bluuebunny/crossref_metadata_2025_split huggingface dataset:
WT1 Tumor Antigen is Overexpressed in Kaposi Sarcoma and is Regulated by KSHV vFLIP
Authors: Morales Ayana , Genovese Caitlyn , Bott Matthew , Alvarez Julio , Mun Sung Soo , Totonchy Jennifer , Gautam Archana , de la Mora Jesus Delgado , Chang Stephanie , de Garayo Maite Ibáñez , Wirth Dagmar , Horenstein Marcelo , Dao Tao , Scheinberg David A. , Rubinstein Paul G. , Semeere Aggrey , Martin Jeffrey , Borok Margaret , Campbell Thomas B. , Krown Susan E. , Cesarman Ethel 
Published: February 2021

AbstractPurposeWilms’ tumor 1 (WT1) is overexpressed in several cancers, and WT1 expression levels are associated with poor prognosis. As a host protein that functions as an oncogene, it represents an important immunotherapeutic target. This study evaluated WT1 expression in Kaposi sarcoma (KS) tumors to assess whether immunotherapy targeting WT1 is a potential therapeutic approach for KS. We also investigated the role of the causal agent of KS, Kaposi sarcoma herpesvirus (KSHV/HHV-8) in regulating WT1 expression.Experimental designImmunohistochemistry for WT1, KSHV, and B and T cells subsets, followed by image analysis, was performed in 363 KS tumor biopsies. Expression of KSHV vFLIP was evaluated by immunofluorescence. Primary endothelial cell cultures and cell lines were infected with KSHV in vitro, or transduced with an inducible vFLIP vector and induced with doxycycline, and then assessed for WT1 expression. Binding of ESK-1, a T cell receptor mimic therapeutic antibody that recognizes WT1 peptides presented on MHC HLA-A0201, was assessed using flow cytometry.ResultsWe report overexpression of WT1 in KS tumors, which was associated with increased with increasing histopathologic stage and the proportion of KSHV-infected cells. Areas with high WT1 expression showed sparse T cell infiltrates. KSHV infection in vitro resulted in WT1 upregulation, mediated by the viral protein vFLIP, which resulted in stronger binding of ESK1.ConclusionsKS lesions express high levels of WT1, a process regulated by the KSHV-encoded vFLIP. These findings suggest that immunotherapy directed against WT1 may represent a therapeutic approach for this cancer.Translational RelevanceKaposi sarcoma (KS) is a vascular neoplasm caused by the Kaposi sarcoma herpesvirus (KSHV/HHV-8). People living with HIV are not only at a significantly higher risk of developing KS, but also often have a more aggressive clinical course. Although antiretroviral therapy may cause regression of HIV-associated KS lesions, advanced cases of KS also require chemotherapy, which is rarely curative. Wilms’ tumor 1 (WT1) has been reported to be overexpressed in various cancers, functioning as an oncogene and associated with a poor prognosis. WT1 is also an important immunotherapeutic target, with several WT1-directed therapies showing promising results in early clinical trials for leukemias and solid tumors. Here we report high expression of WT1 in KS, especially in higher histological stages. Our findings provide pre-clinical evidence that supports conducting anti-WT1 immunotherapy trials in KS, and evaluating WT1 expression as a potential biomarker to identify individuals most likely to benefit.
Informing patients that they are at high risk for serious complications of viral infection increases vaccination rates
Authors: Shermohammed Maheen , Goren Amir , Lanyado Alon , Yesharim Rachel , Wolk Donna M. , Doyle Joseph , Meyer Michelle N. , Chabris Christopher F. 
Published: February 2021

AbstractFor many vaccine-preventable diseases like influenza, vaccination rates are lower than optimal to achieve community protection. Those at high risk for infection and serious complications are especially advised to be vaccinated to protect themselves. Using influenza as a model, we studied one method of increasing vaccine uptake: informing high-risk patients, identified by a machine learning model, about their risk status. Patients (N=39,717) were evenly randomized to (1) a control condition (exposure only to standard direct mail or patient portal vaccine promotion efforts) or to be told via direct mail, patient portal, and/or SMS that they were (2) at high risk for influenza and its complications if not vaccinated; (3) at high risk according to a review of their medical records; or (4) at high risk according to a computer algorithm analysis of their medical records. Patients in the three treatment conditions were 5.7% more likely to get vaccinated during the 112 days post-intervention (p < .001), and did so 1.4 days earlier (p < .001), on average, than those in the control group. There were no significant differences among risk messages, suggesting that patients are neither especially averse to nor uniquely appreciative of learning their records had been reviewed or that computer algorithms were involved. Similar approaches should be considered for COVID-19 vaccination campaigns.
Assessment of presentation patterns of repetitive behaviors in Autism: a cross-sectional video-recording study. Preliminary report
Authors: Grossi Enzo , Caminada Elisa , Vescovo Beatrice , Castrignano Tristana , Piscitelli Daniele , Valagussa Giulio , Vanzulli Franco 
Published: February 2021

