Background: Individual functions of members of the bromodomain (BRD) and extra-terminal (BET) protein family underlying the anti-inflammatory effects of BET inhibitors in rheumatoid arthritis (RA) are incompletely understood. Here, we aimed to analyze the regulatory functions of BRD3, an understudied member of the BET protein family, in RA synovial fibroblasts (FLS). Methods: BRD3 was silenced in FLS prior to stimulation with TNF. Alternatively, FLS were treated with I-BET. Transcriptomes were analyzed by RNA sequencing (RNAseq), followed by pathway enrichment analysis. We confirmed results for selective target genes by real-time PCR, ELISA, and Western blotting. Results: BRD3 regulates the expression of several cytokines and chemokines in FLS, and positively correlates with inflammatory scores in the RA synovium. In addition, RNAseq pointed to a profound role of BRD3 in regulating FLS proliferation, metabolic adaption, and response to stress, including oxidative stress, and autophagy. Conclusions: BRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in FLS and executes many functions of BET proteins that have previously been identified using pan-BET inhibitors.

Introduction Precision oncology aims to provide individualised treatment recommendations based on patient-specific characteristics. In this rapidly evolving field with increasing numbers of biomarkers and potential therapeutic targets, there is a growing unmet need for evidence guiding these individualised treatment recommendations. The Precision Oncology Program (POP) harnesses real-world data (RWD) and imaging mass cytometry (IMC) to evaluate the feasibility and utility of integrating different data modalities to inform personalised treatment recommendations. This program uses patient-matched clinicogenomic data and spatial single-cell proteomics analysis to support profiling-driven decision-making for patients with cancer at the Molecular Tumor Board. Methods and analysis The collaborative POP project recruits patients across all tumour entities and stages at the Comprehensive Cancer Center Zurich (CCCZ). For patients in the POP, a clinically and molecularly matched cohort is identified within the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinicogenomic database (CGDB). It assesses whether clinical, genomic and outcome data of the CGDB cohort can inform treatment recommendations. In addition, multiplexed imaging mass cytometry (IMC) is performed in formalin-fixed paraffin-embedded tissue to assess the potential impact of spatial proteomics on personalised treatment decisions. RWD and IMC information is reviewed in the Molecular Tumor Board to assess the potential impact of this information on therapy decisions. However, since this is an observational study, these additional recommendations remain nonprescriptive and will not be forwarded to the treating physician. Ethics and dissemination The study is registered at ClinicalTrials.gov (NCT06680726) and approved by the Canton of Zurich Ethics Committee (Project ID: 2022-02289). Project-specific informed consent is obtained from all participants. Deceased patients may also be included. In this case, a signed general consent form must be available. Data privacy is ensured by unique patient numbers for pseudo-anonymised data. Study findings will be disseminated through international peer-reviewed journals, conferences, and direct communication with participants and relevant organisations. Trial registration number NCT06680726.

Introduction: Cancer treatment has advanced rapidly in recent decades. Regulatory approval of cancer therapies relies on pivotal clinical trials, with phase III, randomised controlled trials (RCTs) regarded as the gold standard. However, there is growing concern about the increasing use of single-arm trials in cancer approvals. This study provides an overview of cancer drug approvals in Switzerland over the past 20 years. We assessed changes in approval patterns, characteristics of pivotal trials and the use of biomarkers in approvals. Research design and methods: We collected data on Swiss cancer drug approvals from 2001 to 2020, and their respective pivotal trials from Swissmedic’s internal database and performed descriptive analyses. Results: Over 20 years, Swissmedic approved 362 cancer-related indications, 40.6% as new active substances. Solid tumours accounted for 63.3% of approvals, with lung cancer achieving top ranking with 22.3%. Approvals rose from 6 in 2001 to 34 in 2020, with biomarker-associated indications increasing from 16.7% in 2001 to 55.9% in 2020. Indications were mainly approved based on RCTs (71.3%). However, the proportion of single-arm trials supporting approvals for solid tumours increased from 14.3% in 2005 to 34.6% in 2020, with most approvals covering rare cancer entities and biomarker-associated indications. Conclusions: The notable rise in cancer drug approvals and biomarker-associated indications has expanded treatment options. While RCTs remained the primary basis for approvals, the growing reliance on single-arm trials, specifically for biomarker-associated approvals, introduces uncertainty for regulatory agencies in assessing benefit-risk profiles. This highlights the importance of postapproval evidence generation to confirm long-term safety and efficacy.

We previously demonstrated that Homeobox (HOX) transcription factors are differentially expressed between joint locations and can accurately assign synovial fibroblasts (SFs) to their correct joint location. We show here that the expression of the 5’HOXD transcription factors HOXD10, HOXD11, and HOXD13 in SFs strikingly overlaps with predilection sites for the development of rheumatoid arthritis (RA). Changes in SFs gene expression after silencing 5’HOXDs aligned with joint-specific differences of RA SFs. In particular, we identify HOXD13 as regulator or primary cilia function in SFs modulating cell cycle, DNA damage and proteasome activity. Accordingly, we show joint specific differences in primary cilia morphology, DNA damage repair and proteasome activity. We thus propose that HOXD13 and primary cilia play a role in shaping joint-specific SFs functions that might underlie the pathognomic pattern of joint involvement in RA.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation.