A5088431517- Immune Cell Function and Interaction
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Virus-based gene therapy research
- Melanoma and MAPK Pathways
- Mast cells and histamine
- MicroRNA in disease regulation
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Quinazolinone synthesis and applications
- RNA Interference and Gene Delivery
- Viral Infectious Diseases and Gene Expression in Insects
- Circular RNAs in diseases
- Synthesis and biological activity
- HER2/EGFR in Cancer Research
- Adipokines, Inflammation, and Metabolic Diseases
- RNA Research and Splicing
- Chronic Lymphocytic Leukemia Research
- DNA and Nucleic Acid Chemistry
- T-cell and B-cell Immunology
- Beetle Biology and Toxicology Studies
- Bacterial Genetics and Biotechnology
- RNA and protein synthesis mechanisms
- Cancer-related molecular mechanisms research
- Hematopoietic Stem Cell Transplantation
University of Basel
2011-2024
University Hospital of Basel
2015-2024
National Institute of Dental and Craniofacial Research
2015
National Institutes of Health
2015
Novartis (Switzerland)
2009
Novartis Institutes for BioMedical Research
2009
Friedrich Miescher Institute
2004
ETH Zurich
2001
École Polytechnique Fédérale de Lausanne
2001
University of Chicago
1967
Abstract Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for cell immunotherapies. generated with this resemble tumor-infiltrating phenotypic and transcriptional level. Using targeted pooled CRISPR-Cas9 screen individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as mediator of exhaustion. Upon TCR/CD28 stimulation, deletion SNX9 in CD8...
The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110beta (the product PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB(K805R) mutant survived adulthood but showed growth retardation developed mild insulin resistance with age. Pharmacological genetic analyses revealed activity required...
Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation protein kinase B (PKB/Akt) mammalian target rapamycin (mTOR). Here we describe the preclinical characterization compound 1 (PQR309, bimiralisib), potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR balanced fashion at higher concentrations. No off-target interactions were detected for panel kinase, enzyme, receptor ligand assays. Moreover, did not...
Abstract Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but standard care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting transplanted healthy 1 . Antigen-specific cell-depleting therapies hold promise much more targeted elimination diseased cells, as witnessed in past decade by revolution clinical practice B malignancies 2 However,...
Abstract Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein pathways are often constitutively activated in melanoma have thus been considered as promising drug targets. Exposure of cells to NVP-BAG956, NVP-BBD130, NVP-BEZ235, a series novel, potent, stable dual PI3K/mammalian target rapamycin (mTOR) inhibitors, resulted complete G1 growth arrest, reduction cyclin D1, increased levels p27KIP1, but negligible apoptosis. In contrast, treatment with the...
Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody–drug conjugates (ADC), T cell engagers (TCE), chimeric antigen receptor (CAR) is very effective for hematologic diseases. Unlike the breakthrough progress achieved B malignancies, there a pressing need to find suitable antigens myeloid malignancies. CD123, interleukin-3 (IL-3) alpha-chain, highly expressed in various hematological including acute leukemia (AML). However, shared...
Specific adaptor subunits, p84 or p101, of phosphoinositide 3-kinase γ dictate different cellular responses.
Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes other obesity-related diseases. The lipid kinase PI3Kγ central proinflammatory signal transducer that plays major role in leukocyte chemotaxis, mast cell degranulation, endothelial activation. It was also reported activity within hematopoietic cells an important obesity-induced inflammation insulin resistance. Here, we show protection...
Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within spermatogenic lineage have not been characterized so far. Herein, we report that mice expressing a catalytically inactive p110beta develop testicular hypotrophy and impaired spermatogenesis, leading to phenotype oligo-azoospermia defective The examination testes from p110beta-defective tubules demonstrates widespread loss cells, due...
Overexpression of the cyclin-dependent kinase inhibitor p27 and exposure to low temperature (30°C) represent two strategies establish controlled proliferation processes for production therapeutic proteins using Chinese hamster ovary (CHO) cells. Here we analyze effect growth inhibition on quality human model glycoprotein SEAP (secreted alkaline phosphatase) both in monoclonal CHO-derived cell lines. Separation purified samples two-dimensional gel electrophoresis showed that by...
A nuclease present in extracts of Bacillus subtilis inserts breaks deoxyribonucleic acid (DNA) treated with the monofunctional alkylating agent, methyl methanesulfonate (MMS), but nature sites within alkylated macromolecule at which these occur is not known. DNA extracted from B. cells that have recovered MMS damage has lost its susceptibility to enzyme action. The recovery process accompanied by some breakdown and incorporation thymidine. Some ultraviolet irradiation (UV) occurred organisms...
The kinase PI3Kγ aggravates obesity by activating macrophages and triggering inflammation in adipose tissue.
T cells play a crucial role in the adaptive immune system and depend on tightly regulated intracellular signalling pathways to respond an appropriate manner. Adapter proteins have flexible dynamic features, which allow them regulate cell signal transduction pathways. As adapter are enzymatically inert may multiple roles parallel, it has been challenge fully characterise their functions individually. One such protein cells, is specific (TSAd), upregulated following receptor (TCR) stimulation...
Monoclonal antibodies have transformed the therapeutic landscape across oncology, immunology, and infectious diseases by enabling high-affinity, antigen-specific targeting, e.g. to neutralize soluble molecules, block cellular interactions or deplete cells. While high specificity is critical for safety, it may confer an inherent susceptibility even minor variations within target epitope. Here, we present first systematic study investigating impact of natural single nucleotide variants on...
Adoptive cell transfer is an important approach for basic research and emerges as effective treatment various diseases, including infections blood cancers. Direct genetic manipulation of primary immune cells opens up unprecedented opportunities could be applied to enhance cellular therapeutic products. In this article, we report highly efficient genome engineering in murine T using a plasmid-based RNA-guided CRISPR system. We developed straightforward ablate genes 90% introduce precisely...
3′ untranslated regions (3′ UTRs) are critical elements of messenger RNAs, as they contain binding sites for RNA-binding proteins (RBPs) and microRNAs that affect various aspects the RNA life cycle including transcript stability cellular localization. In response to T cell receptor activation, cells undergo massive expansion during effector phase immune dynamically modify their UTRs. Whether this serves directly regulate abundance specific mRNAs or is a secondary effect proliferation remains...
Chronic liver inflammation causes continuous damage with progressive fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas the 10‐year incidence for HCC in patients cirrhosis is approximately 20%, many of these remain tumor free their entire lives. Clarifying mechanisms that define various outcomes chronic a key aspect research. In addition wide variety contributing factors, microRNAs (miRNAs) have also been shown be engaged promoting cancer. Therefore,...
Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well monocyte/macrophages, CD4+ and CD8+ T cells, NK isolated from tumors, liver, blood 48 patients with hepatocellular carcinoma. found that tumor macrophages induce sphingosine-1-phospate-degrading enzyme SGPL1, dampened their inflammatory phenotype anti-tumor function vivo. further discovered signaling scaffold...