bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy
Authors: Wudhikarn Kitsada , Flynn Jessica R. , Rivière Isabelle , Gönen Mithat , Wang Xiuyan , Senechal Brigitte , Curran Kevin J. , Roshal Mikhail , Maslak Peter G. , Geyer Mark B. , Halton Elizabeth F. , Diamonte Claudia , Davila Marco L. , Sadelain Michel , Brentjens Renier J. , Park Jae H. 
Published: April 2021

Abstract
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post–CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post–CAR T progression. Thirty patients (79%) received salvage treatment of post–CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post–CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.
HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis
Authors: Gooptu Mahasweta , Romee Rizwan , St. Martin Andrew , Arora Mukta , Al Malki Monzr , Antin Joseph H. , Bredeson Christopher N. , Brunstein Claudio G. , Chhabra Saurabh , Fuchs Ephraim J. , Ghosh Nilanjan , Grunwald Michael R. , Kanakry Christopher G. , Kekre Natasha , McGuirk Jospeh P. , McNiece Ian K. , Mehta Rohtesh S. , Mielcarek Marco , Milano Fillipo , Modi Dipenkumar , Reshef Ran , Solomon Scott R. , Schroeder Mark A. , Waller Edmund K. , Inamoto Yoshiro , Soiffer Robert J. , Eapen Mary 
Published: April 2021

AbstractPosttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
LncRNA-Fendrr protects against the ubiquitination and degradation of NLRC4 protein through HERC2 to regulate the pyroptosis of microglia
Authors: Wang Li-Qing , Zheng Yue-Ying , Zhou Heng-Jun , Zhang Xiong-Xin , Wu Pin , Zhu Sheng-Mei 
Published: April 2021

Abstract
Objectives
Targeted inhibition of inflammatory response can reduce diabetic cerebral ischemia–reperfusion (I/R) injure. Pyroptosis is characterized by caspase-1 dependence and the release of a large number of pro-inflammatory factors. LncRNA-Fendrr is associated with a variety of diseases, but Fendrr has not been studied in diabetic cerebral I/R. NLR-family CARD-containing protein 4 (NLRC4) regulate the pyroptosis of microglia cells. This study was designed to investigate whether Fendrr is involved in the effects of diabetic cerebral I/R injury.

Methods
The diabetic brain I/R model in mice was constructed. Mouse microglia cell line BV-2 cells were exposed to high glucose followed by hypoxia/reoxygenation (H/R). Fendrr and some pyroptosis-associated proteins were detected by qRT-PCR, western blot or ELISA. HE staining was used to detect pathological changes. Microglia pyroptosis was detected by TUNEL staining. RNA pull-down and RNA Immunoprecipitation were used to detect binding of Fendrr to HERC2 (E3 ubiquitin ligase), and CO-IP detected binding of HERC2 to NLRC4. The ubiquitination of NLRC4 was detected by ubiquitination experiments.

Results
Fendrr was significantly increased in the diabetic cerebral I/R model, and NLRC4 inflammatory complex and pyroptosis mediated inflammatory factors were increased. NLRC4 and inflammatory cytokines associated with pyroptosis were decreased in the high glucose-treated hypoxia/reoxygenation (H/R)-induced microglia after Fendrr knockdown. Fendrr bound to HERC2 protein, and HERC2 bound to NLRC4. Meanwhile, Fendrr could inhibit the ubiquitination of NLRC4, HERC2 promoted the ubiquitination of NLRC4 protein. Moreover, the effect of Fendrr overexpression in the diabetic cerebral I/R model of microglia can be reversed by HERC2 overexpression.

Conclusion
Fendrr can protect against the ubiquitination and degradation of NLRC4 protein through E3 ubiquitin ligase HERC2, thereby accelerating the pyroptosis of microglia.
Clinical implications for dopaminergic and functional neuroimage research in cognitive symptoms of Parkinson’s disease
Authors: Hirano Shigeki 
Published: April 2021

