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Pharmacogenomics and pharmacotranscriptomics of acute lymphoblastic leukemia in childhood: on the way to personalized medicine
No full textPersonalized medicine is focused on research disciplines that contribute to the individualization of
therapy, such as pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL)
is the most common childhood malignancy. It is one of the pediatric malignancies with the highest cure
rate, but still a lethal outcome due to therapy accounts for 1–3% of deaths. Further improvement of
treatment protocols is needed through the implementation of pharmacogenomics and
pharmacotranscriptomics. The research study was aimed at discovering pharmacogenetic and
pharmacotranscriptomic markers of response to therapy with thiopurine and glucocorticoid drugs,
methotrexate and vincristine in children with ALL in Serbia. Blood and bone marrow samples from
children with ALL were collected at the University Children's Hospital in Belgrade. Variants in the
studied genes were detected by PCR and Sanger sequencing. The expression level of NUDT15 in
mononuclear cells was determined by real-time PCR. Next-generation sequencing using cancer panel
TruSeq Amplicon, Illumina was also performed to assess drug resistance. Correlation of
pharmacomarkers with clinical parameters was performed using statistical tests. A polygenic risk score
based prediction model for the development of methotrexate-induced hepatotoxicity was developed. A
number of molecular markers responsible for the efficacy, side effects and toxicity of drugs used to treat
ALL, ie. glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines and methotrexate. Their
application in clinical practice is still insufficient. Research efforts should be focused on analyzing data
and designing predictive models that use machine learning algorithms. Bioinformatics tools and the
implementation of artificial intelligence will help personalized medicine come to life in clinical practice.2ND B&H SYMPOSIUM OF LABORATORY GENETICISTS AND MOLECULAR BIOLOGISTS
(WITH INTERNATIONAL PARTICIPATION)
10TH - 11TH MAY 2024, BANJA LUKA, BOSNIA AND HERZEGOVIN
Cellulose nanocrystals reinforced PHBV/PVA coaxial electrospun nanofibers for active food packaging (CoActivePack)
No full textConventional packaging is designed inherently to protect food products by serving as a simple barrier
betweenfood and external parameters, including microorganisms, moisture, oxygen, odors, physical
forces, and othercontaminants. The most commonly used packaging material is plastic (42%), which
represents more than 30%of global plastic production. Despite their durability, cost efficiency, and
lightweight, single-use plastics used forfood packaging contribute greatly to environmental pollution,
when discarded after food consumption, due tovery slow decomposition (for certain types over 1000
years) and with a very limited quantity recycled (only 9%of all plastic, according to a report by the UN
Environment Programme). A potential alternative topetrochemically derived polymers and packaging
materials are bio-based and biodegradable materials such asbioplastics, that are obtained from
renewable resources such as plants, cells, and microorganisms. Therefore,recent research has been
focused on exploiting natural biodegradable green plastics as packaging materials thatcan partially
substitute nondegradable petroleum-based plastic polymers. Bioplastics can also be naturallyrecycled
by biological processes, thus limiting the use of fossil fuels and protecting the environment,
makingthem sustainable and largely biodegradable. Upcycling strategies have also been developed
showing thatpolyhydroxyalkanoates (PHAs) can be produced by various microorganisms as
intracellular energy and carbon-storage materials, under growth-restraining and carbon-excess
conditions. Making PHA from waste hasemerged as a promising approach for manufacturing PHA in
industrial settings mitigating otherwise high costsof production. Bioactive agents, including
polyphenolic compounds, are incorporated into the packagingmaterial to mitigate or avoid the effects
of microorganism growth and metabolism, and are able to provide areal-time visual color change in
response to pH changes, and formation of toxic substances, odors or gas. Aronia,often known as the
black chokeberry (Aronia melanocarpa), is one of the fruit species with the highestantioxidant activity
and one of the richest sources of polyphenols. During this project biodegradable poly(3-
hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) biopolymer will be produced by microorganisms using
organicwaste as substrate, and purified using green extraction techniques. PHBV and polyvinyl alcohol
(PVA) willbe used to form core-shell based nanofibers by coaxial electrospining to produce novel
biodegradable packagingmaterials. This project will include the addition of aronia to the PVA
component, to assign dual functionalityproviding antioxidant properties and inducible pH-color change
to the packaging material. Structure andproperties of the novel materials will be characterized using
state-of-the-art techniques, and biodegradation willbe assessed by utilizing model compost system.
