bluuebunny/crossref_metadata_2025_split huggingface dataset:
Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review: Efficacy and Safety of Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL)
Authors: Weinstein Bayarmagnai , Muresan Bogdan , Solano Sara , Vaz de Macedo Antonio , Lee YoonJung , Su Yu-Chen , Ahn Yeseul , Henriquez Gabriela , Camargo Cristina , Kim Gwang-Jin , Carpenter David O. 
Published: October 2021

ABSTRACTDespite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.NOVELTY AND IMPACTAlthough currently approved CAR T-cells demonstrated unprecedently high response in relapsed / refractory LBCL in the salvage setting, lack of outcome durability and toxicity remain. We delineated the relative clinical benefit of the innovative experimental CAR T-cell approaches to Yescarta for insights into the ongoing efforts to address these inadequacies. Tandem CAR T-cells may provide higher efficacy and safer profile than Yescarta. Toxicity attenuated CAR T-cells present remarkable safety but no Progression-Free Survival (PFS) benefit.
Metabolic demand regulates selective cell death in Parkinson’s Disease
Authors: Zhao Luke , Nanal Ishaan , Wang Linxi , Looka Andrew , Bezaire Marianne 
Published: October 2021

AbstractParkinson’s Disease (PD) is a debilitating neurodegenerative condition that affects over 10 million people across the world, causing tremors and muscle weakness. Its mechanisms are unknown, but one key feature is selective cell death: neurons in the Substantia Nigra Pars Compacta (SNc) die, but their neighbors, the cells in the Ventral Tegmental Area (VTA), remain healthy. To study this phenomenon, we used an established single neuron model of the SNc, adapting its biophysical and bioenergetic properties to match that of the VTA. We discovered that reducing calcium influx correlates with higher ATP and lower ROS concentrations in the cell, suggesting in silico the importance of calcium influx in metabolic stress and selective vulnerability for Parkinson’s Disease. Future efforts may target calcium channel inhibition as a therapeutic strategy, although caution is needed with potential metabolic side effects.
Substrate preferences, phylogenetic and biochemical properties of proteolytic bacteria present in the digestive tract of Nile tilapia
Authors: Hossain Tanim Jabid , Das Mukta , Ali Ferdausi , Chowdhury Sumaiya Islam , Zedny Subrina Akter 
Published: October 2021

AbstractVertebrate intestine appears an excellent source of proteolytic bacteria for industrial and probiotic use. We therefore aimed obtaining the gut-associated proteolytic species of Nile tilapia. We’ve isolated twenty six bacterial strains from its intestinal tract, seven of which showed exoprotease activity with the formation of clear halos on skim milk. Their depolymerization ability was further assessed on three distinct proteins including casein, gelatin and albumin. All the isolates could successfully hydrolyze the three substrates indicating relatively broad specificity of their secreted proteases. Molecular taxonomy and phylogeny of the proteolytic isolates were determined based on their 16S rRNA gene barcoding which suggested that the seven strains belong to three phyla viz. Firmicutes, Proteobacteria and Actinobacteria, distributed across the genera Priestia, Citrobacter, Pseudomonas, Stenotrophomonas, Burkholderia, Providencia and Micrococcus. The isolates were further characterized by a comprehensive study of their morphological, cultural, cellular and biochemical properties which were consistent with the phylogenetic annotations. To reveal their proteolytic capacity alongside substrate preferences, enzyme-production was determined by the diffusion assay. The Pseudomonas, Stenotrophomonas and Micrococcus isolates appeared most promising with maximum protease production on casein, gelatin and albumin media respectively. Our findings present valuable insights into the phylogenetic and biochemical properties of gut-associated proteolytic strains of Nile tilapia.
Plant structural and nutritional responses to drought differ among common pasture species
Authors: Catunda Karen L. M. , Churchill Amber C. , Power Sally A. , Zhang Haiyang , Fuller Kathryn J. , Moore Ben D. 
Published: October 2021