AbstractEvidence from dopaminergic image and cerebral blood flow/metabolism images have shed light on symptomatology of cognitive aspects in brain physiology of healthy human as well as patients with Parkinson’s disease. Cognitive impairment in Parkinson’s disease is characterized by executive, visuospatial, attentional disturbances. Dopaminergic system includes triadic parallel pathways. The mesostriatal pathway consist of posterolateral putamen and motor areas, the mesocortical pathway of dorsal caudate nucleus and dorsolateral prefrontal cortex, and the mesolimbic pathway of ventral striatum, anterior cingulate cortex. The mesocortical pathway is responsible for the executive function which may change by administration of dopaminergic medication. The mesolimbic pathway is associated with motivation and reward prediction which may result in depression or apathy when dopamine level was suboptimal, impulse control disorder and punding when dopamine was over the optimal level. Abnormal brain metabolism/perfusion related to cognitive impairment in Parkinson’s disease are relatively reduced activity located in frontal and parietal association areas and relatively increased activity in the cerebellum. In the anterior brain, the mesocortical pathway, is responsible for verbal memory and executive function, which originates with caudate dopaminergic system and account for mild cognitive impairment of Parkinson’s disease. The posterior brain system which includes the parietal, temporal, and occipital cortices, is responsible for the memory and visuospatial function, and related to cholinergic dysfunction and possibly glucocerebrosidase gene variants, relating to dementia in Parkinson’s disease. The role of cerebellum in Parkinson’s disease remains unclear but emerging evidence suggests that it may relate to the sequencing detection and affective symptoms. The dual syndrome hypothesis is helpful for understanding the mechanism of cognitive impairment in Parkinson’s disease and optimal symptom management.
The burden attributable to headache disorders in children and adolescents in Lithuania: estimates from a national schools-based study
Authors: Genc Diana , Vaičienė-Magistris Nerija , Zaborskis Apolinaras , Şaşmaz Tayyar , Tunç Aylin Yeniocak , Uluduz Derya , Wöber Christian , Wöber-Bingöl Çiçek , Steiner Timothy J. 
Published: April 2021

Abstract
Background
We recently showed headache to be common in children (aged 7–11 years) and adolescents (aged 12–17) in Lithuania. Here we provide evidence from the same study of the headache-attributable burden.

Methods
Following the generic protocol for Lifting The Burden’s global schools-based study, this cross-sectional survey administered self-completed structured questionnaires to pupils within classes in 24 nationally representative schools selected from seven regions of the country. Headache diagnostic questions were based on ICHD-3 beta criteria but for the inclusion of undifferentiated headache (UdH; defined as mild headache with usual duration < 1 h). Burden enquiry was conducted in multiple domains.

Results
Questionnaires were completed by 2505 pupils (1382 children, 1123 adolescents; participating proportion 67.4%), of whom 1858 reported headache in the preceding year, with mean frequency (±SD) of 3.7 ± 4.5 days/4 weeks and mean duration of 1.6 ± 1.9 h. Mean proportion of time in ictal state, estimated from these, was 0.9% (migraine 1.5%, probable medication-overuse headache [pMOH] 10.9%). Mean intensity on a scale of 1–3 was 1.6 ± 0.6 (mild-to-moderate). Symptomatic medication was consumed on 1.5 ± 2.8 days/4 weeks. Lost school time was 0.5 ± 1.5 days/4 weeks (migraine 0.7 ± 1.5, pMOH 5.0 ± 7.8) based on recall, but about 50% higher for migraine according to actual absences recorded in association with reported headache on the preceding day. More days were reported with limited activity (overall 1.2 ± 2.4, migraine 1.5 ± 2.2, pMOH 8.4 ± 8.5) than lost from school. One in 30 parents (3.3%) missed work at least once in 4 weeks because of their son’s or daughter’s headache. Emotional impact and quality-of-life scores generally reflected other measures of burden, with pMOH causing greatest detriments, followed by migraine and tension-type headache, and UdH least. Burdens were greater in adolescents than children as UdH differentiated into adult headache types.

Conclusions
Headache in children and adolescents in Lithuania is mostly associated with modest symptom burden. However, the consequential burdens, in particular lost school days, are far from negligible for migraine (which is prevalent) and very heavy for pMOH (which, while uncommon in children, becomes four-fold more prevalent in adolescents). These findings are of importance to both health and educational policies in Lithuania.
ChIP-BIT2: a software tool to detect weak binding events using a Bayesian integration approach
Authors: Chen Xi , Shi Xu , Neuwald Andrew F. , Hilakivi-Clarke Leena , Clarke Robert , Xuan Jianhua 
Published: April 2021

