Filip Rázga

Selecta Biotech SE · Headquarters

Oncological diseases represent a significant global health challenge, with high mortality rates. Early detection is crucial for effective treatment, and aptamers, which demonstrate superior specificity and stability compared to antibodies, offer a promising avenue for diagnostic advancement. This study presents the design, development and evaluatio...

Clinical experience with tyrosine kinase inhibitors (TKIs) over the past two decades has shown that, despite the apparent therapeutic benefit, nearly 30% of patients with chronic myelogenous leukemia (CML) display primary resistance or intolerance to TKIs, and approximately 25% of those treated are forced to switch TKIs at least once during therapy...

Introduction Gold nanoparticles are promising candidates as vehicles for drug delivery systems and could be developed into effective anticancer treatments. However, concerns about their safety need to be identified, addressed, and satisfactorily answered. Although gold nanoparticles are considered biocompatible and nontoxic, most of the toxicology...

Here we report on a potent, safe, and highly specific oligonucleotide-based modality against BCR-ABL1 mRNA, ASP210, which effectively induces apoptosis in both BCR-ABL1 dependent and independent TKI-resistant CML cells.

Fundamental studies investigating the biological effects induced by nanoparticles (NPs) explicitly require the correct assessment of their intracellular concentration. Ultrasensitive atomic absorption spectroscopy (AAS) is perceived as one of the gold standard methods for quantifying internalized NPs. Besides its limitation to metal-based NPs thoug...

In only two years, the coronavirus disease 2019 (COVID-19) pandemic has had a devastating effect on public health all over the world and caused irreparable economic damage across all countries. Due to the limited therapeutic management of COVID-19 and the lack of tailor-made antiviral agents, finding new methods to combat this viral illness is now...

The efficient entry of nanotechnology-based pharmaceuticals into target cells is highly desired to reach high therapeutic efficiency while minimizing the side effects. Despite intensive research, the impact of the surface coating on the mechanism of nanoparticle uptake is not sufficiently understood yet. Herein, we present a mechanistic study of ce...

Drug-induced nephrotoxicity is a frequent adverse event and a dose-limiting factor in patient treatment and is a leading cause of prospective drug attrition during pharmaceutical development. Despite the obvious benefits of nanotherapeutics in healthcare strategies, the clearance of imaging agents and nanocarriers from the body following their ther...

Progressive expansion of nanomaterials in our everyday life raises concerns about their safety for human health. Although kidneys are the primary organs of xenobiotic elimination, little attention has been paid to the kidneys in terms of nanotoxicological studies up to now. Here we investigate the cytotoxic and genotoxic potential of four solid-cor...

To see the article click on the link: https://sciencetrends.com/ph-rules-the-fate-of-chitosan-based-complexes/

Chronic myelogenous leukemia (CML) is commonly treated with tyrosine kinase inhibitors (TKIs) that inhibit the pro-leukemic activity of the BCR-ABL1 oncoprotein. Despite the therapeutic progress mediated by TKI use, off-target effects, treatment-induced drug resistance, and the limited effect of these drugs on CML stem cells (SCs) are major drawbac...

Ionically crosslinked chitosan/tripolyphosphate (Chit/TPP) particles have been widely tested in biomedical applications, particularly as potential carriers for controlled drug delivery. Since Chit/TPP particles are typically prepared under acidic conditions, their application in physiological environment and correct evaluation of biological data ul...

The last decade has witnessed a rapid growth of nanoscale-oriented biosensors that becomes one of the most promising and rapidly growing areas of modern research. Despite significant advancements in conception of such biosensors, most are based at evaluation of molecular, or protein interactions. It is however becoming increasingly evident that fun...

A next-generation cure for type 1 diabetes relies on immunoprotection of insulin-producing cells, which can be achieved by their encapsulation in microspheres made of non-covalently crosslinked hydrogels. Treatment success is directly related to the microsphere structure that is characterized by the localization of the polymers constituting the hyd...

Over the years, oligonucleotide derivatization and bioconjugation have shown to be a viable option to address many limitations of oligonucleotide-based drugs. Improvements in their biochemical properties, in vivo stability and biodistribution have paved the way for important advancements in preclinical and clinical studies. Purposeful functionaliza...

