bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient Reductions in Postoperative Pain and Anxiety using Virtual Reality in Children
Authors: Olbrecht Vanessa A. , O’Conor Keith T. , Williams Sara E. , Boehmer Chloe O. , Marchant Gilbert W. , Glynn Susan M. , Geisler Kristie J. , Pickerill Hannah M. , Ding Lili , Yang Gang , King Christopher D. 
Published: September 2020

AbstractObjectiveVirtual reality (VR) is a promising method to manage pain. Distraction-based VR (VR-D) is thought to reduce pain by redirecting attention. While VR-D can reduce pain associated with acutely painful procedures, it is unclear if VR-D can reduce pain after surgery. We assessed the ability of a single VR-D session to decrease acute postoperative pain and anxiety and explored if pain catastrophizing and anxiety sensitivity influenced the ability of VR-D to reduce these outcomes in children following surgery.DesignSingle-center, prospective, pilot studySettingCincinnati Children’s Hospital Medical Center (CCHMC)Subjects50 children/adolescents (age 7-21 years) with postoperative pain followed by the Acute Pain ServiceMethodsPatients received a single VR-D session following surgery. Prior to the VR-D session, patients completed pain catastrophizing (PCS-C) and anxiety sensitivity (CASI) questionnaires. Primary outcome consisted of changes in pain intensity following VR-D (immediately, 15, and 30 minutes). Secondary outcomes included changes in pain unpleasantness and anxiety.ResultsVR-D decreased pain intensity immediately and 15-minutes after VR-D. Reductions in pain unpleasantness were observed up to 30 minutes following VR-D. Anxiety was also reduced immediately and at 15-minutes following VR-D. While patients with higher pain catastrophizing had higher baseline pain intensity and unpleasantness, they did not show larger pain reductions following VR-D compared to those with lower pain catastrophizing.ConclusionsVR-D is beneficial in transiently reducing pain intensity, unpleasantness, and anxiety in children with acute postoperative pain. This study informs design of larger, controlled study assessing VR-D for acute postoperative pain and anxiety.
Molecular characterization of triple negative breast cancer formaldehyde-fixed paraffin-embedded samples by data-independent acquisition proteomics
Authors: García-Adrián Silvia , Trilla-Fuertes Lucía , Gámez-Pozo Angelo , Chiva Cristina , López-Vacas Rocío , López-Camacho Elena , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Lumbreras-Herrera María I. , Hardisson David , Yébenes Laura , Zamora Pilar , Sabidó Eduard , Vara Juan Ángel Fresno , Espinosa Enrique 
Published: September 2020

AbstractTriple negative breast cancer (TNBC) accounts for 15-20% of all breast carcinomas and it is clinically characterized by an aggressive phenotype and bad prognosis. TNBC does not benefit from any targeted therapy, so further characterization is needed to define subgroups with potential therapeutic value. In this work, the proteomes of one hundred twenty-five formalin-fixed paraffin-embedded samples from patients diagnosed with triple negative breast cancer were analyzed by mass spectrometry using data-independent acquisition. Hierarchical clustering, probabilistic graphical models and Significance Analysis of Microarrays were used to characterize molecular groups. Additionally, a predictive signature related with relapse was defined. Two molecular groups with differences in several biological processes as glycolysis, translation and immune response, were defined in this cohort, and a prognostic signature based on the abundance of proteins RBM3 and NIPSNAP1 was defined. This predictor split the population into low-risk and high-risk groups. The differential processes identified between the two molecular groups may serve to design new therapeutic strategies in the future and the prognostic signature could be useful to identify a population at high-risk of relapse that could be directed to clinical trials.
Modelling optimal vaccination strategy for SARS-CoV-2 in the UK
Authors: Moore Sam , Hill Edward M. , Dyson Louise , Tildesley Michael J. , Keeling Matt J. 
Published: September 2020

AbstractThe COVID-19 outbreak has highlighted our vulnerability to novel infections. Faced with this threat and no effective treatment, in line with many other countries, the UK adopted enforced social distancing (lockdown) to reduce transmission– successfully reducing the reproductive numberRbelow one. However, given the large pool of susceptible individuals that remain, complete relaxation of controls is likely to generate a substantial second wave. Vaccination remains the only foreseeable means of both containing the infection and returning to normal interactions and behaviour. Here, we consider the optimal targeting of vaccination within the UK, with the aim of minimising future deaths or quality adjusted life year (QALY) losses. We show that, for a range of assumptions on the action and efficacy of the vaccine, targeting older age groups first is optimal and can avoid a second wave if the vaccine prevents transmission as well as disease.
Enhanced functionality of low-affinity CD19 CAR T-cells is associated with activation priming and a polyfunctional cytokine phenotype
Authors: Michelozzi Ilaria M. , Castaneda Eduardo Gomez , Pohle Ruben V.C. , Rodriguez Ferran Cardoso , Sufi Jahangir , Costa Pau Puigdevall , Subramaniyam Meera , Kirtsios Efstratios , Eddaoudi Ayad , Wu Si Wei , Guvenel Aleks , Fisher Jonathan , Ghorashian Sara , Pule Martin A. , Tape Christopher J. , Castellano Sergi , Amrolia Persis J. , Giustacchini Alice 
Published: September 2020