AbstractTwenty expert caregivers wearing a body cam recorded 1868 videoclips in 67 autistic subjects along a 3 months close follow-up. A team consisting of a senior child neuro-psychiatrist and a senior psychologist selected 780 of them as expressing repetitive behaviors (RB) and made an empirical classification according to components, complexity, body parts and sensory channels involved, with the aim to understand better the pattern complexity and correlate with autism severity. The RB spectrum for each subject ranged from 1 to 33 different patterns (average= 11.6; S.D.= 6.82). Forty subjects expressed prevalent simple pattern and 27 prevalent complex patterns. No significant differences are found between the two groups according to ADOS score severity. This study represents a first attempt to systematically document expression patterns of RB with a data driven approach. This may provide a better understanding of the pathophysiology, diagnosis, and treatment of RB.
Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide
Authors: Shi Hui , Gandhi Alex A. , Smith Stephanie A. , Wang Qiuyu , Chiang Diane , Yalavarthi Srilakshmi , Ali Ramadan A. , Liu Chao , Sule Gautam , Tsou Pei-Suen , Zuo Yu , Kanthi Yogendra , Farkash Evan A. , Lin Jiandie D. , Morrissey James H. , Knight Jason S. 
Published: February 2021

ABSTRACTNeutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/NET-derived histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the FDA-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.
An Autoantigen Profile of Human A549 Lung Cells Reveals Viral and Host Etiologic Molecular Attributes of Autoimmunity in COVID-19
Authors: Wang Julia Y. , Zhang Wei , Roehrl Michael W. , Roehrl Victor B. , Roehrl Michael H. 
Published: February 2021

AbstractWe aim to establish a comprehensive COVID-19 autoantigen atlas in order to understand autoimmune diseases caused by SARS-CoV-2 infection. Based on the unique affinity between dermatan sulfate and autoantigens, we identified 348 proteins from human lung A549 cells, of which 198 are known targets of autoantibodies. Comparison with current COVID data identified 291 proteins that are altered at protein or transcript level in SARS-CoV-2 infection, with 191 being known autoantigens. These known and putative autoantigens are significantly associated with viral replication and trafficking processes, including gene expression, ribonucleoprotein biogenesis, mRNA metabolism, translation, vesicle and vesicle-mediated transport, and apoptosis. They are also associated with cytoskeleton, platelet degranulation, IL-12 signaling, and smooth muscle contraction. Host proteins that interact with and that are perturbed by viral proteins are a major source of autoantigens. Orf3 induces the largest number of protein alterations, Orf9 affects the mitochondrial ribosome, and they and E, M, N, and Nsp proteins affect protein localization to membrane, immune responses, and apoptosis. Phosphorylation and ubiquitination alterations by viral infection define major molecular changes in autoantigen origination. This study provides a large list of autoantigens as well as new targets for future investigation, e.g., UBA1, UCHL1, USP7, CDK11A, PRKDC, PLD3, PSAT1, RAB1A, SLC2A1, platelet activating factor acetylhydrolase, and mitochondrial ribosomal proteins. This study illustrates how viral infection can modify host cellular proteins extensively, yield diverse autoantigens, and trigger a myriad of autoimmune sequelae.
Occupational exposures and mitigation strategies among homeless shelter workers at risk of COVID-19
Authors: Rao Carol Y. , Robinson Tashina , Huster Karin , Laws Rebecca , Keating Ryan , Tobolowsky Farrell , McMichael Temet , Gonzalez Elysia , Mosites Emily 
Published: February 2021