Despite the massive global spend on biology-driven drug discovery, tackling the issue of side effects and adverse events resulting from drug promiscuity represents a persistent challenge. Although delivering authentic medical innovations today is more complex than ever, minimization of off-target effects should be a priority.

Microencapsulation has shown high potential in various applications. It also represents a promising concept for cell therapies, where a robust encapsulation technology belongs to crucial factors for entering the clinics. This article focuses on vibration technology that among other technologies complies the most with diverse requirements for cell e...

Despite the indisputable benefit of curative disease-specific chemotherapy regimens, the systematic administration of drugs is associated with a substantial treatment burden in hemato-oncological patients. The side effects and adverse events related to the applied therapy are generally manageable

Motivation: To evaluate the clinical significance of ABCB1 overexpression as marker for predicting the outcome of CML patients undergoing first-line imatinib therapy Introduction: Overexpression of efflux transporter ABCB1 is one of the long-time studied indicators with a potentially predictive value for therapeutic response of CML patients. Despi...

Comprehensive characterization of nanoparticles associated with investigation of their cellular uptake creates the basis on which fundamental in vitro and in vivo studies can be built. In this work, a complex analysis of various surface-modified magnetite nanoparticles in biologically relevant environment is reported and the promotion of incorrect...

The ability of chitosan to form nano/sub-micron particles as well as its relatively simple modifiability predestine chitosan for numerous applications in biomedicine. Among the variety of methods developed for the preparation of chitosan-based particles, ionic crosslinking based on polyelectrolyte complexation between polycationic chitosan and nega...

Sodium alginate – sodium cellulose sulphate – poly(methylene-co-guanidine) (SA-SCS-PMCG) microcapsules represent a multicomponent polymeric system aimed for pancreatic islets encapsulation in type I diabetes treatment . The SA-SCS-PMCG microcapsule is currently being tested in pre-clinical animal models with the vision for using this concept in hum...

Little is known about the function and phenotype of leukemic stem cells (LSCs) in chronic myeloid leukemia (CML) or about specific markers that discriminate LSCs from normal hematopoietic stem cells (HSCs). CD26 has recently been described as a specific marker of CML LSCs. In the current study, we investigated this marker in a cohort of 31 unselect...

Background: Imatinib mesylate (IMA), an inhibitor of BCR-ABL1 tyrosine kinase activity, has demonstrated significant clinical efficacy in the treatment of chronic myelogenous leukemia (CML) allowing durable response and prolonged survival, and has become the standard treatment for CML. Unfortunately, there is still a significant portion of patients...

In this book, complementary knowledge about the structural and dynamical properties of rRNA secondary motifs (e.g. Kink-turn motifs, GTPase associated center, 16S Helix 44, A-site finger) is presented with prime focus on their intrinsic dynamical properties and related biological functions. The performed molecular dynamics studies provided detailed...

Magnetite nanoparticles (MNPs) are increasingly being investigated for use in a variety of biomedical applications. In the clinics, they have great potential as magnetic resonance imaging (MRI) contrast agents, heating mediators in hyperthermia-based cancer therapy and nanocarriers in targeted drug/gene delivery. Because of the benefits of MNP use,...

Microencapsulation employed in a broad range of applications, including those with a strict demand on standardization, requires to understand the limitations of respective encapsulation technologies. Among the most frequently used technologies, vibration technology has gained a significant interest due to high capacity and capability to produce uni...

Encapsulation based on hydrogels is widely utilized in a variety of biotechnological and medical applications as it allows immobilization, protection, release and functionalization of diverse chemical and biological materials. In the current era of cellular based therapies, special attention is given on cell encapsulation as a modern and promising...

This multicentre study focused on monitoring imatinib mesylate (IMA) trough plasma (C trough) and intracellular (IMA C intrac) concentrations in 228 chronic myelogenous leukaemia patients. The median of measured IMA C trough in our patient group was 905.8 ng ml (range: 27.7–4628.1 ng/ml). We found a correlation between IMA C trough and alpha 1-acid...

Imatinib mesylate is a standard first-line therapy for patients with chronic myelogenous leukemia. However, there is still a significant proportion of these patients who reflect sub-optimal responses or fail imatinib therapy. Knowledge of the distribution within the studied system (e.g., peripheral blood) may be of high importance for understanding...