AbstractWe recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and anti-tumour efficacy compared to the high-affinity (FMC63 based) CAR used in Tisagenlecleucel, in pre-clinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhancedin vivoexpansion, and long-term persistence in a Phase I clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T-cells, we performed a systematicin vitrocharacterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes occurring in T-cells expressing low-affinityvshigh-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.
Microbial metabolites of flavanols in urine are associated with enhanced anti-proliferative activity in bladder cancer cells in vitro
Authors: Griffin Laura E. , Kohrt Sarah E. , Rathore Atul , Kay Colin D. , Grabowska Magdalena M. , Neilson Andrew P. 
Published: September 2020

ABSTRACTDietary flavanols and their metabolites are excreted primarily via the urine, suggesting uroepithelial cells as a site of activity due to lengthy exposure to high concentrations of these compounds. Flavanols are metabolized by the gut microbiota to numerous bioavailable metabolites. The observed effects of flavanols, including cancer chemoprevention, may be due in part to the activities of microbial metabolites. Mostin vitromechanistic work in this area relies on a limited pool of commercially available or synthesized flavanol microbial metabolites, and little work has been done in the area of bladder cancer. The impact of physiologically relevant mixtures of native flavanols and their metabolites generatedin vivoremains unknown. Rats were fed various flavanols after which 48 h urine samples, approximating the total bioavailable metabolome, were collected. Urine samples were profiled by UPLC-MS/MS, and their anti-proliferative activities were assayedin vitroin four bladder cancer cell models. Significant interindividual variability was observed for chemical profiles and anti-proliferative activities. Concentrations of microbial metabolites (valerolactones, phenylalkyl acids and hippuric acids) were positively associated with reduced bladder cancer cell proliferationin vitro, while native flavanols were poorly correlated with activity. These results suggest that microbial metabolites may be the primary compounds responsible for chemoprevention in uroepithelial cell following flavanol consumption. Furthermore, this highlights the potential for exploiting knowledge about individual genetics, microbiome profiles, flavonoid metabolism profiles, tumor characteristics, etc. to design personalized dietary interventions for cancer prevention and/or adjuvant therapy to reduce bladder cancer incidence and improve outcomes.
In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike protein
Authors: Perez-Miller Samantha , Patek Marcel , Moutal Aubin , Cabel Carly R. , Thorne Curtis A. , Campos Samuel K. , Khanna Rajesh 
Published: September 2020

AbstractNeuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth and angiogenesis. In addition to a role in cancer, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain and cancer with the added potential of inhibiting SARS-CoV-2 virus entry.
Comparing two automated methods of DNA extraction from degraded skeletal remains
Authors: Rubinstein Linda 
Published: September 2020

AbstractDNA extraction from degraded skeletal samples is often particularly challenging. The difficulty derives from the fact that variable environment has significant effect on DNA preservation. During the years 2002-2015 unidentified degraded skeletal remains were accumulated at our institute, National Institute of Forensic Medicine (NIFM), most of them with none or partial DNA profile.As new methods rapidly emerge, we revisited the samples with partial DNA profiles. We have chosen to use these samples to compare two automated methods: Prepfiler Express BTA (Applied Biosystems) and QIAcube (Quiagen), in hope of acquiring a more complete DNA profile and eventually even make new identifications. In both methods a preparation step is required, after which the samples undergo automatic DNA extraction.The two protocols are based on different extraction methods. Fresh or non-problematic bone samples as the positive control gave the same results in both methods. In the degraded skeletal samples, the results were significantly better using the QIAcube method.
Smart Film Impacts Stomatal Sensitivity of Greenhouse Capsicum Through Altered Light
Authors: Zhao Chenchen , Chavan Sachin , He Xin , Zhou Meixue , Cazzonelli Christopher I. , Chen Zhong-Hua , Tissue David T. , Ghannoum Oula 
Published: September 2020