AbstractObjectiveTo describe the work environment and COVID-19 mitigation measures for homeless shelter workers and assess occupational risk factors for COVID-19 infectionMethodsBetween June 9-August 10, 2020, we conducted a self-administered survey among homeless shelter workers in Washington, Massachusetts, Utah, Maryland, and Georgia. We calculated frequencies for work environment, personal protective equipment use, and SARS-CoV-2 testing history. We used generalized linear models to produce unadjusted prevalence ratios (PR) to assess risk factors for SARS-CoV-2 infection.ResultsOf the 106 respondents, 43.4% reported frequent close contact with clients; 75% were worried about work-related SARS-CoV-2 infections; 15% reported testing positive. Close contact with clients was associated with testing positive for SARS-CoV-2 (PR 3.97, 95%CI 1.06, 14.93).ConclusionsHomeless shelter workers may be at higher risk of being infected with SARS-CoV-2 during the course of their work. Protecting these critical essential workers by implementing mitigation measures and prioritizing for COVID-19 vaccination, is imperative during the pandemic.
Analyzing Socioeconomic Factors and Health Disparity of COVID-19 Spatiotemporal Spread Patterns at Neighborhood Levels in San Diego County
Authors: Tsou Ming-Hsiang , Xu Jian , Lin Chii-Dean , Daniels Morgan , Embury Jessica , Ko Eunjeong , Gibbons Joseph 
Published: February 2021

AbstractThis study analyzed spatiotemporal spread patterns of COVID-19 confirmed cases at the zip code level in the County of San Diego and compared them to neighborhood social and economic factors. We used correlation analysis, regression models, and geographic weighted regression to identify important factors and spatial patterns. We broke down the temporal confirmed case patterns into four stages from 1 April 2020 to 31 December 2020. The COVID-19 outbreak hotspots in San Diego County are South Bay, El Cajon, Escondido, and rural areas. The spatial patterns among different stages may represent fundamental health disparity issues in neighborhoods. We also identified important variables with strong positive or negative correlations in these categories: ethnic groups, languages, economics, and education. The highest association variables were Pop5andOlderSpanish (Spanish-speaking) in Stage 4 (0.79) and Pop25OlderLess9grade (Less than 9thgrade education) in Stage 4 (0.79). We also observed a clear pattern that regions with more well-educated people have negative associations with COVID-19. Additionally, our OLS regression models suggested that more affluent populations have a negative relationship with COVID-19 cases. Therefore, the COVID-19 outbreak is not only a medical disease but a social inequality and health disparity problem.
Near real-time determination of B.1.1.7 in proportion to total SARS-CoV-2 viral load in wastewater using an allele-specific primer extension PCR strategy
Authors: Graber Tyson E. , Mercier Élisabeth , Bhatnagar Kamya , Fuzzen Meghan , D’Aoust Patrick M. , Hoang Huy-Dung , Tian Xin , Towhid Syeda Tasneem , Diaz Julio Plaza , Alain Tommy , Butler Ainslie , Goodridge Lawrence , Servos Mark , Delatolla Robert 
Published: February 2021

AbstractThe coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed millions of lives to date. Antigenic drift has resulted in viral variants with putatively greater transmissibility, virulence, or both. Early and near real-time detection of these variants of concern (VOC) and the ability to accurately follow their incidence and prevalence in communities is wanting. Wastewater-based epidemiology (WBE), which uses nucleic acid amplification tests to detect viral fragments, is a faithful proxy of COVID-19 incidence and prevalence, and thus offers the potential to monitor VOC viral load in a given population. Here, we describe and validate a primer extension PCR strategy targeting a signature mutation in the N gene of SARS-CoV-2. This allows quantification of the proportional expression of B.1.1.7 versus non-B.1.1.7 alleles in wastewater without the need to employ quantitative RT-PCR standard curves. We show that the wastewater B.1.1.7 profile correlates with its clinical counterpart and benefits from a near real-time and facile data collection and reporting pipeline. This assay can be quickly implemented within a current SARS-CoV-2 WBE framework with minimal cost; allowing early and contemporaneous estimates of B.1.1.7 community transmission prior to, or in lieu of, clinical screening and identification. Our study demonstrates that this strategy can provide public health units with an additional and much needed tool to rapidly triangulate VOC incidence/prevalence with high sensitivity and lineage specificity.
The early dynamics of the SARS-CoV-2 epidemic in Portugal
Authors: Borges V , Isidro J , Trovão NS , Duarte S , Cortes-Martins H , Martiniano H , Gordo I , Leite R , Vieira L ,   Portuguese network for SARS-CoV-2 genomics (Consortium), Guiomar R , Gomes JP 
Published: February 2021

ABSTRACTBackgroundGenomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. This unprecedented collaborative effort culminated in the generation of 1275 SARS-CoV-2 genome sequences, which represent 15.5% of all confirmed cases in March 2020, making Portugal one of the countries generating the highest volumes of SARS-CoV-2 genomic data during early COVID-19 pandemic.MethodsWe reconstructed and characterized the spatio-temporal dynamics of SARS-CoV-2 introductions and early dissemination in Portugal using recent phylodynamic models that allow integration of individual-based travel history, in order to obtain a more realistic reconstruction of the viral dynamics.ResultsWe detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy and Switzerland), which was broadly consistent with the available travel history data, as well as with the countries with most frequent connectivity and/or with the highest number of Portuguese immigrants. Although most introductions were estimated to have occurred during the last week of February and the first week of March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal several weeks before the first confirmed local cases on March 2, 2020.Discussion and ConclusionWhile the implemented preventive and early control measures seem to have been successful in mitigating community transmission from most independent introductions, our results suggest that their earlier implementation could have largely minimized the number of introductions and subsequent virus expansion. Here we lay the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlight the need for systematic, continuous and geographically-representative genomic surveillance to guide national and international public health authorities toward the characterization and control of SARS-CoV-2 circulating diversity.
Group IIA Secreted Phospholipase A2 Plays a Central Role in the Pathobiology of COVID-19
Authors: Snider Justin M. , You Jeehyun Karen , Wang Xia , Snider Ashley J , Hallmark Brian , Seeds Michael C. , Sergeant Susan , Johnstone Laurel , Wang Qiuming , Sprissler Ryan , Zhang Hao Helen , Luberto Chiara , Kew Richard R. , Hannun Yusuf A , McCall Charles E. , Yao Guang , Del Poeta Maurizio , Chilton Floyd H. 
Published: February 2021

AbstractThere is an urgent need to identify cellular and molecular mechanisms responsible for severe COVID-19 disease accompanied by multiple organ failure and high mortality rates. Here, we performed untargeted/targeted lipidomics and focused biochemistry on 127 patient plasma samples, and showed high levels of circulating, enzymatically active secreted phospholipase A2 Group IIA (sPLA2-IIA) in severe and fatal COVID-19 disease compared with uninfected patients or mild illness. Machine learning demonstrated that sPLA2-IIA effectively stratifies severe from fatal COVID-19 disease. We further introduce a PLA-BUN index that combines sPLA2-IIA and blood urea nitrogen (BUN) threshold levels as a critical risk factor for mitochondrial dysfunction, sustained inflammatory injury and lethal COVID-19. With the availability of clinically tested inhibitors of sPLA2-IIA, our study opens the door to a precision intervention using indices discovered here to reduce COVID-19 mortality.
Ketamine and attentional bias to threat: dynamic causal modeling of magnetoencephalographic connectivity in treatment-resistant depression
Authors: Gilbert Jessica R. , Galiano Christina S. , Nugent Allison C. , Zarate Carlos A. 
Published: February 2021

AbstractThe glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with MDD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and six to nine hours after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across timepoints using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in MDD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in MDD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine’s antidepressant effects.
TGF-β promotes microtube formation in glioblastoma through Thrombospondin 1
Authors: Joseph Justin V. , Magaut Capucine R. , Storevik Simon , Geraldo Luiz H. , Mathivet Thomas , Latif Md Abdul , Rudewicz Justine , Guyon Joris , Gambaretti Matteo , Haukas Frida , Trones Amalie , Rømo Ystaas Lars A. , Hossain Jubayer A. , Sandra Ninzima S , Zhou Wenjing , Tomar Tushar , Klink Barbara , Rane Lalit , Irving Bronwyn K. , Marrison Joanne , O’Toole Peter , Wurdak Heiko , Wang Jian , Di Zhang , Winkler Frank , Kruyt Frank A. E. , Bikfalvi Andreas , Bjerkvig Rolf , Daubon Thomas , Miletic Hrvoje 
Published: February 2021

AbstractMicrotubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. To identify potential signaling pathways involved in MT formation we performed a bioinformatics analysis of TCGA data showing that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. In particular we observed that signaling pathways involved in extracellular matrix organization are differentially expressed between these tumor entities. Using patient-derived GBM stem cell lines, we demonstrated that TGF-β1 stimulation promotes enhanced MT formation and communication via Calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo. In conclusion, TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT driven invasion/ resistance network.