AbstractBackgroundChIP-seq combines chromatin immunoprecipitation assays with sequencing and identifies genome-wide binding sites for DNA binding proteins. While many binding sites have strong ChIP-seq ‘peak’ observations and are well captured, there are still regions bound by proteins weakly, with a relatively low ChIP-seq signal enrichment. These weak binding sites, especially those at promoters and enhancers, are functionally important because they also regulate nearby gene expression. Yet, it remains a challenge to accurately identify weak binding sites in ChIP-seq data due to the ambiguity in differentiating these weak binding sites from the amplified background DNAs.ResultsChIP-BIT2 (http://sourceforge.net/projects/chipbitc/) is a software package for ChIP-seq peak detection. ChIP-BIT2 employs a mixture model integrating protein and control ChIP-seq data and predicts strong or weak protein binding sites at promoters, enhancers, or other genomic locations. For binding sites at gene promoters, ChIP-BIT2 simultaneously predicts their target genes. ChIP-BIT2 has been validated on benchmark regions and tested using large-scale ENCODE ChIP-seq data, demonstrating its high accuracy and wide applicability.ConclusionChIP-BIT2 is an efficient ChIP-seq peak caller. It provides a better lens to examine weak binding sites and can refine or extend the existing binding site collection, providing additional regulatory regions for decoding the mechanism of gene expression regulation.
Predicting tumor response to drugs based on gene-expression biomarkers of sensitivity learned from cancer cell lines
Authors: Li Yuanyuan , Umbach David M. , Krahn Juno M. , Shats Igor , Li Xiaoling , Li Leping 
Published: April 2021

Abstract
Background
Human cancer cell line profiling and drug sensitivity studies provide valuable information about the therapeutic potential of drugs and their possible mechanisms of action. The goal of those studies is to translate the findings from in vitro studies of cancer cell lines into in vivo therapeutic relevance and, eventually, patients’ care. Tremendous progress has been made.

Results
In this work, we built predictive models for 453 drugs using data on gene expression and drug sensitivity (IC50) from cancer cell lines. We identified many known drug-gene interactions and uncovered several potentially novel drug-gene associations. Importantly, we further applied these predictive models to ~ 17,000 bulk RNA-seq samples from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database to predict drug sensitivity for both normal and tumor tissues. We created a web site for users to visualize and download our predicted data (https://manticore.niehs.nih.gov/cancerRxTissue). Using trametinib as an example, we showed that our approach can faithfully recapitulate the known tumor specificity of the drug.

Conclusions
We demonstrated that our approach can predict drugs that 1) are tumor-type specific; 2) elicit higher sensitivity from tumor compared to corresponding normal tissue; 3) elicit differential sensitivity across breast cancer subtypes. If validated, our prediction could have relevance for preclinical drug testing and in phase I clinical design.
The Pectobacterium pangenome, with a focus on Pectobacterium brasiliense, shows a robust core and extensive exchange of genes from a shared gene pool
Authors: Jonkheer Eef M. , Brankovics Balázs , Houwers Ilse M. , van der Wolf Jan M. , Bonants Peter J. M. , Vreeburg Robert A. M. , Bollema Robert , de Haan Jorn R. , Berke Lidija , Smit Sandra , de Ridder Dick , van der Lee Theo A. J. 
Published: April 2021

Abstract
Background
Bacterial plant pathogens of the Pectobacterium genus are responsible for a wide spectrum of diseases in plants, including important crops such as potato, tomato, lettuce, and banana. Investigation of the genetic diversity underlying virulence and host specificity can be performed at genome level by using a comprehensive comparative approach called pangenomics. A pangenomic approach, using newly developed functionalities in PanTools, was applied to analyze the complex phylogeny of the Pectobacterium genus. We specifically used the pangenome to investigate genetic differences between virulent and avirulent strains of P. brasiliense, a potato blackleg causing species dominantly present in Western Europe.

Results
Here we generated a multilevel pangenome for Pectobacterium, comprising 197 strains across 19 species, including type strains, with a focus on P. brasiliense. The extensive phylogenetic analysis of the Pectobacterium genus showed robust distinct clades, with most detail provided by 452,388 parsimony-informative single-nucleotide polymorphisms identified in single-copy orthologs. The average Pectobacterium genome consists of 47% core genes, 1% unique genes, and 52% accessory genes. Using the pangenome, we zoomed in on differences between virulent and avirulent P. brasiliense strains and identified 86 genes associated to virulent strains. We found that the organization of genes is highly structured and linked with gene conservation, function, and transcriptional orientation.

