Gerrit Jansen

Amsterdam University Medical Center | VUmc · Department of Rheumatology

Background L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stere...

Several conjugates between folic acid and a series of kinetically stable lanthanide complexes have been synthesized, using amide coupling and azide–alkyne cycloaddition methodologies to link the metal-binding domain to folate through a variety of spacer groups. While all these complexes exhibit affinity for the folate receptor, it is clear that the...

Background Intracellular methotrexate polyglutamates (MTX‐PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX‐PG 3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX‐PGs accumulation in...

Background One of the main characteristics of rheumatoid arthritis (RA) is angiogenesis, which is linked to both the disease’s activity and duration. Two key proteins, vimentin and αvβ3 integrin, are critically involved in angiogenesis in RA. As a result, both may be used as diagnostic candidates for early detection and precise RA treatment. Positr...

Background Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial inflammation and infiltration of various immune cells, including macrophages. Novel whole-body molecular imaging with positron emission tomography (PET) and the use of specific PET tracers can non-invasively detect and quantify the presence of mac...

Background The use of biologics has significantly improved the therapy of rheumatoid arthritis, however, approximately 30% of patients remain clinically active regardless of the therapy [1]. Synovial pathotypes, determined by the immune cell subtypes, can guide treatment decisions by targeting specific cell populations in inflamed tissue [2]. Howev...

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potentia...

Aim: The therapeutic targeting of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors in cancer, including non-small cell lung cancer (NSCLC), is a widely studied approach for tumor selective apoptotic cell death therapy. However, apoptosis resistance is often encountered. The main aim of this study was to inve...

Objective We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). Methods This post hoc analysis included 812 treatment‐naïve patients with early RA who were randomized (1:1:1:1) in the...

Purpose This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes. Recent Findings Recent studies comparing the...

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) cells. Methods: U937 cells and their sublines with low and high levels of acquired resistanc...

Macrophages constitute important immune cell targets of the antifolate methotrexate (MTX) in autoimmune diseases, including rheumatoid arthritis. Regulation of folate/MTX metabolism remains poorly understood upon pro-inflammatory (M1-type/GM-CSF-polarized) and anti-inflammatory (M2-type/M-CSF-polarized) macrophages. MTX activity strictly relies on...

Introduction Current scientific evidence guiding the decision whether men with an active desire to become a father should be treated with methotrexate (MTX) remains controversial. We aimed to prospectively evaluate the testicular toxicity profile of MTX focusing on several markers of male fertility, including semen parameters and sperm DNA fragment...

Background We have previously showed that exposure to methotrexate (MTX) was not associated with sperm quality abnormalities or with sperm DNA damage [1]. Nonetheless, a question that remains unanswered is whether MTX and its bioactive forms, the MTX-polyglutamates (MTX-PGs) can be found in spermatozoa. The intracellular conversion of MTX to MTX-PG...

Background Three different synovial immunopathotypes of rheumatoid arthritis (RA) have been identified: Fibroid-Pauci immune (FP, fibroblast-rich), Diffuse-Myeloid (DM, macrophage-rich) and Lympho-Myeloid (LM, lymphocyte- and macrophage-rich), and have been associated with treatment outcome to biologicals [1]. Therefore, identification of the synov...

Background The role of pathological angiogenesis is widely recognized in cancer and various inflammatory diseases, including rheumatoid arthritis (RA). In RA, angiogenesis and inflammation are mutually dependent and play a cooperative role in the disease progression. Angiogenesis mainly relies on the interaction of vascular endothelial cells (ECs),...

Objective To investigate the pharmacokinetics of methotrexate polyglutamate (MTX-PG) accumulation in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) in patients with early rheumatoid arthritis (RA) after oral and subcutaneous MTX treatment. Methods In a clinical prospective cohort study (Methotrexate Monitoring study), newly...

Methotrexate (MTX) is an antifolate drug used as a chemotherapeutic agent for acute lymphoblastic leukemia, where MTX improves patients’ prognosis. Macrophage reprogramming is being increasingly assessed as an antitumor therapeutic strategy. However, and although MTX limits the pathogenic action of macrophages in chronic inflammatory diseases, its...

Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease sever...

Background Pharmacokinetics of methotrexate (MTX) after oral and subcutaneous administration to RA patients differs: MTX levels in plasma and MTX-polyglutamate (MTX-PG) accumulation in erythrocytes are higher during equidosed subcutaneous compared to oral MTX treatment. (1,2) No data are available whether administration route of MTX differentially...

