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NAR Genomics and Bioinformatics Jun 2024In eukaryotes, translation initiation is a highly regulated process, which combines regulatory sequences located on the messenger RNA along with acting factors like...
In eukaryotes, translation initiation is a highly regulated process, which combines regulatory sequences located on the messenger RNA along with acting factors like eukaryotic initiation factors (eIF). One critical step of translation initiation is the start codon recognition by the scanning 43S particle, which leads to ribosome assembly and protein synthesis. In this study, we investigated the involvement of secondary structures downstream the initiation codon in the so-called START (STructure-Assisted RNA translation) mechanism on AUG and non-AUG translation initiation. The results demonstrate that downstream secondary structures can efficiently promote non-AUG translation initiation if they are sufficiently stable to stall a scanning 43S particle and if they are located at an optimal distance from non-AUG codons to stabilize the codon-anticodon base pairing in the P site. The required stability of the downstream structure for efficient translation initiation varies in distinct cell types. We extended this study to genome-wide analysis of functionally characterized alternative translation initiation sites in . This analysis revealed that about 25% of these sites have an optimally located downstream secondary structure of adequate stability which could elicit START, regardless of the start codon. We validated the impact of these structures on translation initiation for several selected uORFs.
PubMed: 38863530
DOI: 10.1093/nargab/lqae065 -
World Journal of Surgical Oncology May 2024In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence...
BACKGROUND
In clinical practice, genetic testing has become standard for many cancerous diseases. While a diagnosis of a single hereditary syndrome is not uncommon, the coexistence of two genetic diseases, even with partially common symptoms, remains unusual. Therefore, targeted next-generation sequencing (NGS), along with genetic consultation and imaging studies, is essential for every patient with confirmed paraganglioma. In this report, we present two sisters diagnosed with multiple endocrine neoplasia type 2 (MEN2A) and familial paraganglioma syndrome type 1 (FPGL1).
CASE PRESENTATION
After presenting to the clinic with neck tumors persisting for several months, both patients underwent tumor removal procedures following imaging and laboratory studies. Pathological reports confirmed the diagnosis of paragangliomas. Subsequently, genetic testing, including NGS, revealed a mutation in the rearranged during transfection (RET) gene: the heterozygous change (c.2410G > A), (p.Val804Met), and a variant of the succinate dehydrogenase complex subunit D (SDHD) gene: (c.64 C > T), (p.Arg22Ter). Subsequently, thyroidectomy procedures were scheduled in both cases.
CONCLUSION
To the best of our knowledge, this is the first report presenting these two mutations in two related patients, resulting in distinctive genetic syndromes with similar manifestations. This underscores that although infrequent, multiple hereditary disorders may co-occur in the same individual.
Topics: Humans; Female; Multiple Endocrine Neoplasia Type 2a; Siblings; Succinate Dehydrogenase; Adult; Proto-Oncogene Proteins c-ret; Prognosis; Thyroidectomy; Mutation; Genetic Testing; Pedigree; Paraganglioma; High-Throughput Nucleotide Sequencing
PubMed: 38802890
DOI: 10.1186/s12957-024-03418-1 -
Journal of Clinical Medicine Research Apr 2024A 67-year-old woman was admitted to the Hematology Department in 2014 with complaints of weakness and a low-grade fever. After conducting various tests, it was confirmed...
A 67-year-old woman was admitted to the Hematology Department in 2014 with complaints of weakness and a low-grade fever. After conducting various tests, it was confirmed that she had Waldenstrom macroglobulinemia. She underwent several rounds of chemotherapy and maintenance therapy with rituximab, which resulted in a good clinical response. However, in 2019, an abnormal growth in the soft tissues of patient's frontal region was discovered, which was diagnosed as lymphoplasmacytic lymphoma. This later progressed to an intracranial lesion. The patient underwent radiation therapy for both the extramedullary and intracranial growths, which had a positive effect. A year later, she developed a lesion in her lymph nodes and soft tissues of her right leg, which was confirmed to be a recurrence of Waldenstrom disease. She underwent further treatment and is currently in complete remission. This case highlights the rare occurrence of relapse in Waldenstrom disease and the challenges in diagnosing extramedullary lesions. It also demonstrates the success of modern treatment approaches using a combination of therapies.