AbstractOptical films that alter light transmittance may reduce energy consumption in high-tech greenhouses, but their impact on crop physiology remains unclear. We compared the stomatal responses of capsicum plants grown hydroponically under control glass (70% diffuse light) or smart glass (SG) film ULR-80, which blocked >99% of ultraviolet light and 19% of photosynthetically active radiation (PAR). SG had no significant effects on steady-state (gs) or maximal (gmax) stomatal conductance. In contrast, SG reduced stomatal pore size and sensitivity to exogenous ABA thereby increasing rates of leaf water loss, guard cell K+and Cl-efflux, and Ca2+influx. The transition between low (100 μmol m−2s−1) and high (1500 μmol m−2s−1) PAR induced faster stomatal closing and opening rates in SG relative to control plants. The fraction of blue light (0% or 10%) did not affectgs, but induced stomatal oscillations in SG plants. Increased expression of stomatal closure and photoreceptor genes in epidermal peels of SG plants is consistent with fast stomatal responses to light changes. In conclusion, light intensity was more critical than spectral quality for optimal stomatal responses of capsicum under SG, and re-engineering of the SG should maximize PAR transmission to maintain a better stomatal development.HighlightsCapsicum plants grown under SG film exhibit decreased stomatal pore area, higher water loss and reduced ABA-sensitivity.SG-grown plants have faster rates of stomatal closing and opening in response to light intensity changes.SG increases efflux of K+and Cl-and influx of Ca2+of guard cells.SG upregulated the expression of key genes involved in stomatal regulation and light sensing.
Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline
Authors: Williams Owen A. , Shafer Andrea T. , Rivera Evian Perez , An Yang , Landman Bennett A. , Ferrucci Luigi , Resnick Susan M. 
Published: September 2020

AbstractINTRODUCTIONLittle is known about longitudinal decline in white matter (WM) microstructure and its associations with cognition in preclinical Alzheimer’s disease (AD).METHODSLongitudinal diffusion tensor imaging and neuropsychological testing from 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired, SI) and 200 cognitively normal controls. Rates of WM decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in WM and cognition were examined.RESULTSSI had faster decline in fractional anisotropy (FA) in the right inferior fronto-occipital fasciculus (R.IFOF) and bilateral splenium of the corpus callosum. Decline in R.IFOF FA was related to decline in verbal memory, visuospatial ability, processing speed, and MMSE (p≤ 0.05). Decline in bilateral splenium FA was related to decline in verbal fluency, processing speed, and MMSE (p≤ 0.05).DISCUSSIONAccelerated regional WM decline is characteristic of preclinical AD and related to domain specific cognitive decline.
LRRK2p.M1646T is associated with glucocerebrosidase activity and with Parkinson’s disease
Authors: Sosero Yuri L. , Yu Eric , Krohn Lynne , Rudakou Uladzislau , Mufti Kheireddin , Ruskey Jennifer A. , Asayesh Farnaz , Laurent Sandra B. , Spiegelman Dan , Fahn Stanley , Waters Cheryl , Sardi S. Pablo ,   International Parkinson Disease Genomics Consortium (IPDGC), Bandres-Ciga Sara , Alcalay Roy N. , Gan-Or Ziv , Senkevich Konstantin 
Published: September 2020

AbstractBackground and objectivesTheLRRK2p.G2019S Parkinson’s disease (PD) variant is associated with elevated glucocerebrosidase (GCase) activity in peripheral blood. We aimed to evaluate the association of otherLRRK2variants with PD and its association with GCase activity.MethodsLRRK2andGBAwere fully sequenced in 1,123 PD patients and 576 controls from the Columbia and PPMI cohorts, in which GCase activity was measured in dried blood spots by liquid chromatography-tandem mass spectrometry.ResultsLRRK2p.M1646T was associated with increased GCase activity in the Columbia University cohort (β=1.58,p=0.0003), and increased but not significantly in the PPMI cohort (β=0.29,p=0.58). p.M1646T was associated with PD (OR=1.18, 95%CI=1.09-1.28,p=7.33E-05) in 56,306 PD patients and proxy-cases, and 1.4 million controls.ConclusionsOur results suggest that the p.M1646T variant is associated with risk of PD with a small effect and with increased GCase activity in peripheral blood.
Epidemiological measures for informing the general public during the SARS-CoV-2-outbreak: simulation study about bias by incomplete case-detection
Authors: Brinks Ralph , Küchenhoff Helmut , Timm Jörg , Kurth Tobias , Hoyer Annika 
Published: September 2020