Conclusion
The pangenome analysis demonstrates that evolution in Pectobacteria is a highly dynamic process, including gene acquisitions partly in clusters, genome rearrangements, and loss of genes. Pectobacterium species are typically not characterized by a set of species-specific genes, but instead present themselves using new gene combinations from the shared gene pool. A multilevel pangenomic approach, fusing DNA, protein, biological function, taxonomic group, and phenotypes, facilitates studies in a flexible taxonomic context.
Predicting the allergenicity of legume proteins using a PBMC gene expression assay
Authors: Smits Mark , Meijerink Marjolein , Le Thuy-My , Knulst André , de Jong Aard , Caspers Martinus Petrus Maria , Lima Everton Souto , Babé Lilia , Ladics Gregory , McClain Scott , Houben Geert , Verhoeckx Kitty 
Published: April 2021

Abstract
Background
Food proteins differ in their allergenic potential. Currently, there is no predictive and validated bio-assay to evaluate the allergenicity of novel food proteins. The objective of this study was to investigate the potential of a human peripheral blood mononuclear cell (PBMC) gene expression assay to identify biomarkers to predict the allergenicity of legume proteins.

Results
PBMCs from healthy donors were exposed to weakly and strongly allergenic legume proteins (2S albumins, and 7S and 11S globulins from white bean, soybean, peanut, pea and lupine) in three experiments. Possible biomarkers for allergenicity were investigated by exposing PBMCs to a protein pair of weakly (white bean) and strongly allergenic (soybean) 7S globulins in a pilot experiment. Gene expression was measured by RNA-sequencing and differentially expressed genes were selected as biomarkers. 153 genes were identified as having significantly different expression levels to the 7S globulin of white bean compared to soybean. Inclusion of multiple protein pairs from 2S albumins (lupine and peanut) and 7S globulins (white bean and soybean) in a larger study, led to the selection of CCL2, CCL7, and RASD2 as biomarkers to distinguish weakly from strongly allergenic proteins. The relevance of these three biomarkers was confirmed by qPCR when PBMCs were exposed to a larger panel of weakly and strongly allergenic legume proteins (2S albumins, and 7S and 11S globulins from white bean, soybean, peanut, pea and lupine).

Conclusions
The PBMC gene expression assay can potentially distinguish weakly from strongly allergenic legume proteins within a protein family, though it will be challenging to develop a generic method for all protein families from plant and animal sources. Graded responses within a protein family might be of more value in allergenicity prediction instead of a yes or no classification.
Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 −/− mouse model
Authors: Behary J. , Raposo A. E. , Amorim N. M. L. , Zheng H. , Gong L. , McGovern E. , Chen J. , Liu K. , Beretov J. , Theocharous C. , Jackson M. T. , Seet-Lee J. , McCaughan G. W. , El-Omar E. M. , Zekry A. 
Published: April 2021

Abstract
Background
Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 −/− mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development.

Results
Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred.

Conclusion
In Mdr2 −/− mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.
Correlation between the spatial distribution and colony size was common for monogenetic bacteria in laboratory conditions
Authors: Xue Heng , Kurokawa Masaomi , Ying Bei-Wen 
Published: April 2021

Abstract
Background
Geographically separated population growth of microbes is a common phenomenon in microbial ecology. Colonies are representative of the morphological characteristics of this structured population growth. Pattern formation by single colonies has been intensively studied, whereas the spatial distribution of colonies is poorly investigated.

Results
The present study describes a first trial to address the questions of whether and how the spatial distribution of colonies determines the final colony size using the model microorganism Escherichia coli, colonies of which can be grown under well-controlled laboratory conditions. A computational tool for image processing was developed to evaluate colony density, colony size and size variation, and the Voronoi diagram was applied for spatial analysis of colonies with identical space resources. A positive correlation between the final colony size and the Voronoi area was commonly identified, independent of genomic and nutritional differences, which disturbed the colony size and size variation.

Conclusions
This novel finding of a universal correlation between the spatial distribution and colony size not only indicated the fair distribution of spatial resources for monogenetic colonies growing with identical space resources but also indicated that the initial localization of the microbial colonies decided by chance determined the fate of the subsequent population growth. This study provides a valuable example for quantitative analysis of the complex microbial ecosystems by means of experimental ecology.