PubMed: 38715560
DOI: 10.14740/jocmr5115 -
Biomedicine & Pharmacotherapy =... Jun 2024Relationships between protective enzymatic and non-enzymatic pro-antioxidant mechanisms and addictive substances use disorders (SUDs) are analyzed here, based on the... (Review)
Review
Relationships between protective enzymatic and non-enzymatic pro-antioxidant mechanisms and addictive substances use disorders (SUDs) are analyzed here, based on the results of previous research, as well as on the basis of our current own studies. This review introduces new aspects of comparative analysis of associations of pro-antixidant and neurobiological effects in patients taking psychoactive substances and complements very limited knowledge about relationships with SUDs from different regions, mainly Europe. In view of the few studies on relations between antioxidants and neurobiological processes acting in patients taking psychoactive substances, this review is important from the point of view of showing the state of knowledge, directions of diagnosis and treatment, and further research needed explanation. We found significant correlations between chemical elements, pro-antioxidative mechanisms, and lipoperoxidation in the development of disorders associated with use of addictive substances, therefore elements that show most relations (Pr, Na, Mn, Y, Sc, La, Cr, Al, Ca, Sb, Cd, Pb, As, Hg, Ni) may be significant factors shaping SUDs. The action of pro-antioxidant defense and lipid peroxidation depends on the pro-antioxidative activity of ions. We explain the strongest correlations between Mg and Sb, and lipoperoxidation in addicts, which proves their stimulating effect on lipoperoxidation and on the induction of oxidative stress. We discussed which mechanisms and neurobiological processes change susceptibility to SUDs. The innovation of this review is to show that addicted people have lower activity of dismutases and peroxidases than healthy ones, which indicates disorders of antioxidant system and depletion of enzymes after long-term tolerance of stressors. We explain higher level of catalases, reductases, ceruloplasmin, bilirubin, retinol, α-tocopherol and uric acid of addicts. In view of poorly understood factors affecting addiction, analysis of interactions allows for more effective understanding of pathogenetic mechanisms leading to formation of addiction and development the initiation of directed, more effective treatment (pharmacological, hormonal) and may be helpful in the diagnosis of psychoactive changes.
Topics: Humans; Antioxidants; Substance-Related Disorders; Oxidative Stress; Lipid Peroxidation; Animals; Neurobiology
PubMed: 38692055
DOI: 10.1016/j.biopha.2024.116604 -
Nature Communications Apr 2024Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven...
Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven venous sprouting process involving parenchymal to vein cross-talk regulating venous endothelial Vegfa signaling strength and subsequent formation of a specialized angiogenic cell, prefabricated with an intact lumen and pericyte coverage, termed L-Tip cell. L-Tip cell selection in the venous domain requires genetic interaction between vascular Aplnra and Kdrl in a subset of venous endothelial cells and exposure to parenchymal derived Vegfa and Apelin. Parenchymal Esm1 controls the spatial positioning of venous sprouting by fine-tuning local Vegfa availability. These findings may provide a conceptual framework for understanding how Vegfa generates organo-typical vascular networks based on the selection of competent endothelial cells, induced via spatio-temporal control of endothelial Kdrl signaling strength involving multiple parenchymal derived cues generated in a tissue dependent metabolic context.
Topics: Angiogenesis; Endothelial Cells; Neovascularization, Physiologic; Veins
PubMed: 38600061
DOI: 10.1038/s41467-024-47434-x -
Radiology. Cardiothoracic Imaging Apr 2024Purpose To assess the feasibility of monitoring the effects of elexacaftor-tezacaftor-ivacaftor (ETI) therapy on lung ventilation and perfusion in people with cystic...