AbstractDuring the SARS-CoV-2 outbreak, several epidemiological measures, such as cumulative case-counts, incidence rates, effective reproduction numbers and doubling times, have been used to inform the general public and to justify interventions such as lockdown.During the course of the epidemic, it has been very likely that not all infectious people have been identified, which lead to incomplete case-detection. Apart from asymptomatic infections, possible reasons for incomplete case-detection are availability of test kits and changes in test policies during the course of the epidemic. So far, it has not been examined how biased the reported epidemiological measures are in the presence of incomplete case detection.In this work, we assess the four frequently used measures with respect to incomplete case-detection: 1) cumulative case-count, 2) incidence rate, 3) effective reproduction number and 4) doubling time. We apply an age-structured SIR model to simulate a SARS-CoV-2 outbreak followed by a lockdown in a hypothetical population. Different scenarios about temporal variations in case-detection are applied to the four measures during outbreak and lockdown. The biases resulting from incomplete case-detection on the four measures are compared. It turns out that the most frequently used epidemiological measure, the cumulative case count is most prone to bias in all of our settings. The effective reproduction number is the least biased measure.With a view to future reporting about this or other epidemics, we recommend to use of the effective reproduction number for informing the general public and policy makers.
Using Histopathology Images to Predict Chromosomal Instability in Breast Cancer: A Deep Learning Approach
Authors: Xu Zhuoran , Verma Akanksha , Naveed Uska , Bakhoum Samuel , Khosravi Pegah , Elemento Olivier 
Published: September 2020

AbstractChromosomal instability (CIN) is a hallmark of human cancer that involves mis-segregation of chromosomes during mitosis, leading to aneuploidy and genomic copy number heterogeneity. CIN is a prognostic marker in a variety of cancers, yet, gold-standard experimental assessment of chromosome mis-segregation is difficult in the routine clinical setting. As a result, CIN status is not readily testable for cancer patients in such setting. On the other hand, the gold-standard for cancer diagnosis and grading, histopathological examinations, are ubiquitously available. In this study, we sought to explore whether CIN status can be predicted using hematoxylin and eosin (H&E) histology in breast cancer patients. Specifically, we examined whether CIN, defined using a genomic aneuploidy burden approach, can be predicted using a deep learning-based model. We applied transfer learning on convolutional neural network (CNN) models to extract histological features and trained a multilayer perceptron (MLP) after aggregating patch features obtained from whole slide images. When applied to a breast cancer cohort of 1,010 patients (Training set: n=858 patients, Test set: n=152 patients) from The Cancer Genome Atlas (TCGA) where 485 patients have high CIN status, our model accurately classified CIN status, achieving an area under the curve (AUC) of 0.822 with 81.2% sensitivity and 68.7% specificity in the test set. Patch-level predictions of CIN status suggested intra-tumor spatial heterogeneity within slides. Moreover, presence of patches with high predicted CIN score within an entire slide was more predictive of clinical outcome than the average CIN score of the slide, thus underscoring the clinical importance of spatial heterogeneity. Overall, we demonstrated the ability of deep learning methods to predict CIN status based on histopathology slide images. Our model is not breast cancer subtype specific and the method can be potentially extended to other cancer types.
Tuning TPO-R signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia
Authors: Cui Lu , Moraga Ignacio , Lerbs Tristan , Neste Camille Van , Wilmes Stephan , Tsutsumi Naotaka , Trotman-Grant Aaron Claudius , Gakovic Milica , Andrews Sarah , Gotlib Jason , Darmanis Spyridon , Enge Martin , Quake Stephen , Hitchcock Ian S. , Piehler Jacob , Garcia K. Christopher , Wernig Gerlinde 
Published: September 2020

AbstractThrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL)) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable, both experimentally and clinically. We have developed a series of surrogate protein-ligands for TPO-R, in the form of diabodies, that homodimerize the TPO-R on the cell surface in different geometries, in effect ‘tuning’ downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism and antagonism, thus decoupling the dual functions of TPO/TPO-R. Using scRNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in Essential Thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.Significance StatementThe TPO cytokine, which signals through its receptor c-MPL (or TPO-R), is essential for megakaryocyte differentiation and maintenance of hematopoietic stem cells (HSCs). Its signaling is deregulated in Essential Thrombocythemia (ET). Here, we engineered diabodies (DBs) against the TPO-R as surrogate TPO ligands to manipulate TPO-R signaling, from full to partial to antagonism, thus decoupling the dual functions of TPO/TPO-R (i.e, HSC maintenance versus megakaryopoiesis). We subsequently discovered that partial agonistic DBs, by reducing the strength of the TPO-R signal, not only preserved HSCs in culture, but also blocked oncogenic signaling in ET. This finding has the potential to improve HSC cultures for transplants, as well as serve as a unique therapeutic approach for ET.