Background Optimal dosing of methotrexate (MTX) in rheumatoid arthritis (RA) remains challenging. To this end, monitoring of intracellular MTX polyglutamates (MTX-PGs) in red blood cells (RBCs) has been investigated as a potential marker of MTX (non-)response, with contradictory results. As enucleated, non-proliferative cells, mature RBCs lack regu...

Mitochondria are the main energy factory in living cells. To rapidly proliferate and metastasize, neoplastic cells increase their energy requirements. Thus, mitochondria become one of the most important organelles for them. Indeed, much research shows the interplay between cancer chemoresistance and altered mitochondrial function. In this review we...

Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions but their contribution to human macrophage polarization remains unclear. The LXR pathway is enriched in pro-inflammatory macrophages from rheumatoid arthritis as well as in tumors-associated macrophages from human tumors. We now report that LXR activation inh...

Non-invasive imaging modalities constitute an increasingly important tool in diagnostic and therapy response monitoring of patients with autoimmune diseases, including rheumatoid arthritis (RA). In particular, macrophage imaging with positron emission tomography (PET) using novel radiotracers based on differential expression of plasma membrane prot...

The identification of “trained immunity/tolerance” in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA)....

Background Computational tools analyzing RNA-sequencing data have boosted alternative splicing research by identifying and assessing differentially spliced genes. However, common alternative splicing analysis tools differ substantially in their statistical analyses and general performance. This report compares the computational performance (CPU uti...

The study by Safy-Khan, et al in the current issue of The Journal of Rheumatology ¹ reports that in a methotrexate (MTX)-based treatment regimen for patients with early arthritis, current smoking was significantly associated with a smaller reduction of Disease Activity Score in 28 joints (DAS28) over time compared to noncurrent smoking. This negati...

Background Tocilizumab (TCZ) is a monoclonal antibody that binds to the interleukin 6 receptor (IL-6R), inhibiting IL-6R signal transduction to downstream inflammatory mediators. TCZ has shown to be effective as monotherapy in early rheumatoid arthritis (RA) patients (1). However, approximately one third of patients inadequately respond to therapy...

Background Optimal dosing of methotrexate (MTX) for individual rheumatoid arthritis (RA) patients to achieve adequate disease control is an ongoing challenge. Assessment of erythrocyte MTX-polyglutamates (PGs) levels has been employed as a tool to monitor clinical response of RA patients in the first 3-12 months of treatment and MTX-PG 2-4 and tota...

The physio-pathological relevance of the one-carbon metabolism (OCM) is illustrated by the chemotherapeutic and anti-inflammatory effects of the antifolates Pemetrexed (PMX) and Methotrexate (MTX) in cancer and rheumatoid arthritis (RA). We report that OCM determines the functional and gene expression profile of human macrophages. PMX induces the a...

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). The mechanism of action (proteasome subu...

Alternative splicing is a tightly regulated process whereby non-coding sequences of pre-mRNA are removed and protein-coding segments are assembled in diverse combinations, ultimately giving rise to proteins with distinct or even opposing functions. In the past decade, whole genome/transcriptome sequencing studies revealed the high complexity of spl...

Pralatrexate (Folotyn; PLX) and belinostat (Beleodaq; BLS) are registered for the treatment of patients with peripheral T-cell lymphoma (PTCL) and are being considered for other lymphomas. In this study we investigated whether BLS had the ability to potentiate the cytotoxicity of PLX. A panel of lymphoma cell lines was used for the combination stud...

Objectives: An efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and...

Introduction: Methotrexate (MTX) constitutes the first-line therapy in rheumatoid arthritis (RA), yet approximately 30% of the patients do not benefit from MTX. Recently, we reported a prognostic multivariable prediction model for insufficient clinical response to MTX at 3 months of treatment in the treatment in the Rotterdam Early Arthritis Cohor...

[This corrects the article DOI: 10.1371/journal.pone.0231588.].

Dexamethasone (DEX) is often used in the initial treatment of leukemia. Earlier we demonstrated that DEX decreased the activity of deoxycytidine kinase (dCK) which is essential for the activation of cytarabine (ara-C). Therefore we investigated the effect of DEX on the in vivo sensitivity of acute myeloid leukemia (AML) to ara-C and another deoxycy...

In autoimmune diseases like rheumatoid arthritis (RA), multidrug resistance (MDR) transporters of the ATP-binding cassette (ABC) transporter superfamily harbor dual functions by extruding pro-inflammatory mediators and exporting disease modifying anti-rheumatics drugs (DMARDs), hence contributing to diminished treatment response. Herein we determin...

