imagine (Institute of molecular genetics and genetic engineering)
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INFUSION-RELATED REACTIONS TO RITUXIMAB BIOSIMILARS IN PATIENTS WITH CHRONIC B-LYMPHOPROLIFERATIVE DISORDERS: SINGLE CENTER EXPERIENCE
No full textUvod: Infuzione reakcije (IR) predstavljaju česte komplikacije primene rituksimaba,
koje se uglavnom uspešno prevazilaze. U literaturi nismo pronašli poređenje
različitih biosimilara rituksimaba u pogledu IR.
Cilj: Sagledati različite aspekte IR na biosimilare rituksimaba, Rixathon® i Blitzima
® kojima su lečeni pacijenti sa hroničnim B-limfoproliferativnim bolestima
(hBLPB) na Klinici za hematologiju UKCS 2020–2022. godine.
Metode: Iz medicinske dokumentacije su izdvojeni podaci 200 konsekutivnih
pacijenata sa hBLPB koji su lečeni imunohemioterapijom u našoj ustanovi. Svi
pacijenti su primili standardnu premedikaciju pre primene rituksimaba.
Rezultati: IR su se manifestovale kod 24% pacijenata. Učestalost IR nije bila
povezana sa polom, starosnom dobi, stadijumom, lokalizacijom (nodalna/ekstranodalna),
B simptomima, „bulky” masom, performans statusom, tipom hemioterapije
(HT) koja je primenjivana uz rituksimab niti sa vremenom primene
rituksimaba u odnosu na ciklus HT (od I ciklusa vs. od II+ ciklusa). Pacijenti sa
difuznim B krupnoćelijskim limfomom (DBKL) su ispoljili značajno manji broj IRR
u poređenju sa drugima (p = 0,033), u prvom redu hroničnom limfocitnom leukemijom
(15% vs. 34%; p = 0,045). Oni koji su lečeni u drugoj ili kasnijim terapijskim
linijama češće su imali IR (p = 0,0233).
Zaključak: Nije uočena značajna razlika u učestalosti IR između različitih biosimilara.
Pacijenti sa DBKL i oni koji su primali rituksimab u prvoj liniji, ređe su
ispoljili IR u odnosu na pacijente sa drugim tipovima hBLPB, odnosno lečene u
drugoj ili kasnijim linijama. Incidenca IR kod pacijenata koji su primali različite
vrste biosimilara rituksimaba nije se značajno razlikovala. Arterijska hipertenzija,Introduction: Infusion-related reactions (IRRs) represent frequent, although
manageable complications of rituximab administration. To the best of our
knowledge, no comparisons between different biosimilars in this setting have
been published to date.
Objective: To assess different aspects of IRRs to rituximab biosimilars Rixathon®
and Blitzima® administered to patients with chronic B-lymphoproliferative disorders
(cBLPDs) treated at Clinic for Hematology, UCCS, from 2020 to 2022.
Methods: We assessed medical records of 200 consecutive patients with cBLPDs
treated at our institution with immunochemotherapy in regard to clinical
features and IRR occurence. All patients received standard premedication before
rituximab administration.
Results: IRRs manifested in 24% of all patients. IRR rate was not associated with
gender, age, stage, disease localization (extranodal/nodal), “B” symptoms, bulky
mass, performance status, type of chemotherapy adjunct to rituximab, or rituximab
timing (from 1st cycle vs. from 2nd + cycle). Patients with DLBCL exhibited
significantly fewer IRRs compared to others (p = 0.033), CLL in the first place (15%
vs. 34%, respectively; p = 0.045). Patients treated in 2nd or later therapeutic lines
more frequently exhibited IRR, compared to patients treated in 1st treatment line
(p = 0.0233). Incidence of IRR in patients receiving different rituximab biosimilars
was similar. Arterial hypertension, diabetes mellitus, coronary artery disease,
and smoking did not influence IRR occurrence.
Conclusion: No difference in IRR rates between studied biosimilars was observed.
DLBCL patients and patients receiving rituximab in 1st treatment line suffered
from IRRs less frequently than patients with other cBLPDs and those treated
in 2nd+ line, respectively.Abstract book: Nacionalni kongres, 6. KONGRES HEMATOLOGA SRBIJE, Crowne Plaza, Beograd 17–19. oktobar 2024. godin
Toxicology Transformed: Harnessing Artificial Intelligence for Advanced Research
No full textOver the past few decades, toxicology has made a sharp turn from an observational
science focused on analyzing chemical-induced endpoints to a data-rich discipline.
The amount of new data stemming from the literature, high-throughput screening
(HTS) assays, omics, and other technologies is rapidly accumulating, creating a fruitful
ground for the application of artificial intelligence (AI). Through machine learning (ML),
deep learning, large language models, and natural language processing techniques, AI
can effectively navigate this complex data landscape, deciphering patterns, elucidating
toxicity mechanisms, and enhancing risk prediction.