Purpose To assess the feasibility of monitoring the effects of elexacaftor-tezacaftor-ivacaftor (ETI) therapy on lung ventilation and perfusion in people with cystic fibrosis (CF), using phase-resolved functional lung (PREFUL) MRI. Materials and Methods This secondary analysis of a multicenter prospective study was carried out between August 2020 and March 2021 and included participants 12 years or older with CF who underwent PREFUL MRI, spirometry, sweat chloride test, and lung clearance index assessment before and 8-16 weeks after ETI therapy. For PREFUL-derived ventilation and perfusion parameter extraction, two-dimensional coronal dynamic gradient-echo MR images were evaluated with an automated quantitative pipeline. T1- and T2-weighted MR images and PREFUL perfusion maps were visually assessed for semiquantitative Eichinger scores. Wilcoxon signed rank test compared clinical parameters and PREFUL values before and after ETI therapy. Correlation of parameters was calculated as Spearman ρ correlation coefficient. Results Twenty-three participants (median age, 18 years [IQR: 14-24.5 years]; 13 female) were included. Quantitative PREFUL parameters, Eichinger score, and clinical parameters (lung clearance index = 21) showed significant improvement after ETI therapy. Ventilation defect percentage of regional ventilation decreased from 18% (IQR: 14%-25%) to 9% (IQR: 6%-17%) ( = .003) and perfusion defect percentage from 26% (IQR: 18%-36%) to 19% (IQR: 13%-24%) ( = .002). Areas of matching normal (healthy) ventilation and perfusion increased from 52% (IQR: 47%-68%) to 73% (IQR: 61%-83%). Visually assessed perfusion scores did not correlate with PREFUL perfusion ( = .11) nor with ventilation-perfusion match values ( = .38). Conclusion The study demonstrates the feasibility of PREFUL MRI for semiautomated quantitative assessment of perfusion and ventilation changes in response to ETI therapy in people with CF. Pediatrics, MR-Functional Imaging, Pulmonary, Lung, Comparative Studies, Cystic Fibrosis, Elexacaftor-Tezacaftor-Ivacaftor Therapy, Fourier Decomposition, PREFUL, Free-Breathing Proton MRI, Pulmonary MRI, Perfusion, Functional MRI, CFTR, Modulator Therapy, Kaftrio Clinical trial registration no. NCT04732910 © RSNA, 2024.
Topics: Adolescent; Female; Humans; Aminophenols; Benzodioxoles; Cystic Fibrosis; Feasibility Studies; Indoles; Lung; Magnetic Resonance Imaging; Perfusion; Prospective Studies; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Respiration; Male; Young Adult
PubMed: 38573129
DOI: 10.1148/ryct.230104 -
Virology Journal Mar 2024RNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects...
BACKGROUND
RNA helicases are emerging as key factors regulating host-virus interactions. The DEAD-box ATP-dependent RNA helicase DDX5, which plays an important role in many aspects of cellular RNA biology, was also found to either promote or inhibit viral replication upon infection with several RNA viruses. Here, our aim is to examine the impact of DDX5 on Sindbis virus (SINV) infection.
METHODS
We analysed the interaction between DDX5 and the viral RNA using imaging and RNA-immunoprecipitation approaches. The interactome of DDX5 in mock- and SINV-infected cells was determined by mass spectrometry. We validated the interaction between DDX17 and the viral capsid by co- immunoprecipitation in the presence or absence of an RNase treatment. We determined the subcellular localization of DDX5, its cofactor DDX17 and the viral capsid protein by co-immunofluorescence. Finally, we investigated the impact of DDX5 depletion and overexpression on SINV infection at the viral protein, RNA and infectious particle accumulation level. The contribution of DDX17 was also tested by knockdown experiments.
RESULTS
In this study we demonstrate that DDX5 interacts with the SINV RNA during infection. Furthermore, the proteomic analysis of the DDX5 interactome in mock and SINV-infected HCT116 cells identified new cellular and viral partners and confirmed the interaction between DDX5 and DDX17. Both DDX5 and DDX17 re-localize from the nucleus to the cytoplasm upon SINV infection and interact with the viral capsid protein. We also show that DDX5 depletion negatively impacts the viral replication cycle, while its overexpression has a pro-viral effect. Finally, we observed that DDX17 depletion reduces SINV infection, an effect which is even more pronounced in a DDX5-depleted background, suggesting a synergistic pro-viral effect of the DDX5 and DDX17 proteins on SINV.
CONCLUSIONS
These results not only shed light on DDX5 as a novel and important host factor to the SINV life cycle, but also expand our understanding of the roles played by DDX5 and DDX17 as regulators of viral infections.
Topics: Humans; Capsid Proteins; Proteomics; Virus Replication; RNA; DEAD-box RNA Helicases; Alphavirus Infections; Sindbis Virus
PubMed: 38553727
DOI: 10.1186/s12985-024-02349-3 -
JACS Au Feb 2024Peptide-based covalent inhibitors targeted to nucleophilic protein residues have recently emerged as new modalities to target protein-protein interactions (PPIs) as they...