Hyperglycemia represents frequent adverse event reported in chronic myelogenous leukemia (CML) patients treated with nilotinib. In order to determine the major mechanism of glucose metabolism impairment, we performed a metabolic analysis using an oral glucose tolerance test as well as assessment of incretins and adipokines at baseline and after 3 m...

The nucleophosmin 1 (NPM1) gene is one of the most commonly mutated genes in acute myeloid leukemia (AML), occurring in approximately 60% of adult cytogenetically normal AML (CN-AML). To date, these mutations have only been detected in cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. I...

The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss...

Background and Objective It has been shown that the occurrence of the BCR-ABL1 T315I mutation leads to a very poor therapeutic outcome in chronic myelogenous leukemia (CML) patients treated with tyrosine kinase inhibitors. Therefore, early detection of this mutation could potentially lead to early therapeutic intervention and a better prognosis wit...

Few studies have examined the treatment of molecular relapse in patients with acute myeloid leukemia (AML) using different treatment regimens. We describe for the first time in the literature experiences with administration of clofarabine monotherapy in the treatment of eight patients with AML with molecular relapse of the disease.

3755 Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by excessive production of myeloid cells and the presence of the BCR-ABL fusion oncogene resulting from the t(9;22) reciprocal translocation. The leukemic clone in CML often accumulates other somatic lesions that may collaborate with BCR-ABL oncogenicity or co...

2495 Background The intracellular concentration of imatinib (IM) in patients with chronic myeloid leukemia (CML) is supposed to be influenced by the expression of its main cellular transporters, hOCT1 (influx) and ABCB1 (efflux). The assessment of the genes expression may be potentially important in clinical practice to effectively manage the ther...

In this study, we investigated the predictive value of pretreatment mRNA expression levels of hOCT-1 and ABCB1 in different cell populations with regard to the response to therapy at 6 and 12 months of IMA therapy. Expression levels were assessed in peripheral blood (PB) leukocytes (LEU, n = 30), polymorphonuclear cells (PMNC, n = 23), and mononucl...

Imatinib (IM) dramatically improved the prognosis of chronic myeloid leukemia (CML), particularly with newly diagnosed patients in a chronic phase (CP) [1]. The most robust source of data about IM efficacy in this setting is the IRIS trial. However, every day clinical practice data are still scarce. We analyzed IM efficacy and safety in the first-l...

The reoccurrence or increase in autologous hematopoiesis after allogeneic transplantation has been linked to incipient leukemia relapse. However, the importance of such an emergency regarding microchimerism (i.e. mixed chimerism below 1% of autologous cells) still remains controversial, as fluctuating microchimerism can be observed for a very long...

In this study, we investigated differences in ABCB1 mRNA expression measured in peripheral blood (PB) leukocytes (LEU) as well as polymorphonuclear (PMNCs) and mononuclear cells (MNCs) of PB LEU obtained from healthy volunteers and patients with de novo CML. In addition, we analyzed the relationship between the percentage of individual cells that c...

Nucleophosmin (NPM1) mutations in exon 12 are the most common genetic alternation in cytogenetically normal AML (CN-AML). Although mutation types A, B, and D represent the majority of cases, rare mutation variants of the NPM1 gene in individual patients do occur. In this study, we have evaluated a novel, DNA-based real-time quantitative polymerase...

In conclusion, our data demonstrate that, within the cohort of tested individuals, the IDH2 mutations are associated with AML (in contrast to healthy volunteers), suggesting a role for these mutations in disease pathogenesis. In addition, we show an association of the observed IDH2 mutations with disease status, indicating their potential for MRD m...

The monitoring of hOCT1 mRNA expression in patients with chronic myelogenous leukemia (CML) was used for predicting the response to imatinib treatment. However, different cell populations from patients who received various degrees of pretreatment were used for this analysis. Therefore, several biases in the results and their interpretation may aris...

Acute promyelocytic leukemia (APL) with atypical breakpoints in the promyelocytic leukemia (PML) and retinoic acid receptor-alpha (RARA) genes represents a rare leukemic event, which occurs preferentially in patients with variant types of the PML/RARA fusion gene. Here we report on a patient with APL with a unique PML/RARA fusion transcript that ha...