Here, some of the applications of ML in toxicology will be presented. The ML models were
used to unravel the intricate mechanisms underlying chemical-induced female infertility.
The adverse outcome pathway (AOP), a theoretical concept describing biological events
leading to adverse effects, was used as a backbone in developing the ML models for female
infertility. Utilizing eighteen HTS bioassays, these models tracked key biological processes
outlined in AOP7 – receptor binding as a molecular initiating event, and gene expression
and steroid production as key events – leading to adverse outcomes. These ML models
efficiently simulated and predicted perturbations in each event within toxicity pathways
for novel chemicals, revealing a group of chemicals that can affect all events in the AOP,
thus forming a linear molecular pathway that can lead to female reproductive disorders.
The ML models were also used to assess the potency of novel chemicals in binding to
the progesterone receptor and to discriminate between agonists and antagonists of this
receptor.
These examples underscore the vast potential of AI in toxicology research, offering a
multitude of avenues for exploration. AI has the potential to transform toxicology into a
more predictive, mechanism-based, and evidence-integrated scientific discipline to better
safeguard human and environmental health from chemical hazards.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
Alternatively spliced exons manifest coordinated multi-domain alteration in synapse specific genes
No full textBased on publicly available RNA-seq data of human hippocampus samples, we
identified alternatively spliced (AS) exons genome wide along with assessing the
genes percentage spliced in (psi) values. The data has been compiled on more than
30 samples for each gene. Along with psi values we compiled pairwise covariation
matrix across all AS (exon skipping) exons based on Pearson r2. Further Agglomerative
Hierarchical Clustering (AHC) procedure on matrix revealed dense AS exons clusters
with linked exons, with clusters size in the iterval of [2..19] (pairwise correlation
pvalue<1E-6). There were around 2200 genes with clusters of coordinated AS exons.
Further analysis revealed AS clusters maintain antagonistic or independent relations within
a gene. We explored the traits of genes abundant with AS clusters: the majority proved
to be neurospecific genes, including synapse, and cytoskeletal (axonal) genes. Notably,
Neurospecific splice factors (SFs) also maintain expanded coordinated AS regulation.
While the previous study observed coordinated splicing before [1], the scale of the
phenomenon has not been explicitly highlighted. From the evolutionary point of
view, and, given the information complexity of splicing decreases upon exon covaritaion,
we may speculate that the rapid response to the homeostatic environment
favors quick coordinated splicing mediated tune-up of the gene’s isoform. Still, the
mechanistic background of phenonenon is not elucidated. One of the viable hypothesis
is the specific secondary structure of mRNA favoring the quick coordinated SFs binding.
In our report we address the phenomenon and consider several examples of coordinated AS.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
Enhancing Biomedical Information Retrieval with Semantic Search: A Comparative Analysis Using PubMed Data
No full textPubMed excels in retrieving scientific articles through keyword matching in biomedical
literature. However, its efficacy in comprehending and addressing natural language
queries is limited due to its emphasis on basic text matching and absence of contextual
understanding. This limitation becomes challenging when users pose inquiries in natural
language that do not align with the structured vocabulary of the database. To address this,
we are presenting an Information Retrieval System utilizing indexed data sourced from
PubMed articles (title+abstract), which employs a combination of lexical and semantic
search to retrieve the most accurate responses to user inquiries.
For the vector representation of concatenated titles and abstracts, we employed a sentence
transformer model optimized for asymmetric semantic search, given our focus on shorter
queries searching through longer texts. Lexical indexing utilized the OpenSearch database,
while semantic indexing was facilitated by Qdrant. Tuning the hybrid search results
achieved an optimal balance between lexical and semantic search parameters. Evaluation
was conducted using the BioASQ dataset comprising 5049 questions, each paired with
PubMed articles and annotated by domain experts. We also used this dataset to assess the
performance of the PubMed Search Engine in biomedical question answering, enabling a
comparative analysis.