Expression of proton-coupled folate transporter (PCFT) is associated with survival of mesothelioma patients treated with pemetrexed, and is reduced by hypoxia, prompting studies to elucidate their correlation. Modulation of glycolytic gene expression was evaluated by PCR arrays in tumour cells and primary cultures growing under hypoxia, in spheroid...

We have recently established a protocol to grow wildtype human oral mucosa organoids. These three-dimensional structures can be maintained in culture long-term, do not require immortalization, and recapitulate the multilayered composition of the epithelial lining of the oral mucosa. Here, we validate the use of this model to study the effect of Leu...

Cellular uptake of clinically important deoxynucleoside analogs is mediated by nucleoside transporters including the human equilibrative nucleoside transporter 1 (hENT1) and the concentrative nucleoside transporter-1 (hCNT1). These transporters are responsible for influx of cytarabine and reduced hENT1 expression is a major resistance mechanism in...

Glucocorticoid (GC) resistance is a crucial determinant of inferior response to chemotherapy in pediatric acute lymphoblastic leukemia (ALL); however, molecular mechanisms underlying this phenomenon are poorly understood. Deregulated splicing is a common feature of many cancers, which impacts drug response and constitutes an attractive therapeutic...

Non-invasive imaging of arthritis activity in rheumatoid arthritis (RA) patients using macrophage PET holds promise for early diagnosis and therapeutic response monitoring. Previously obtained results with macrophage tracer (R)-[11C]PK11195 were encouraging, but the imaging signal could be further improved by reduction of background uptake. Recentl...

This study aimed to identify baseline metabolic biomarkers for response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) using an untargeted method. In total, 82 baseline plasma samples (41 insu cient responders and 41 su cient responders to MTX) were selected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, trial numbe...

Abstract Folate receptors and transporters and one-carbon metabolism continue to be important areas of study given their essential roles in an assortment of diseases and as targets for treatment of cancer and inflammation. Reflecting this, every 2 years, the Folate Receptor Society organizes an international meeting, alternating between North Ameri...

Objectives: Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages. Methods: First, we undertook to examine whether the...

Background Low-dose methotrexate (MTX) serves as the first-line treatment for rheumatoid arthritis (RA). Conversely, for hematological malignancies, high-dose MTX treatment is indicated in combination with folinic acid/leucovorin to prevent untoward toxicity. For both disease modalities, efficient pharmacological response critically depends on the...

A major challenge in the application of cytotoxic anti-cancer drugs is their general lack of selectivity, which often leads to systematic toxicity due to their inability to discriminate between malignant and healthy cells. A particularly promising target for selective targeting are the folate receptors (FR) that are often over-expressed on cancer c...

Background: Folylpolyglutamate synthetase (FPGS) is a crucial enzyme in both cellular folate homeostasis and the intracellular retention of folate analogue drugs such as methotrexate (MTX), which is commonly used for the treatment of (pediatric) leukemia and the anchor drug in rheumatoid arthritis (RA) treatment. To date, assessment of FPGS cataly...

Chemoresistance is an important factor in the treatment failure of childhood acute lymphoblastic leukemia (ALL). One underlying mechanism of chemoresistance involves (over)expression of ATP-dependent drug efflux transporters such as multidrug resistance protein 1–5 (MRP1–5) and breast cancer resistance protein (BCRP), which can extrude the importan...

PB induces aberrant splicing of protein kinases involved in the pathogenesis of malignant mesothelioma.

Rotational BLI scan (MARS system) of an orthotopic DMPM model.

PET-CT scan of two orthotopic DMPM models.

Differential gene expression analysis output (edgeR) in DMPM cells after 4h treatment with 30 nM Pladienolide-B.

Single nucleotide variants detected in MesoII and STO cells by RNA-seq (ANNOVAR annotation).

MRI scan of an orthotopic DMPM model.

Differential splicing analysis output (rMATS) in DMPM cells after 4h treatment with 30 nM Pladienolide-B.

Antibody fragment F8- mediated Interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in-vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patie...

Tyrosine kinase inhibitors are a class of chemotherapeutic drugs that target specific protein kinases. These tyrosine kinase inhibitors constitute a relatively new class of drugs which target for instance Bcr-Abl, Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR). Despite some initial successes, the ove...

Introduction Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we...

Tosedostat represents a next generation oral aminopeptidase inhibitor prodrug that has recently demonstrated promising activity in elderly patients with relapsed and refractory acute myeloid leukemia (AML). This prodrug is bio-activated to its hydrophilic active metabolite by intracellular esterases including carboxylesterase 1 (CES1) hence enhanci...

Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Fol...