expressed by the web of their interrelationships, formed by network edges. Here, we underscore the important contributions made by brain network edges for understanding distributed brain organization. Different types of edges represent different types of relationships, including connectivity and similarity among nodes. Adopting a specific definition of edges can fundamentally alter how we analyze and interpret a brain network. Furthermore, edges can associate into collectives and higher order arrangements, describe time series, and form edge communities that provide insights into brain network topology complementary to the traditional node-centric perspective. Focusing on the edges, and the higher order or dynamic information they can provide, discloses previously underappreciated aspects of structural and functional network organization.
The “State” of Active Learning in the Atmospheric Sciences: Strategies Instructors Use and Directions for Future Research
Authors: Handlos Zachary J. , Davenport Casey , Kopacz Dawn 
Published: August 2021

Abstract
Extensive research within science, technology, engineering, and mathematics (STEM) fields has demonstrated that active learning leads to greater educational success for students relative to traditional lecture methods. While studies have explored active learning use across various STEM fields, minimal research has focused specifically on the atmospheric sciences. A baseline knowledge of the use of active learning in this field is vital for determining instructional effectiveness and can identify areas for improvement. The goal of this study is to provide a baseline regarding the state of active learning within the atmospheric sciences, including understanding what active learning strategies are most widely used, their frequency of use, and who is using them. Atmospheric science instructors were invited to participate in an online survey to provide information about their active learning use in the classroom and resources used to learn more about active learning strategies. Survey results indicate that case studies are the most popular high-use active learning strategy across all levels of instruction, though how they are implemented within the classroom is not clear. New atmospheric science instructors, instructors beyond the typical 5-yr tenure mark, and female instructors exhibit the highest number of unique active learning strategies. Future work stresses the need for a larger sample size and more direct classroom observation of instructors using active learning.
The Evolution of Hail Production in Simulated Supercell Storms
Authors: Kumjian Matthew R. , Lombardo Kelly , Loeffler Scott 
Published: August 2021

AbstractHailstorms pose a significant socioeconomic risk, necessitating detailed assessments of how the hail threat changes throughout their lifetimes. Hail production involves the favorable juxtaposition of ingredients, but how storm evolution affects these ingredients is unknown, limiting understanding of how hail production evolves. Unfortunately, neither surface hail reports nor radar-based swath estimates have adequate resolution or details needed to assess evolving hail production. Instead, we use a novel approach of coupling a detailed hail trajectory model to idealized convective storm simulations to better understand storm evolution’s influence on hail production. Hail production varies substantially throughout storms’ mature phases: maximum sizes vary by a factor of two, and the concentration of severe hail more than fivefold during 45-60-min periods. This variability arises from changes in updraft properties, which come from (i) changes in low-level convergence, and (ii) internal storm dynamics, including anticyclonic vortex shedding/storm splitting, and the response of the updraft’s airflow and supercooled liquid water content to these events. Hodograph shape strongly affects such behaviors. Straighter hodographs lead to more prolific hail production through wider updrafts and weaker mesocyclones, and a periodicity in hail size metrics associated with anticyclonic vortex shedding and/or storm splitting. In contrast, a curved hodograph (favorable for tornadoes) led to a storm with a stronger but more compact updraft, which occasionally produced giant (10-cm) hail, but that was a less-prolific severe hail producer overall. Unless storms are adequately sampled throughout their lifecycles, snapshots from ground reports will insufficiently resolve the true nature of hail production.
The Inland Maintenance and Reintensification of Tropical Storm Bill (2015) Part 1: Contributions of the Brown Ocean Effect
Authors: Wakefield Ryann A. , Basara Jeffrey B. , Shepherd J. Marshall , Brauer Noah , Furtado Jason C. , Santanello Joseph A. , Edwards Roger 
Published: August 2021

AbstractLandfalling tropical cyclones (TCs) often decay rapidly due to a decrease in moisture and energy fluxes over land when compared to the ocean surface. Occasionally, however, these cyclones maintain intensity or reintensify over land. Post-landfall maintenance and intensification of TCs over land may be a result of fluxes of moisture and energy derived from anomalously wet soils. These soils act similarly to a warm sea surface, in a phenomenon coined the “Brown Ocean Effect.” Tropical Storm (TS) Bill (2015) made landfall over a region previously moistened by anomalously heavy rainfall and displayed periods of reintensification and maintenance over land. This study evaluates the role of the Brown Ocean Effect on the observed maintenance and intensification of TS Bill using a combination of existing and novel approaches, including the evaluation of precursor conditions at varying temporal scales and making use of composite backward trajectories. Comparisons were made to landfalling TCs with similar paths that did not undergo TC maintenance and/or intensification (TCMI) as well as to TS Erin (2007), a known TCMI case. We show that the antecedent environment prior to TS Bill was similar to other known TCMI cases, but drastically different from the non-TCMI cases analyzed in this study. Furthermore, we show that contributions of evapotranspiration to the overall water vapor budget were non-negligible prior to TCMI cases and that evapotranspiration along storm inflow was significantly (p<0.05) greater for TCMI cases than non-TCMI cases suggesting a potential upstream contribution from the land surface.
Assessing the benefits of specific attenuation for quantitative precipitation estimation with a C-band radar network
Authors: Chen Ju-Yu , Trömel Silke , Ryzhkov Alexander , Simmer Clemens 
Published: August 2021

AbstractRecent advances demonstrate the benefits of radar-derived specific attenuation at horizontal polarization (AH) for quantitative precipitation estimation (QPE) at S and X band. To date the methodology has, however, not been adapted for the widespread European C-band radars such as installed in the network of the German Meteorological Service (DWD, Deutscher Wetterdienst). Simulations based on a large dataset of drop size distributions (DSDs) measured over Germany are performed to investigate the DSD dependencies of the attenuation parameter αH for the AH estimates. The normalized raindrop concentration (Nw) and the change of differential reflectivity (ZDR) with reflectivity at horizontal polarization (ZH) are used to categorize radar observations into regimes for which scan-wise optimized αH values are derived. For heavier continental rain with ZH > 40 dBZ, the AH-based rainfall retrieval R(AH) is combined with a rainfall estimator using a substitute of specific differential phase (). We also assess the performance of retrievals based on specific attenuation at vertical polarization (AV). Finally, the regime-adapted hybrid QPE algorithms are applied to four convective cases and one stratiform case from 2017 to 2019, and compared to DWD’s operational RAdar-OnLine-ANeichung (RADOLAN) RW rainfall product, which is based on Zh only but adjusted to rain gauge measurements. For the convective cases, our hybrid retrievals outperform the traditional R(Zh) and pure R(AH/V) retrievals with fixed αH/V values when evaluated with gauge measurements and outperform RW when evaluated by disdrometer measurements. Potential improvements using ray-wise αH/V and segment-wise applications of the ZPHI method along the radials are discussed.
This Is My Body: A Reflection on Medical and Spiritual Distancing During the COVID19 Pandemic
Authors: Acosta Lealani Mae Y. 
Published: August 2021

As sentient beings and as patients, clinicians, and Catholics, we long for touch and union. With COVID19, the distancing inherent during the pandemic manifests itself in medical and spiritual ways as we yearn to connect with our patients, our physicians, and the Eucharist. Summary: As sentient beings and as patients, clinicians, and Catholics, we long for touch and union. With COVID19, the distancing inherent during the pandemic manifests itself in medical and spiritual ways as we yearn to connect with our patients, our physicians, and the Eucharist. COVID19 distancing manifests in medical & spiritual ways as we yearn to connect with our patients, our physicians, and the Eucharist.