This multidisciplinary project will also promotecollaboration between Serbian and Turkish scientific
research groups. Altogether, we expect this project toprovide considerable advances in producing
novel functional biomaterials for the use as biodegradablepackaging materials, resistant to
microorganism growth and metabolism, produced by green process. Suchmaterials might generate
benefits both in health and economic respect in addition to building the academicknowledge base,
thus having a great impact in both research centers.Principal Investigator:Dr Vuk Filipović, IMGGEDuration period: 2024-202
ASSESSMENT OF SEASONAL AIRBORNE RESISTOME DYNAMICS IN RESPONSE TO AIR POLLUTION EXPOSURE IN THE BELGRADE METRPOLITAN AREA
Get PDFAntimicrobial resistance (AMR) and air pollution have been
identified as one of the most serious threats to human health
worldwide. The scarce data demonstrating their interdependence
indicates a need to obtain evidence from a broader global area,
especially from regions exposed to high air pollution. Considering
that Serbia is a country struggling with excessive antibiotics use and
misuse, a high percentage of multidrug-resistant bacterial isolates,
and poor air quality, the Serbian capital Belgrade has been recognized
as an interesting research model for the effects of air pollution on the
airborne transmission of AMR. Hence, this abstract aims to present the concept of an ongoing project (AirPollRes) that points to the
additional risk dimension of air pollution to human, animal, and
environmental health. After optimization of air sampling and DNA
extraction protocol, the air samples will be collected at nine locations
in the Belgrade metropolitan area selected according to air pollution
level during four seasons. The state-of-the-art shotgun metagenomic
sequencing and bioinformatic analysis of obtained sequences will
provide information about microbial community composition of
airborne metagenomes. In addition, sequenced airborne
metagenomes will be analyzed for the abundance and diversity of
resistomes (antibiotic and biocide/metal resistance genes) and
mobilomes using several databases and tools. Correlation analyses
will offer us insight into the effect of air pollution and seasonal
variations on abundance and diversity of airborne pathogens,
resistome and mobilome in the Belgrade metropolitan area. In-depth
approach of the AirPollRes project will provide the first insights into
intersection of AMR and air pollution in the Belgrade metropolitan
area, which is highly vulnerable to these health threats. As the AirPollRes is a pioneering project in this field, the expected shortterm
impact is the introduction of routine monitoring of pathogenic
microbes and resistance determinants in the air in Belgrade, while the
longer-term impact will be reflected in the improvement of human
and animal health, allowing for a longer life with higher quality.Book of abstracts and conference proceedings / 3rd International Conference Antimicrobial Resistance - Current State and Perspectives, 16-18. May 2024, Novi Sad, Serbi
A new approach in inhibiting Alpha-1 antitrypsin polymerization (ATLEA)
Get PDFAlpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder that results in lung and liver disease. This
disorder is characterised by polymers and aggregates of mutant alpha-1 antitrypsin which are retained
within liver cells causing liver damage and in severe cases requiring liver transplantation. ATLEA project is
focused on identifying peptides capable of blocking AAT polymerization thereby targeting the root cause
of the disease.Principal Investigator: Dr Mila Ljujic, IMGGEDuration period: 2024-202
Biotransforming waste streams into biomolecules and biomaterials
Get PDFOur consumption habits—from food to cosmetics, clothing, and various other
products—urgently require a shift towards being more sustainable and environmentally
friendly. Biotechnology emerges as a promising solution to address this pressing need.
Microorganisms, though unseen to the naked eye, play a pivotal role in maintaining the
health of our global ecosystem due to their abundance and diversity. They actively
participate in crucial processes such as carbon and nutrient cycling, and contribute to
human, animal, and plant health. Additionally, they serve as a valuable source of diverse
products spanning industries like pharmaceuticals, chemicals, food, environmental
management, and agriculture.