Utilizing the lexical index for document retrieval yielded MAP@10 of 0.411. Through
experimentation, we determined that the optimal hybrid query combination entails weights
of 0.7 and 0.3 for lexical and semantic components, respectively. Integrating the best lexical
results with the semantic index led to an enhanced MAP@10 of 0.425. Assessment of the
PubMed search engine on the same BioASQ dataset unveiled MAP@10 of 0.153 when
MeSH terms were omitted and MAP@10 of 0.191 when they were included in the search
of the PubMed database. Our system notably advances biomedical information retrieval by
leveraging a fusion of lexical and semantic search, resulting in heightened precision when
responding to natural language queries, surpassing PubMed’s keyword-based approach.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
Transcriptome-wide detection of RNA cleavage sites revealed tRNA cleavage by target-activated CRISPR-Cas13a effector
No full textType VI CRISPR-Cas systems exclusively recognize and cleave RNA molecules. A distinct
feature of Type VI systems is collateral RNA damage. Specifically, the binding of a target
transcript by Cas13a, charged with cognate CRISPR RNA (crRNA), activates the Cas13a
enzyme, turning it into an active ribonuclease that mediates the cleavage of noncomplementary
RNA molecules. Previously, Cas13a-mediated collateral RNA cleavage
was observed in in vitro experiments and was described to be nonspecific. In Escherichia
coli, targeting of nonessential transcripts by heterologously expressed Leptotrichia shahii
Cas13a enzyme (LshCas13a) leads to cell growth retardation, which was proposed to be a
consequence of collateral degradation of essential cellular transcripts. However, the direct
link between collateral RNA cleavage and cell growth retardation was not established.
Specifically, the products of collateral RNA cleavage mediated by target-activated Cas13a
enzyme were not identified in living cells.
To detect RNA cleavage sites associated with collateral Cas13a activity, a specific
approach based on high-throughput RNA sequencing was developed. This approach
was successfully applied to detect RNA cleavage sites introduced by target-activated
LshCas13a enzyme in both in vivo and in vitro experiments. In E. coli cells, the targetactivated
LshCas13a enzyme cleaves tRNA molecules within anticodon loops, leading
to protein synthesis inhibition and slowing down cell growth. Additionally, LshCas13amediated
collateral tRNA cleavage indirectly activates cellular ribonucleases encoded by
Type II toxin-antitoxin systems.
Together, the results suggest that the L. shahii Type VI CRISPR-Cas system mediates the
immune response by inhibiting translation through collateral tRNA cleavage.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
PHF19 gene transcripts as potential biomarkers of early colorectal cancer
No full textRecent pan-cancer transcriptome study demonstrated differential activity of PHF19 gene
promoters. Promoter found to be upregulated in colorectal cancer gives rise to PHF19-207
transcript. In this study we aim to evaluate expression of PHF19 gene transcripts in colorectal
cancer using transcriptomes of cell lines, representing diferent stages of colorectal
carcinogenesis, and public transcriptomic data.
Normal colon gut mucosa cell line (HCEC-1CT) and malignant colon cell lines representing
differenct stages of tumor development (HCT116, DLD1 and SW620) were cultivated in 3D
and sequenced using Illumina NovaSeq 6000 platform. Publicly available RNA sequencing
data GSE164541, GSE139546 and GSE1552746 were retrieved from GEO database.
Corresponding raw sequencing reads were mapped and quantified with HISAT2 and StringTie
tools.
RNA sequencing of the cell lines showed progressive upregulation of PHF19-207 transcript
trough tumor stages which suggests its potential use as biomarker for early colon tumor
detection. This transcript showed the same pattern in data retrieved from public dataset
representing normal, adenoma and tumor tissue (GSE164541). There was no significant
difference of the expression of PHF19-207 between primary tumor and metastatic tissue
according to GSE139546 dataset. No expression of this transcript is observed in data from
HCEC-1CT and HCEC-1CT APC knockdown cells (GSE1552746). APC represents first-ever
deregulation in most cases of the colorectal cancers which suggests that deregulation of PHF19-
207 transcript occurs after first step of carcinogenesis. However, this dataset showed
upregulation of PHF19-201 transcript. This supports our finding that wild-type APC cell lines
(HCEC-1CT and HCT116) show low expression and APC deregulated cell lines (DLD1 and
SW620) show significant upregulation of PHF19-201 and that relations of this transcript and
APC and Wnt/β-catenin signaling pathway should be explored.
This study pointed potential use of PHF19-207 and PHF19-201 transcripts as diagnostic
biomarkers in early tumor detection and suggested further research on functional role of
PHF19-207 and PHF19-201.Cancer Genomics, Multiomics and Computational Biology
Bergamo, Italy : 30 April - 2 May 202
WGS approach to identify potential genetic modifiers in Glycogen Storage Disease Ib
No full textUniversity of Belgrade, Serbia
[email protected]
Glycogen Storage Disease Ib (GSD Ib) is a rare metabolic disorder characterized by a deficiency
of glucose-6-phosphate translocase, leading to metabolic disruptions and neutropenia.
Varying severity and progression of neutropenia were detected among individuals with the
same genotype, indicating a complex genotype-phenotype correlation. We aim to explore
potential modifier genes influencing neutropenia in GSD Ib, focusing on five patients with
the homozygous c.1042_1043delCT variant in the SLC37A4 gene. These patients exhibit
diverse neutropenia profiles, with two displaying mild and intermittent neutropenia, while
the remaining three develop severe and persistent neutropenia.
Whole genome sequencing (MGISEQ-G400, BGITech) was conducted on five unrelated
subjects, all presenting with previously identified pathogenic homozygous SLC37A4 variant.
We followed GATK best practices for genomic data processing to identify genetic variations
associated with observed clinical differences. A unique pipeline was constructed focusing
on neutropenia-related genes and genes involved in glucose-6-phosphate metabolism,
neutrophil function pathways, immune system regulation, ER stress, and UPR response.
In patients with severe neutropenia, we identified two heterozygous variants (c.-70G>C and
c.96T>C, p.Thr32Thr) in the JAGN1 gene, which is essential for neutrophil differentiation.
Additionally, severe neutropenia patients had variants in CTLA4 (c.49A>G, p.Thr17Ala) and
TGFB1 (c.29C>T, p.Pro10Leu), genes involved in immune regulation and cell survival and which
have previously been recognized as modifier genes in various immunological conditions.
This research underscores the potential significance of modifier genes in shaping the diverse
course of neutropenia in GSD Ib, highlighting the need for further functional studies to
elucidate the precise roles of these variants in disease presentation. Investigating potential
genetic modifiers can provide valuable insights into the molecular base of the disease and
guide future research focused on developing customized therapeutic approaches for the
specific neutropenic phenotype.Book of abstracts: 5th Belgrade Bioinformatics Conference, Serbia, Belgrade,17-20 june 2024
Detection of new genetic variants in patients with idiopathic recurrent venous thrombosis
No full textBackground: Despite significant advancements in molecular genetics knowledge, identification
of genetic risk factors of familial thrombophilia remains a major challenge.Aims: The current study aimed to identify new putative genetic biomarkers that would contribute
to elucidating the causes of idiopathic venous thrombosis.
Methods: The study included 16 patients diagnosed with recurrent idiopathic thrombotic events,
patiently selected from the repository of the Laboratory for Molecular Biology, IMGGE, which
includes about 5000 patients with thrombotic events. All patients had a positive family history of
thrombophilia, and repeated thrombotic events, with the first occurring at an early age. The
patients were screened for hemostatic parameters and subjected to whole exome sequencing
(WES) analysis. Generated variant calling files (VCFs) were searched for thrombophilia risk
factors using clinical interpretation tools (ClinVar and ACMG), gene ontology and interaction
databases (OMIM and STRING), and in silico prediction tools (CADD Phred, PolyPhen-2 and
SIFT). Damaging potential of selected missense variants was further analyzed based on
predicted modulation of protein intramolecular and intermolecular, as well as protein-metal
interactions by using VarMap web tool.
Results: Notably, increased factor VIII concentrations were detected in 12 patients, whereas 1
patient had elevated tissue factor. Putative thrombophilia risk factors were detected in 8 patients.
These included rare heterozygous missense or stop-gain variants in F5, SERPINC1, KNG1 and
HABP2 genes. Association between these variants and venous thrombosis has not yet been
documented and requires further studies. Besides, potentially significant missense variants were
also found in ADAMTS13, PLAT, APOH, F13B and SRRM2 genes.
Conclusion(s): Use of WES analysis has led to identification of new putative thrombophilia risk
factors in investigated patients with recurrent idiopathic thrombotic events. Functional analysis
will be performed to further estimate significance of the selected genetic variants
Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies
No full textChildhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets
Exploring altered translation in Autism Spectrum Disorder (ASD)
No full textAutism spectrum disorder (ASD) is a complex, prevalent neurodevelopmental disorder with significant
genotype and phenotype heterogeneity. Recent studies suggest dysregulated protein synthesis as a
key mechanism in ASD. This study explores altered translation in ASD using induced pluripotent stem
cells (iPSCs), a promising tool for disease modelling. We introduced ASD-relevant mutations in FMR1,
PTEN, and TSC2 into iPSCs from healthy donors via CRISPR/Cas9. The iPSCs were then differentiated
into iNeurons and cortical organoids, and their proteomes were analysed using mass spectrometry.
TSC2 and PTEN mutants showed similar profiles in both models, while FMR1 showed differences only
in organoids, not in iNeurons. GO enrichment analysis revealed increased abundance of proteins
associated with mitochondrial processes, such as cellular respiration and protein synthesis, reflecting
mTORC1 hyperactivation due to PTEN and TSC2 mutations. Downregulated proteins were related to
transcriptional and epigenetic regulation. Notably, dysregulated proteins included genes linked to ASD
(SFARI gene list), emphasizing the proteomic data's relevance. These findings are expected to
elucidate ASD's molecular underpinnings, covering both specific mutations and shared alterations
among different ASD-related mutations.FENS Forum 2024, 25-29 June in Vienna, Austri