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1.
Clin Cancer Res ; 29(21): 4449-4463, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37379429

ABSTRACT

PURPOSE: Target-dependent TCB activity can result in the strong and systemic release of cytokines that may develop into cytokine release syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome. EXPERIMENTAL DESIGN: We explored the cellular and molecular players involved in TCB-mediated cytokine release by single-cell RNA-sequencing of whole blood treated with CD20-TCB together with bulk RNA-sequencing of endothelial cells exposed to TCB-induced cytokine release. We used the in vitro whole blood assay and an in vivo DLBCL model in immunocompetent humanized mice to assess the effects of dexamethasone, anti-TNFα, anti-IL6R, anti-IL1R, and inflammasome inhibition, on TCB-mediated cytokine release and antitumor activity. RESULTS: Activated T cells release TNFα, IFNγ, IL2, IL8, and MIP-1ß, which rapidly activate monocytes, neutrophils, DCs, and NKs along with surrounding T cells to amplify the cascade further, leading to TNFα, IL8, IL6, IL1ß, MCP-1, MIP-1α, MIP-1ß, and IP-10 release. Endothelial cells contribute to IL6 and IL1ß release and at the same time release several chemokines (MCP-1, IP-10, MIP-1α, and MIP-1ß). Dexamethasone and TNFα blockade efficiently reduced CD20-TCB-mediated cytokine release whereas IL6R blockade, inflammasome inhibition, and IL1R blockade induced a less pronounced effect. Dexamethasone, IL6R blockade, IL1R blockade, and the inflammasome inhibitor did not interfere with CD20-TCB activity, in contrast to TNFα blockade, which partially inhibited antitumor activity. CONCLUSIONS: Our work sheds new light on the cellular and molecular players involved in cytokine release driven by TCBs and provides a rationale for the prevention of CRS in patients treated with TCBs. See related commentary by Luri-Rey et al., p. 4320.


Subject(s)
Antibodies, Bispecific , Tumor Necrosis Factor-alpha , Humans , Mice , Animals , Chemokine CCL3 , Chemokine CCL4 , Antibodies, Bispecific/pharmacology , Interleukin-8 , Chemokine CXCL10 , Interleukin-6 , Cytokine Release Syndrome , Endothelial Cells , Inflammasomes , Cytokines , T-Lymphocytes , Dexamethasone/pharmacology , RNA
2.
Genome Biol ; 24(1): 119, 2023 05 17.
Article in English | MEDLINE | ID: mdl-37198712

ABSTRACT

Computational methods represent the lifeblood of modern molecular biology. Benchmarking is important for all methods, but with a focus here on computational methods, benchmarking is critical to dissect important steps of analysis pipelines, formally assess performance across common situations as well as edge cases, and ultimately guide users on what tools to use. Benchmarking can also be important for community building and advancing methods in a principled way. We conducted a meta-analysis of recent single-cell benchmarks to summarize the scope, extensibility, and neutrality, as well as technical features and whether best practices in open data and reproducible research were followed. The results highlight that while benchmarks often make code available and are in principle reproducible, they remain difficult to extend, for example, as new methods and new ways to assess methods emerge. In addition, embracing containerization and workflow systems would enhance reusability of intermediate benchmarking results, thus also driving wider adoption.


Subject(s)
Benchmarking , Computational Biology , Computational Biology/methods , Workflow
3.
Life Sci Alliance ; 6(7)2023 07.
Article in English | MEDLINE | ID: mdl-37142439

ABSTRACT

Continuity, correctness, and completeness of genome assemblies are important for many biological projects. Long reads represent a major driver towards delivering high-quality genomes, but not everybody can achieve the necessary coverage for good long read-only assemblies. Therefore, improving existing assemblies with low-coverage long reads is a promising alternative. The improvements include correction, scaffolding, and gap filling. However, most tools perform only one of these tasks and the useful information of reads that supported the scaffolding is lost when running separate programs successively. Therefore, we propose a new tool for combined execution of all three tasks using PacBio or Oxford Nanopore reads. gapless is available at: https://github.com/schmeing/gapless.


Subject(s)
High-Throughput Nucleotide Sequencing , Software , Genome
4.
Genome Biol ; 22(1): 67, 2021 02 19.
Article in English | MEDLINE | ID: mdl-33608040

ABSTRACT

In high-throughput sequencing data, performance comparisons between computational tools are essential for making informed decisions at each step of a project. Simulations are a critical part of method comparisons, but for standard Illumina sequencing of genomic DNA, they are often oversimplified, which leads to optimistic results for most tools. ReSeq improves the authenticity of synthetic data by extracting and reproducing key components from real data. Major advancements are the inclusion of systematic errors, a fragment-based coverage model and sampling-matrix estimates based on two-dimensional margins. These improvements lead to more faithful performance evaluations. ReSeq is available at https://github.com/schmeing/ReSeq .


Subject(s)
Computational Biology/methods , High-Throughput Nucleotide Sequencing , Sequence Analysis, DNA , Software , Algorithms , Computational Biology/standards , Databases, Nucleic Acid , Genomics/methods , High-Throughput Nucleotide Sequencing/methods , Reproducibility of Results , Sequence Analysis, DNA/methods , Species Specificity , Web Browser
5.
Science ; 365(6460): 1457-1460, 2019 09 27.
Article in English | MEDLINE | ID: mdl-31467189

ABSTRACT

In insects, rapidly evolving primary sex-determining signals are transduced by a conserved regulatory module controlling sexual differentiation. In the agricultural pest Ceratitis capitata (Mediterranean fruit fly, or Medfly), we identified a Y-linked gene, Maleness-on-the-Y (MoY), encoding a small protein that is necessary and sufficient for male development. Silencing or disruption of MoY in XY embryos causes feminization, whereas overexpression of MoY in XX embryos induces masculinization. Crosses between transformed XY females and XX males give rise to males and females, indicating that a Y chromosome can be transmitted by XY females. MoY is Y-linked and functionally conserved in other species of the Tephritidae family, highlighting its potential to serve as a tool for developing more effective control strategies against these major agricultural insect pests.


Subject(s)
Ceratitis capitata/genetics , Genes, Y-Linked , Sex Determination Processes , Y Chromosome/genetics , Animals , Conserved Sequence , Embryo, Nonmammalian , Female , Genes, Insect , Male , RNA Interference
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