Splenomegaly belongs among typical findings on physical examination in patients with newly diagnosed chronic myelogenous leukemia (CML) [1]. Its disappearance is a part of achieving complete hematological response (CHR), that is nowadays (when second generation of tyrosine kinase inhibitors are available) of particular interest during imatinib trea...

Helix 38 (H38) of the large ribosomal subunit, with a length of 110 Å, reaches the small subunit through intersubunit bridge B1a. Previous cryo-EM studies revealed that the tip of H38 moves by more than 10 Å from the non-ratcheted to the ratcheted state of the ribosome while mutational studies implicated a key role of flexible H38 in attenuation of...

In recent years, several independent prognostic factors in cytogenetically normal acute myeloid leukemia (CN-AML) have been reported. Mutations or the expression levels of certain genes have been often used as molecular markers for prediction of a patient's outcome or for evaluation of treatment outcome. One of them, the gene encoding CCAAT/enhance...

Helix 38 (H38) of the large ribosomal subunit is a long, bent structure connecting with the small subunit through intersubunit bridge B1a. Its elbow segment, known as a kink-turn (Kt-38) in the Haloarcula marismortui ribosome, is the likely source of its dynamical properties, important for translational fidelity. The archaeal and bacterial crystal...

FLT3 (FMS-like tyrosine kinase 3) is a tyrosine kinase receptor expressed by early hematopoietic progenitor cells and is essential for its normal development and proliferation. Activating mutations of this kinase are found in approximately 40% of all AML cases and are therefore one of the most common genetic alterations observed in AML. Mutations i...

The lack of reliable molecular markers is responsible for difficult detection and monitoring of Ph-negative myeloproliferative diseases, such as polycythemia vera, essential thrombocythemia or idiopathic myelofibrosis. In recent years, the V617F point mutation in the JAK2 gene (JAK2V617F) come to be a feasible marker for confirmation and evaluation...

In the presented PhD thesis, I complement the knowledge about the structural and dynamical properties of RNA secondary motifs (e.g. RNA Kink turn motifs, GTPase associated center rRNA, 16S rRNA Helix 44) performing state-of-the art computational techniques, focused on their intrinsic dynamical properties and related biological functions. These MD s...

MD simulation technique captures qualitative differences in intrinsic flexibilities of rRNA building blocks possessing contrasting intrinsic flexibility signatures. The basic intrinsic physico-chemical properties of the RNA motifs can in many cases be maintained in the RNA assemblies and contribute to function and sequence constraints. Kink-turns s...

Explicit solvent molecular dynamics (MD) was used to describe the intrinsic flexibility of the helix 42–44 portion of the 23S rRNA (abbreviated as Kt-42+rGAC; kink-turn 42 and GTPase-associated center rRNA). The bottom part of this molecule consists of alternating rigid and flexible segments. The first flexible segment (Hinge1) is the highly anharm...

Molecular dynamics (MD) simulations were employed to investigate the structure, dynamics, and local base-pair step deformability of the free 16S ribosomal helix 44 from Thermus thermophilus and of a canonical A-RNA double helix. While helix 44 is bent in the crystal structure of the small ribosomal subunit, the simulated helix 44 is intrinsically s...

The presence of Kink-turns (Kt) at key functional sites in the ribosome (e.g., A-site finger and L7/L12 stalk) suggests that some Kink-turns can confer flexibility on RNA protuberances that regulate the traversal of tRNAs during translocation. Explicit solvent molecular dynamics demonstrates that Kink-turns can act as flexible molecular elbows. Kin...

Kink-turn (K-turn) motifs are asymmetric internal loops found at conserved positions in diverse RNAs, with sharp bends in phosphodiester backbones producing V-shaped structures. Explicit-solvent molecular dynamics simulations were carried out for three K-turns from 23S rRNA, i.e., Kt-38 located at the base of the A-site finger, Kt-42 located at the...

Ribosomal RNA K-turn motifs are asymmetric internal loops characterized by a sharp bend in the phosphodiester backbone resulting in "V" shaped structures, recurrently observed in ribosomes and showing a high degree of sequence conservation. We have carried out extended explicit solvent molecular dynamics simulations of selected K-turns, in order to...