Peptide-based covalent inhibitors targeted to nucleophilic protein residues have recently emerged as new modalities to target protein-protein interactions (PPIs) as they may provide some benefits over more classic competitive inhibitors. Covalent inhibitors are generally targeted to cysteine, the most intrinsically reactive amino acid residue, and to lysine, which is more abundant at the surface of proteins but much less frequently to histidine. Herein, we report the structure-guided design of targeted covalent inhibitors (TCIs) able to bind covalently and selectively to the bacterial sliding clamp (SC), by reacting with a well-conserved histidine residue located on the edge of the peptide-binding pocket. SC is an essential component of the bacterial DNA replication machinery, identified as a promising target for the development of new antibacterial compounds. Thermodynamic and kinetic analyses of ligands bearing different mild electrophilic warheads confirmed the higher efficiency of the chloroacetamide compared to Michael acceptors. Two high-resolution X-ray structures of covalent inhibitor-SC adducts were obtained, revealing the canonical orientation of the ligand and details of covalent bond formation with histidine. Proteomic studies were consistent with a selective SC engagement by the chloroacetamide-based TCI. Finally, the TCI of SC was substantially more active than the parent noncovalent inhibitor in an in vitro SC-dependent DNA synthesis assay, validating the potential of the approach to design covalent inhibitors of protein-protein interactions targeted to histidine.
PubMed: 38425897
DOI: 10.1021/jacsau.3c00572 -
Current Oncology (Toronto, Ont.) Feb 2024Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific... (Review)
Review
Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.
Topics: Humans; Nanomedicine; Melanoma; Immunotherapy; Molecular Biology; Uveal Neoplasms
PubMed: 38392052
DOI: 10.3390/curroncol31020058 -
Canadian Urological Association Journal... Apr 2024We investigated the incidence of secondary bladder (BCa) and rectal cancers (RCa) after external beam radiotherapy (EBRT) for prostate cancer (PCa) compared to radical...
INTRODUCTION
We investigated the incidence of secondary bladder (BCa) and rectal cancers (RCa) after external beam radiotherapy (EBRT) for prostate cancer (PCa) compared to radical prostatectomy (RP) alone, and compared cancer-specific survival (CSS) of these secondary neoplasms to their primary counterparts.
METHODS
This retrospective cohort study included men in the SEER cancer registry with a diagnosis of non-metastatic, clinically node-negative PCa treated with either RP or EBRT from 1995-2011 and allowed a minimum five-year lag period for the development of secondary BCa or RCa. Patients were divided into two eras, 1995-2002 and 2003-2011, to examine differences in incidence of secondary malignancies over time. Univariable and multivariable competing risk analyses with Fine-Gray subdistribution hazard and cause-specific hazard models were used to examine the risk of developing a secondary BCa or RCa. Competing risks analyses were used to compare CSS of primary vs. secondary BCa and RCa.
RESULTS
A total of 198 184 men underwent RP and 190 536 underwent EBRT for PCa. The cumulative incidence of secondary BCa at 10 years was 1.71% for RP, and 3.7% for EBRT (p<0.001), while that of RCa was 0.52% for RP and 0.99% for EBRT (p<0.001). EBRT was associated with almost twice the risk of developing a secondary BCa and RCa compared to RP. The hazard of secondary BCa following EBRT delivered during 2003-2011 was 20% less than from 1995-2002 (p<0.09, Fine-Gray model), while that of secondary RCa was 31% less (p<0.001) (hazard ratio 0.78, p<0.001) for Fine-Gray and cause-specific hazard models. In the Fine-Gray model, the risk of death from BCa was 27% lower for secondary BCa after RP compared to primary BCa, while the risk of death was 9% lower for secondary BCa after EBRT compared to primary BCa. There was no difference in RCa-specific survival between primary or secondary RCa after RP or EBRT.
CONCLUSIONS
The risk of BCa and RCa is almost twice as high for men undergoing EBRT for localized PCa vs. RP, but that risk is declining, likely reflecting advances in radiation delivery. The development of secondary RCa or BCa does not confer elevated risk of death compared to their primary counterparts.
PubMed: 38381941
DOI: 10.5489/cuaj.8508