Microorganisms can be turned into efficient factories for the production of various
compounds and materials. Leveraging microbial capabilities, we can extract economic and
environmental value through bio-upcycling, converting diverse waste streams into
biomaterials (polyhydroxyalkanoates and bacterial nanocellulose), but also into
next-generation, eco-friendly therapeutics. Focus is placed on bacterially derived natural
products such as pyocyanin, prodigiosin, and actinomycin, which exhibit proven bioactivities
like anticancer, antifungal, antibiofilm, and antiviral properties. Their greener production,
processing and, formulation using innovative techniques such as fermentative bioprocess
intensification, structural optimization via biocatalysis and formulations using metals, as well
as biopolymeric drug carriers will be highlighted. In this way, harnessing the capabilities of
microorganisms, we can effectively address both environmental and biomedical challenges,
ushering in a new era of sustainability and innovation.Book of abstracts: 6th Symposium on Biotransformations for
Pharmaceutical and Cosmetic Industry
June 17-21, 2024, Kraków, Polan
Biomimetic tumor engineering to enhance drug discovery (BioengineeredTumor)
Get PDFDevelopment of novel anti-cancer therapies is still slow and cumbersome partially due to
weaknesses of current preclinical studies based on simple monolayer cell cultures followed by
animal testing. Consequently, there is a clear need for development of more reliable in vitro three
dimensional (3D) tumor models, which will capture key features of the in vivo tumor cell
microenvironment and provide drug testing results relevant for human patients. The proposed
project aims to develop 2 novel, simple and robust 3D models for cultures of carcinoma and
osteosarcoma cells by applying systematic and integrated methodology to comprehensively
define the key model components in conjunction with developing/adapting analytical methods
for reliable and reproducible characterization of cells within 3D scaffolds. In specific, different
human and animal cancer cell lines will be immobilized in novel alginate-based scaffolds as
artificial extracellular matrices imitating tumor environment and the obtained constructs will be
cultivated in perfusion bioreactors providing enhanced mass transport at adequate
hydrodynamic conditions. The models will be validated in short- and longer-term cell cultures
with the application of standard anti-cancer drugs in clinically relevant regimens. By
comprehensive analyses of the cells regarding morphology, viability, proliferation, apoptosis,
immunological and gene expression profiles, and response to anti-cancer drugs the developed
models will be critically evaluated regarding the attained level of resemblance of physiological
cancer features. Thus, the strategic goal of the project is to establish a sufficiently simple, but
relevant, adaptable and scalable platform suited to the use by scientists without technical
expertise for in vitro studies of cancer cells for applications in: (i) anti-cancer drug discovery and
validation, (ii) development of personalized medical treatments, and (iii) cancer research.Principal Investigator: Dr. Bojana Obradović, Faculty of Technology and Metallurgy, University of
BelgradeCoordinator for IMGGE: Dr. Milena Milivojević, Jelena PejićDuration period: 2024-202
New Labeled PET Analogues Enable the Functional Screening and Characterization of PET-Degrading Enzymes
No full textThe discovery and engineering of novel biocatalysts capable of depolymerizing polyethylene terephthalate (PET) have gained significant attention since the need for green technologies to combat plastic pollution has become increasingly urgent. This study focuses on the development of novel substrates that can indicate enzymes with PET hydrolytic activity, streamlining the process of enzyme evaluation and selection. Four novel substrates, mimicking the structure of PET, were chemically synthesized and labeled with fluorogenic or chromogenic moieties, enabling the direct analysis of candidate enzymes without complex preparatory or analysis steps. The fluorogenic substrates, mUPET1, mUPET2, and mUPET3, not only identify enzymes capable of PET breakdown but also differentiate those with exceptional performance on the polymer, such as the benchmark PETase, LCCICCG. Among the substrates, the chromogenic p-NPhPET3 stands out as a reliable tool for screening both pure and crude enzymes, offering advantages over fluorogenic substrates such as ease of assay using UV–vis spectroscopy and compatibility with crude enzyme samples. However, ferulic acid esterases and mono-(2-hydroxyethyl) terephthalate esterases (MHETases), which exhibit remarkably high affinity for PET oligomers, also show high catalytic activity on these substrates. The substrates introduced in this study hold significant value in the function-based screening and characterization of enzymes that degrade PET, as well as the the potential to be used in screening mutant libraries derived from directed evolution experiments. Following this approach, a rapid and dependable assay method can be carried out using basic laboratory infrastructure, eliminating the necessity for intricate preparatory procedures before analysis.The Supporting Information [https://pubs.acs.org/doi/10.1021/acssuschemeng.4c00143]This is the peer reviewed version of the paper: Taxeidis, G., Djapovic, M., Nikolaivits, E., Maslak, V., Nikodinovic-Runic, J., & Topakas, E. (2024). New Labeled PET Analogues Enable the Functional Screening and Characterization of PET-Degrading Enzymes. ACS Sustainable Chemistry & Engineering. [https://doi.org/10.1021/acssuschemeng.4c00143
NEW APPROACHES IN THE TREATMENT OF CHRONIC BACTERIAL INFECTIONS
Get PDFThe rapid emergence and spread of multidrug-
resistant pathogens present a global
healthcare challenge. One common cause of
resistance and/or tolerance to antibiotics is
biofilms, a complex communities of bacteria
embedded in a self-produced matrix. Biofilm
formation and maturation are regulated by
quorum sensing, a cell density-dependent communication
system that relies on the synthesis,
diffusion, and detection of small signaling molecules
- autoinducers (AIs). Quorum quenching
(QQ) enzymes that cut Ais emerged as a promising
strategy for persistent bacterial infections.
