A5038003121- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- HIV/AIDS drug development and treatment
- Peptidase Inhibition and Analysis
- Chronic Lymphocytic Leukemia Research
- Histone Deacetylase Inhibitors Research
- HIV Research and Treatment
- MicroRNA in disease regulation
- Cancer Genomics and Diagnostics
- Lymphoma Diagnosis and Treatment
- Drug Transport and Resistance Mechanisms
- Cancer Mechanisms and Therapy
- Immunotherapy and Immune Responses
- Acute Myeloid Leukemia Research
- Circular RNAs in diseases
- Phagocytosis and Immune Regulation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Virus-based gene therapy research
- Cancer therapeutics and mechanisms
- Genetic factors in colorectal cancer
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- Chronic Myeloid Leukemia Treatments
- Renal Transplantation Outcomes and Treatments
University of St. Gallen
2017-2024
Masaryk University
2014-2024
Université Paris-Saclay
2024
Institut Curie
2024
Centre National de la Recherche Scientifique
2024
Inserm
2024
Columbia University Irving Medical Center
2023
Kantonsspital St. Gallen
2015-2023
Azienda Sanitaria Unità Locale di Reggio Emilia
2023
Istituti di Ricovero e Cura a Carattere Scientifico
2023
Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in combined quantitative functional...
Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects insufficient plasma concentrations. Proteomics analysis identified...
The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to define surfaceome at baseline, in drug resistance, response acute treatment. We provide a scoring system antigens identify CCR10 promising target this disease expressed widely on malignant plasma cells. engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting using its...
T cells play a central role in cancer immunotherapy, yet the lack of standardized vitro models limits reproducibility and translational potential immune-cancer cell interaction studies. Existing often due to variability experimental conditions, immune sources, functional assays. To address this gap, we established robust reproducible co-culture model, which serves evaluate efficacy cell-based cytotoxicity using peripheral blood mononuclear (PBMCs) multiple lines. Healthy donor PBMCs...
Extramedullary disease in multiple myeloma patients is an uncommon event occurring either at the time of diagnosis, or during progression/relapse. This manifestation frequently associated with poor outcome and resistance to treatment. We evaluated chromosomal alterations plasma cells extramedullary relapse, bone marrow (BM) sites, previous BM collection by interphase fluorescence situ hybridization.Thirty-one [25 (BMPCs), 18 tumor cells], which 12 had paired samples 14 BM, were investigated...
Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors innate immune responses. To understand pathophysiology cirrhosis, we detailed receptor expression relation monocyte function disease severity prior onset acute decompensation. TNF-α/IL-6 responses lipopolysaccharide were...
Abstract Objectives Progress in multiple myeloma treatment allows patients to achieve deeper responses, for which the assessment of minimal residual disease (MRD) is critical. Typically, bone marrow samples are used this purpose; however, approach site‐limited. Liquid biopsy represents a minimally invasive and more comprehensive technique that not site‐limited, but equally challenging. Methods While majority current data comes from short‐term studies, we present long‐term study on...
Abstract The antiretroviral agent nelfinavir has antimyeloma activity and can overcome resistance to bortezomib. Our phase I/II trial investigated whether adding lenalidomide–dexamethasone lenalidomide in lenalidomide-refractory multiple myeloma (MM). Twenty-nine patients were included (high-risk cytogenetic aberrations 31%; ≥2 prior therapy lines 93%; lenalidomide–bortezomib double-refractory 34%). Twenty-four (83%) had bortezomib 10 (34%) double-refractory. They received four cycles of...
Poor outcome of extramedullary disease in multiple myeloma patients and lack predictors prompt continued search for new markers the disease. In this report, we show circulating microRNA distinguishing with from without such manifestation healthy donors. MicroRNA-130a was identified by TaqMan Low Density Arrays verified quantitative PCR on 144 serum samples (59 myeloma, 55 disease, 30 donors) test validation cohorts as being down-regulated Circulating microRNA-130a distinguished donors...
Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well experimental the field (dalanzomib, oprozomib, ixazomib), by design target rate-limiting β5 subunit. It is unknown whether β2-selective inhibition can also be exploited toward anticancer treatment. Combining with pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears...
Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy, accounting for approximately 1% of all cancers. Despite recent advances in the treatment MM, due to introduction proteasome inhibitors (PIs) such as bortezomib (BTZ) and carfilzomib (CFZ), relapses disease progression remain common. Therefore, a major challenge development novel therapeutic approaches overcome drug resistance, improve patient outcomes, broaden PIs applicability other pathologies. Methods We...
Abstract Antiapoptotic Bcl-2 family members have recently (re)emerged as key drug targets in cancer, with a tissue- and tumor-specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 has been described major gatekeeper apoptosis. This discovery led to the rapid establishment clinical trials evaluating impact various inhibitors. However, our understanding about optimal use inhibitors is still limited. We therefore explored mechanisms acquired inhibitor resistance...
<h3>Background:</h3> Sjögren's disease (SjD) is an autoimmune condition marked by lymphocytic infiltration of exocrine glands, where salivary gland epithelial cells (SGECs) play a crucial role in initiating and amplifying inflammation. To address dysfunction, understanding the mechanisms behind pro-inflammatory signaling SGECs vital. Epitranscriptomics, recent field, highlights RNA modifications' impact on gene expression regulation. Writers such as METTL3/14 add methyl groups to RNA, while...
Abstract Background Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC dependent on proteasomes; however, clinical observations indicate efficacy proteasome inhibitors may be limited, suggesting need for combination therapies. Methods We compared bortezomib and carfilzomib their combinations nelfinavir lopinavir cell lines primary cells regard cytotoxic activity, functional inhibition,...
Objectives To assess the potential of second‐generation proteasome inhibition by carfilzomib and its combination with human immunodeficiency virus ( HIV ) protease inhibitors ‐ PI s) lopinavir nelfinavir in vitro for improved treatment clear cell renal cancer (cc RCC ). Materials Methods Cytotoxicity, reactive oxygen species ROS production, unfolded protein response UPR activation inhibitors, s, their were assessed three lines primary cells derived from cc tumours MTS assay, flow cytometry,...
Multiple myeloma (MM) is characterized by malignant proliferation of plasma cells (PC) which accumulate in the bone marrow (BM). The advent new drugs has changed course disease from incurable to treatable, but most patients eventually relapse. One group MM (10-15%) considered high-risk because they relapse within 24 months. Recently, extramedullary (EM) been observed more frequently. Due its aggressivity and shorter survival, EM also high-risk.The goal this study was determine if so-called...
The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts. In patients with advanced, proteasome (PI)-refractory multiple myeloma, nelfinavir-based therapy resulted 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option setting. mechanism of action implies it interferes fundamental aspects cancer cell biology. We combined proteome-wide affinity-purification nelfinavir-interacting...