ABSTRACTIn the face of a changing climate, research indicates that more frequent and severe drought conditions are critical problems that will constrain production of high-quality forage and influence the performance of grazing animals in the future. In addition, the duration of drought and potential trade-offs between plant morphology and nutritional composition may influence plant drought adaptation strategies across pasture species, and the consequences for forage quality are not well understood. Here we present the results of a study investigating the effects of drought on biomass productivity, dead material, leaf:stem biomass allocation and nutritional composition (whole-plant and tissue-specific) across nine diverse pasture species. For this, we conducted a field experiment exposing species to a 6-month period of simulated severe drought (60% rainfall reduction during winter and spring) and samples were collected at multiple harvests. We found that drought had different, harvest-specific effects on plant biomass structure and nutritional composition among pasture species. The severity of drought impacts on productivity, but not on nutritional quality, increased with drought duration. In general, drought strongly reduced productivity, increased the percentage of dead material and had mixed effects (increases, decreases and no effect) on leaf:stem ratio and concentrations of crude protein, non-structural carbohydrates, neutral detergent fibre and lignin. Changes in plant-level nutritional quality were driven by simultaneous changes in both leaf and stem tissues for most, but not all, species. Our findings may be especially helpful for selection of adapted species/cultivars that could minimize potential drought risks on forage, thereby optimising pasture performance under future drought scenarios.
ReviewR: A light-weight and extensible tool for manual review of clinical records
Authors: Mayer David A. , Rasmussen Luke V. , Roark Christopher D. , Kahn Michael G. , Schilling Lisa M. , Wiley Laura K. 
Published: October 2021

ABSTRACTOBJECTIVESManual record review is a crucial step for electronic health record (EHR)-based research, but it has poor workflows and is error prone. We sought to build a tool that provides a unified environment for data review and chart abstraction data entry.MATERIALS AND METHODSReviewR is an open-source R Shiny application that can be deployed on a single machine or made available to multiple users. It supports multiple data models and database systems, and integrates with the REDCap API for storing abstraction results.RESULTSWe describe two real-world uses and extensions of ReviewR. Since its release in April 2021 as a package on CRAN it has been downloaded 2,204 times.DISCUSSION AND CONCLUSIONReviewR provides an easily accessible review interface for clinical data warehouses. Its modular, extensible, and open source nature afford future expansion by other researchers.LAY SUMMARYWhen doing research using data from electronic health records (EHRs), data may need to be extracted by hand, either to perform the study or to ensure its accuracy. However many researchers can’t access the EHR for this purpose. Even when researchers have access, they must flip between their review list, the EHR, and the location they are recording the results of their review, which is difficult and can cause errors. We developed a software application, ReviewR, to make this process easier and less error prone and have used it in two real-world projects.
Safety and Immunogenicity of the COVID-19 Vaccine BNT162b2 in Patients Undergoing Chemotherapy for Solid Cancer
Authors: Funakoshi Yohei , Yakushijin Kimikazu , Ohji Goh , Hojo Wataru , Sakai Hironori , Takai Ryo , Nose Taku , Ohata Shinya , Nagatani Yoshiaki , Koyama Taiji , Kitao Akihito , Nishimura Meiko , Imamura Yoshinori , Kiyota Naomi , Harada Kenichi , Tanaka Yugo , Mori Yasuko , Minami Hironobu 
Published: October 2021

AbstractBackgroundAlthough COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported.MethodsWe investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination.ResultsAnti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063-1.205] and 0.161 [0.07-0.857] vs 0.644 [0.259-1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups.ConclusionAlthough there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.Mini abstractTiters of anti-S1 antibody after the second dose of BNT162b2 were significantly lower in patients with solid tumors undergoing active anticancer treatment than in the healthy volunteers.
Metacognitive insight into cognitive performance in pre and early-stage Huntington’s disease
Authors: Hewitt Samuel RC , White Alice J , Mason Sarah L , Barker Roger A 
Published: October 2021

ABSTRACTObjectivesInsight is an important predictor of quality of life in Huntington’s disease and other neurodegenerative conditions. However, estimating insight with traditional methods such as questionnaires is challenging and subject to limitations. This cross-sectional study experimentally quantified metacognitive insight into cognitive performance in Huntington’s disease gene-carriers.MethodsWe dissociated perceptual decision-making performance and metacognitive insight into performance in healthy controls (n=29), premanifest (n=19) and early-manifest (n=10) Huntington’s disease gene-carriers. Insight was operationalised as the degree to which a participant’s confidence in their performance was informative of their actual performance (metacognitive efficiency) and estimated using a computational model (HMeta-d).ResultsWe found that pre and early-manifest Huntington’s disease gene-carriers were impaired in making perceptual decisions compared to controls. Gene-carriers required more evidence in favour of the correct choice to achieve similar performance and perceptual impairments were increased in those with manifest disease. Surprisingly, despite marked perceptual impairments, Huntington’s disease gene-carriers retained metacognitive insight into their perceptual performance. This was the case after controlling for confounding variables and regardless of disease stage.ConclusionWe report for the first time a dissociation between impaired cognition and intact metacognition (trial-by-trial insight) in the early-stages of a neurodegenerative disease. This unexpected finding contrasts with the prevailing assumption that cognitive deficits are associated with impaired insight. Future studies should investigate how intact metacognitive insight could be used by some early Huntington’s disease gene-carriers to positively impact their quality of life.
Immunoprecipitation-targeted proteomics assays facilitate rational development of SARS-CoV-2 serological diagnostics
Authors: Fu Zhiqiang , Rais Yasmine , Drabovich Andrei P. 
Published: October 2021

ABSTRACTCurrent design of serological tests employs conservative immunoassay approaches and is often focused on convenience, speed of manufacturing, and affordability. Limitations of such serological tests include semi-quantitative measurements, lack of standardization, potential cross-reactivity, and inability to distinguish between antibody subclasses. As a result of cross- reactivity, diagnostic specificity of serological antibody tests may not be sufficiently high to enable screening of the general asymptomatic populations for the acquired immunity against low-prevalence infectious diseases, such as COVID-19. Likewise, lack of a single standard for assay calibration limits inter-laboratory and international standardization of serological tests. In this study, we hypothesize that combination of immunoaffinity enrichments with targeted mass spectrometry measurements would enable rational design of serology diagnostics of infectious diseases, such as COVID-19. The same instrumental platform allows for sensitive and specific measurements of viral protein antigens, as wells as anti-viral antibodies circulating in human serum. Our proof-of-concept immunoprecipitation - parallel reaction monitoring (IP-PRM) assays quantified NCAP_SARS2 protein with a limit of detection of 313 pg/mL in serum. In addition, a multiplex IP-selected reaction monitoring (IP-SRM) assay facilitated differential quantification of anti-SARS-CoV-2 antibody isotypes and subclasses in patient sera. Simultaneous evaluation of numerous antigen-antibody subclass combinations revealed a receptor-binding domain (RBD)-IgG1 as a combination with the highest diagnostic specificity and sensitivity. Anti-RBD IgG1, IgG3, IgM and IgA1 subclasses, but not IgG2, IgG4 and IgA2, were found elevated in COVID-19-positive sera. Synthetic heavy isotope-labeled peptide internal standards as calibrators revealed elevated anti-RBD IgG1 in positive (510-6700 ng/mL; 0.02-0.22% of total serum IgG1) versus negative sera (60 [interquartile range 41-81] ng/mL). Likewise, anti-RBD IgM was elevated in positive (190-510 ng/mL; 0.06-0.16% of total serum IgM) versus negative sera (76 [31-108] ng/mL). Further validation of immunoprecipitation-targeted proteomics assays as a platform for serological assays will facilitate standardization and improvement of the existing serological tests, enable rational design of novel tests, and offer tools for comprehensive investigation of antibody isotype and subclass cooperation in immunity response.
Malaria parasites utilize pyrophosphate to fuel an essential proton pump in the ring stage and the transition to trophozoite stage
Authors: Solebo Omobukola , Ling Liqin , Zhou Jing , Fu Tian-Min , Ke Hangjun 
Published: October 2021

AbstractThe malaria parasite relies on anaerobic glycolysis for energy supply when growing inside RBCs as its mitochondrion does not produce ATP. The ring stage lasts ∼ 22 hours and is traditionally thought to be metabolically quiescent. However, recent studies show that the ring stage is active for several energy-costly processes including gene transcription/translation, protein export, and movement inside the RBC. It has remained unclear if a low glycolytic flux can meet the energy demand of the ring stage. Here we show that the metabolic by-product, pyrophosphate, is a critical energy source for the development of the ring stage and its transition to the trophozoite stage. During early phases of the asexual development, the parasite utilizes Plasmodium falciparum vacuolar pyrophosphatase 1 (PfVP1), an ancient pyrophosphate-driven proton pump, to pump protons across the parasite plasma membrane to maintain the membrane potential and cytosolic pH. Conditional deletion of PfVP1 leads to delayed ring stage development and a complete blockage of the ring-to-trophozoite transition, which can be partially rescued by Arabidopsis thaliana vacuolar pyrophosphatase 1, but not by the soluble pyrophosphatase from Saccharomyces cerevisiae. Proton-pumping pyrophosphatases are absent in humans, which highlights the possibility of developing highly selective VP1 inhibitors against the malaria parasite.
Homosalate boosts the release of tumor-derived Extracellular Vesicles with anti-anoikis properties
Authors: Grisard Eleonora , Lescure Aurianne , Nevo Nathalie , Corbé Maxime , Jouve Mabel , Lavieu Gregory , Joliot Alain , Nery Elaine Del , Martin-Jaular Lorena , Théry Clotilde 
Published: October 2021