However, a significant drawback for the use of
QQ enzymes as therapeutics is their poor stability
and efficacy in vivo. Since one of the major
health issues linked to biofilm development is
persistent wound infections, our goal was to
improve enzyme properties by immobilizing it
on a natural biopolymer to make it suitable for
use as a wound dressing. The best candidate for immobilization was YtnP lactonase from Bacillus
paralicheniformis ZP1, as in concentrations
higher than 25 μg/mL it improved the survival of
Pseudomonas aeruginosa PAO1-infected zebrafish,
rescuing 80% of embryos. When combined
with tobramycin or gentamicin, the survival
rate of zebrafish embryos increased to 100%.
Purified YtnP lactonase at a concentration of 1
mg was immobilized on 10 mg of polymer disks
by crosslinking with glutaraldehyde. Specific
modifications of the polymer were also made to
eliminate the use of glutaraldehyde, which is a
skin irritant. In in vivo experiments on a murine
chronic wound model, immobilized enzyme
inhibited biofilm development, cleared already
formed biofilms, and overall improved wound
healing. These results provide a foundation for
the development of advanced wound dressings
that will prevent infection development in
wounds and enable proper therapy for infected
chronic wounds.Book of abstract: From biotechnology to human and planetary health XIII congress of microbiologists of Serbia with international participation Mikromed regio 5, ums series 24: 4th – 6th april 2024, Mona Plaza hotel, Belgrade, Serbi
Multi-scale modeling uncovers 7q11.23 copy number variation-dependent alterations in ribosomal biogenesis, neuronal maturation and excitability
No full textCopy number variation (CNV) at 7q11.23 causes Williams-Beuren (WBS) and 7q microduplication syndrome (7Dup), neurodevelopmental disorders (NDDs) featuring intellectual disability accompanied by symmetrically opposite neurocognitive features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiology, the propagation of CNV dosage across gene expression layers and their interplay remains elusive. Here we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are post-transcriptionally buffered. Consistently, we found phospho-RPS6 (pRPS6) downregulated in WBS and upregulated in 7Dup. Surprisingly, phospho-4EBP (p4EBP) was altered in the opposite direction reflecting dosage-specific changes in total 4EBP levels. This highlights different dosage-sensitive deregulations of the mTOR pathway as well as distinct roles of pRPS6 and p4EBP during neurogenesis. Our work demonstrates the importance of multi-scale disease modeling across molecular and functional layers and uncovers the pathophysiological relevance of ribosomal biogenesis in a paradigmatic pair of NDDs and uncouples the roles of pRPS6 and p4EBPs as mechanistically actionable relays in NDDs.The Brain Conference - Federation of European Neuroscience Societies (FENS) and Lundbeck Foundation:
The Brain Conference: Neuronal Protein SynthesisMechanisms in Health and Disease.
Rungsted Kyst, Denmark, 13—16 Oct 202
Mood disorders and 5-HTR2A genetic variants – the moderator effect of inflammation on expression of affective polarity phenotype
No full textAlthough repeatedly confirmed, the molecular nature of gene-environment (GxE) interactions has rarely been investigated in the clinical context of mood disorders. This study assesses the relationship between HTR2A genetic variants and the modulatory effect of inflammation in a collective cohort of patients with major depressive disorder (MDD) and bipolar disorder (BD), as a unified group with two distinct phenotypes