AbstractEukaryotic cells, including cancer cells, secrete highly heterogeneous populations of extracellular vesicles (EVs). EVs could have different subcellular origin, composition and functional properties, but tools to distinguish between EV subtypes are scarce. Here, we tagged CD63- or CD9-positive EVs secreted by triple negative breast cancer cells with Nanoluciferase enzyme, to set-up a miniaturized method to quantify secretion of these two EV subtypes directly in the supernatant of cells. We performed a cell-based high-content screening to identify clinically-approved drugs able to affect EV secretion. One of the identified hits is Homosalate, an anti-inflammatory drug found in sunscreens which robustly increased EVs’ release. Comparing EVs induced by Homosalate with those induced by Bafilomycin A1, we discovered that: 1) the two drugs act on EVs generated in distinct subcellular compartments and 2) EVs released upon treatment with Homosalate, but not with Bafilomycin A1, conferred anti-anoikis properties to another recipient tumor cell line. In conclusion, we identified a new drug modifying EV release and demonstrated that under influence of different drugs, triple negative breast cancer cells release EV subpopulations from different subcellular origins harboring distinct functional properties.
Evolution of diapause in the African turquoise killifish by remodeling ancient gene regulatory landscape
Authors: Singh Param Priya , Reeves G. Adam , Contrepois Kévin , Ellenberger Mathew , Hu Chi-Kuo , Snyder Michael P. , Brunet Anne 
Published: October 2021

ABSTRACTSuspended animation states such as hibernation or diapause allow organisms to survive extreme environments. But the mechanisms underlying the evolution of these extreme survival states are unknown. The African turquoise killifish has evolved diapause as a form of suspended development to survive the complete drought that occurs every year in its habitat. Here we show that many gene duplicates – paralogs – exhibit specialized expression in diapause versus normal development in the African turquoise killifish. Surprisingly, paralogs with specialized expression in diapause are evolutionarily very ancient, and they are also present even in vertebrates that do not exhibit diapause. Profiling the chromatin accessibility landscape among different fish species reveals an evolutionarily recent increase in chromatin accessibility at these very ancient paralogs, suggesting rewiring of their regulatory landscape. The increase in chromatin accessibility in the African turquoise killifish is linked to the presence of new binding sites for transcription factors (e.g., FOXO, REST, and PPAR), due to both de novo mutations and transposable element insertion. Interestingly, accessible chromatin regions in diapause are enriched for lipid metabolism genes. By performing lipidomics in different fish species, we uncover a specific lipid profile in African turquoise killifish embryos in diapause. Notably, select very long-chain fatty acids are high in diapause, suggesting they may be used for long-term survival in this state. Together, our multi-omic analysis indicates that diapause is driven by regulatory innovation of very ancient gene programs that are critical for survival. Our work also suggests a mechanism for how complex adaptations evolve in nature and offers strategies by which a suspended animation program could be reactivated in other species for long-term preservation.
Disentangling single-cell omics representation with a power spectral density-based feature extraction
Authors: Zandavi Seid Miad , Koch Forrest , Vijayan Abhishek , Zanini Fabio , Mora Fa Valdes , Ortega David Gallego , Vafaee Fatemeh 
Published: October 2021

AbstractEmerging single-cell technologies provide high-resolution measurements of distinct cellular modalities opening new avenues for generating detailed cellular atlases of many and diverse tissues. The high dimensionality, sparsity, and inaccuracy of single cell sequencing measurements, however, can obscure discriminatory information, mask cellular subtype variations and complicate downstream analyses which can limit our understanding of cell function and tissue heterogeneity. Here, we present a novel pre-processing method (scPSD) inspired bypower spectral densityanalysis that enhances the accuracy for cell subtype separation from large-scale single-cell omics data. We comprehensively benchmarked our method on a wide range of single-cell RNA-sequencing datasets and showed that scPSD pre-processing, while being fast and scalable, significantly reduces data complexity, enhances cell-type separation, and enables rare cell identification. Additionally, we applied scPSD to transcriptomics and chromatin accessibility cell atlases and demonstrated its capacity to discriminate over 100 cell types across the whole organism and across different modalities of single-cell omics data.